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    Parathyroid Hormone Analogs and Modifiers

    DEA CLASS

    Rx

    DESCRIPTION

    Oral calcimimetic agent that directly reduces parathyroid hormone
    Used for chronic kidney disease with secondary hyperparathyroidism (dialysis patients) and hypercalcemia due to parathyroid carcinoma or primary hyperparathyroidism in patients unable to undergo parathyroidectomy
    Contraindicated in patients with hypocalcemia

    COMMON BRAND NAMES

    Sensipar

    HOW SUPPLIED

    Cinacalcet/Cinacalcet Hydrochloride/Sensipar Oral Tab: 30mg, 60mg, 90mg

    DOSAGE & INDICATIONS

    For the treatment of hypercalcemia in patients with parathyroid carcinoma.
    Oral dosage
    Adults

    Initially, 30 mg PO twice daily. Dosage should be titrated every 2 to 4 weeks through sequential doses of 60 mg PO twice daily, 90 mg PO twice daily, and 90 mg PO 3 to 4 times daily as necessary to normalize serum calcium concentrations. Measure serum calcium within 1 week of initiation or dose adjustment. Once maintenance dose has been established, measure serum calcium every 2 months.

    For the treatment of hyperparathyroidism.
    For patients with secondary hyperparathyroidism and chronic kidney disease undergoing dialysis (CKD Stage 5).
    Oral dosage
    Adults

    Initially, 30 mg PO once daily. Serum calcium and phosphorus should be measured within 1 week. Intact parathyroid hormone (iPTH) serum concentration should be measured 1 to 4 weeks after initiation or dose adjustment. Titrate every 2 to 4 weeks through sequential doses of 60, 90, 120, and 180 mg PO once daily to a target iPTH concentration consistent with the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) recommendation for CKD patients undergoing dialysis (150 to 300 pg/mL). During dose titration, serum calcium concentrations should be monitored frequently; low concentrations of calcium should be treated with supplemental calcium, a calcium-based phosphate binder, or initiating/increasing the dose of vitamin D. Doses of cinacalcet titrated up to 300 mg PO once daily have been safely administered to patients receiving dialysis.

    For patients with secondary hyperparathyroidism and chronic kidney disease not undergoing dialysis (e.g., CKD stage 3 and 4)†.
    Oral dosage
    Adults

    Preliminary data from a study in 54 patients with stage 3 or 4 CKD indicate that cinacalcet is effective in decreasing iPTH concentrations. In this study, patients were initiated on 30 mg PO once daily and titrated every 3 weeks to a maximum dose of 180 mg PO once daily for iPTH concentrations that did not decrease by at least 30% as compared to baseline. After 18 weeks of treatment, 56% of patients receiving cinacalcet compared to 19% of patients receiving placebo experienced a decrease in iPTH concentrations of 30% or more (p = 0.006); furthermore, iPTH concentrations decreased by a mean of 32% compared to baseline in patients taking cinacalcet compared to an increase of 6% in patients taking placebo (p less than 0.001). At study end, 52% of patients were receiving 30 mg PO once daily, and 30% were receiving 60 mg PO once daily. Serum calcium concentrations decreased by an average of 7% and the mean calcium concentration remained within the normal range throughout the study. Approximately 28% of patients were receiving vitamin D analogs at study start, and approximately 43% were receiving phosphate binders. Of note, the manufacturer reports of another study in which the majority of patients (80%) not requiring dialysis experienced at least one serum concentration of calcium less than 8.4 mg/dL.

    For severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy.
    Oral dosage
    Adults

    Initially, 30 mg PO twice daily. Dosage should be titrated every 2 to 4 weeks through sequential doses of 60 mg PO twice daily, 90 mg PO twice daily, and 90 mg PO 3 to 4 times daily as necessary to normalize serum calcium concentrations. Measure serum calcium within 1 week of initiation or dose adjustment. Once maintenance dose has been established, measure serum calcium every 2 months.

    For patients with secondary hyperparathyroidism and chronic kidney disease undergoing dialysis (CKD Stage 5) switching from etelcalcetide to cinacalcet.
    Oral dosage
    Adults

    Initially, 30 mg PO once daily after discontinuing etelcalcetide for at least 4 weeks prior to initiating cinacalcet. Ensure corrected serum calcium is at or above the lower limit of normal prior to cinacalcet initiation.[28126]

    MAXIMUM DOSAGE

    Adults

    300 mg/day PO for dialysis patients with secondary hyperparathyroidism; 360 mg/day PO for hypercalcemia associated with parathyroid carcinoma or primary hyperparathyroidism.

    Geriatric

    300 mg/day PO for dialysis patients with secondary hyperparathyroidism; 360 mg/day PO for hypercalcemia associated with parathyroid carcinoma or primary hyperparathyroidism.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    In patients with moderate and severe hepatic impairment, parathyroid hormone and serum calcium concentrations should be closely monitored throughout treatment with cinacalcet. Dosage reduction may be necessary, however, no quantitative guidelines are available. The AUC values for cinacalcet in patients with moderate to severe hepatic disease are 2.4 and 4.2 times greater, respectively, than the values observed for normal patients.

