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  • CLASSES

    HMG-CoA Reductase Inhibitors (Statins)

    DEA CLASS

    Rx

    DESCRIPTION

    Least potent, oral, HMG Co-A reductase inhibitor; used 1-2 times daily to treat hypercholesterolemia; indicated to reduce LDL and total cholesterol, plasma triglycerides, and apolipoprotein B; documented to slow the progression of coronary atherosclerosis in patients with CAD.

    COMMON BRAND NAMES

    Lescol, Lescol XL

    HOW SUPPLIED

    Fluvastatin/Fluvastatin Sodium/Lescol Oral Cap: 20mg, 40mg
    Fluvastatin/Fluvastatin Sodium/Lescol XL Oral Tab ER: 80mg

    DOSAGE & INDICATIONS

    For the treatment of hypercholesterolemia, including hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary controll, for the purpose of reducing the risk of cardiovascular events (e.g., myocardial infarction prophylaxis, stroke prophylaxis).
    Oral dosage (regular-release capsules)
    Adults

    20 to 40 mg PO once daily (22% to 25% LDL reduction), titrated up to 40 mg PO twice daily (or switch to extended-release fluvastatin 80 mg PO once daily) to achieve 35% to 36% LDL reduction. In patients with coronary heart disease, fluvastatin 40 mg PO twice daily has been demonstrated to be effective for secondary prevention in post-PCI patients (LIPS trial).[27453] Serum lipid determinations and dosage adjustments should be made at intervals of 4 four weeks or more. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Due to the doubling of costs associated with twice daily administration of 40 mg regular-release capsules, consider reserving the twice daily dosage for those patients with inadequate LDL-lowering at 40 mg once daily (also see dosage information for the alternative extended-release 80 mg tablets designed for once-daily administration). The LIPS trial has demonstrated that initiation of fluvastatin 40 mg twice daily within days following PCI significantly reduces the risk of major cardiac events (cardiac death, nonfatal MI, coronary revascularization).[27453] Based on prior results from the 2.5-year LCAS trial [23946], the FDA, fluvastatin received approval for use to slow the progression of coronary atherosclerosis; the study utilized fluvastatin 20 mg twice daily in patients with coronary heart disease.

    Children and Adolescents 10 to 17 years (females should be at least 1 year post-menarche)

    20 mg PO once daily; may titrate up to 40 mg twice daily. Adjust dosage at intervals of 6 weeks or more to attain desired cholesterol reduction. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In 2 open-label studies of heterozygous familial hypercholesterolemia (n = 114, age 9 to 16 years) serum total cholesterol and LDL were decreased by 21% to 22% and 27% to 28%, respectively, after two years of treatment with fluvastatin. The majority of patients in both studies were titrated to the maximum dosage (80 mg/day).

    Oral dosage (extended-release tablets)
    Adults

    Patients requiring 25% or more LDL reduction may be started on extended-release fluvastatin 80 mg PO once daily (35% LDL reduction). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. For patients requiring lower LDL reductions, see dosage information for regular-release capsules. In general, the recommended dosage range for fluvastatin is 20 to 80 mg/day PO. Elderly patients may have greater LDL reductions at usual doses. Serum lipid determinations and dosage adjustments should be made at intervals of 4 weeks or more.

    Children and Adolescents 10 to 17 years (females should be at least 1 year post-menarche)

    Patients who have been titrated up to 40 mg PO twice daily of fluvastatin may be transitioned to 80 mg PO once daily of the extended-release formulation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In 2 open-label studies of heterozygous familial hypercholesterolemia (n = 114, age 9 to 16 years), the majority of patients in both studies were titrated to the maximum dosage (80 mg/day). In these trials, serum total cholesterol and LDL decreased by 21% to 22% and 27% to 28%, respectively, after 2 years of treatment with fluvastatin.

    MAXIMUM DOSAGE

    Adults

    80 mg/day PO.

    Geriatric

    80 mg/day PO.

    Adolescents

     80 mg/day PO.

    Children

    10 to 12 years: 80 mg/day PO.
    1 to 9 years: 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

    Contraindicated in patients with active hepatic disease or with unexplained or persistent hepatic transaminase elevations.

    Renal Impairment

    No initial dosage adjustment is needed for adult patients mild to moderate renal impairment. Fluvastatin has not been evaluated at doses more than 40 mg/day in adult patients with severe renal impairment; therefore, use caution when treating such patients at higher doses. Specific recommendations for dosage adjustment in pediatric patients with renal impairment are not available.
     
    Intermittent hemodialysis
    The hemodialyzability of fluvastatin is unknown.

    ADMINISTRATION

    NOTE: Patients should also be placed on a standard cholesterol-lowering diet, and this diet should be continued throughout fluvastatin therapy. Serum lipoprotein concentrations should be determined periodically and dosage adjusted according to individual response and established NCEP treatment guidelines.
     

    Oral Administration

    If administered concomitantly with a bile-acid resin (e.g., colestipol, cholestyramine), administer fluvastatin at least 1 hour before (or possibly longer for the extended-release product) or 4 hours after the resin to avoid significant interactions.

    Oral Solid Formulations

    Regular-release Capsules: Fluvastatin may be administered without regard to meals. Do not open fluvastatin capsules prior to administration.
    Extended-release Tablets: Fluvastatin may be administered without regard to meals since no differences in antilipemic effects have been observed when administered with the evening meal or 4 hours after the evening meal. Do not break, crush or chew fluvastatin extended-release tablets prior to administration.

    STORAGE

    Lescol:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Lescol XL:
    - Keep away from heat and flame
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Fluvastatin is contraindicated in any patient with fluvastatin hypersensitivity or hypersensitive to any component of the medication.
     
    Fluvastatin has not been evaluated in patients with rare homozygous familial hypercholesterolemia. In general, HMG-CoA reductase inhibitors have been less effective in these patients because they lack functional LDL receptors.

