Fluvastatin is an oral competitive HMG-CoA reductase inhibitor approved as an adjunct to diet for the treatment of primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb) in adults and heterozygous familial hypercholesterolemia in adults and pediatric patients aged 10 years and older. It is also approved to reduce the risk of undergoing coronary revascularization procedures and to slow the progression of coronary atherosclerosis in adults with clinically evident coronary heart disease. Fluvastatin immediate-release 40 mg twice daily or fluvastatin extended-release 80 mg once daily is considered to be a moderate-intensity statin (expected to lower low-density lipoprotein cholesterol [LDL-C] by 30% to 49%), while fluvastatin immediate-release 20 mg or 40 mg once daily is considered to be a low-intensity statin (expected to lower LDL-C by less than 30%). Fluvastatin is the first synthetically prepared HMG-CoA reductase inhibitor. It has some similarities to lovastatin, simvastatin, and pravastatin, but it is structurally distinct, resulting in unique biopharmaceutic properties. Purported advantages of fluvastatin over other HMG-CoA reductase inhibitors include short half-life with no active metabolites, extensive protein binding, and minimal CSF penetration, characteristics that suggest fluvastatin may be less likely to cause systemic adverse reactions than other agents in this class. Fluvastatin is effective in reducing total cholesterol and LDL-C as well as plasma triglycerides and apolipoprotein B. Based on results from the Lipoprotein and Coronary Atherosclerosis Study, fluvastatin was approved for slowing of progression of coronary atherosclerosis in patients with coronary artery disease. Fluvastatin immediate-release and fluvastatin extended-release were approved for secondary prevention of coronary events in patients with coronary heart disease based on the findings of the LIPS trial. The LIPS trial demonstrated that initiation of fluvastatin 80 mg/day within days following PCI significantly reduces the risk of major cardiac events (cardiac death, nonfatal MI, coronary revascularization). Additionally, a large retrospective study demonstrated that continuation of statin therapy provides an ongoing reduction in all-cause mortality in patients with and without known coronary heart disease (CHD), with the greatest risk reduction among patients with a baseline LDL-C of 190 mg/dL or more and patients initiated on higher efficacy statins (i.e., simvastatin, pravastatin, or lovastatin 80 mg/day; atorvastatin 20 mg/day or more; rosuvastatin 10 mg/day or more). Among patients with a proportion of days covered (PDC) of 90% or more, determined by the number of statin prescriptions dispensed during the time between the first statin prescription and the end of follow up, there was a 45% and 51% lower mortality risk in the primary (patients without known CHD) and secondary (patients with known CHD) prevention groups, respectively, compared to patients with a PDC 10% or less. The mean length of follow up was 4 and 5 years in the primary and secondary prevention groups, respectively, with a maximum length of follow up of 9.5 years.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer fluvastatin with or without meals.
-If administered concomitantly with cholestyramine, a bile-acid resin, administration times should be staggered by at least 4 hours to avoid impairing fluvastatin bioavailability.
Oral Solid Formulations
-Immediate-release Capsules: For once daily dosing regimen, administer immediate-release capsules in the evening. Do not open fluvastatin capsules.
-Extended-release Tablets: Administer extended-release tablets once daily at any time during the day. Swallow whole; do not break, crush or chew fluvastatin extended-release tablets prior to administration.
In clinical trials with fluvastatin, gastrointestinal (GI) effects such as dyspepsia (3.5% to 7.9%), diarrhea (3.3% to 4.9%), abdominal pain (3.7% to 6.3%), constipation (3.3%), flatulence (1.4% to 2.6%), and nausea (2.5% to 3.2%) were noted. Postmarketing pancreatitis, anorexia, and vomiting have also been reported.
