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    Direct Renin Inhibitor and Calcium Channel Blocker Combinations

    BOXED WARNING

    Pregnancy

    Aliskiren; amlodipine is classified as FDA pregnancy risk category D. Once pregnancy is detected, every effort should be made to discontinue aliskiren; amlodipine therapy. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters can cause fetal and neonatal morbidity and even death. Drugs such as ACE inhibitors have been associated with fetal and neonatal injury when administered to pregnant women. The reported adverse fetal and neonatal effects include hypotension, neonatal skull hypoplasia and craniofacial deformation, fetal limb contractures, hypoplastic lung development, anuria, oligohydramnios, reversible or irreversible renal failure, and death. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. Inform women of reproductive age about the potential fetal risks of aliskiren; amlodipine exposure throughout pregnancy. While it was previously thought that adverse effects do not result from first-trimester drug exposure, an observational study based on Tennessee Medicaid data reported that the risk of congenital malformations is significantly increased during first-trimester exposure to ACE inhibitors. However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in infants exposed to ACE inhibitors during the first trimester, in infants exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated. Infants born to mothers with hypertension, either treated or untreated, had a higher risk of birth defects than those born to mothers without hypertension. The authors concluded that the presence of hypertension likely contributed to the development of birth defects rather than the use of medications. Women taking aliskiren; amlodipine should tell their healthcare professionals if they are planning to become pregnant or think they might be pregnant. Pregnant women should only be prescribed drugs acting on the renin-angiotensin system if the expected benefits clearly exceed the potential risks. Rarely (probably less often than once per every thousand pregnancies), no alternative to this type of medications will be found. In these rare cases, the pregnant women should be apprised of the potential hazards to their fetus, and serial ultrasound examinations should be performed to assess the intraamniotic environment.

    DEA CLASS

    Rx

    DESCRIPTION

    Combination of a direct renin inhibitor and calcium-channel blocker for hypertension.

    COMMON BRAND NAMES

    Tekamlo

    DOSAGE & INDICATIONS

    For the treatment of hypertension, either alone or in combination with other antihypertensive agents.
    For initial therapy in patients likely to need multiple antihypertensive agents to achieve their blood pressure goals.
    Oral dosage
    Adults

    Initially, give 1 tablet of aliskiren; amlodipine 150/5 mg PO once daily. Do not use as initial therapy in patients with intravascular volume depletion. Antihypertensive effects are usually attained within 1—2 weeks; titrate up to a maximum of aliskiren; amlodipine 300/10 mg if hypertension remains uncontrolled after 2—4 weeks of therapy.

    For patients already receiving aliskiren and amlodipine who desire to switch to the combination tablet or patients not adequately controlled on aliskiren or amlodipine alone.
    Oral dosage
    Adults

    1 tablet PO once daily. The combination product may be substituted for the individually titrated components or as add-on/switch therapy in patients not achieving optimal blood pressure control with aliskiren or a calcium-channel blocker alone. After initiation of aliskiren; amlodipine, the dosage may be increased after 2—4 weeks, usually by increasing one component at a time. A patient who experiences dose-limiting adverse reactions to an individual component while on any dual combination of the components of Tekamlo may be switched to a Tekamlo tablet that contains a lower dose of that component; similar blood pressure reductions may be achieved. The maximum recommended strength of the fixed-dose tablet is amlodipine 10 mg and aliskiren 300 mg.

    MAXIMUM DOSAGE

    Adults

    300 mg/day aliskiren; 10 mg/day PO amlodipine.

    Elderly

    300 mg/day aliskiren; 10 mg/day PO amlodipine.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No initial dosage adjustment is required in patients with mild or moderate hepatic disease. Slow dose titration is recommended in patients with hepatic impairment. In patients with severely impaired hepatic function, the half-life of amlodipine is 56 hours, and an initial dose of 2.5 mg PO once daily is recommended. Of note, the lowest available dose of amlodipine in Tekamlo is 5 mg.

    Renal Impairment

    According to the manufacturer, no dosage adjustment of the starting dose of aliskiren; amlodipine is necessary in patients with mild to moderate renal impairment. Clinical experience with aliskiren; amlodipine is limited in patients with moderate renal impairment. There are no data available in patients with severe renal impairment; however, the manufacturer recommends cautious use of aliskiren in patients with a CrCl < 30 mL/min (SCr >= 1.7 mg/dL in females or 2 mg/dL in males); clinical trials of aliskiren excluded patients with a CrCl < 30 mL/min.
     
    Intermittent hemodialysis
    Amlodipine is highly protein bound and is not likely to be significantly removed by hemodialysis; no dosage adjustment of aliskiren is necessary in patients with end stage renal disease undergoing hemodialysis.

    ADMINISTRATION

    Oral Administration

    May be taken with or without food; however, advise patients to establish a routine pattern for taking aliskiren; amlodipine with regard to meals because high-fat meals decrease absorption substantially.

    STORAGE

    Tekamlo:
    - Avoid exposure to heat
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: This monograph discusses the use of the combination product aliskiren; amlodipine. Clinicians may wish to consult the individual drug monographs for more information.

    ACE-inhibitor induced angioedema, angioedema, Black patients, hereditary angioedema, surgery

    Following administration of aliskiren, angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported; discontinue aliskiren; amlodipine and provide appropriate therapy and monitoring until complete and sustained resolution of the signs and symptoms has occurred. Angioedema may occur at any time during treatment, and has been reported in patients with and without a history of angioedema from ACE-inhibitors or angiotension receptor blockers. It is unknown if the occurrence of angioedema is higher in Black patients compared to other demographic subgroups, as has been reported with the use of angiotensin-converting enzyme inhibitors (ACE inhibitors). Black patients do, however, experience a slightly smaller reduction in blood pressure as compared to other subgroups, a trend that is consistent with experience in ACE inhibitor and angiotensin receptor antagonists therapy. Patients may require prolonged observation even with minor reactions where only swelling of the tongue is initially seen, without respiratory complications. In these patients, treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Also, experience with ACE inhibitors has shown that rare fatalities can occur in patients with angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis, or larynx, and especially a history of airway surgery are more likely to experience airway obstruction. ACE-inhibitors are contraindicated in patients with a history of ACE-inhibitor induced angioedema, hereditary angioedema, or idiopathic angioedema, similar precautions should be observed when administering aliskiren.

    Aortic stenosis, hyponatremia, hypotension, hypovolemia

    Aliskiren; amlodipine should be used with caution in patients who exhibit hypotension. A transient hypotensive response is not a contraindication to further treatment, and the drug can usually be continued without difficulty once the blood pressure has stabilized. Rarely (0.2%), an excessive fall in blood pressure was observed in patients with uncomplicated hypertension treated with aliskiren; amlodipine. Symptomatic hypotension is more likely to occur during amlodipine therapy in patients with severe aortic stenosis. Hypotension is also more likely to occur if aliskiren; amlodipine is administered to patients with preexisting hypovolemia or hyponatremia or with combined use of aliskiren and other agents acting on the renin-angiotensin-aldosterone system. Volume depletion should be corrected prior to the administration of aliskiren; amlodipine.

    Angina, coronary artery disease, myocardial infarction

    Rarely, an increase in the frequency, duration, and/or severity of angina or myocardial infarction have occurred during calcium channel blocker (such as amlodipine) initiation or dosage increase, particularly in those patients with severe obstructive coronary artery disease. Additionally. the addition of aliskiren to optimal medical therapy (i.e., antiplatelets, statins, beta-blockers, and either an ACE inhibitor or an angiotensin-receptor blocker) in patients who have had a myocardial infarction accompanied by left ventricular dysfunction may not improve outcomes and may result in increased adverse events. The Aliskiren Study in Post-MI Patients to Reduce Remodeling (ASPIRE) randomized 820 patients with left ventricular dysfunction to placebo or aliskiren 75 mg/day PO and titrated the dose up to 300 mg daily within two weeks. After 36 weeks, there was no significant reduction in left ventricular end-systolic volume compared to placebo as well as no significant difference in the ejection fraction or the end-diastolic volume. There was also a higher incidence of low potassium concentrations, low blood pressure, and kidney dysfunction in patients receiving aliskiren compared to placebo.

    Renal artery stenosis, renal failure, renal impairment

    Monitor renal function periodically in patients treated with aliskiren; amlodipine. The safety and effectiveness of aliskiren have not been established in patients with severe renal impairment or renal failure (CrCl < 30 mL/min); these patients were excluded from clinical trials. In patients with moderate renal impairment (GFR < 60 mL/min), use of aliskiren in combination with angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin II receptor antagonists (ARBs) should be avoided. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or patients receiving ARBs, ACE inhibitors or NSAIDs may be at particular risk for developing acute renal failure on aliskiren. Consider holding or discontinuing therapy in patients who develop a clinically significant reduction in renal function while receiving aliskiren.

    Biliary cirrhosis, hepatic disease

    Aliskiren; amlodipine should be used with caution in patients with severe hepatic disease and those with biliary cirrhosis. Amlodipine is extensively metabolized by the liver and the plasma elimination half-life is prolonged to 56 hours in patients with impaired hepatic function. Because hepatobiliary excretion seems to be prominent in the elimination of aliskiren, clinicians should observe caution when prescribing aliskiren; amlodipine in patients with biliary cirrhosis or Child-Pugh class B or C until further data become available.