    Renal Impairment

    No adjustments are necessary.
     
    Intermittent hemodialysis
    No adjustments are necessary. Cinacalcet is highly protein bound and is not significantly removed by dialysis.

    ADMINISTRATION

    Oral Administration

    Administer with food or shortly after a meal.

    Oral Solid Formulations

    Administer whole. Do not chew, crush, or divide tablets.

    STORAGE

    Sensipar:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Hypocalcemia

    Cinacalcet is contraindicated in patients with hypocalcemia (i.e., serum calcium concentrations less than the lower limit of the normal range). Cinacalcet lowers serum calcium concentrations. Life threatening events and fatal outcomes associated with hypocalcemia have been reported in patients treated with cinacalcet. Significant hypocalcemia can cause paresthesias, myalgias, muscle spasms, tetany, seizures, QT interval prolongation, and ventricular arrhythmias. Measure serum calcium concentrations within 1 week after dosage initiation or adjustment and then approximately once every month after establishing a maintenance dose. If serum calcium concentrations decrease below the normal range, supplement with calcium, start or increase dosage of calcium-based phosphate binder or vitamin D sterol, or temporarily withhold cinacalcet therapy. The long-term safety and efficacy of cinacalcet in non-dialysis patients has not been established. Patients with chronic kidney disease that are not on dialysis who are receiving cinacalcet appear to be at increased risk for hypocalcemia possibly because these patients tend to have lower baseline serum calcium concentrations.

    Seizure disorder

    Monitor serum calcium concentrations in patients with seizure disorder receiving cinacalcet. During clinical trials, seizures were reported with a higher incidence in patients treated with cinacalcet compared to placebo. While the basis for the difference in seizure rate is unclear, the seizure threshold is lowered by significant reductions in serum calcium concentrations. Concurrent administration of cinacalcet with calcium-lowering drugs could result in severe hypocalcemia. Educate patients on the symptoms of hypocalcemia and instruct them to contact a healthcare provider if they occur. If corrected serum calcium falls below the lower limit of normal or symptoms of hypocalcemia develop, start or increase calcium supplementation. Cinacalcet dosage reduction or discontinuation may be necessary.

    Long QT syndrome

    Decreases in serum calcium can prolong the QT interval, potentially resulting in ventricular arrhythmias. Patients with congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia may be at increased risk of QT prolongation and ventricular arrhythmias if they develop hypocalcemia. Closely monitor corrected serum calcium and QT interval in at-risk patients receiving cinacalcet.

    Hepatic disease

    Monitor serum calcium, serum phosphorus, and intact parathyroid hormone concentrations closely throughout cinacalcet treatment in patients with moderate to severe hepatic disease. Cinacalcet exposure (AUC) is increased by 2.4 and 4.2-fold in patients with moderate and severe hepatic disease, respectively.

    Esophagitis, gastritis, peptic ulcer disease, vomiting

    Monitor patients with risk factors for upper GI bleeding (e.g., gastritis, esophagitis, peptic ulcer disease, severe vomiting) for worsening of common GI adverse reactions of nausea and vomiting and for signs and symptoms of GI bleeding and ulcerations associated with cinacalcet. Promptly evaluate and treat any suspected GI bleeding. Patients with risk factors for upper GI bleeding may be at increased risk for GI bleeding during treatment with cinacalcet. Cases of GI bleeding, mostly upper GI bleeding, have occurred in patients receiving cinacalcet. The exact cause of GI bleeding in these patients is unknown.

    Children, infants, neonates

    The safety and efficacy of cinacalcet in neonates, infants, children, and adolescents have not been established. Cinacalcet use for the treatment of secondary hyperparathyroidism in pediatric patients with chronic kidney disease on dialysis was evaluated in 2 randomized, controlled studies of 47 patients (6 to 17 years; Study 1 and 2) and in a single-arm study of 17 patients (28 days to 5 years; Study 3) who received at least 1 dose of cinacalcet. Study 1 was terminated because of a fatality in a cinacalcet-treated patient who was noted to be severely hypocalcemic at the time of death. The cause of death was multifactorial; however, a contribution of cinacalcet to the death could not be excluded. Changes in cinacalcet dosing were implemented in the other studies to minimize the risk of severe hypocalcemia. Data from those studies did not establish a safe and effective cinacalcet dosage in pediatric populations.

    Pregnancy

    Data on the use of cinacalcet in human pregnancy are limited to case reports and insufficient to inform a drug associated risk of adverse developmental outcomes. In animal reproduction studies of rats exposed to cinacalcet at 2 to 3 times the systemic concentrations (based on AUC) at the maximum recommended human dose (MRHD) of 180 mg/day during organogenesis through weaning, peripartum and early postnatal pup loss and reduced pup body weight gain were observed in the presence of maternal hypocalcemia. When rats and rabbits were given oral doses resulting in exposures less than with a human oral dose of 180 mg/day based on AUC comparisons, no adverse fetal effects were observed. Reductions in maternal food consumption and body weight gain were noted. Cinacalcet has been shown to cross the placental barrier in rabbits.