HMG-CoA reductase inhibitors have been associated with toxicity to the skeletal muscle system. Myopathy and elevations of CPK to greater than 10 times normal have been reported during fluvastatin therapy and were less than 0.1% in clinical trials. Myalgia was noted in 2.2 to 5% of patients, and rhabdomyolysis with acute renal failure secondary to myoglobinuria has also been associated with statins including fluvastatin. Postmarketing, muscle cramps, myalgia, myopathy, rhabdomyolysis, muscle spasms, muscle weakness, and myositis were noted. Discontinue fluvastatin if markedly elevated CPK concentrations occur or if myopathy is diagnosed or suspected. Any evidence of unexplained myalgia, myasthenia (muscle weakness), or elevated CPK values may indicate myopathy, particularly if symptoms include fever, lethargy/drowsiness, asthenia/weakness, and/or malaise. Instruct patients to promptly report such symptoms. Statin-induced myopathy is generally dose-related. Rhabdomyolysis may occur anytime during drug treatment, and the risk may be increased by a number of confounding factors including age, concomitant drug therapy, renal dysfunction, and concomitant disease states. Many cases result in hospitalization and a need for dialysis for treatment. Vigilant clinical monitoring during prescribing can help limit serious adverse events.
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred rarely (1 to 3 of every 100,000 patients) with HMG-CoA reductase inhibitors, such as fluvastatin. Recurrence of IMNM has been reported following administration of the same or a different statin. IMNM is characterized by myalgia with symmetrical and proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment. Some cases have occurred months to years after starting HMG-CoA reductase therapy and the myopathy progressed following therapy discontinuation. Other characteristics include positive anti-HMG-CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. 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.
Arthralgia (2.1%), arthritis (1.3% to 2.1%), and arthropathy (3.2%) have been reported with fluvastatin.
Elevated hepatic enzymes (transaminases, alkaline phosphatase, gamma-glutanyl transpeptidase, billirubin) have been reported with fluvastatin. In most cases, these changes appeared soon after initiation, were transient, were not associated with symptoms, and resolved or improved on continued therapy or after temporary discontinuation of therapy. In very rare cases, possibly drug-related hepatitis was observed in patients receiving fluvastatin that resolved upon discontinuation. Postmarketing, hepatitis including chronic active hepatitis, cholestatic jaundice (cholestasis), fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, and fatal and non-fatal hepatic failure have been noted. Assess hepatic enzymes prior to initiating fluvastatin and repeat as clinically indicated. Instruct patients and caregivers to promptly report any symptoms of hepatic injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice). Discontinue fluvastatin if serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs. If an alternate etiology is not found, do not restart fluvastatin. Approximately 1.1% of adults who received fluvastatin during clinical trials developed dose-related, persistent elevated hepatic enzymes to more than 3 times the upper limit of normal (ULN). Most individuals were asymptomatic. In a pooled analysis of all placebo-controlled studies for fluvastatin, persistent transaminase elevations (greater than 3 times the ULN on two consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of adults treated with 20 mg, 40 mg, and 80 mg of fluvastatin, respectively. A majority (91%) of the cases of persistent liver function test abnormalities occurred within 12 weeks of therapy; in all patients with persistent liver function test abnormalities, there was an abnormal liver function test present at baseline or by the week 8 of therapy. In a pooled analysis of trials which included the fluvastatin extended-release formulation, persistent transaminase levels occurred in 1.8%, 4.9%, and 1.9%, respectively, of adult patients treated with fluvastatin immediate-release 40 mg once daily, fluvastatin immediate-release 40 mg twice daily, and fluvastatin extended-release 80 mg once daily. Of the 16 patients treated with the fluvastatin extended-release formulation, 13 individuals experienced persistent transaminase elevations within 12 weeks of starting therapy.
Rash (unspecified), dermatitis including bullous dermatitis, eczema, alopecia, pruritus, and a variety of general skin changes (e.g., nodules, discoloration, dryness of skin or mucous membranes, changes to hair/nails) have been reported during postmarketing use of fluvastatin. An apparent hypersensitivity syndrome has rarely been reported with HMG-CoA reductase inhibitors and has included one or more of the following features: anaphylaxis (anaphylactoid reactions), angioedema, lupus-like symptoms, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson syndrome. Lichen planus-like eruption has also been reported with fluvastatin postmarketing experience.