    Gastroesophageal reflux disease (GERD), hiatal hernia

    Aliskiren; amlodipine should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Calcium channel blockers such as amlodipine relax the lower esophageal sphincter.

    Heart failure

    An increase in the AUC of amlodipine of approximately 40—60% has been observed in patients with heart failure; the manufacturer of aliskiren; amlodipine recommends slow dosage titration in these patients. In general, most calcium-channel blockers are not recommended in patients with heart failure (HF), because they can lead to worsening HF and have been associated with an increased risk of cardiovascular events. However, amlodipine has not been shown to adversely affect survival in these patients. The PRAISE-1 and PRAISE-2 trials have shown that amlodipine did not worsen heart failure in patients with NYHA Class II or III heart failure. In the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, 1153 patients (80% with class III heart failure, either due to ischemic or nonischemic disease) were randomized to receive amlodipine 5—10 mg PO once daily or placebo. One month after randomization, the average amlodipine dosage was 8.8 +/- 0.6 mg/day PO. In the ischemic heart failure subgroup of PRAISE-1, the results with amlodipine therapy were similar to placebo. In the subgroup of patients with nonischemic dilated cardiomyopathy, however, amlodipine-treated patients demonstrated a significant decrease in the primary endpoint of combined risk of either death or life-threatening cardiovascular event after 14 months. A follow-up trial (PRAISE-2) of non-ischemic heart failure (NYHA Class III or IV) demonstrated no significant benefit with amlodipine. In the PRAISE-2 trial, no difference was observed in all-cause mortality vs. placebo, but there were more reports of pulmonary edema.

    Diabetes mellitus

    Aliskiren; amlodipine is contraindicated in patients with diabetes mellitus who are receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin II receptor antagonists (ARBs). In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of renal impairment (14.5% vs. 12.4%), hypotension (19.9% vs. 16.3%), and hyperkalemia (38.9% vs. 28.8%) compared to placebo. These adverse events were also reported as serious adverse events more frequently in aliskiren-treated patients compared to placebo: renal impairment (5.7% vs. 4.3%), hypotension (2.3% vs. 1.9%), and hyperkalemia (1% vs. 0.5%). The risk of stroke (3.4% vs. 2.7%) and death (8.4% vs. 8%) were numerically higher in aliskiren-treated patients. The manufacturer has instructed healthcare professionals to discontinue aliskiren; amlodipine in patients with diabetes who are also receiving an ACE inhibitor or an ARB and to consider alternative antihypertensive treatment as necessary.

    Hyperkalemia, hypokalemia

    Patients with pre-existing hyperkalemia or hypokalemia should have their electrolyte imbalances corrected before aliskiren; amlodipine is initiated. Hyperkalemia may be associated with serious cardiac arrhythmias. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, and the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists (ARBs), NSAIDs, potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. Increases in serum potassium > 5.5 mEq/L were infrequent with aliskiren alone (0.9%, compared to 0.6% with placebo). However, when aliskiren was administered to patients with diabetes and renal disease receiving an ACE inhibitor or an ARB, the incidence of hyperkalemia was 36.9% compared to 27.1% in the placebo group. Hyperkalemia resulting in a serious adverse event was also reported more frequently in the aliskiren group compared to placebo (1.1% vs. 0.3%, respectively).

    Geriatric

    Although in clinical evaluation of aliskiren; amlodipine, blood pressure responses and adverse events were similar in geriatric patients as compared to younger patients, greater sensitivity of some older individuals, particularly those with hepatic or renal impairment, cannot be ruled out.

    Children, infants, neonates

    The safety and efficacy of aliskiren; amlodipine in neonates, infants, children, and adolescents have not been established. FDA-approved labeling warns that preclinical studies suggest a potential for substantially increased aliskiren exposure in pediatric patients; however, this warning is based on animal data from 8 to 14 day old rats. The increased aliskiren exposure in newborn rats appears to be primarily attributed to the lack of maturation of P-glycoprotein (P-gp). There are limited data on the ontogeny of P-gp in humans; however, growth and development may be important determinants of its expression and activity.

    Pregnancy

    Aliskiren; amlodipine is classified as FDA pregnancy risk category D. Once pregnancy is detected, every effort should be made to discontinue aliskiren; amlodipine therapy. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters can cause fetal and neonatal morbidity and even death. Drugs such as ACE inhibitors have been associated with fetal and neonatal injury when administered to pregnant women. The reported adverse fetal and neonatal effects include hypotension, neonatal skull hypoplasia and craniofacial deformation, fetal limb contractures, hypoplastic lung development, anuria, oligohydramnios, reversible or irreversible renal failure, and death. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. Inform women of reproductive age about the potential fetal risks of aliskiren; amlodipine exposure throughout pregnancy. While it was previously thought that adverse effects do not result from first-trimester drug exposure, an observational study based on Tennessee Medicaid data reported that the risk of congenital malformations is significantly increased during first-trimester exposure to ACE inhibitors. However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in infants exposed to ACE inhibitors during the first trimester, in infants exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated. Infants born to mothers with hypertension, either treated or untreated, had a higher risk of birth defects than those born to mothers without hypertension. The authors concluded that the presence of hypertension likely contributed to the development of birth defects rather than the use of medications. Women taking aliskiren; amlodipine should tell their healthcare professionals if they are planning to become pregnant or think they might be pregnant. Pregnant women should only be prescribed drugs acting on the renin-angiotensin system if the expected benefits clearly exceed the potential risks. Rarely (probably less often than once per every thousand pregnancies), no alternative to this type of medications will be found. In these rare cases, the pregnant women should be apprised of the potential hazards to their fetus, and serial ultrasound examinations should be performed to assess the intraamniotic environment.

    Breast-feeding

    According to the manufacturer, because of the potential for serious adverse reactions in a nursing infant from aliskiren; amlodipine, a decision should be made whether to discontinue nursing or discontinue aliskiren; amlodipine, taking into account the importance of the drug to the mother. It is not known whether aliskiren or amlodipine are excreted in human milk. Both aliskiren and amlodipine were secreted in the milk of lactating rats. Because neonatal myocardium is very sensitive to changes in calcium status and amlodipine is a calcium-channel blocker, it may be prudent to avoid using aliskiren; amlodipine in breast-feeding mothers until more safety data are available. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    atrial fibrillation / Early / 0-1.0
    vasculitis / Delayed / 0-1.0
    bradycardia / Rapid / 0-1.0
    arrhythmia exacerbation / Early / 0-1.0
    ventricular tachycardia / Early / 0-1.0
    pancreatitis / Delayed / 0-1.0
    seizures / Delayed / 0-1.0
    visual impairment / Early / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    hyperkalemia / Delayed / 0.9-0.9
    angioedema / Rapid / Incidence not known
    teratogenesis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known