    Breast-feeding

    There are no data on the presence of cinacalcet in human milk, the effects on the breast-fed infant, or the effects on milk production. Cinacalcet is excreted into the milk of rats. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for cinacalcet and any potential adverse effects on the breast-fed infant from cinacalcet or the underlying maternal condition.

    Heart failure

    Use cinacalcet with caution in patients with heart failure; isolated cases of hypotension, worsening heart failure, and/or arrhythmia exacerbation were reported in patients with impaired cardiac function taking cinacalcet. A causal relationship to cinacalcet could not be excluded and may be due to a reduction in serum calcium concentrations.[28126]

    ADVERSE REACTIONS

    Severe

    bone fractures / Delayed / 17.0-17.0
    heart failure / Delayed / 2.0-2.0
    seizures / Delayed / 1.4-1.4
    arrhythmia exacerbation / Early / Incidence not known
    angioedema / Rapid / Incidence not known
    GI bleeding / Delayed / Incidence not known

    Moderate

    hypocalcemia / Delayed / 66.0-80.0
    hypercalcemia / Delayed / 17.0-17.0
    dehydration / Delayed / 15.0-15.0
    constipation / Delayed / 13.0-13.0
    depression / Delayed / 13.0-13.0
    anemia / Delayed / 13.0-13.0
    hypotension / Rapid / 7.0-7.0
    hypertension / Early / 7.0-7.0
    chest pain (unspecified) / Early / 6.0-6.0
    osteodystrophy / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known