    Alcoholism, cholestasis, hepatic disease, hepatic encephalopathy, hepatitis, jaundice

    Fluvastatin sodium is contraindicated in patients with active hepatic disease (e.g., cholestasis, hepatic encephalopathy, hepatitis, jaundice) or unexplained persistent elevations in serum aminotransferase concentrations. In addition, patients should minimize ethanol intake while receiving fluvastatin therapy. The drug should be used with caution in patients with alcoholism. Assess liver enzymes prior to initiate fluvastatin therapy and repeat as clinically indicated. After extensive data review, the FDA concluded that the risk of serious liver injury is very low and routine periodic monitoring of liver enzymes has not been effective in detection or prevention of serious hepatic injury. Instruct patients to promptly report any symptoms of hepatic injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice). If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with fluvastatin, therapy should be interrupted. If an alternate etiology is not found, do not restart fluvastatin.

    Electrolyte imbalance, endocrine disease, females, hypotension, hypothyroidism, infection, myopathy, organ transplant, renal disease, renal failure, renal impairment, rhabdomyolysis, seizure disorder, surgery, trauma

    Myopathy, as well as rhabdomyolysis with renal dysfunction secondary to myoglobinuria, have been reported with fluvastatin and other HMG-CoA reductase inhibitors. Myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine kinase (CK) values more than 10 times upper limit of normal (ULN), should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of creatine phosphokinase (CPK). Any evidence of myalgia, muscle weakness, or elevated CPK values may indicate myopathy, particularly if symptoms include fever or malaise. Predisposing risk factors for myopathy include include females, advanced age, renal disease, renal impairment, hypotension, acute infection, endocrine disease such as uncontrolled hypothyroidism, electrolyte imbalance, uncontrolled seizure disorder, major surgery, and trauma. The risk of myopathy and/or rhabdomyolysis is also increased by concomitant therapy with either cyclosporine, gemfibrozil, erythromycin, or niacin, as well as other medications. Fluvastatin should be temporarily withheld in conditions of decreased renal perfusion because renal failure is possible if fluvastatin-induced rhabdomyolysis occurs. HMG-CoA reductase inhibitors should be used with caution in organ transplant patients receiving immunosuppressant therapy such as cyclosporine because of an increased risk of rhabdomyolysis and renal failure. Fluvastatin is minimally (5%) eliminated renally. Renal impairment does not alter the pharmacokinetics following a single 40 mg oral dose of fluvastatin. Fluvastatin has not been evaluated at doses greater than 40 mg/day in adult patients with severe renal impairment; therefore caution should be exercised when treating such patients at higher doses; pediatric dose adjustment recommendations are not available.

    Diabetes mellitus

    If fluvastatin is initiated in a patient with diabetes, increased monitoring of blood glucose control may be warranted. Increased hemoglobin A1c, hyperglycemia, and worsening glycemic control have been reported during therapy with HMG-CoA reductase inhibitors. Because the use of statins has been associated with significant benefit for cardiovascular risk reduction and all-cause mortality at comparable rates in diabetic and non-diabetic patients , no changes to clinical practice guidelines have been recommended in either population. However, the increased risk of diabetes mellitus should be considered when initiating fluvastatin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established. Although an analysis of participants from the JUPITER trial found an increased incidence of developing diabetes in patients allocated to rosuvastatin compared to placebo (270 reports of diabetes vs. 216 in the placebo group; HR 1.25, 95% CI 1.05 to 1.49, p = 0.01), the cardiovascular and mortality benefits of statin therapy exceeded the diabetes hazard even in patients at high risk for developing diabetes (i.e., patients with one or more major diabetes risk factor: metabolic syndrome, impaired fasting glucose, BMI 30 kg/m2 or more, or A1C greater than 6%). In patients at high risk for developing diabetes, treatment with rosuvastatin was associated with a 39% reduction in the primary endpoint (composite of non-fatal myocardial infarction, non-fatal stroke, unstable angina or revascularization, and cardiovascular death) (HR 0.61, 95% CI 0.47 to 0.79, p = 0.0001), nonsignificant reductions in venous thromboembolism (VTE) (HR 0.64, CI 0.39 to 1.06, p = 0.08) and total mortality (HR 0.83, CI 0.64 to 1.07, p = 0.15), and a 28% increase in diabetes (HR 1.28, CI 1.07 to 1.54, p = 0.01). In patients with no major diabetes risk factor, treatment with rosuvastatin was associated with a 52% reduction in the primary endpoint (HR 0.48, 95% CI 0.33 to 0.68, p = 0.0001), nonsignificant reductions in VTE (HR 0.47, CI 0.21 to 1.03, p = 0.05) and total mortality (HR 0.78, CI 0.59 to 1.03, p = 0.08), and no increase in diabetes (HR 0.99, CI 0.45 to 2.21, p = 0.99). For those at high risk for developing diabetes, 134 total cardiovascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. In those without major risk factors, 86 total cardiovascular events or deaths were avoided with no excess new cases of diabetes diagnosed.

    Immune-mediated necrotizing myopathy

    Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred with HMG-CoA reductase inhibitors, such as atorvastatin. IMNM is characterized by proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment; positive anti-HMG-CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents.  Statin-induced IMNM is a rare event making it difficult to determine the true incidence of this adverse reaction; however, available literature reports a range of 1 to 3 of every 100,000 patients treated with an HMG-CoA reductase inhibitor develop IMNM. Based on the available data, patients with IMNM have myalgia with symmetrical and proximal weakness that occurs months to years after starting HMG-CoA reductase therapy and the myopathy persists or even progress following therapy discontinuation. Dysphagia and respiratory failure have also been reported in patients with IMNM. Reported serum creatine phosphokinase levels have ranged from 576 to 35,000 International Units/L. Patients who develop IMNM may require additional neuromuscular and serologic testing. If IMNM develops, HMG-CoA reductase inhibitor therapy should be discontinued and treatment with immunosuppressants, such as high dose corticosteroids, intravenous immune globulin (IVIG), or other immunosuppressive agents, may be needed.    Prior to starting the patient on another HMG-CoA reductase inhibitor, the risks of therapy should be carefully considered. Any patient started on an alternate HMG-CoA reductase inhibitor should be monitored for signs and symptoms of IMNM. 