    Moderate

    peripheral edema / Delayed / 6.2-8.9
    impotence (erectile dysfunction) / Delayed / 0-2.0
    chest pain (unspecified) / Early / 0-1.0
    orthostatic hypotension / Delayed / 0-1.0
    gingival hyperplasia / Delayed / 0-1.0
    dysphagia / Delayed / 0-1.0
    constipation / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    conjunctivitis / Delayed / 0-1.0
    erythema / Early / 0-1.0
    depression / Delayed / 0-1.0
    dyspnea / Early / 0-1.0
    hyperglycemia / Delayed / 0-1.0
    hyperuricemia / Delayed / 0.4-0.4
    gout / Delayed / 0.2-0.2
    nephrolithiasis / Delayed / 0.2-0.2
    anemia / Delayed / 0.1-0.1
    hypotension / Rapid / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    diarrhea / Early / 0-2.3
    dyspepsia / Early / 0-2.0
    pruritus / Rapid / 0-2.0
    asthenia / Delayed / 0-2.0
    muscle cramps / Delayed / 0-2.0
    cough / Delayed / 1.1-1.1
    rash (unspecified) / Early / 1.0-1.0
    syncope / Early / 0-1.0
    xerostomia / Early / 0-1.0
    anorexia / Delayed / 0-1.0
    flatulence / Early / 0-1.0
    vomiting / Early / 0-1.0
    increased urinary frequency / Early / 0-1.0
    nocturia / Early / 0-1.0
    vertigo / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    tremor / Early / 0-1.0
    purpura / Delayed / 0-1.0
    diplopia / Early / 0-1.0
    tinnitus / Delayed / 0-1.0
    ocular pain / Early / 0-1.0
    diaphoresis / Early / 0-1.0
    maculopapular rash / Early / 0-1.0
    weight loss / Delayed / 0-1.0
    back pain / Delayed / 0-1.0
    malaise / Early / 0-1.0
    arthralgia / Delayed / 0-1.0
    weight gain / Delayed / 0-1.0
    myalgia / Early / 0-1.0
    flushing / Rapid / 0-1.0
    insomnia / Early / 0-1.0
    nightmares / Early / 0-1.0
    anxiety / Delayed / 0-1.0
    epistaxis / Delayed / 0-1.0
    libido decrease / Delayed / 0-1.0
    abdominal pain / Early / Incidence not known
    gastroesophageal reflux / Delayed / Incidence not known
    gynecomastia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Dextromethorphan; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Acetaminophen; Dichloralphenazone; Isometheptene: Isometheptene has sympathomimetic properties. Patients taking antihypertensive agents may need to have their therapy modified. Careful blood pressure monitoring is recommended.
    Acetaminophen; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Propoxyphene: Amlodipine is a CYP3A4 substrate. CYP3A4 inhibitors, such as propoxyphene, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when propoxyphene is coadministered with amlodipine; therapeutic response should be monitored.
    Acetaminophen; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Acrivastine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Aldesleukin, IL-2: Calcium channel blockers may potentiate the hypotension seen with aldesleukin, IL 2.
    Alemtuzumab: Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Alfentanil: Alfentanil may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with alfentanil is increased in patients receiving calcium-channel blockers. In addition to additive hypotensive effects, calcium-channel blockers that are CYP3A4 inhibitors (e.g., diltiazem, nicardipine, and verapamil) can theoretically decrease hepatic metabolism of some opiates (CYP3A4 substrates), such as alfentanil. Diltiazem increases the half-life of alfentanil by 50% via inhibition of cytochrome P450 (CYP) 3A4 metabolism and may delay tracheal extubation after anesthesia. Reduced clearance of alfentanil should be considered when recovery from alfentanil infusions for anesthesia is evaluated in patients receiving concurrent diltiazem therapy.
    Aliskiren; Valsartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Alogliptin; Pioglitazone: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Alprostadil: The concomitant use of systemic alprostadil injection and antihypertensive agents, like calcium channel blockers, may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
    Amifostine: Patients receiving antihypertensive agents should be closely monitored during amifostine infusions due to additive effects. If possible, patients should not take their antihypertensive medication 24 hours before receiving amifostine. Patients who can not stop their antihypertensive agents should not receive amifostine or be closely monitored during the infusion and, possibly, given lower doses.
    Amiloride: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Amiloride; Hydrochlorothiazide, HCTZ: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Amiodarone: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as amiodarone, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when amiodarone is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Atorvastatin: Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
    Amlodipine; Benazepril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Amlodipine; Olmesartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Amlodipine; Telmisartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Amlodipine; Valsartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Amobarbital: Concurrent use of amobarbital with antihypertensive agents may lead to hypotension. Monitor for decreases in blood pressure during times of coadministration.
    Amoxicillin; Clarithromycin; Lansoprazole: Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. A retrospective, case cross-over study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent.
    Amoxicillin; Clarithromycin; Omeprazole: Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. A retrospective, case cross-over study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent.
    Amphetamine; Dextroamphetamine Salts: Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as calcium-channel blockers. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Amprenavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Amyl Nitrite: Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Angiotensin II receptor antagonists: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Angiotensin-converting enzyme inhibitors: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Apomorphine: Patients receiving apomorphine may experience orthostatic hypotension, hypotension, and/or syncope. Extreme caution should be exercised if apomorphine is used concurrently with antihypertensive agents, or vasodilators such as nitrates.
    Apraclonidine: Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically. Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically.
    Aprepitant, Fosaprepitant: Use caution if aliskiren and aprepitant, fosaprepitant are used concurrently and monitor for an increase in aliskiren-related adverse effects for several days after administration of a multi-day aprepitant regimen. Aliskiren is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of aliskiren. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Use caution if amlodipine and a multi-day regimen of oral aprepitant are used concurrently; monitor for an increase in amlodipine-related adverse effects for several days after administration. Amlodipine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of amlodipine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: Aripiprazole may enhance the hypotensive effects of antihypertensive agents.
    Armodafinil: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Asenapine: Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Atazanavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. The plasma concentrations of aliskiren may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
    Atazanavir; Cobicistat: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. Coadministration of cobicistat (a CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as amlodipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. The plasma concentrations of aliskiren may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4. The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate.
    Atenolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Atenolol; Chlorthalidone: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Atorvastatin: Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
    Atorvastatin; Ezetimibe: Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
    Avanafil: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Axitinib: Use caution if coadministration of axitinib with amlodipine is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers.The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents.
    Azilsartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Azilsartan; Chlorthalidone: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Baclofen: Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Barbiturates: Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: Because of the potential to cause coronary vasospasm , ergotamine theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergotamine and increase the risk of ergot toxicity.
    Benazepril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Benazepril; Hydrochlorothiazide, HCTZ: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Bendroflumethiazide; Nadolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Benzonatate: Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Benzphetamine: Benzphetamine can increase both systolic and diastolic blood pressure and may counteract the activity of calcium-channel blockers. This represents a pharmacodynamic, and not a pharmacokinetic, interaction. Close monitoring of blood pressure, especially in patients who are taking antihypertensive agents, may be needed
    Beta-blockers: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Betaxolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Bexarotene: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Bisoprolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Bisoprolol; Hydrochlorothiazide, HCTZ: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Black Cohosh, Cimicifuga racemosa: Actein and certain acids isolated from the rhizome of Cimicifuga spp. have been noted to antagonize the influx of calcium and norepinephrine-induced contraction of the aorta in rats. Black cohosh, Cimicifuga racemosa has potentiated the effects of antihypertensive medications in some animal studies, and actein may have peripheral vasodilatory activity. Clinical reports of interactions between black cohosh and antihypertensive agents in humans are not available, and remain theoretical. However, isolated cases of hypertension or hypotension have been reported with black cohosh use.
    Boceprevir: Close clinical monitoring is advised when administering aliskiren with boceprevir due to an increased potential for aliskiren-related adverse events. If aliskiren dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of aliskiren. Aliskiren is metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated aliskiren plasma concentrations. Close clinical monitoring is advised when administering amlodipine with boceprevir due to an increased potential for amlodipine-related adverse events. A reduction in the dose of amlodipine may be considered. If amlodipine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Predictions about the interaction can be made based on the metabolic pathway of amlodipine. Amlodipine is metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated amlodipine plasma concentrations.
    Bortezomib: Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
    Bosentan: Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with calcium-channel blockers. In addition, bosentan may induce hepatic metabolism of calcium-channel blockers metabolized by CYP3A4 isoenzymes. Diltiazem and verapamil have potential to inhibit CYP3A4 metabolism of bosentan. Bosentan has been shown to have no pharmacokinetic interactions with nimodipine.
    Brimonidine; Timolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Bromocriptine: Bromocriptine has only minimal affinity for adrenergic receptors; however, hypotension can occur during bromocriptine administration. Orthostatic hypotension occurs in 6% of acromegaly patients receiving the drug. Hypotension occurred frequently (approximately 30%) in postpartum studies, which in rare cases approached a decline in supine pressure of almost 60 mmHg. It is unknown if bromocriptine is the exact cause of this effect. However, the drug should be used cautiously with other medications known to lower blood pressure such as antihypertensive agents. Monitoring of blood pressure should be considered, especially during the initial weeks of concomitant therapy.
    Brompheniramine; Carbetapentane; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Brompheniramine; Hydrocodone; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Brompheniramine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Bumetanide: Aliskiren can enhance the effects of loop-diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Patients with hyponatremia or hypovolemia may also develop reversible renal insufficiency. When aliskiren is administered in combination with furosemide, the AUC and Cmax of furosemide are reduced by approximately 30% and 50%, respectively; the pharmacokinetics of aliskiren are not affected. Patients should be monitored for loss of effect of furosemide when aliskiren is initiated. Blood pressure and electrolytes should be routinely monitored.
    Bupivacaine; Lidocaine: Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Cabergoline: Cabergoline has minimal affinity for adrenergic receptors; however, it has been associated with hypotension in some instances. Cabergoline should be used cautiously in those receiving antihypertensive agents.
    Cabozantinib: Monitor for an increase in aliskiren-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of aliskiren may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and aliskiren is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Caffeine; Ergotamine: Because of the potential to cause coronary vasospasm , ergotamine theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergotamine and increase the risk of ergot toxicity.
    Candesartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Candesartan; Hydrochlorothiazide, HCTZ: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Captopril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Captopril; Hydrochlorothiazide, HCTZ: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Carbamazepine: Carbamazepine may induce the hepatic metabolism of calcium-channel blockers by the CYP3A4 isoenzyme; which reduces the oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Carbetapentane; Chlorpheniramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Diphenhydramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Phenylephrine; Pyrilamine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Carbidopa; Levodopa: Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Carbinoxamine; Hydrocodone; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Carbinoxamine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbinoxamine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Cariprazine: Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Carteolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Carvedilol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Celecoxib: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Cetirizine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlophedianol; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chloramphenicol: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as chloramphenicol, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when chloramphenicol is coadministered with amlodipine; therapeutic response should be monitored.
    Chloroprocaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlorpheniramine; Hydrocodone; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlorpheniramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chondroitin; Glucosamine: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Ciprofloxacin: Administering amlodipine with CYP3A4 inhibitors, such as ciprofloxacin, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when ciprofloxacin is coadministered with amlodipine; therapeutic response should be monitored. The plasma concentrations of aliskiren may be elevated when administered concurrently with ciprofloxacin. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ciprofloxacin is a CYP3A4 inhibitor and aliskiren is a CYP3A4 substrate.
    Citric Acid; Potassium Citrate: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Citric Acid; Potassium Citrate; Sodium Citrate: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Clarithromycin: Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. A retrospective, case cross-over study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent.
    Clobazam: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Clopidogrel: Administer clopidogrel and amlodipine together with caution and monitor for reduced therapeutic response to clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps. The CYP3A4 isoenzyme is involved in one of the metabolic steps. Amlodipine is a weak inhibitor of CYP3A4 and may decrease the hepatic metabolism of clopidogrel to its active metabolite. In a study of 200 patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI), coadministration with a calcium-channel blocker (CCB) was associated with a reduced response to clopidogrel. Concomitant use of a CCB was also associated with a worse clinical outcome with the primary end point, a composite of death from cardiovascular causes, non-fatal myocardial infarction, stent thrombosis, and revascularization (PCI or CABG surgery), occurring more frequently in patients receiving a concomitant CCB. Amlodipine represented the largest subgroup of CCBs in the study, therefore it is unknown if these results can be applied to all CCBs. Another study compared concomitant use of amlodipine, a non-P-glycoprotein (P-gp) inhibiting CCB, with concomitant use of a P-gp inhibiting CCB (e.g., verapamil, nifedipine, diltiazem) on the effect of clopidogrel. Only amlodipine was associated with a poor response to clopidogrel suggesting the interaction between amlodipine and clopidogrel may be more clinically relevant compared to P-gp inhibiting CCBs. The authors theorized that by inhibiting P-gp, the intestinal efflux of clopidogrel may be decreased, thereby increasing clopidogrel plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition.
    Clozapine: Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Cobicistat: Coadministration of cobicistat (a CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as amlodipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: Coadministration of cobicistat (a CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as amlodipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: Coadministration of cobicistat (a CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as amlodipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate.
    Cod Liver Oil: Fish oil supplements may cause mild, dose-dependent reductions in systolic or diastolic blood pressure in untreated hypertensive patients. Relatively high doses of fish oil are required to produce any blood pressure lowering effect. Additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Codeine; Phenylephrine; Promethazine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Co-Enzyme Q10, Ubiquinone: Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Conivaptan: Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. Avoid concurrent use of conivaptan and aliskiren. Coadministration of conivaptan and aliskiren may result in increased serum concentrations of aliskiren. Conivaptan inhibits CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with aliskiren. Subsequent treatment with CYP3A substrates, such as aliskiren, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: Use caution if coadministration of crizotinib with amlodipine is necessary, due to the risk of increased amlodipine- and crizotinib-related adverse reactions. Crizotinib is a moderate CYP3A4 inhibitor both in vitro and in vivo. Amlodipine is a CYP3A4 substrate. Coadministration of crizotinib with another CYP3A4 substrate, midazolam, increased the AUC of oral midazolam by 3.7-fold compared to midazolam alone. Exposure to both drugs may increase. Additionally, crizotinib is primarily metabolized by CYP3A4/5 and amlodipine is a weak CYP3A4 inhibitor. Coadministration of a single dose of crizotinib with a strong CYP3A4 inhibitor increased the crizotinib AUC and Cmax by 3.2-fold and 1.4-fold, respectively; weak CYP3A4 inhibitors may also affect crizotinib exposure. The effect of CYP3A4 inhibitors on steady-state crizotinib exposure has not been evaluated.