    Mild

    nausea / Early / 31.0-63.0
    vomiting / Early / 27.0-46.0
    diarrhea / Early / 21.0-21.0
    paresthesias / Delayed / 20.0-20.0
    fatigue / Early / 17.0-17.0
    anorexia / Delayed / 6.0-15.0
    myalgia / Early / 15.0-15.0
    asthenia / Delayed / 7.0-15.0
    headache / Early / 13.0-13.0
    arthralgia / Delayed / 13.0-13.0
    infection / Delayed / 5.0-11.0
    dizziness / Early / 10.0-10.0
    rash / Early / 2.2-2.2
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with cinacalcet may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Cinacalcet is a strong inhibitor of CYP2D6.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a strong inhibitor of CYP2D6.
    Acetaminophen; Dextromethorphan: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Amiodarone: (Moderate) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Therefore, caution is recommended when coadministering cinacalcet with other CYP3A4 enzyme inhibitors, such as amiodarone.
    Amoxapine: (Major) Because most cyclic antidepressants are partially metabolized by CYP2D6, caution is advisable during co-administration of amoxapine and potent CYP2D6 inhibitors such as cinacalcet. Elevated plasma concentrations of amoxapine may result in more pronounced anticholinergic effects and the risk of seizures may be increased.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include clarithromycin. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Amphetamines: (Moderate) Warn patients that there are potentially serious drug interactions between cinacalcet and prescription amphetamine therapy or illicit amphetamine use. The risk of amphetamine toxicity may be increased during concurrent use of potent CYP2D6 inhibitors such as cinacalcet. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
    Anagrelide: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including cinacalcet, could lead to increases in the serum concentrations of cinacalcet and, thus, adverse effects. Monitor patients for an increase in toxicity of cinacalcet if anagrelide is coadministered.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if cinacalcet and aprepitant, fosaprepitant are used concurrently and monitor for an increase in cinacalcet-related adverse effects for several days after administration of a multi-day aprepitant regimen. Cinacalcet 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 cinacalcet. 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: (Major) Because aripiprazole is partially metabolized by CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving potent inhibitors of CYP2D6 such as cinacalcet. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if a potent CYP2D6 inhibitor is used for more than 14 days. Adults receiving 662 mg or 882 mg of Aristada every 4 weeks should have their Aristada dose reduced to the next lower strength if a potent CYP2D6 inhibitor is used for more than 14 days. For patients receiving Aristada 882 mg every 6 weeks or 1,064 mg every 2 months, reduce the dose to 441 mg every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Avoid use of combination therapy with a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days in patients receiving 662 mg, 882 mg, or 1,064 mg of Aristada; no dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP2D6 inhibitors because the dose of Aristada Initio cannot be modified.
    Artemether; Lumefantrine: (Moderate) Lumefantrine is an inhibitor and cinacalcet is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased cinacalcet concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a strong inhibitor of CYP2D6.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with cinacalcet may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Cinacalcet is a strong inhibitor of CYP2D6.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a strong inhibitor of CYP2D6.
    Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with cinacalcet as there is a potential for elevated cinacalcet concentrations. Cinacalcet is a CYP3A4 substrate. Atazanavir is an inhibitor of CYP3A4.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with cinacalcet as there is a potential for elevated cinacalcet concentrations. Cinacalcet is a CYP3A4 substrate. Atazanavir is an inhibitor of CYP3A4. (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with cobicistat; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Atomoxetine: (Major) Dosage reduction of atomoxetine is recommended in patients receiving cinacalcet due to the potential for increased atomoxetine exposure and related adverse effects. In children and adolescents up to 70 kg receiving cinacalcet, atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. In children and adolescents over 70 kg and adults receiving cinacalcet, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. inacalcet is a strong CYP2D6 inhibitor; atomoxetine is a CYP2D6 substrate. Coadministration of a strong CYP2D6 inhibitor and atomoxetine in extensive metabolizers of CYP2D6, increased atomoxetine steady-state plasma concentrations by approximately 6 to 8-fold. This increase is similar to exposures observed in poor metabolizers. Concurrent use of a strong CYP2D6 inhibitor with atomoxetine in poor metabolizers is not expected to increase atomoxetine exposure.
    Barbiturates: (Moderate) Coadministration of cinacalcet with a CYP3A4 enzyme inducer, such as a barbiturate, may result in a decreased effect of cinacalcet.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering cinacalcet with boceprevir due to an increased potential for cinacalcet-related adverse events. If cinacalcet 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 cinacalcet. Cinacalcet is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated cinacalcet plasma concentrations.
    Bosentan: (Moderate) Co-administration of cinacalcet with bosentan, a CYP3A4 enzyme inducer, may result in a decreased effect of cinacalcet. Monitor parathyroid hormone (iPTH), serum calcium, and serum phosphorous levels during coadministration.
    Brexpiprazole: (Major) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving a strong CYP2D6 inhibitor and one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. It should be noted that no dosage adjustment is needed in patients taking a strong CYP2D6 inhibitor who are receiving brexpiprazole as adjunct treatment for major depressive disorder because CYP2D6 considerations are already factored into general dosing recommendations.
    Brimonidine; Timolol: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including timolol.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a strong inhibitor of CYP2D6.
    Carbamazepine: (Moderate) Co-administration of cinacalcet with a CYP3A4 enzyme inducer may result in a decreased effect of cinacalcet. Agents that may significantly induce the CYP3A4 metabolism of cinacalcet include carbamazepine. Since these medications may increase the metabolism of cinacalcet, intact parathyroid hormone, serum calcium and serum phosphorous levels may need to be monitored.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Carvedilol: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase concentrations of other drugs metabolized by this enzyme, including carvedilol.
    Celecoxib; Tramadol: (Moderate) Coadministration of cinacalcet, a strong CYP2D6 inhibitor, with tramadol, a CYP2D6 substrate, may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Ceritinib: (Major) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with ceritinib; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; ceritinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Cevimeline: (Moderate) Cevimeline is partially metabolized by CYP2D6. Inhibitors of this isoenzyme, like cinacalcet, would be expected to lead to an increase in cevimeline plasma concentrations.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Dextromethorphan: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with cinacalcet may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Cinacalcet is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with cinacalcet may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Cinacalcet is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Clarithromycin: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include clarithromycin. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Clozapine: (Moderate) Caution is advisable during concurrent use of cinacalcet and clozapine. Cinacalcet is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with cobicistat; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Codeine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a strong inhibitor of CYP2D6.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a strong inhibitor of CYP2D6.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a strong inhibitor of CYP2D6.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a strong inhibitor of CYP2D6.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a strong inhibitor of CYP2D6.