    Geriatric

    Since advanced age (65 years or more) is a predisposing risk factor for myopathy, fluvastatin should be prescribed with caution in the geriatric patient. Geriatric patients have an increased LDL-lowering response to fluvastatin, which is consistent with other HMG-Co-A reductase inhibitors. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, HMG-CoA reductase inhibitors may impair liver function, and liver function monitoring should occur consistent with individual manufacturer recommendations (e.g., baseline, 12 weeks after initiation, after any dose increase, and periodically thereafter). HMG-CoA reductase inhibitors may cause myalgia, myopathy, and rhabdomyolysis that can precipitate kidney failure, particularly in combination with other cholesterol-lowering medications.

    Contraception requirements, pregnancy

    Fluvastatin is contraindicated for use during pregnancy because of the potential effects of HMG-CoA reductase inhibitors on cholesterol pathways and the potential for fetal harm. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Treatment should be immediately discontinued as soon as pregnancy is recognized. Other HMG-CoA reductase inhibitors have been shown to cause malformations of vertebrae and ribs in fetal rats when given in high doses. In a prospective review of about 100 pregnancies in women exposed to simvastatin or another structurally related HMG-CoA reductase inhibitor, the incidence of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. However, atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. If the patient becomes pregnant while taking this drug, fluvastatin should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus. Fluvastatin should only be administered to females of child-bearing potential, including adolescents at least 1 year post-menarche, when such patients are highly unlikely to conceive and have been informed of the potential hazards. Contraception requirements are advised; females of child-bearing potential should be counseled regarding appropriate methods of contraception while on therapy. The effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of fluvastatin on the pituitary-gonadal axis in pre-menopausal females are unknown. Patients treated with fluvastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately.

    Breast-feeding

    Fluvastatin is contraindicated for use during breast-feeding. Fluvastatin is excreted into breast milk. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for infant growth and development, including synthesis of steroids and cell membranes. HMG-CoA reductase inhibitors decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, and may have other adverse effects for the nursing infant. The importance of continued fluvastatin therapy to the mother should be considered in making the decision whether to discontinue nursing or discontinue the medication. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    Safe use of fluvastatin in infants and children under 10 years of age or in pre-pubertal females has not been established. Because cholesterol plays a crucial role in growth and development, the clinical implications of using pharmacologic therapy to alter the normal production of cholesterol in young children is not clear. Because of these potential safety concerns and lack of safety data, most experts generally recommend delaying cholesterol-lowering medications until the child is at least 8 to 10 years old. In some cases of severe familial hypercholesterolemia, however, HMG-CoA reductase inhibitors have been used in younger children with careful monitoring of growth and development.

    Myasthenia gravis

    Exacerbation and induction of myasthenia gravis have been reported during treatment with statins, including fluvastatin. The onset of symptoms following initiation of statin therapy has ranged from 1 week to 4 months for exacerbation and 6 months to 6 years for induction of myasthenia gravis. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents. Though this appears to be a rare adverse reaction, clinicians should closely monitor patients with myasthenia gravis for disease exacerbation and encourage them to report any muscle-related symptoms.

    ADVERSE REACTIONS

    Severe

    atrial fibrillation / Early / 2.4-2.4
    immune-mediated necrotizing myopathy / Delayed / 0-1.0
    pancreatitis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    myoglobinuria / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    cirrhosis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known
    muscle paralysis / Delayed / Incidence not known
    cranial nerve palsies / Delayed / Incidence not known
    myasthenia gravis / Delayed / Incidence not known

    Moderate

    hypertension / Early / 5.8-5.8
    elevated hepatic enzymes / Delayed / 0.2-4.9
    peripheral edema / Delayed / 4.4-4.4
    constipation / Delayed / 3.3-3.3
    myopathy / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    confusion / Early / Incidence not known
    amnesia / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known
    dysarthria / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known

    Mild

    headache / Early / 4.7-8.9
    dyspepsia / Early / 3.5-7.9
    influenza / Delayed / 5.1-7.1
    abdominal pain / Early / 3.7-6.3
    myalgia / Early / 2.2-5.0
    diarrhea / Early / 3.3-4.9
    sinusitis / Delayed / 2.6-3.5
    nausea / Early / 2.5-3.2
    arthropathy / Delayed / 3.2-3.2
    pharyngitis / Delayed / 2.8-2.8
    fatigue / Early / 1.6-2.7
    insomnia / Early / 0.8-2.7
    infection / Delayed / 1.6-2.7
    flatulence / Early / 1.4-2.6
    syncope / Early / 2.4-2.4
    arthralgia / Delayed / 2.1-2.1
    vomiting / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    fever / Early / Incidence not known
    malaise / Early / Incidence not known
    weakness / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    purpura / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    tremor / Early / Incidence not known
    dysesthesia / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    dizziness / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    dysgeusia / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    Co-Enzyme Q-10 deficiency / Delayed / Incidence not known