    Cyclosporine: Concomitant use of aliskiren with cyclosporine is not recommended because of significantly increased aliskiren blood concentrations and an increase in the number and/or intensity of adverse events such as headache, hot flushes, nausea, vomiting, and somnolence. Cyclosporine is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. As compared with aliskiren monotherapy, the maximum serum concentration (Cmax) of aliskiren was increased approximately 2.5-fold, and the systemic exposure was increased approximately 4.3-fold after a single 75 mg dose was given with a single cyclosporine 200 mg dose to healthy patients. Also, as compared with aliskiren receipt alone, prolongation of the median aliskiren elimination half-life (43 to 45 hours versus 26 hours) and the time to the maximum serum concentration (1.5 to 2 hours versus 0.5 hours) were noted. The mean systemic exposure and Cmax of cyclosporine were comparable to reported literature values. Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
    Dabrafenib: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Daclatasvir: Systemic exposure of aliskiren, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of aliskiren; monitor patients for potential adverse effects.
    Danazol: Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Dantrolene: Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Darunavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. The plasma concentrations of aliskiren may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
    Darunavir; Cobicistat: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. Coadministration of cobicistat (a CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as amlodipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate. The plasma concentrations of aliskiren may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. The plasma concentrations of aliskiren may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp.
    Dasatinib: Dasatinib inhibits CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme, such as calcium-channel blockers, are administered concurrently with dasatinib as increased adverse reactions may occur. Diltiazem, nicardipine and verapamil may also inhibit the metabolism of dasatinib.
    Deferasirox: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Delavirdine: Administering amlodipine with CYP3A4 inhibitors, such as delavirdine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when delavirdine is coadministered with amlodipine; therapeutic response should be monitored.
    Desloratadine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Dexamethasone: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dexamethasone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Dexmedetomidine: In general, the concomitant administration of dexmedetomidine with antihypertensive agents could lead to additive hypotensive effects. Dexmedetomidine can produce bradycardia or AV block and should be used cautiously in patients who are receiving antihypertensive drugs that lower the heart rate such as calcium-channel blockers.
    Dexmethylphenidate: Dexmethylphenidate may reduce the hypotensive effect of antihypertensive agents, such as calcium-channel blockers. Dexmethylphenidate may reduce the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of dexmethylphenidate and antihypertensive agents, particularly during initial co-administration and after dosage increases of dexmethylphenidate. Methylphenidate reduces the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial co-administration and after dosage increases of methylphenidate.
    Dextromethorphan; Diphenhydramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Dextromethorphan; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Dextromethorphan; Quinidine: Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Diazoxide: Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents. Aliskiren can enhance the effects of vasodilators on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Diclofenac: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Diclofenac; Misoprostol: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Diethylpropion: Diethylpropion has vasopressor effects and may limit the benefit of calcium-channel blockers. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.
    Diflunisal: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Dihydroergotamine: Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Diltiazem: Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Diphenhydramine; Hydrocodone; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Diphenhydramine; Ibuprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Diphenhydramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Dorzolamide; Timolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Dronabinol, THC: Use caution if coadministration of dronabinol with amlodipine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; amlodipine is a weak inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Diltiazem and verapamil are inhibitors of CYP3A4 and substrates of CYP3A and P-gp; nifedipine and amlodipine are substrates for CYP3A4. In clinical trials, the coadministration of dronedarone and calcium-channel blockers (diltiazem, verapamil, and nifedipine) resulted in an increase in exposure of calcium channel blockers by 1.4 to 1.5 fold and an increase in dronedarone exposure by 1.4 to1.7 fold. Furthermore, calcium channel blockers may potentiate the electrophysiologic effects of dronedarone (e.g., decreased AV and sinus node conduction). If coadministration of calcium channel blockers and dronedarone cannot be avoided, administer low doses of the calcium channel blocker and increase dosage only after ECG verification of tolerability. Dronedarone is metabolized by and is an inhibitor of CYP3A. Aliskiren is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Drospirenone; Ethinyl Estradiol: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Drospirenone; Ethinyl Estradiol; Levomefolate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Duloxetine: Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
    Dutasteride; Tamsulosin: The concomitant administration of tamsulosin with other antihypertensive agents can cause additive hypotensive effects. In addition, diltiazem, nicardipine, and verapamil may increase tamsulosin plasma concentrations via CYP3A4 inhibition. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Efavirenz: Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Efavirenz; Emtricitabine; Tenofovir: Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Elbasvir; Grazoprevir: Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eletriptan: Eletriptan may reduce the effectiveness of antihypertensive agents. Patients on antihypertensives need to have their blood pressure adequately controlled if they are to receive eletriptan. If eletriptan is used, regular blood pressure monitoring is recommended.
    Empagliflozin: Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Empagliflozin; Linagliptin: Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Empagliflozin; Metformin: Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Enalapril, Enalaprilat: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Enalapril; Felodipine: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Enalapril; Hydrochlorothiazide, HCTZ: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Enflurane: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression. General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Enzalutamide: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as enzalutamide, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Ephedrine: The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by calcium-channel blockers. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Epirubicin: Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant treatment with epirubicin and calcium-channel blockers. Individuals receiving these medications concurrently are at increased risk of developing heart failure.
    Eplerenone: Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Epoprostenol: Aliskiren can enhance the effects of epoprostenol on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren. Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Eprosartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Eprosartan; Hydrochlorothiazide, HCTZ: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Ergonovine: Because of its potential to cause coronary vasospasm, ergonovine could theoretically antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. In addition, calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergonovine and increase the risk of ergot toxicity.
    Ergotamine: Because of the potential to cause coronary vasospasm , ergotamine theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergotamine and increase the risk of ergot toxicity.
    Erlotinib: Use caution if coadministration of erlotinib with amlodipine is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both amlodipine and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%. Coadministration with amlodipine may also increase erlotinib exposure.
    Erythromycin: Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapami) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Erythromycin; Sulfisoxazole: Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapami) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Eslicarbazepine: In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary.
    Esmolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Esomeprazole; Naproxen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Estradiol Cypionate; Medroxyprogesterone: Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Estradiol: Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Ethacrynic Acid: Aliskiren can enhance the effects of loop-diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Patients with hyponatremia or hypovolemia may also develop reversible renal insufficiency. When aliskiren is administered in combination with furosemide, the AUC and Cmax of furosemide are reduced by approximately 30% and 50%, respectively; the pharmacokinetics of aliskiren are not affected. Patients should be monitored for loss of effect of furosemide when aliskiren is initiated. Blood pressure and electrolytes should be routinely monitored.
    Ethanol: Ethanol interacts with antihypertensive agents by potentiating their hypotensive effect.
    Ethinyl Estradiol: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Desogestrel: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Ethynodiol Diacetate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Etonogestrel: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norelgestromin: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone Acetate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norgestimate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norgestrel: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethotoin: Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Etodolac: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Etomidate: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression. General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Etoposide, VP-16: Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with aldesleukin, IL-2. Aldesleukin is a weak inhibitor of CYP3A4 and etoposide, VP-16 is a CYP3A4 substrate. Coadministration may increase etoposide concentrations.
    Etravirine: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as etravirine, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Ezetimibe; Simvastatin: Simvastatin and amlodipine should be coadministered with caution due to an increased risk of myopathy, including rhabdomyolysis. If amlodipine and simvastatin must be administered together, do not exceed 20 mg/day simvastatin in adults. For adult patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, the manufacturer of simvastatin recommends switching to an alternative statin with less potential for interactions.
    Famotidine; Ibuprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Fenoldopam: Aliskiren can enhance the effects of vasodilators on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Fenoprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Fentanyl: The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Fexofenadine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10. High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Fluconazole: Fluconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism. Monitor blood pressure closely during concurrent use of these medications.
    Fluoxetine: Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
    Fluoxetine; Olanzapine: Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored. Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Flurbiprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Flutamide: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as flutamide, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Fluvoxamine: Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluvoxamine is coadministered with amlodipine; therapeutic response should be monitored.
    Fosamprenavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. Caution is advised when administering aliskiren with fosamprenavir, as concurrent use may alter the plasma concentrations of aliskiren. Aliskiren is a substrate for the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is an inducer of P-gp and a potent inhibitor and moderate inducer of CYP3A4.
    Fosinopril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Fosinopril; Hydrochlorothiazide, HCTZ: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Fosphenytoin: Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Fospropofol: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression. General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Furosemide: Aliskiren can enhance the effects of loop-diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Patients with hyponatremia or hypovolemia may also develop reversible renal insufficiency. When aliskiren is administered in combination with furosemide, the AUC and Cmax of furosemide are reduced by approximately 30% and 50%, respectively; the pharmacokinetics of aliskiren are not affected. Patients should be monitored for loss of effect of furosemide when aliskiren is initiated. Blood pressure and electrolytes should be routinely monitored.
    General anesthetics: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression. General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Ginkgo, Ginkgo biloba: Ginkgo biloba appears to inhibit the metabolism of calcium-channel blockers, perhaps by inhibiting the CYP3A4 isoenzyme. A non-controlled pharmacokinetic study in healthy volunteers found that the concurrent administration of ginkgo with nifedipine resulted in a 53% increase in nifedipine peak concentrations. More study is needed regarding ginkgo's effects on CYP3A4 and whether clinically significant drug interactions result.
    Ginseng, Panax ginseng: Ginseng appears to inhibit the metabolism of calcium-channel blockers, perhaps by inhibiting the CYP3A4 isoenzyme. A non-controlled pharmacokinetic study in healthy volunteers found that the concurrent administration of ginseng with nifedipine resulted in a 30% increase in nifedipine peak concentrations. More study is needed regarding ginseng's effects on CYP3A4 and whether clinically significant drug interactions result.
    Glimepiride; Pioglitazone: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Glucosamine: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Griseofulvin: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as griseofulvin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Guaifenesin; Hydrocodone; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Guaifenesin; Potassium Guaiacolsulfonate: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Guaifenesin; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Haloperidol: In general, antipsychotics like haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension.
    Halothane: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression. General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Hawthorn, Crataegus laevigata: Hawthorn, Crataegus laevigata (also known as C. oxyacantha) may potentially interact with antihypertensive, heart failure, or arrhythmia medications such as the calcium-channel blockers. Following hawthorn administration, the cardiac action potential duration is increased and the refractory period is prolonged. Hawthorn may also lower peripheral vascular resistance. Patients with hypertension or heart failure should be advised to only use hawthorn with their prescribed medications after discussion with their prescriber. Patients who choose to take hawthorn should receive periodic blood pressure and heart rate monitoring.
    Heparin: Concomitant use of amlodipine with potassium-sparing diuretics, potassium salts, salt substitutes containing potassium, or other drugs that may increase potassium concentrations such as heparin may lead to increases in serum potassium.
    Hetastarch; Dextrose; Electrolytes: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Hydantoins: Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Hydralazine: Aliskiren can enhance the effects of vasodilators on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Hydralazine; Hydrochlorothiazide, HCTZ: Aliskiren can enhance the effects of vasodilators on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Hydralazine; Isosorbide Dinitrate, ISDN: Aliskiren can enhance the effects of vasodilators on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren. Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Hydrochlorothiazide, HCTZ; Irbesartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Hydrochlorothiazide, HCTZ; Lisinopril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Hydrochlorothiazide, HCTZ; Losartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Hydrochlorothiazide, HCTZ; Metoprolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Hydrochlorothiazide, HCTZ; Moexipril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Hydrochlorothiazide, HCTZ; Olmesartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Hydrochlorothiazide, HCTZ; Propranolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Hydrochlorothiazide, HCTZ; Quinapril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Hydrochlorothiazide, HCTZ; Spironolactone: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Hydrochlorothiazide, HCTZ; Telmisartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Hydrochlorothiazide, HCTZ; Triamterene: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Hydrochlorothiazide, HCTZ; Valsartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Hydrocodone; Ibuprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Hydrocodone; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Hydrocodone; Potassium Guaiacolsulfonate: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Hydrocodone; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Ibritumomab Tiuxetan: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Ibuprofen lysine: NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs.
    Ibuprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Ibuprofen; Oxycodone: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Ibuprofen; Pseudoephedrine: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Idelalisib: Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with aliskiren, a CYP3A substrate, as aliskiren toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with amlodipine, a CYP3A substrate, as amlodipine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Iloprost: Aliskiren can enhance the effects of iloprost on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren. Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Imatinib, STI-571: Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
    Indapamide: Aliskiren can enhance the effects of indapamide on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Of note, patients with hyponatremia or hypovolemia may also develop reversible renal insufficiency when given aliskiren and diuretics concomitantly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Indinavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Indomethacin: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Iodine; Potassium Iodide, KI: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Irbesartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Isavuconazonium: Concomitant use of isavuconazonium with aliskiren may result in increased serum concentrations of aliskiren. Aliskiren is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together. Concomitant use of isavuconazonium with amlodipine may result in increased serum concentrations of amlodipine. Amlodipine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Isoflurane: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression. General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Isoniazid, INH: CYP3A4 inhibitors, such as isoniazid, INH, may increase the plasma level of amlodipine (a CYP3A4 substrate) via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when isoniazid, INH is coadministered with amlodipine and therapeutic response should be monitored.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: CYP3A4 inhibitors, such as isoniazid, INH, may increase the plasma level of amlodipine (a CYP3A4 substrate) via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when isoniazid, INH is coadministered with amlodipine and therapeutic response should be monitored. Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of calcium-channel blockers. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Isoniazid, INH; Rifampin: CYP3A4 inhibitors, such as isoniazid, INH, may increase the plasma level of amlodipine (a CYP3A4 substrate) via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when isoniazid, INH is coadministered with amlodipine and therapeutic response should be monitored. Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of calcium-channel blockers. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Isoproterenol: The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.
    Isosorbide Dinitrate, ISDN: Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Isosorbide Mononitrate: Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Itraconazole: Avoid concurrent use and use of aliskiren for up to 2 weeks after discontinuation of itraconazole treatment unless benefits of treatment outweigh the potentially increased risk of side effects. Coadministration of 100 mg itraconazole with 150 mg aliskiren resulted in an approximate 5.8-fold increase in Cmax and 6.5-fold increase in AUC of aliskiren. If this combination cannot be avoided, monitor blood pressure very carefully. Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommmended when administering these medication in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
    Ivacaftor: Use caution when administering ivacaftor and aliskiren concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Co-administration of ivacaftor with CYP3A and P-gp substrates, such as aliskiren, can increase aliskiren exposure leading to increased or prolonged therapeutic effects and adverse events. Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure.
    Ketamine: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression. General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Ketoconazole: Coadmistration of aliskiren with ketoconazole, causes a significant increase in the plasma concentration of aliskiren. When 200 mg of ketoconazole twice daily was administered with aliskiren, the plasma concentrations of aliskiren increased by 80%. Although a 400 mg dose of ketoconazole was not studied, it is expected that the higher dose would further increase plasma concentrations of aliskiren. Blood pressure should be monitored in patients taking both of these medications. Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Ketoprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Ketorolac: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Labetalol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Lacosamide: Lacosamide causes PR interval prolongation in some patients. Caution is advised during coadministration of lacosamide with other drugs that cause PR prolongation, such as calcium-channel blockers, since further PR prolongation is possible. If concurrent use is necessary, an ECG is recommended prior to initiation of lacosamide and after the drug is titrated to the maintenence dose. Patients receiving intravenous lacosamide should be closely monitored due to the potential for profound bradycardia and AV block during coadministration.
    Lanreotide: Lanreotide may cause a decrease in heart rate. Administering drugs that also decrease the heart rate (e.g., calcium-channel blockers) in combination with lanreotide may increase the risk of bradycardia. Dose adjustments of calcium-channel blockers may be necessary.
    Lansoprazole; Naproxen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Lesinurad: Lesinurad may decrease the systemic exposure and therapeutic efficacy of aliskiren; monitor for potential reduction in efficacy. Aliskiren is a CYP3A substrate, and lesinurad is a weak CYP3A inducer. Lesinurad may decrease the systemic exposure and therapeutic efficacy of amlodipine; monitor blood pressure closely. Amlodipine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Levobetaxolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Levobunolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Levodopa: Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Levomilnacipran: Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents like aliskiren may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including amlodipine, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Lidocaine: Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Lisdexamfetamine: Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed. Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents. This represents a pharmacodynamic interaction and not a pharmacokinetic one. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Lisinopril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Lithium: Lithium neurotoxicity has been reported during co-administration of lithium and verapamil or diltiazem, and is possible during concurrent use of other calcium-channel blockers with lithium. Symptoms of toxicity have included ataxia, tremors, nausea, vomiting, diarrhea, and tinnitus. The interaction between verapamil and lithium is variable and unpredictable. Both decreased lithium concentrations and lithium toxicity have been reported after the addition of verapamil. The possibility of a loss of lithium's therapeutic effect due to lower serum lithium concentrations may be offset somewhat by the fact that calcium-channel blocking agents share some neuropharmacological actions with lithium; limited data suggest that oral verapamil is effective in controlling an acute manic episode either as a single agent or in combination with lithium. Regarding diltiazem, although neurotoxicity was reported after the addition of diltiazem, other drugs were administered concomitantly. Worsened psychosis has been reported with the combination of diltiazem and lithium. Until more data are available, diltiazem and verapamil should be used cautiously in patients receiving lithium. In theory, direct renin inhibitors, such as aliskiren, have the potential to interact with lithium; therefore, the combination should be used cautiously and with careful monitoring of lithium levels. Related drug classes, such as ACE inhibitors, may substantially increase lithium levels, sometimes resulting in lithium toxicity. Because aliskerin has demonstrated significant natriuresis, increased renal tubular reabsorption of lithium may be possible. If alternative therapies are not possible, monitoring for lithium toxicity (e.g., nausea, vomiting, anorexia, drowsiness, dysarthria, tremor, confusion, lethargy, EKG changes, etc.) is advisable. More frequent assessments of lithium levels and adjustment of lithium dosage may be needed.
    Lomitapide: Concomitant use of lomitapide and amlodipine may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Amlodipine is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors. Concomitant use of lomitapide and aliskiren may result in increased serum concentrations of aliskiren. According to the manufacturer of lomitapide, dose reduction of aliskiren should be considered during concurrent use. Lomitapide is an inhibitor of P-glycoprotein (P-gp) and aliskiren is a P-gp substrate.
    Loop diuretics: Aliskiren can enhance the effects of loop-diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Patients with hyponatremia or hypovolemia may also develop reversible renal insufficiency. When aliskiren is administered in combination with furosemide, the AUC and Cmax of furosemide are reduced by approximately 30% and 50%, respectively; the pharmacokinetics of aliskiren are not affected. Patients should be monitored for loss of effect of furosemide when aliskiren is initiated. Blood pressure and electrolytes should be routinely monitored.
    Loperamide: The plasma concentration of loperamide, a CYP3A4 substrate, may be increased when administered concurrently with amlodipine, a weak inhibitor of CYP3A4. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: The plasma concentration of loperamide, a CYP3A4 substrate, may be increased when administered concurrently with amlodipine, a weak inhibitor of CYP3A4. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. The plasma concentrations of aliskiren may be elevated when administered concurrently with lopinavir; ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Lopinavir; ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp. The plasma concentrations of aliskiren may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp.
    Loratadine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Losartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Lovastatin; Niacin: Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Lumacaftor; Ivacaftor: Lumacaftor; ivacaftor may alter the systemic exposure of aliskiren. If used together, monitor blood pressure closely and adjust the aliskiren dosage as appropriate. Aliskiren is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of aliskiren through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Lumacaftor; Ivacaftor: Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer. Use caution when administering ivacaftor and aliskiren concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Co-administration of ivacaftor with CYP3A and P-gp substrates, such as aliskiren, can increase aliskiren exposure leading to increased or prolonged therapeutic effects and adverse events. Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure.
    Lurasidone: Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Maraviroc: Use caution if coadministration of maraviroc with amlodipine is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and amlodipine is a weak CYP3A4 inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Meclofenamate Sodium: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Mefenamic Acid: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Melatonin: Melatonin may impair the efficacy of some calcium-channel blockers, and caution is advised with concurrent use. In one placebo-controlled study, melatonin evening ingestion led to significant increases in blood pressure (6.5 mmHg systolic and 4.9 mmHg diastolic) and heart rate (3.9 bpm) throughout the day in patients taking nifedipine (GITS formulation). Melatonin appeared to antagonize the antihypertensive effects of nifedipine. The mechanism of this interaction is unclear. It may be prudent to avoid melatonin use during calcium-channel blocker therapy.
    Meloxicam: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Mepivacaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects.
    Mepivacaine; Levonordefrin: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects.
    Mestranol; Norethindrone: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.
    Metformin; Pioglitazone: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Methamphetamine: Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium channel blockers. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Methoxsalen: Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylergonovine: Because of its potential to cause coronary vasospasm, methylergonovine could theoretically antagonize the therapeutic effects of calcium-channel blockers. In addition, calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of methylergonovine and increase the risk of ergot toxicity.
    Methylphenidate: Methylphenidate reduces the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial co-administration and after dosage increases of methylphenidate.
    Methysergide: Because of the potential to cause coronary vasospasm , methysergide theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, verapamil, may also reduce the hepatic metabolism of selected ergot alkaloids and increase the risk of ergot toxicity.
    Metoprolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Metyrapone: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as metyrapone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Mifepristone, RU-486: Mifepristone, RU-486 inhibits CYP3A4 and coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP3A4 substrates, including calcium-channel blockers.
    Milnacipran: Milnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents like amlodipine may be diminished during concurrent use of milnacipran. It is advisable to monitor blood pressure if the combination is necessary. Milnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents may be diminished during concurrent use of milnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Milrinone: Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Minoxidil: Aliskiren can enhance the effects of vasodilators on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Mitotane: Use caution if mitotane and aliskiren are used concomitantly, and monitor for decreased efficacy of aliskiren and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and aliskiren is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of aliskiren. Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
    Modafinil: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Moexipril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Nabumetone: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Nadolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Nafcillin: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Nanoparticle Albumin-Bound Paclitaxel: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like amlodipine. These patients may require monitoring and information.
    Naproxen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Naproxen; Pseudoephedrine: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Naproxen; Sumatriptan: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Nebivolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Nebivolol; Valsartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Nefazodone: Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored. Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Nelfinavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Nesiritide, BNP: The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Netupitant; Palonosetron: Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
    Neuromuscular blockers: Calcium-channel blockers may prolong neuromuscular blockade.
    Nevirapine: Nevirapine is an inducer of the cytochrome P4503A enzyme. Concomitant administration of nevirapine with drugs that are extensively metabolized by this enzyme, including calcium-channel blockers may require dosage adjustments.
    Niacin, Niacinamide: Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Niacin; Simvastatin: Simvastatin and amlodipine should be coadministered with caution due to an increased risk of myopathy, including rhabdomyolysis. If amlodipine and simvastatin must be administered together, do not exceed 20 mg/day simvastatin in adults. For adult patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, the manufacturer of simvastatin recommends switching to an alternative statin with less potential for interactions. Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Nilotinib: Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Nitrates: Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Nitroglycerin: Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Nitroprusside: Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure. Aliskiren can enhance the effects of vasodilators on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Nonsteroidal antiinflammatory drugs: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Octreotide: Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as octreotide, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Olanzapine: Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olaparib: Use caution if coadministration of olaparib with amlodipine is necessary, due to an increased risk of olaparib-related adverse reactions. Olaparib is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor. Simulations have suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and Cmax of olaparib by 2.2-fold and 1.2-fold, respectively, but data are not available with weak CYP3A4 inhibitors. Use caution if coadministration of olaparib with aliskiren is necessary, due to an increased risk of aliskiren-related adverse reactions. Aliskiren is a P-glycoprotein (P-gp) substrate. Olaparib is an in vitro P-gp inhibitor, although the clinical relevance is unknown.
    Olmesartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Ombitasvir; Paritaprevir; Ritonavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. The plasma concentrations of aliskiren may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp.
    Oritavancin: Amlodipine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of amlodipine may be reduced if these drugs are administered concurrently.
    Oxaprozin: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Oxcarbazepine: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as oxcarbazepine, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Oxymetazoline: The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by calcium-channel blockers. If these drugs are used together, closely monitor for changes in blood pressure.
    Paliperidone: Paliperidone may cause orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses of paliperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    Pasireotide: Pasireotide may cause a decrease in heart rate. Closely monitor patients who are also taking drugs associated with bradycardia such as calcium-channel blockers. Dose adjustments of calcium-channel blockers may be necessary.
    Pazopanib: Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and aliskiren, a CYP3A4 substrate, may cause an increase in systemic concentrations of aliskiren. Use caution when administering these drugs concomitantly. Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and amlodipine, a CYP3A4 substrate, may cause an increase in systemic concentrations of amlodipine. Use caution when administering these drugs concomitantly.
    Penbutolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Pentoxifylline: Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