Dizziness has been reported in 3.9% of patients taking fluvastatin. Postmarketing, tremor, vertigo, paresthesias, hypoesthesia, dysesthesia, and peripheral neuropathy have been noted. An association between HMG-CoA reductase inhibitors (statins), including fluvastatin, and peripheral neuropathy has been reported in the literature (case series, case-control studies, cohort studies). In a nested case-control study of a Danish population, the odds ratio for idiopathic peripheral neuropathy in 166 patients that ever or were currently taking a statin, was 3.7 (95% CI 1.8 to 7.6); similar results have been found in other population based studies, although the number of patients studied was significantly smaller. Case reports and series indicate that the onset of neuropathy is typically 1 year or more after drug initiation and is reversible with drug discontinuation. However, cases describing irreversible neuropathy are also reported. The adverse effect appears to be a class effect because in all cases, when a patient is either re-challenged or treated with a different statin, the symptoms of neuropathy return. While the data appear to support an association between HMG-CoA reductase inhibitors and peripheral neuropathy, the incidence is rare and estimated to be approximately 1 per 14,000 person-years. Furthermore, a causal relationship cannot be definitively established based on the observational nature of the available data. The benefits of statin therapy far outweigh any risk of peripheral neuropathy; however, until more information is available, health care providers should be aware of this adverse effect.
Rare cases of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) have been associated with the use of all statins including fluvastatin. A review of available data by the FDA did not find an association between the event and a specific statin, statin dose, concomitant medication, or age of the patient. In general, post-marketing reports described patients over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon statin discontinuation. The cases did not appear to be associated with progressive or fixed dementia. The time to symptom onset (1 day to years) and resolution (median 3 weeks) is variable.
In trials, headache (4.7% to 8.9%), fatigue (1.6% to 2.7%), and insomnia (0.8% to 2.7%) were noted with fluvastatin. Postmarketing, anxiety, psychic disturbances, and depression were reported.
Postmarketing, dysfunction of certain cranial nerves (including symptoms possibly indicative of cranial nerve palsies, such as alteration of taste (dysgeusia), impairment of extra-ocular movement, facial paresis), and peripheral nerve palsy was noted with fluvastatin. Amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease) has been reported to the FDA in a higher than expected number of patients taking statins like fluvastatin. ALS is a progressive motor neuron disorder with symptoms such as difficulty walking or standing, difficulty with fine motor skills, atrophy of tongue and hand muscles, dysphagia, dysarthria, and muscle paralysis. Due to the seriousness of ALS and the extensive use of statins, FDA further examined data from 41 long-term controlled clinical trials. The results of the review showed no increased incidence of ALS in patients treated with a statin compared with placebo. Specifically, 9 of approximately 64,000 patients treated with a statin (4.2 cases per 100,000 patient-years) and 10 of approximately 56,000 patients treated with placebo (5 case per 100,000 patient-years) were diagnosed with ALS. FDA is examining the feasibility of performing additional epidemiologic studies to further examine the incidence and clinical course of ALS in patients taking statins.
Increased hemoglobin A1c and fasting serum glucose (hyperglycemia) have been reported with HMG-CoA reductase inhibitors. A meta-analysis of 13 statin trials with 91,140 participants showed a 9% increase in the likelihood of the development of diabetes mellitus (OR 1.09; 95% CI 1.02 to 1.17). The incidence of diabetes was higher in high-risk patients (i.e., age 70 to 82 years with or at high risk of cardiovascular disease, myocardial infarction within the last 6 months, or heart failure) compared to patients with low diabetes risk (i.e., low BMI). Additionally, an analysis of the data from the Women's Health Initiative (WHI) trial found that statin use in postmenopausal individuals is associated with an increased risk of new-onset diabetes mellitus (multivariate-adjusted HR 1.48; 95% CI 1.38 to 1.59). No difference in the risk for diabetes between statins was detected in either analysis. Because the use of statins has been associated with significant benefit for cardiovascular risk reduction and all-cause mortality at comparable rates in people with and without diabetes, no changes to clinical practice guidelines have been recommended in either population. However, the increased risk of diabetes should be considered when initiating statin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established.