    DRUG INTERACTIONS

    Amiodarone: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as amiodarone, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity, including myopathy and rhabdomyolysis.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Concomitant administration of omeprazole with fluvastatin can decrease fluvastatin clearance by 18 to 23%, and increase AUC by 24 to 33%. (Moderate) Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and fluvastatin. Use together with caution and monitor for symptoms of myopathy and/or rhabdomyolysis.
    Amprenavir: (Moderate) Concomitant use of amprenavir with fluvastatin should be done cautiously. Coadministration of fluvastatin with amprenavir may increase the risk of myopathy and rhabdomyolysis, though this risk is much lower than with other HMG-CoA reductase inhibitors.
    Aprepitant, Fosaprepitant: (Minor) Use caution if fluvastatin and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of fluvastatin. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Fluvastatin is a CYP2C9 substrate and aprepitant is a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant. When a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy (another CYP2C9 substrate), a 34% decrease in S-warfarin trough concentrations was noted, accompanied by a 14% decrease in the INR at five days after completion of aprepitant.
    Aspirin, ASA; Omeprazole: (Moderate) Concomitant administration of omeprazole with fluvastatin can decrease fluvastatin clearance by 18 to 23%, and increase AUC by 24 to 33%.
    Atazanavir: (Moderate) Concurrent use of atazanavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Atazanavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, atazanavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
    Atazanavir; Cobicistat: (Major) The plasma concentrations of fluvastatin may increase when administered with cobicistat. Use the lowest starting dose of fluvastatin and carefully titrate while monitoring for adverse events. (Moderate) Concurrent use of atazanavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Atazanavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, atazanavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
    Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like HMG-CoA reductase inhibitors; the risk of peripheral neuropathy may be additive.
    Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with fluvastatin is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and fluvastatin is a weak CYP2C9 inhibitor.
    Cholestyramine: (Moderate) Concomitant administration of cholestyramine with fluvastatin (immediate-release capsules) significantly reduces fluvastatin serum concentrations (reduces AUC by 89%). Cholestyramine produces a complex with fluvastatin that is unavailable for absorption. However, administration of fluvastatin 4 hours after cholestyramine resulted in a clinically significant additive effect compared with that achieved with either component drug. If a patient is to receive both medications, administration times should be staggered by at least 4 hours to avoid impairing fluvastatin bioavailability.
    Cimetidine: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Clarithromycin: (Moderate) Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and fluvastatin. Use together with caution and monitor for symptoms of myopathy and/or rhabdomyolysis.
    Cobicistat: (Major) The plasma concentrations of fluvastatin may increase when administered with cobicistat. Use the lowest starting dose of fluvastatin and carefully titrate while monitoring for adverse events.
    Colchicine: (Major) Use caution and the lowest HMG-CoA reductase inhibitor dose necessary if coadministration with colchicine is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Case reports exist describing the development of myotoxicity with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin).
    Cyclosporine: (Major) Do not exceed 40 mg/day of fluvastatin when coadministered with cyclosporine. The risk of developing myopathy/rhabdomyolysis increases when fluvastatin is used concomitantly with cyclosporine. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. The fluvastatin AUC was increased by 90% with the concomitant cyclosporine administration.
    Daclatasvir: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Daptomycin: (Major) Temporarily suspend HMG-CoA reductase inhibitors in patients taking daptomycin as cases of rhabdomyolysis have been reported with concomitant use. Both agents can cause myopathy and rhabdomyolysis when given alone and the risk may be increased when given together.
    Darolutamide: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; darolutamide is an inhibitor of OATP1B3.
    Darunavir: (Moderate) Concurrent use of darunavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Darunavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, darunavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
    Darunavir; Cobicistat: (Major) The plasma concentrations of fluvastatin may increase when administered with cobicistat. Use the lowest starting dose of fluvastatin and carefully titrate while monitoring for adverse events. (Moderate) Concurrent use of darunavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Darunavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, darunavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) The plasma concentrations of fluvastatin may increase when administered with cobicistat. Use the lowest starting dose of fluvastatin and carefully titrate while monitoring for adverse events. (Moderate) Concurrent use of darunavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Darunavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, darunavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir is an inhibitor of CYP3A4 and may increase exposure to drugs metabolized by this enzyme, such as fluvastatin. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism (approximately 20%), ritonavir may not interact to the same extent as expected with other HMG-CoA reductase inhibitors. Elevated serum concentrations of fluvastatin may increase the risk for adverse reactions, such as myopathy.
    Deferasirox: (Moderate) Deferasirox inhibits CYP2C8. Fluvastatin is a substrate for CYP2C8. The concomitant administration of deferasirox and the CYP2C8 substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide Cmax by 62% and an increase in AUC 2.3-fold. Although specific drug interaction studies of deferasirox and fluvastatin are not available, a similar interaction may occur. The dose of fluvastatin may need to be decreased if coadministered with deferasirox.
    Delavirdine: (Moderate) Concurrent use of delavirdine with fluvastatin should be done cautiously. Coadministration of fluvastatin with delavirdine may increase the risk of myopathy and rhabdomyolysis. Delavirdine inhibits CYP2C9, which is the isoenzyme primarily responsible for the metabolism of fluvastatin.
    Diclofenac: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as fluvastatin; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events. In addition, exposure to fluvastatin may also be increased during concurrent use.
    Diclofenac; Misoprostol: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as fluvastatin; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events. In addition, exposure to fluvastatin may also be increased during concurrent use.
    Digoxin: (Moderate) Due to data that indicate high doses of fluvastatin, 80mg/day, increase digoxin serum concentrations, the manufacturer recommends closer monitoring of patients stabilized on digoxin if fluvastatin is added.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with fluvastatin is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; fluvastatin is a weak inhibitor of CYP2C9. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Efavirenz: (Moderate) Efavirenz inhibits CYP2C9, which is the isoenzyme primarily responsible for the metabolism of fluvastatin. Coadministration of fluvastatin with efavirenz may increase the risk of myopathy and rhabdomyolysis.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Efavirenz inhibits CYP2C9, which is the isoenzyme primarily responsible for the metabolism of fluvastatin. Coadministration of fluvastatin with efavirenz may increase the risk of myopathy and rhabdomyolysis.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz inhibits CYP2C9, which is the isoenzyme primarily responsible for the metabolism of fluvastatin. Coadministration of fluvastatin with efavirenz may increase the risk of myopathy and rhabdomyolysis.