    Perampanel: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Perindopril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Perindopril; Amlodipine: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Phenelzine: Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Phentermine; Topiramate: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Phenylephrine; Promethazine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Phenytoin: Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Photosensitizing agents: Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Pindolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Pioglitazone: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Piroxicam: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Ponatinib: Concomitant use of ponatinib, a P-gp inhibitor, and aliskiren, a P-gp substrate, may increase the exposure of aliskiren.
    Posaconazole: Posaconazole and aliskiren should be coadministered with caution due to an increased potential for aliskiren-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of aliskiren. These drugs used in combination may result in elevated aliskiren plasma concentrations, causing an increased risk for aliskiren-related adverse events. Theoretically, posaconazole may inhibit the metabolism of many calcium-channel blockers via inhibition of CYP3A4. Use caution when coadministering posaconazole and any calcium-channel blocker.
    Potassium Citrate: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Potassium Iodide, KI: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Potassium Phosphate; Sodium Phosphate: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Potassium Salts: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Potassium: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Potassium-sparing diuretics: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Prazosin: Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used. Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used. The use of alpha-blockers with verapamil can lead to excessive hypotension; In addition, verapamil has been reported to increase the AUC and Cmax of prazosin.
    Procainamide: Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.
    Procaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Propofol: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression. General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Propoxyphene: Amlodipine is a CYP3A4 substrate. CYP3A4 inhibitors, such as propoxyphene, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when propoxyphene is coadministered with amlodipine; therapeutic response should be monitored.
    Propranolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Protease inhibitors: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Quinapril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Quinidine: Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Quinine: Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as quinine, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Ramipril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Rasagiline: Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider during concurrent use of an MAOI and a calcium-channel blocker. Orthostatic hypotension has been reported during administration of rasagiline. Therefore, caution is advised during concurrent use with antihypertensive agents. Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious hypertensive reactions with agents affecting catecholamine release (e.g., guanabenz, reserpine, guanethidine) are unlikely. Nevertheless, patients receiving rasagiline in combination with an antihypertensive should be instructed to rise slowly from a sitting position, and to report syncope, and changes in heart rate or blood pressure to their health care provider.
    Remifentanil: The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving calcium-channel blockers due to additive hypotensive effects.
    Ribociclib: Use caution if coadministration of ribociclib with aliskiren is necessary, as the systemic exposure of aliskiren may be increased resulting in an increase in aliskiren-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and aliskiren is a CYP3A4 substrate. Use caution if coadministration of ribociclib with amlodipine is necessary, as the systemic exposure of amlodipine may be increased resulting in an increase in treatment-related adverse reactions including hypotension and edema. Exposure to ribociclib may also increase, increasing ribociclib-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib is a moderate CYP3A4 inhibitor and is extensively metabolized by CYP3A4. Amlodipine is a CYP3A4 substrate and a weak CYP3A4 inhibitor.
    Rifabutin: Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Rifampin: Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of calcium-channel blockers. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Rifapentine: Rifapentine may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Risperidone: Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    Ritonavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. The plasma concentrations of aliskiren may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp.
    Rituximab: Patients should not take antihypertensive agents 12 hours prior to rituximab infusions due to the possibility of hypotension occurring during the rituximab infusion.
    Rofecoxib: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Sacubitril; Valsartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Sapropterin: Caution is advised with the concomitant use of sapropterin and aliskiren as coadministration may result in increased systemic exposure of aliskiren. Aliskiren is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of aliskiren.
    Saquinavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Selegiline: Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. Orthostatic hypotension has been reported during administration of selegiline. Therefore, caution is advised during concurrent use with antihypertensive agents.
    Sevoflurane: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression. General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Sibutramine: Sibutramine may raise blood pressure or heart rate. Patients who are controlled on antihypertensive agents should be monitored for changes in blood pressure while taking sibutramine.
    Sildenafil: Aliskiren can enhance the effects of sildenafil on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren. Monitor for additive hypotension if amlodipine; valsartan is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure.
    Silodosin: During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents. During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents. Silodosin is extensively metabolized by CYP450 3A4 and is a substrate for P-glycoprotein (P-gp). In theory, antihypertensive drugs that inhibit CYP3A4 such as diltiazem, verapamil, and nicardipine may cause significant increases in silodosin plasma concentrations. Verapamil may also interact with silodosin through its effects as a P-gp inhibitor.
    Simeprevir: Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Simvastatin: Simvastatin and amlodipine should be coadministered with caution due to an increased risk of myopathy, including rhabdomyolysis. If amlodipine and simvastatin must be administered together, do not exceed 20 mg/day simvastatin in adults. For adult patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, the manufacturer of simvastatin recommends switching to an alternative statin with less potential for interactions.
    Simvastatin; Sitagliptin: Simvastatin and amlodipine should be coadministered with caution due to an increased risk of myopathy, including rhabdomyolysis. If amlodipine and simvastatin must be administered together, do not exceed 20 mg/day simvastatin in adults. For adult patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, the manufacturer of simvastatin recommends switching to an alternative statin with less potential for interactions.
    Sincalide: Sincalide-induced gallbladder ejection fraction may be affected by calcium-channel blockers. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of results.
    Sofosbuvir; Velpatasvir: Use caution when administering velpatasvir with amlodipine. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
    Sotalol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Spironolactone: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    St. John's Wort, Hypericum perforatum: St. John's wort appears to induce the metabolism of the calcium-channel blockers, apparently by the induction of the CYP3A4 isoenzyme. A non-controlled pharmacokinetic study in healthy volunteers found that concurrent administration of St. John's wort with nifedipine resulted in a 53% decrease in nifedipine peak concentrations. The metabolism of other calcium channel blockers may also be increased; it is assumed the reductions in calcium-channel blocker concentrations could reduce clinical efficacy.
    Streptogramins: Dalfopristin; quinupristin may inhibit the CYP3A4 metabolism of amlodipine, resulting in elevated amlodipine plasma concentrations. Monitor patients for increased side effects, such as hypotension.
    Sufentanil: The incidence and degree of bradycardia and hypotension during induction with sufentanil may be increased in patients receiving calcium-channel blockers. In addition to additive hypotensive effects, calcium-channel blockers that are CYP3A4 inhibitors (e.g., diltiazem, nicardipine, and verapamil) can theoretically decrease hepatic metabolism of some opiates (CYP3A4 substrates), such as sufentanil.
    Sulindac: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Tacrolimus: Coadministration of amlodipine may result in increased serum concentrations of tacrolimus. Monitor tacrolimus concentrations and make dose adjustments as necessary to avoid toxicity of tacrolimus toxicity during concurrent use.
    Tamsulosin: The concomitant administration of tamsulosin with other antihypertensive agents can cause additive hypotensive effects. In addition, diltiazem, nicardipine, and verapamil may increase tamsulosin plasma concentrations via CYP3A4 inhibition. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Telaprevir: Close clinical monitoring is advised when administering aliskiren with telaprevir due to an increased potential for aliskiren-related adverse events. If aliskiren dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of aliskiren. Aliskiren is metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated aliskiren plasma concentrations. Close clinical monitoring is advised when administering amlodipine with telaprevir due to an increased potential for amlodipine-related adverse events. A reduction in the dose of amlodipine should be considered. If amlodipine dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Predictions about the interaction can be made based on the metabolic pathway of amlodipine. Amlodipine is metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated amlodipine plasma concentrations.
    Telithromycin: Serious adverse events, including hypotension, have been reported in patients taking telithromycin concomitantly with calcium channel blockers metabolized by the cytochrome P450 CYP3A4 isoenzyme, such as amlodipine. Telithromycin is a substrate and inhibitor of the CYP3A4 isozyme. Concurrent administration may result in increased serum concentrations of the calcium channel blocker and increased risk for adverse events.
    Telmisartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Telotristat Ethyl: Use caution if coadministration of telotristat ethyl and aliskiren is necessary, as the systemic exposure of aliskiren may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of aliskiren; consider increasing the dose of aliskiren if necessary. Aliskiren is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Use caution if coadministration of telotristat ethyl and amlodipine is necessary, as the systemic exposure of amlodipine may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of amlodipine; consider increasing the dose of amlodipine if necessary. Amlodipine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temsirolimus: Use caution if coadministration of temsirolimus with aliskiren is necessary, and monitor for an increase in aliskiren-related adverse reactions including hypotension. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro. Aliskiren is a CYP3A4 substrate; however, preclinical studies indicate it is also a substrate for P-gp. Concomitant use may cause increased exposure to aliskiren.
    Tetrabenazine: Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
    Tetracaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
    Thalidomide: Thalidomide and other agents that slow cardiac conduction such as calcium-channel blockers should be used cautiously due to the potential for additive bradycardia.
    Thiothixene: Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
    Timolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Tipranavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Tizanidine: Aliskiren can enhance the effects of tizanidine on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Tolmetin: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Topiramate: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Torsemide: Aliskiren can enhance the effects of loop-diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Patients with hyponatremia or hypovolemia may also develop reversible renal insufficiency. When aliskiren is administered in combination with furosemide, the AUC and Cmax of furosemide are reduced by approximately 30% and 50%, respectively; the pharmacokinetics of aliskiren are not affected. Patients should be monitored for loss of effect of furosemide when aliskiren is initiated. Blood pressure and electrolytes should be routinely monitored.
    Trandolapril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Trandolapril; Verapamil: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. Administration of 240 mg verapamil with 300 mg aliskiren resulted in an approximately 2-fold increase in AUC and Cmax of aliskiren; however, no dosage adjustment is necessary. Blood pressure should be closely monitored in patients taking both of these medications. When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    Tranylcypromine: The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated. The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated.
    Trazodone: Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Treprostinil: Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Triamterene: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Valdecoxib: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Valproic Acid, Divalproex Sodium: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Valsartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Vandetanib: Use caution if coadministration of vandetanib with aliskiren is necessary, due to a possible increase in aliskiren-related adverse reactions. Aliskiren is a CYP3A4 substrate; preclinical studies indicate it is also a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively.
    Vasodilators: Aliskiren can enhance the effects of vasodilators on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Vemurafenib: Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
    Verapamil: Administration of 240 mg verapamil with 300 mg aliskiren resulted in an approximately 2-fold increase in AUC and Cmax of aliskiren; however, no dosage adjustment is necessary. Blood pressure should be closely monitored in patients taking both of these medications. When verapamil (non-dihydropyridine calcium channel blocker) and amlodipine (dihydropyridine calcium-channel blocker) are given, hypotension and impaired cardiac performance may occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Also, amlodipine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of diltiazem (moderate CYP3A4 inhibitor) with amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. A similar pharmacokinetic effect may occur with verapamil. While concomitant use may be beneficial for carefully selected patients, caution is warranted; blood pressure, heart rate, and therapeutic response should be closely monitored.
    Voriconazole: Voriconazole may inhibit the metabolism of many calcium-channel blockers via inhibition of CYP3A4. Although clinical data are lacking, it may be prudent to exercise caution when co-administering voriconazole and any calcium-channel blocker. Monitor patients heart rate and blood pressure.
    Warfarin: Coadministration of warfarin with aliskrien decreases the absorption (Cmax) of warfarin by up to 12%. During clinical evaluation, coadministration did not reveal any significant effect on blood coagulation parameters in tested blood samples. Nevertheless, blood coagulation markers should be closely monitored in patients taking both of these medications.
    Yohimbine: Yohimbine (a selective central alpha 2-adrenoceptor antagonist) can increase blood pressure, and therefore can antagonize the therapeutic action of antihypertensive drugs in general. One study in patients with essential hypertension (n = 25) reported an average rise of 5 mmHg in mean blood pressure and a 66% increase in plasma norepinephrine (NE) concentrations following yohimbine administration (4 x 5.4 mg tablets PO). Use with particular caution in hypertensive patients with high or uncontrolled BP.
    Zafirlukast: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
    Zileuton: Zileuton is a CYP3A4 inhibitor, which theoretically may decrease the hepatic metabolismof amlodipine, a CYP3A4 substrate.
    Ziprasidone: Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Zonisamide: Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and aliskiren is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    Aliskiren; amlodipine is classified as FDA pregnancy risk category D. Once pregnancy is detected, every effort should be made to discontinue aliskiren; amlodipine therapy. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters can cause fetal and neonatal morbidity and even death. Drugs such as ACE inhibitors have been associated with fetal and neonatal injury when administered to pregnant women. The reported adverse fetal and neonatal effects include hypotension, neonatal skull hypoplasia and craniofacial deformation, fetal limb contractures, hypoplastic lung development, anuria, oligohydramnios, reversible or irreversible renal failure, and death. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. Inform women of reproductive age about the potential fetal risks of aliskiren; amlodipine exposure throughout pregnancy. While it was previously thought that adverse effects do not result from first-trimester drug exposure, an observational study based on Tennessee Medicaid data reported that the risk of congenital malformations is significantly increased during first-trimester exposure to ACE inhibitors. However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in infants exposed to ACE inhibitors during the first trimester, in infants exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated. Infants born to mothers with hypertension, either treated or untreated, had a higher risk of birth defects than those born to mothers without hypertension. The authors concluded that the presence of hypertension likely contributed to the development of birth defects rather than the use of medications. Women taking aliskiren; amlodipine should tell their healthcare professionals if they are planning to become pregnant or think they might be pregnant. Pregnant women should only be prescribed drugs acting on the renin-angiotensin system if the expected benefits clearly exceed the potential risks. Rarely (probably less often than once per every thousand pregnancies), no alternative to this type of medications will be found. In these rare cases, the pregnant women should be apprised of the potential hazards to their fetus, and serial ultrasound examinations should be performed to assess the intraamniotic environment.