    Darunavir: (Moderate) Caution is warranted when darunavir is administered with cinacalcet as there is a potential for elevated cinacalcet concentrations. Cinacalcet is a CYP2D6 and CYP3A4 substrate. Darunavir is an inhibitor of both CYP3A4 and CYP2D6.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when darunavir is administered with cinacalcet as there is a potential for elevated cinacalcet concentrations. Cinacalcet is a CYP2D6 and CYP3A4 substrate. Darunavir is an inhibitor of both CYP3A4 and CYP2D6. (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with cobicistat; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when darunavir is administered with cinacalcet as there is a potential for elevated cinacalcet concentrations. Cinacalcet is a CYP2D6 and CYP3A4 substrate. Darunavir is an inhibitor of both CYP3A4 and CYP2D6. (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with cobicistat; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of cinacalcet with ritonavir may result in elevated plasma concentrations of cinacalcet. Cinacalcet is a substrate of CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Denosumab: (Moderate) Monitor serum calcium, phosphorus, and magnesium concentrations within 14 days of denosumab injection during concurrent treatment with calcimimetics such as cinacalcet. The risk for hypocalcemia and other disturbances of mineral metabolism may increase during coadministration. Monitor serum calcium concentrations closely in patients with severe renal impairment (CrCl less than 30 mL/minute) or renal failure (and/or on dialysis) receiving calcimimetics. An increased risk of hypocalcemia was seen in clinical trials involving patients with renal dysfunction. Instruct patients to seek medical care if symptoms of hypocalcemia develop.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Quinidine: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with cinacalcet may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Cinacalcet is a strong inhibitor of CYP2D6.
    Diltiazem: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include diltiazem. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Donepezil: (Moderate) In theory, co-administration of cinacalcet and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. Cinacalcet is a potent inhibitor of CYP2D6, one isoenzyme partially involved in the metabolism of donepezil.
    Donepezil; Memantine: (Moderate) In theory, co-administration of cinacalcet and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. Cinacalcet is a potent inhibitor of CYP2D6, one isoenzyme partially involved in the metabolism of donepezil.
    Dorzolamide; Timolol: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including timolol.
    Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like cinacalcet, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if CYP450 inhibitors are coadministered with doxercalciferol.
    Doxorubicin Liposomal: (Major) Cinacalcet is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of cinacalcet and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Doxorubicin: (Major) Cinacalcet is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of cinacalcet and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronedarone: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP2D6 and CYP3A. Cinacalcet is a substrate for CYP2D6 and CYP3A4. The concomitant administration of dronedarone with CYP2D6 and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Duloxetine: (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with cinacalcet. Concurrent use may result in increased duloxetine exposure resulting in excessive serotonin activity. Cinacalcet is a strong CYP2D6 inhibitor; duloxetine is a CYP2D6 substrate. Coadministration with another strong CYP2D6 inhibitor increased the duloxetine AUC by about 60%.
    Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP2D6 inhibitor such as cinacalcet. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure; interactions with moderate CYP2D6 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Elbasvir; Grazoprevir: (Moderate) Administering cinacalcet with elbasvir; grazoprevir may result in elevated cinacalcet plasma concentrations. Cinacalcet is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), coadministration of cinacalcet and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily; however, coadministration of eliglustat with both cinacalcet and a strong or moderate CYP3A inhibitor is contraindicated. Cinacalcet is a substrate and strong inhibitor of CYP2D6; eliglustat is a CYP2D6 and CYP3A substrate and a CYP2D6 inhibitor. Coadministration of eliglustat with CYP2D6 inhibitors, such as cinacalcet, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). In addition, coadministration of eliglustat with CYP2D6 substrates (e.g., cinacalcet) may result in increased concentrations of the concomitant drug; monitor patients closely for adverse events, and consider reducing the dosage of cinacalcet and titrating to clinical effect.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with cobicistat; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with cobicistat; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Encainide: (Major) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering cinacalcet with other CYP2D6 substrates that have a narrow therapeutic range or where large increases in serum concentrations may be associated with significant adverse reactions. Patients should be monitored for toxicity if cinacalcet is administered with strong CYP2D6 substrates. Other affected CYP2D6 substrates may include encainide.
    Erythromycin: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include erythromycin. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Erythromycin; Sulfisoxazole: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include erythromycin. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Etelcalcetide: (Major) Avoid the concomitant use of etelcalcetide and cinacalcet. Discontinue cinacalcet at least 7 days prior to starting etelcalcetide, and initiate etelcalcetide treatment at 5 mg IV 3 times weekly. Ensure corrected serum calcium is at or above lower limit of normal prior to etelcalcetide initiation. Concurrent use of etelcalcetide with another oral calcium-sensing receptor agonist may result in severe, life-threatening, hypocalcemia.
    Flecainide: (Major) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering cinacalcet with other CYP2D6 substrates that have a narrow therapeutic range or where large increases in serum concentrations may be associated with significant adverse reactions. Patients should be monitored for toxicity if cinacalcet is administered with strong CYP2D6 substrates. Other affected CYP2D6 substrates may include flecainide.
    Fluconazole: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include fluconazole. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Fluoxetine: (Moderate) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as fluoxetine.
    Fosphenytoin: (Moderate) Co-administration of cinacalcet with a CYP3A4 enzyme inducer may result in a decreased effect of cinacalcet. Agents that may significantly induce the CYP3A4 metabolism of cinacalcet include phenytoin and fosphenytoin (which is metabolized to phenytoin). Since these medications may increase the metabolism of cinacalcet, intact parathyroid hormone (iPTH), serum calcium and serum phosphorous levels may need to be monitored.
    Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cinacalcet is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and cinacalcet is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Grapefruit juice: (Major) Grapefruit juice contains a compound that inhibits the CYP3A4 isozyme in the gut wall. Co-administration can potentially decrease hepatic metabolism and increase the serum concentration of cinacalcet. Since the extent to which this interaction occurs is not known, patients should be counseled to avoid grapefruit juice while taking cinacalcet.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Haloperidol: (Moderate) Cinacalcet is a substrate of CYP3A4 and an inhibitor of CYP2D6, the isoenzymes responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and substrates or inhibitors of CYP3A4 or CYP2D6. Elevated haloperidol concentrations occurring through inhibition of CYP2D6 or CYP3A4 may increase the risk of adverse effects, including QT prolongation. Until more data are available, it is advisable to closely monitor for adverse events when these medications are co-administered.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with cinacalcet, a CYP3A substrate, as cinacalcet toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) Reduce the iloperidone dose by one-half if coadministered with cinacalcet. If cinacalcet is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP2D6 substrate. Cinacalcet is a strong inhibitor of CYP2D6. Coadministration of other strong CYP2D6 inhibitors increased mean steady-state peak concentrations of iloperidone and its metabolite P88, by up to 3-fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with cinacalcet may result in increased serum concentrations of cinacalcet. Cinacalcet 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.
    Itraconazole: (Major) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with itraconazole; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; itraconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Ketoconazole: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include clarithromycin. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Letermovir: (Moderate) Administering letermovir with cinacalcet may increase cinacalcet concentration and risk for adverse events. Closely monitor serum intact parathyroid hormone (iPTH) and calcium concentrations in patients who are also receiving cyclosporine because the magnitude of the interaction may be increased. Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with both letermovir and cyclosporine. Cinacalcet is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Levoketoconazole: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Lofexidine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and cinacalcet. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; cinacalcet is a strong CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
    Lonafarnib: (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with lonafarnib; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of cinacalcet with ritonavir may result in elevated plasma concentrations of cinacalcet. Cinacalcet is a substrate of CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of cinacalcet by decreasing its systemic exposure; if used together, monitor intact parathyroid hormone (iPTH), serum calcium, and serum phosphorus concentrations. Cinacalcet is partially metabolized by CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Maprotiline: (Moderate) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as maprotiline.
    Meperidine: (Moderate) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as meperidine.
    Meperidine; Promethazine: (Moderate) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as meperidine.
    Methadone: (Moderate) Coadministration of cinacalet, a strong CYP2D6 inhibitor, may increase the serum concentration of methadone, a CYP2D6 substrate. Monitor for an increased incidence of methadone-related adverse effects during concurrent use.
    Metoclopramide: (Major) Due to the risk of increased metoclopramide plasma concentrations and extrapyramidal adverse reactions, dose adjustments of oral metoclopramide are recommended when administered in combination with strong CYP2D6 inhibitors. In patients with gastroesophageal reflux receiving a strong CYP2D6 inhibitor, the recommended dose of metoclopramide is 5 mg PO four times daily or 10 mg PO three times daily. In patients with diabetic gastroparesis receiving a strong CYP2D6 inhibitor, the recommended dose of metoclopramide is 5 mg PO four times daily times daily. Metoclopramide is a substrate of CYP2D6 and cinacalcet is a strong CYP2D6 inhibitor.
    Metoprolol: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including metoprolol.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including metoprolol.
    Mexiletine: (Moderate) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as mexiletine.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as cinacalcet may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mitotane: (Moderate) Use caution if mitotane and cinacalcet are used concomitantly, and monitor for decreased efficacy of cinacalcet and a possible change in dosage requirements. Intact parathyroid hormone (iPTH), serum calcium and serum phosphorous levels may need to be monitored. Mitotane is a strong CYP3A4 inducer and cinacalcet is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of cinacalcet.
    Nebivolol: (Major) Avoid the concomitant use of nebivolol and cinacalcet. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cinacalcet, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    Nebivolol; Valsartan: (Major) Avoid the concomitant use of nebivolol and cinacalcet. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cinacalcet, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    Nefazodone: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include nefazodone. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Nevirapine: (Moderate) Coadministration of cinacalcet with a CYP3A4 enzyme inducer, such as nevirapine, may result in a decreased effect of cinacalcet.
    Nirmatrelvir; Ritonavir: (Moderate) Concurrent administration of cinacalcet with ritonavir may result in elevated plasma concentrations of cinacalcet. Cinacalcet is a substrate of CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as cinacalcet. Therapeutic monitoring is recommended with coadministration.
    Olanzapine; Fluoxetine: (Moderate) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as fluoxetine.
    Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and cinacalcet is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and cinacalcet may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If cinacalcet is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP2D6 substrate and cinacalcet is a strong CYP2D6 inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of cinacalcet with ritonavir may result in elevated plasma concentrations of cinacalcet. Cinacalcet is a substrate of CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Oritavancin: (Moderate) Cinacalcet is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of cinacalcet may be reduced if these drugs are administered concurrently. Intact parathyroid hormone (iPTH), serum calcium, and serum phosphorous levels may need to be monitored.
    Paroxetine: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including paroxetine.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and cinacalcet, a CYP3A4 substrate, may cause an increase in systemic concentrations of cinacalcet. Use caution when administering these drugs concomitantly.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to cinacalcet if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 and CYP2D6 inhibitor, while cinacalcet is a CYP1A2 and CYP2D6 substrate.
    Perphenazine: (Moderate) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as perphenazine.
    Perphenazine; Amitriptyline: (Moderate) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as perphenazine.