    Elbasvir; Grazoprevir: (Moderate) The manufacturer of elbasvir; grazoprevir recommends caution during concurrent administration with fluvastatin. Although this interaction has not been studied, use of these drugs together may result in elevated fluvastatin plasma concentrations. Use the lowest effective fluvastatin dose and monitor patients for statin-related adverse events (such as myopathy).
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for fluvastatin-related adverse reactions (i.e., myopathy/rhabdomyolysis) during coadministration of elexacaftor; tezacaftor; ivacaftor as concurrent use may increase exposure of fluvastatin. Fluvastatin is a substrate for the transporter OATP1B1; elexacaftor; tezacaftor; ivacaftor may inhibit uptake of OATP1B1. (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as fluvastatin. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Eltrombopag: (Moderate) Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as fluvastatin, may exhibit an increase in systemic exposure if coadministered with eltrombopag; monitor patients for adverse reactions if these drugs are coadministered.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) The plasma concentrations of fluvastatin may increase when administered with cobicistat. Use the lowest starting dose of fluvastatin and carefully titrate while monitoring for adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) The plasma concentrations of fluvastatin may increase when administered with cobicistat. Use the lowest starting dose of fluvastatin and carefully titrate while monitoring for adverse events.
    Enasidenib: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; enasidenib is an inhibitor of OATP1B3.
    Erythromycin: (Major) The risk of developing myopathy and/or rhabdomyolysis with HMG-CoA reductase inhibitors, such as fluvastatin, is increased if coadministered with erythromycin. Fluvastatin is partially metabolized by CYP3A4, and erythromycin is a potent CYP3A4 inhibitor. However, according to the manufacturer, coadministration of erythromycin did not significantly alter the pharmacokinetic disposition of fluvastatin.
    Erythromycin; Sulfisoxazole: (Major) The risk of developing myopathy and/or rhabdomyolysis with HMG-CoA reductase inhibitors, such as fluvastatin, is increased if coadministered with erythromycin. Fluvastatin is partially metabolized by CYP3A4, and erythromycin is a potent CYP3A4 inhibitor. However, according to the manufacturer, coadministration of erythromycin did not significantly alter the pharmacokinetic disposition of fluvastatin.
    Esomeprazole: (Moderate) Concomitant administration of cimetidine, ranitidine, or omeprazole with fluvastatin can decrease fluvastatin clearance by 18 to 23%, and increase AUC by 24 to 33%. A similar interaction might be expected with esomeprazole.
    Ethanol: (Moderate) Heavy use of alcohol during fluvastatin therapy can increase the risk of hepatotoxicity. Alcohol intake should be minimized or avoided during therapy with fluvastatin. (Moderate) Heavy use of alcohol during fluvastatin therapy can increase the risk of hepatotoxicity. Alcohol intake should be minimized or avoided during therapy with fluvastatin.
    Etravirine: (Moderate) The risk of myopathy, including rhabdomyolysis, may be increased when antiretrovirals are given in combination with HMG-CoA reductase inhibitors. Concomitant use of fluvastatin (CYP2C9 substrate) may result in higher fluvastatin plasma concentrations; dose adjustments may be necessary.
    Everolimus: (Moderate) Carefully weigh the benefits of combined use of everolimus and fluvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of fluvastatin to 40 mg/day if combined with everolimus.
    Fenofibrate: (Major) Use caution when coadministering fluvastatin and fenofibrate. The risk of myopathy increases when HMG-Co-A reductase inhibitors ('statins'), including fluvastatin, are administered concurrently with fibric acid derivatives. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Fenofibric Acid: (Major) Use caution when coadministering fluvastatin and fenofibric acid. The risk of myopathy increases when HMG-Co-A reductase inhibitors ('statins'), including fluvastatin, are administered concurrently with fibric acid derivatives. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Fluconazole: (Major) Coadministration of fluconazole and fluvastatin increases fluvastatin exposure, therefore increasing the risk of myopathy and rhabdomyolysis. If used together, limit fluvastatin to 20 mg PO twice daily in adult patients. Fluconazole is an inhibitor of CYP2C9 and fluvastatin is a major CYP2C9 substrate.
    Fluoxetine: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as fluoxetine, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity including myopathy and rhabdomyolysis.
    Fluvoxamine: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as fluvoxamine, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity including myopathy and rhabdomyolysis.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with fluvastatin. Fluvastatin is an inhibitor of CYP2C9, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with fluvastatin, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosamprenavir: (Moderate) Concurrent use of fosamprenavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Fosamprenavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, fosamprenavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
    Fosphenytoin: (Moderate) Monitor for a decrease in fluvastatin efficacy and for an increase in phenytoin/fosphenytoin-related adverse effects if concomitant use is necessary. Concomitant use may decrease fluvastatin exposure and may increase phenytoin/fosphenytoin concentrations.
    Fostemsavir: (Moderate) Use the lowest possible starting dose for fluvastatin when administered concurrent with fostemsavir and monitor for signs of fluvastatin-associated adverse events, such as rhabdomyolysis. Use of these drugs together may increase the systemic exposure of fluvastatin. Fluvastatin is a substrate for the transporter OATP1B1 and fostemsavir is an inhibitor of OATP1B1.
    Gemfibrozil: (Major) Avoid the concomitant administration of fluvastatin and gemfibrozil. The risk of myopathy/rhabdomyolysis increases when HMG-CoA reductase inhibitors are administered concurrently with gemfibrozil. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Glecaprevir; Pibrentasvir: (Major) Use the lowest approved fluvastatin dose (i.e., 20 mg PO once daily) when coadministered with glecaprevir due to an increased risk of myopathy, including rhabdomyolysis. If a higher dose is necessary, use the lowest necessary dose based on a risk/benefit assessment. Coadministration may increase the plasma concentrations of fluvastatin. Fluvastatin is a substrate of the drug transporters OATP1B1 and BRCP; glecaprevir is an inhibitor of these transporters. Additionally, glecaprevir is a P-gp substrate and fluvastatin is a P-gp inhibitor; concentrations of glecaprevir may also be increased. (Major) Use the lowest approved fluvastatin dose (i.e., 20 mg PO once daily) when coadministered with pibrentasvir due to an increased risk of myopathy, including rhabdomyolysis. If a higher dose is necessary, use the lowest necessary dose based on a risk/benefit assessment. Coadministration may increase the plasma concentrations of fluvastatin. Fluvastatin is a substrate of the drug transporters OATP1B1 and BRCP; pibrentasvir is an inhibitor of these transporters. Additionally, pibrentasvir is a P-gp substrate and fluvastatin is a P-gp inhibitor; concentrations of pibrentasvir may also be increased.
    Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like fluvastatin. Monitor serum glucose concentrations if glimepiride is coadministered with fluvastatin. Dosage adjustments may be necessary.