    According to the manufacturer, because of the potential for serious adverse reactions in a nursing infant from aliskiren; amlodipine, a decision should be made whether to discontinue nursing or discontinue aliskiren; amlodipine, taking into account the importance of the drug to the mother. It is not known whether aliskiren or amlodipine are excreted in human milk. Both aliskiren and amlodipine were secreted in the milk of lactating rats. Because neonatal myocardium is very sensitive to changes in calcium status and amlodipine is a calcium-channel blocker, it may be prudent to avoid using aliskiren; amlodipine in breast-feeding mothers until more safety data are available. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Aliskiren; amlodipine combines two antihypertensive agents with different mechanisms to lower blood pressure.
    Aliskiren: Aliskiren is a renin inhibitor and acts within the renin-angiotensin-aldosterone system (RAAS), a hormone system important in the regulation of blood pressure, electrolyte homeostasis, and vascular growth. The RAAS includes a cascade of events, beginning with renin, which cleaves the inactive peptide angiotensinogen, converting it to angiotensin I (Ang I). Ang I is then converted by angiotensin-converting enzyme (ACE) to angiotensin II (Ang II). Ang II is a potent vasoconstrictor and promotes aldosterone secretion and sodium reabsorption; these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. Agents that inhibit the RAAS suppress the negative feedback loop, which results in a compensatory rise in plasma renin activity (PRA). During treatment with ACE inhibitors and angiotensin II receptor antagonists, this causes increased levels of PRA; however, because aliskiren blocks the effect of increased renin levels, PRA is reduced whether aliskiren is used as monotherapy or in combination with other antihypertensive agents. Aliskiren significantly inhibits the RAAS in a dose-dependent manner with maximum reductions in Ang II observed within one hour following oral administration. Because renin catalyzes the first and rate-limiting step of the RAAS and has high specificity for angiotensinogen (its substrate), renin inhibitors present a novel mechanism for blocking this complex hormonal system at its initial point of activation, which results in major potential benefits in blood pressure control and perhaps an improved side effect profile. Whether aliskiren affects other RAAS components (e.g., ACE or non-ACE pathways) is not known.
    Amlodipine: Amlodipine is a peripheral arterial vasodilator that acts directly on the vascular smooth muscle to decrease peripheral vascular resistance and blood pressure. Amlodipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. Amlodipine inhibits this influx, and the resultant decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries. As with other calcium-channel blockers of the dihydropyridine class, amlodipine exerts its effects mainly on arteriolar vasculature. It has no significant effect on sinus node function or cardiac conduction, nor does it possess negative inotropic effects at clinical doses. Because it has a gradual onset when administered orally and chronically, reflex tachycardia does not occur, a side effect that is common with other peripheral vasodilators.