    Phenytoin: (Moderate) Co-administration of cinacalcet with a CYP3A4 enzyme inducer may result in a decreased effect of cinacalcet. Agents that may significantly induce the CYP3A4 metabolism of cinacalcet include phenytoin and fosphenytoin (which is metabolized to phenytoin). Since these medications may increase the metabolism of cinacalcet, intact parathyroid hormone (iPTH), serum calcium and serum phosphorous levels may need to be monitored.
    Pimozide: (Contraindicated) Coadministration of pimozide and cinacalcet is contraindicated due to the potential for increased pimozide exposure. Elevated concentrations of pimozide can lead to QT prolongation, ventricular arrhythmias, and sudden death. Cinacalcet is a strong CYP2D6 inhibitor; pimozide is a CYP2D6 substrate. Coadministration of pimozide with another strong CYP2D6 inhibitor increased the pimozide AUC by 151%.
    Pitolisant: (Major) Initiate pitolisant at 8.9 mg once daily in patients taking cinacalcet; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If cinacalcet is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate; cinacalcet is a strong CYP2D6 inhibitor. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold.
    Posaconazole: (Moderate) Posaconazole and cinacalcet should be coadministered with caution due to an increased potential for cinacalcet-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of cinacalcet. These drugs used in combination may result in elevated cinacalcet plasma concentrations, causing an increased risk for cinacalcet related adverse events.
    Promethazine; Dextromethorphan: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Propafenone: (Major) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering cinacalcet with other CYP2D6 substrates that have a narrow therapeutic range or where large increases in serum concentrations may be associated with significant adverse reactions. Patients should be monitored for toxicity if cinacalcet is administered with strong CYP2D6 substrates. Other affected CYP2D6 substrates may include propafenone.
    Propranolol: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including propranolol.
    Propranolol; Hydrochlorothiazide, HCTZ: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including propranolol.
    Ranolazine: (Moderate) Ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Cinacalcet is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects.
    Ribociclib: (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with ribociclib; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Ribociclib; Letrozole: (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with ribociclib; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Risperidone: (Major) Initiate risperidone at a reduced dose in patients receiving cinacalcet as increased plasma concentrations of risperidone and toxicity may occur. Do not exceed 8 mg PO per day of risperidone if these drugs are coadministered. For the long-acting risperidone injection, the current adult dosage should be closely monitored when cinacalcet is initiated or discontinued. An adjustment of the dose may be required. Risperidone is a CYP2D6 substrate; cinacalcet is a potent CYP2D6 inhibitor.
    Ritonavir: (Moderate) Concurrent administration of cinacalcet with ritonavir may result in elevated plasma concentrations of cinacalcet. Cinacalcet is a substrate of CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Rolapitant: (Major) Use caution if cinacalcet and rolapitant are used concurrently, and monitor for cinacalcet-related adverse effects. Cinacalcet is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Simeprevir: (Moderate) Simeprevir, a mild CYP1A2 and a mild intestinal CYP3A4 inhibitor, may increase the side effects of cinacalcet, which is a CYP1A2 and CYP3A4 substrate. Monitor PTH and calcium concentrations.
    St. John's Wort, Hypericum perforatum: (Moderate) St. John's wort, Hypericum perforatum, is well documented as a CYP3A4 isoenzyme inducer. However, the effect of an interaction with cinacalcet, CYP3A4 substrate. is not known. Coadministration may theoretically lead to increased hepatic metabolism and a subsequent decrease in intended effect of cinacalcet. Patients should be cautioned to avoid concomitant use of these agents.
    Tamoxifen: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with cinacalcet is necessary. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Cinacalcet is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors; plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
    Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP2D6 inhibitor such as cinacalcet. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure; interactions with moderate CYP2D6 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering cinacalcet with telaprevir due to an increased potential for cinacalcet-related adverse events. If cinacalcet 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 cinacalcet. Cinacalcet is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated cinacalcet plasma concentrations.
    Telithromycin: (Major) Concentrations of cinacalcet may be increased with concomitant use of telithromycin. Cinacalcet is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Patients should be monitored for increased side effects.
    Teriflunomide: (Moderate) Use caution when administering teriflunomide and cinacalcet concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as cinacalcet, may decrease cinacalcet exposure and lead to a reduction in efficacy. Monitor serum calcium concentrations.
    Thioridazine: (Contraindicated) Coadministration of cinacalcet, a strong CYP2D6 inhibitor, and thioridazine, a CYP2D6 substrate, is contraindicated, as concurrent use may result in increased exposure to thioridazine. Elevated thioridazine concentrations would be expected to augment the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes.
    Timolol: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including timolol.
    Tramadol: (Moderate) Coadministration of cinacalcet, a strong CYP2D6 inhibitor, with tramadol, a CYP2D6 substrate, may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Tramadol; Acetaminophen: (Moderate) Coadministration of cinacalcet, a strong CYP2D6 inhibitor, with tramadol, a CYP2D6 substrate, may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Trandolapril; Verapamil: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include verapamil. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Tricyclic antidepressants: (Moderate) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as tricyclic antidepressants.
    Tucatinib: (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with tucatinib; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Valbenazine: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as cinacalcet. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and cinacalcet may result in altered concentrations of cinacalcet. Vemurafenib is an inhibitor of CYP1A2 and CYP2D6 and an inducer of CYP3A4. Cinacalcet is a substrate of CYP1A2, CYP2D6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Venlafaxine: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including venlafaxine.
    Verapamil: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include verapamil. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Voriconazole: (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with voriconazole; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; voriconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Vortioxetine: (Major) Concurrent use of cinacalcet and vortioxetine may result in increased plasma concentrations of vortioxetine due to CYP2D6 inhibition by cinacalcet. Because the primary isoenzyme involved in the metabolim of vortioxetine is CYP2D6, the manufacturer recommends a reduction in the vortioxetine dose by one-half during co-administration with strong inhibitors of CYP2D6. The vortioxetine dose should be increased to the original level when the CYP2D6 inhibitor is discontinued.
    Zafirlukast: (Moderate) Caution is recommended when coadministering cinacalcet with other CYP3A4 enzyme inhibitors, such as zafirlukast.
    Zileuton: (Moderate) Caution is recommended when coadministering cinacalcet with other CYP3A4 enzyme inhibitors, such as zileuton.