    Glimepiride; Rosiglitazone: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like fluvastatin. Monitor serum glucose concentrations if glimepiride is coadministered with fluvastatin. Dosage adjustments may be necessary.
    Glyburide: (Moderate) Monitor the blood glucose of patients on glyburide when fluvastatin therapy is initiated or when the fluvastatin dose is changed. Concurrent administration results in increased glyburide exposure, which could lead to hypoglycemia and other adverse effects. Glyburide is a CYP2C9 substrate; fluvastatin inhibits this enzyme. The glyburide AUC increased by 70% when glyburide 5 to 20 mg daily for 22 days was coadministered with fluvastatin 40 mg daily for 8 days.
    Glyburide; Metformin: (Moderate) Monitor the blood glucose of patients on glyburide when fluvastatin therapy is initiated or when the fluvastatin dose is changed. Concurrent administration results in increased glyburide exposure, which could lead to hypoglycemia and other adverse effects. Glyburide is a CYP2C9 substrate; fluvastatin inhibits this enzyme. The glyburide AUC increased by 70% when glyburide 5 to 20 mg daily for 22 days was coadministered with fluvastatin 40 mg daily for 8 days.
    Imatinib: (Moderate) Monitor for evidence of fluvastatin-related toxicity including myopathy and rhabdomyolysis if fluvastatin is coadministered with imatinib. Concurrent use may result in clinically significant increased levels of fluvastatin. Imatinib is a moderate CYP3A4 inhibitor; fluvastatin is a CYP3A4 substrate.
    Indinavir: (Moderate) Concurrent use of indinavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Indinavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, indinavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors. Monitor serum lipid concentrations during coadministration of rifampin with fluvastatin.
    Isoniazid, INH; Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors. Monitor serum lipid concentrations during coadministration of rifampin with fluvastatin.
    Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as fluvastatin. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and fluvastatin. Use together with caution and monitor for symptoms of myopathy and/or rhabdomyolysis.
    Lanthanum Carbonate: (Major) To limit absorption problems, HMG-CoA reductase inhibitors ("statins") should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like statin cholesterol treatments, may also be bound by lanthanum carbonate. Separate the times of administration appropriately. Monitor the patient's lipid profile to ensure the appropriate response to statin therapy is obtained.
    Leflunomide: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
    Lesinurad: (Moderate) Use lesinurad and fluvastatin together with caution; fluvastatin may increase the systemic exposure of lesinurad. Fluvastatin is a mild inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and fluvastatin together with caution; fluvastatin may increase the systemic exposure of lesinurad. Fluvastatin is a mild inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Letermovir: (Moderate) Closely monitor for fluvastatin-related adverse events (myopathy, rhabdomyolysis) and consider a fluvastatin dose reduction if administered with letermovir. Do not exceed a fluvastatin dose of 20 mg daily if the patient is also receiving cyclosporine. The magnitude of this interaction may be increased if letermovir is given with cyclosporine. Concurrent administration of letermovir, an organic anion-transporting polypeptide (OATP1B1) inhibitor, with fluvastatin, an OATP1B1 substrate, may result in a clinically relevant increase in fluvastatin plasma concentration.
    Lonafarnib: (Major) Avoid coadministration of lonafarnib and fluvastatin; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and fluvastatin is a CYP2C9 inhibitor.
    Lopinavir; Ritonavir: (Moderate) Monitor for fluvastatin-related adverse reactions (myopathy, rhabdomyolysis) during concurrent administration with lopinavir as use of these drugs together may increase fluvastatin exposure. Fluvastatin is a substrate of the organic anion transporting peptide (OATP1B1); lopinavir inhibits OATP1B1. (Moderate) Ritonavir is an inhibitor of CYP3A4 and may increase exposure to drugs metabolized by this enzyme, such as fluvastatin. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism (approximately 20%), ritonavir may not interact to the same extent as expected with other HMG-CoA reductase inhibitors. Elevated serum concentrations of fluvastatin may increase the risk for adverse reactions, such as myopathy.
    Lovastatin; Niacin: (Major) There is no clear indication for routine use of niacin in combination with fluvastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with fluvastatin. If coadministered, consider lower starting and maintenance does of fluvastatin. Monitor patients closely for myopathy or rhabdomyolysis, particularly in the early months of treatment or after upward dose titration of either drug. Consider monitoring serum creatinine phosphokinase (CPK) and potassium periodically in such situations. Discontinue fluvastatin immediately if myopathy is diagnosed or suspected.
    Lumacaftor; Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as fluvastatin. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Maralixibat: (Minor) Maralixibat may reduce the oral absorption of HMG-CoA reductase inhibitors, also known as statins, which may reduce their efficacy. This risk is greatest with maralixibat doses greater than 4.75 mg. Monitor statin therapy and adjust the dose as needed based on clinical response. Maralixibat is a OATP2B1 inhibitor and statins are OATP2B1 substrates.
    Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with fluvastatin is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and fluvastatin is a weak CYP2C9 inhibitor.
    Mifepristone: (Major) When mifepristone is used chronically in the treatment of hormonal conditions, such as Cushing's syndrome, and given with fluvastatin, the lowest dose of fluvastatin should be used and the patient monitored closely for an increased risk for fluvastatin-related adverse events, such as myopathy and rhabdomyolysis. Consider an alternative to fluvastatin if possible. Mifepristone inhibits CYP2C8/C9 and CYP3A4. In drug interaction studies, significantly increased the exposure of fluvastatin. Fluvastatin is primarily metabolized by CYP2C9, and to a lesser extent, CYP2C8 and CYP3A4. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
    Nanoparticle Albumin-Bound Sirolimus: (Moderate) Carefully weigh the benefits of combined use of sirolimus and fluvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of fluvastatin to 40 mg/day if combined with sirolimus.
    Naproxen; Esomeprazole: (Moderate) Concomitant administration of cimetidine, ranitidine, or omeprazole with fluvastatin can decrease fluvastatin clearance by 18 to 23%, and increase AUC by 24 to 33%. A similar interaction might be expected with esomeprazole.
    Nelfinavir: (Moderate) Concurrent use of nelfinavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Nelfinavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, nelfinavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
    Niacin, Niacinamide: (Major) There is no clear indication for routine use of niacin in combination with fluvastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with fluvastatin. If coadministered, consider lower starting and maintenance does of fluvastatin. Monitor patients closely for myopathy or rhabdomyolysis, particularly in the early months of treatment or after upward dose titration of either drug. Consider monitoring serum creatinine phosphokinase (CPK) and potassium periodically in such situations. Discontinue fluvastatin immediately if myopathy is diagnosed or suspected.
    Niacin; Simvastatin: (Major) There is no clear indication for routine use of niacin in combination with fluvastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with fluvastatin. If coadministered, consider lower starting and maintenance does of fluvastatin. Monitor patients closely for myopathy or rhabdomyolysis, particularly in the early months of treatment or after upward dose titration of either drug. Consider monitoring serum creatinine phosphokinase (CPK) and potassium periodically in such situations. Discontinue fluvastatin immediately if myopathy is diagnosed or suspected.