    PHARMACOKINETICS

    Aliskiren; amlodipine is administered orally.
    Aliskiren: Aliskiren has an approximate accumulation half-life of 24 hours, allowing for once daily dosing. Approximately 25% of the absorbed dose appears in the urine as parent drug. It is not known how much of the absorbed dose is metabolized. Based on in vitro studies, the major enzyme responsible for aliskiren metabolism is CYP3A4; no inhibition or induction of CYP450 isoenzymes by aliskiren have been noted.
    Amlodipine: Like other calcium-channel blockers, amlodipine is primarily metabolized by CYP3A4 isoenzymes. The drug is approximately 93% bound to plasma proteins, but drug interactions secondary to displacement from binding sites have not been documented. Amlodipine is extensively metabolized to inactive compounds, and 10% of the parent compound and 60% of the inactive metabolites are excreted in the urine. The terminal half-life is about 30—50 hours, which is significantly longer than other dihydropyridines that are currently available. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

    Oral Route

    The rate and extent of absorption of aliskiren and amlodipine from the combination tablet are the same as when administered as individual tablets.
    Aliskiren: Aliskiren is poorly absorbed following oral administration and has a bioavailability of about 2.5%. After oral administration of aliskiren; amlodipine, median peak plasma concentrations of aliskiren are reached within 3 hours. Administration of aliskiren; amlodipine with a high fat meal decreases the mean aliskiren AUC and Cmax by 79% and 90%, respectively.
    Amlodipine: Amlodipine is slowly absorbed. Oral bioavailability ranges from 64—90%. After oral administration of aliskiren; amlodipine, median peak plasma concentrations of amlodipine are reached within 8 hours. Food does not appear to influence these parameters.