    PREGNANCY AND LACTATION

    Pregnancy

    Data on the use of cinacalcet in human pregnancy are limited to case reports and insufficient to inform a drug associated risk of adverse developmental outcomes. In animal reproduction studies of rats exposed to cinacalcet at 2 to 3 times the systemic concentrations (based on AUC) at the maximum recommended human dose (MRHD) of 180 mg/day during organogenesis through weaning, peripartum and early postnatal pup loss and reduced pup body weight gain were observed in the presence of maternal hypocalcemia. When rats and rabbits were given oral doses resulting in exposures less than with a human oral dose of 180 mg/day based on AUC comparisons, no adverse fetal effects were observed. Reductions in maternal food consumption and body weight gain were noted. Cinacalcet has been shown to cross the placental barrier in rabbits.

    There are no data on the presence of cinacalcet in human milk, the effects on the breast-fed infant, or the effects on milk production. Cinacalcet is excreted into the milk of rats. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for cinacalcet and any potential adverse effects on the breast-fed infant from cinacalcet or the underlying maternal condition.

    MECHANISM OF ACTION

    The course of chronic kidney disease leads to the development of altered calcium (hypocalcemia) and phosphorus (hyperphosphatemia) metabolism, increased parathyroid hormone (PTH) levels and eventually to subsequent bone disease and vascular and soft tissue calcifications. Hyperphosphatemia results from decreased renal elimination of phosphorus. Increased phosphorus levels directly suppress calcitriol production. Calcium levels decrease as a result of suppressed calcitriol production from the hyperphosphatemia and reduced calcium absorption from the GI tract. Through a feedback mechanism, hypocalcemia, hyperphosphatemia and decreased calcitriol production stimulate the release of parathyroid hormone and proliferation of parathyroid cells leading to secondary hyperparathyroidism. Bone resorption and formation are influenced by many hormonal and non-hormonal factors; hormonal factors affecting bone structure include altered PTH concentrations. When parathyroid hormone levels are too high, osteoclasts are stimulated and result in high bone turnover, leading to decreased cortical bone and bone strength and increased risk of fracture.
     
    The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Cinacalcet, mimicking calcium, increases the sensitivity of this calcium-sensing receptor, and PTH secretion is reduced. The reduction in PTH is associated with a concomitant decrease in serum calcium levels. The feedback loop is hindered and eventually slows the progression of bone disease and the systemic consequences of deranged mineral metabolism.

    PHARMACOKINETICS

    Cinacalcet is administered orally. It is approximately 93 to 97% bound to plasma protein(s). The volume of distribution is approximately 1,000 L, indicating extensive distribution. The plasma concentrations of major circulating metabolites, including hydrocinnamic and glucuronidated dihydrodiols, markedly exceed parent drug concentrations. The hydrocinnamic metabolite was shown to be inactive while the glucuronide conjugates have minimal or no calcimimetic activity. The primary route of elimination of the metabolites was renal excretion. Approximately 80% of the oral dose was recovered in the urine and 15% in the feces.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4, CYP1A2
    Cinacalcet is a strong inhibitor of CYP2D6. It is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2.

    Oral Route

    After oral administration of cinacalcet, Cmax is achieved in approximately 2 to 6 hours. Administration with a high-fat meal increased Cmax and AUC by 82% and 68%, respectively, and increased 65% and 50% when given with a low-fat meal compared to a fasting state. The terminal half-life is 30 to 40 hours and steady-state drug concentrations are achieved within 7 days. The Cmax and AUC increase proportionally over the dose range of 30 to 180 mg PO once daily. However, the pharmacokinetic profile does not change over time with this dose range.