    Nirmatrelvir; Ritonavir: (Moderate) Ritonavir is an inhibitor of CYP3A4 and may increase exposure to drugs metabolized by this enzyme, such as fluvastatin. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism (approximately 20%), ritonavir may not interact to the same extent as expected with other HMG-CoA reductase inhibitors. Elevated serum concentrations of fluvastatin may increase the risk for adverse reactions, such as myopathy.
    Olanzapine; Fluoxetine: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as fluoxetine, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity including myopathy and rhabdomyolysis.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir is an inhibitor of CYP3A4 and may increase exposure to drugs metabolized by this enzyme, such as fluvastatin. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism (approximately 20%), ritonavir may not interact to the same extent as expected with other HMG-CoA reductase inhibitors. Elevated serum concentrations of fluvastatin may increase the risk for adverse reactions, such as myopathy.
    Omeprazole: (Moderate) Concomitant administration of omeprazole with fluvastatin can decrease fluvastatin clearance by 18 to 23%, and increase AUC by 24 to 33%.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Concomitant administration of omeprazole with fluvastatin can decrease fluvastatin clearance by 18 to 23%, and increase AUC by 24 to 33%. (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors. To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
    Omeprazole; Sodium Bicarbonate: (Moderate) Concomitant administration of omeprazole with fluvastatin can decrease fluvastatin clearance by 18 to 23%, and increase AUC by 24 to 33%.
    Oritavancin: (Moderate) Fluvastatin is metabolized by CYP2C9; oritavancin is a weak CYP2C9 inhibitor. Coadministration may result in elevated fluvastatin plasma concentrations. If these drugs are administered concurrently, monitor patients for signs of fluvastatin toxicity, such as muscle aches, muscle pain or tenderness, general weakness or fatigue, side or back pain, or decreased urination.
    Phenytoin: (Moderate) Monitor for a decrease in fluvastatin efficacy and for an increase in phenytoin-related adverse effects if concomitant use is necessary. Concomitant use may decrease fluvastatin exposure and may increase phenytoin concentrations.
    Pioglitazone; Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like fluvastatin. Monitor serum glucose concentrations if glimepiride is coadministered with fluvastatin. Dosage adjustments may be necessary.
    Probenecid; Colchicine: (Major) Use caution and the lowest HMG-CoA reductase inhibitor dose necessary if coadministration with colchicine is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Case reports exist describing the development of myotoxicity with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin).
    Raltegravir: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Ranitidine: (Moderate) Concomitant administration of ranitidine with fluvastatin can decrease fluvastatin clearance by 18 to 23%, and increase AUC by 24 to 33%.
    Red Yeast Rice: (Contraindicated) Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with HMG-CoA reductase inhibitors. The administration of more than one HMG-CoA reductase inhibitor at one time would be duplicative therapy and perhaps increase the risk of drug-related toxicity including myopathy and rhabdomyolysis.
    Regorafenib: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with regorafenib is necessary. Fluvastatin is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Rifabutin: (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors. To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
    Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors. Monitor serum lipid concentrations during coadministration of rifampin with fluvastatin.
    Ritonavir: (Moderate) Ritonavir is an inhibitor of CYP3A4 and may increase exposure to drugs metabolized by this enzyme, such as fluvastatin. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism (approximately 20%), ritonavir may not interact to the same extent as expected with other HMG-CoA reductase inhibitors. Elevated serum concentrations of fluvastatin may increase the risk for adverse reactions, such as myopathy.
    Rucaparib: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with rucaparib is necessary. Fluvastatin is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor.
    Saquinavir: (Moderate) Concurrent use of saquinavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Saquinavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, saquinavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
    Simeprevir: (Moderate) Although coadministration of fluvastatin with simeprevir has not been studied, use of these drugs together is expected to increase fluvastatin exposure. If these drugs are given together, titrate the fluvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Sirolimus: (Moderate) Carefully weigh the benefits of combined use of sirolimus and fluvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of fluvastatin to 40 mg/day if combined with sirolimus.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Caution is advised when administering voxilaprevir with fluvastatin. Taking these drugs together may increase fluvastatin plasma concentrations; thereby increasing the risk for adverse events, such as myopathy or rhabdomyolysis. Initiate fluvastatin at the lowest approved dose. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment.
    Sulfinpyrazone: (Moderate) In theory, concurrent use sulfinpyrazone, a CYP2C9 inhibitor, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin. Monitor patients for signs of fluvastatin toxicity.
    Sulfonamides: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as sulfonamides, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity.
    Tacrolimus: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and fluvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. A maximum dose of fluvastatin of 40 mg/day is recommended.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering fluvastatin with telaprevir due to the potential for fluvastatin-related adverse events. When used in combination, the plasma concentrations of fluvastatin may be elevated.
    Telbivudine: (Moderate) The risk of myopathy may be increased if an HMG-CoA reductase inhibitor is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Telithromycin: (Major) Fluvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Coadministration of fluvastatin with inhibitors of OATP, such as telithromycin may theoretically result in increased concentrations of fluvastatin.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering fluvastatin. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9; fluvastatin is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Teriflunomide: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
    Tezacaftor; Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as fluvastatin. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Tipranavir: (Moderate) Concurrent use of tipranavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Tipranavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, saquinavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and fluvastatin may result in increased fluvastatin concentrations. Vemurafenib is a CYP2C9 inhibitor and fluvastatin is a CYP2C9 substrate. Patients should be monitored for toxicity.
    Voclosporin: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with voclosporin is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; voclosporin is an inhibitor of OATP1B3.
    Voriconazole: (Moderate) The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if fluvastatin is administered concomitantly with CYP 3A4 inhibitors including voriconazole.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with fluvastatin is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fluvastatin is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Zafirlukast: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as fluvastatin.

    PREGNANCY AND LACTATION

    Pregnancy

    Fluvastatin is contraindicated for use during pregnancy because of the potential effects of HMG-CoA reductase inhibitors on cholesterol pathways and the potential for fetal harm. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Treatment should be immediately discontinued as soon as pregnancy is recognized. Other HMG-CoA reductase inhibitors have been shown to cause malformations of vertebrae and ribs in fetal rats when given in high doses. In a prospective review of about 100 pregnancies in women exposed to simvastatin or another structurally related HMG-CoA reductase inhibitor, the incidence of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. However, atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. If the patient becomes pregnant while taking this drug, fluvastatin should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus. Fluvastatin should only be administered to females of child-bearing potential, including adolescents at least 1 year post-menarche, when such patients are highly unlikely to conceive and have been informed of the potential hazards. Contraception requirements are advised; females of child-bearing potential should be counseled regarding appropriate methods of contraception while on therapy. The effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of fluvastatin on the pituitary-gonadal axis in pre-menopausal females are unknown. Patients treated with fluvastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately.

    MECHANISM OF ACTION

    Fluvastatin interferes with the activity of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, a hepatic enzyme. Inhibition of HMG-CoA reductase interrupts the pathway within the body responsible for the majority of human cholesterol biosynthesis. The amount of mevalonic acid, a precursor of cholesterol, is reduced. Cholesterol levels in hepatic cells are subsequently reduced, stimulating uptake of LDL cholesterol. Fluvastatin reduces plasma total cholesterol, LDL cholesterol, and serum triglycerides; and it raises plasma HDL-cholesterol concentrations.
     
    HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.

    PHARMACOKINETICS

    Fluvastatin is administered orally. It is highly (> 98%) bound to protein and does not cross the blood-brain barrier. Hepatic metabolism occurs primarily (75%) via CYP2C9 isoenzymes; other metabolic pathways include CYP 2C8 (5%) and CYP 3A4 (20%). Active hydroxylated metabolites do not circulate systemically. The mean half-life ranges from 2.5—2.7 hours for the immediate-release capsules. Following administration of the extended-release tablets (Lescol XL), the half-life is approximately 9 hours. It is completely metabolized before excretion via the bile into the feces. About 5% is excreted by the renal route.
     
    Affected cytochrome P450 (CYP450) enzymes: CYP2C8, CYP2C9, CYP3A4
    Fluvastatin is completely metabolized and hepatic metabolism occurs primarily (75%) via CYP2C9 isoenzymes; other metabolic pathways include CYP2C8 (5%) and CYP3A4 (20%). If one pathway is inhibited in the elimination process, in theory, other pathways may compensate. Drugs that are CYP2C9 inhibitors or inducers have greater potential to alter plasma concentrations and cause potential toxicity relative to drugs which affect the CYP3A4 pathway. Fluvastatin also is a CYP2C9 inhibitor.
     

    Oral Route

    Following administration of regular-release fluvastatin, absorption of the active form from the stomach is rapid and almost complete, but a significant first-pass effect reduces mean absolute bioavailability to 24% following a 10 mg dose (range 9—50%). In the fasting state, bioavailability is dose-dependent and is subject to first-pass metabolism. Food reduces the rate but not extent of absorption. Following administration of the regular-release formulation (20 or 40 mg capsules), peak fluvastatin concentrations are achieved in less than an hour in the fasting state and can be delayed up to 6 hours post-dose when administered with food. The pharmacokinetics following administration of extended-release fluvastatin (Lescol XL 80 mg tablets) is highly variable due to its absorption characteristics and first-pass metabolism, especially following a high-fat meal. Extended-release fluvastatin tablets result in peak concentrations in about 3 hours in the fasting state, with a mean relative bioavailability of 29% (range 9—66%) compared to the regular-release capsules. Administration of Lescol XL tablets with a high-fat meal delayed the absorption (Tmax 6 hours) and increased the bioavailability by about 50%. However, Lescol XL may be administered without regard to meals since no differences in antilipemic effects have been observed when administered with the evening meal or 4 hours after the evening meal, despite pharmacokinetic differences. Once absorption of Lescol XL begins, fluvastatin plasma concentrations rise rapidly; multiple peaks in plasma concentrations may occur. Fluvastatin is highly (>98%) bound to protein. It does not cross the blood-brain barrier. Fluvastatin undergoes significant first-pass metabolism. Both human and animal studies suggest a saturable first-pass effect.