Gynecomastia, libido decrease, and impotence (erectile dysfunction) have been reported with statins but not necessarily fluvastatin. Statins interfere with cholesterol synthesis and lower circulating cholesterol concentrations and theoretically may blunt gonadal steroid hormone production. Small declines in total serum testosterone have been noted among statin recipients, but no commensurate elevation in LH occurred, which suggests that the lowered total serum testosterone was not due to a direct effect upon testosterone production. No effect upon FSH in males was noted. In a study, fluvastatin 80 mg daily for 28 weeks reduced the mean total testosterone response after HCG stimulation relative to baseline. However, the mean total testosterone response after 80 mg was not significant in comparison to the changes noted in groups receiving either fluvastatin 40 mg or placebo. Evaluate patients who develop clinical evidence of endocrine dysfunction. Use caution if a statin or other agent used to lower cholesterol concentrations is administered to patients receiving other drugs that may decrease the concentrations of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.
Atrial fibrillation (2.4%), syncope (2.4%), hypertension (5.8%), intermittent claudication (2.3%), and peripheral edema (4.4%) were reported in adult patients receiving fluvastatin in clinical trials.
Respiratory and infectious adverse reactions reported in adult patients receiving fluvastatin in clinical trials include sinusitis (2.6 to 3.5%), bronchitis (1.8 to 2.6%), urinary tract infection (1.6 to 2.7%), influenza-like symptoms (5.1 to 7.1%), and naso-pharyngitis (2.8%).
HMG-CoA reductase inhibitors (statins), such as fluvastatin, inhibit the synthesis of mevalonate and decrease Co-Enzyme Q-10 concentrations, which may lead to Co-Enzyme Q-10 deficiency. Supplementation with vitamin Co-Enzyme Q-10 may limit potential adverse reactions.
Statin therapy, including fluvastatin, has been associated with rare reports of new-onset or exacerbation of myasthenia gravis (including ocular myasthenia) and reports of recurrence when the same or different statin was administered. In a review of adult patients enrolled at a neuromuscular disease clinic over a 4-year time period, 6 of 54 myasthenia gravis patients (11%) receiving statin therapy experienced worsening myasthenia gravis. In a disproportionality analysis of the World Health Organization's VigiBase pharmacovigilance database, 169 of 3,967 (4.2%) of adverse reactions with the term 'myasthenia gravis and related conditions' were related to statin therapy. The reporting odds ratio (ROR) of myasthenia gravis relative to all other adverse reactions was 2.66 [95% CI: 2.28, 3.1] for statin therapy. In addition, the ROR was greater than 1 and statistically significant for all individual statins except lovastatin. 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.
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.
Fluvastatin extended-release is contraindicated in patients with acute hepatic failure or decompensated cirrhosis (hepatic decompensation). Fluvastatin immediate-release is contraindicated in patients with active hepatic disease, including persistent elevations in serum aminotransferase concentrations. Increases in hepatic transaminases have been reported with fluvastatin. In most cases, increases in hepatic transaminases occurred soon after initiation, were transient, were not associated with symptoms, and resolved or improved on continued therapy or after temporary discontinuation of therapy. Marked persistent increases in hepatic transaminases have also occurred with fluvastatin. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin. Patients with alcoholism or those who consume substantial quantities of alcohol and/or have a history of hepatic disease (i.e., hepatitis) may be at increased risk for hepatic injury. Assess liver enzymes prior to treatment initiation and repeat as clinically indicated if signs or symptoms of hepatic injury occur. Promptly discontinue fluvastatin if hepatic injury with clinical symptoms, hyperbilirubinemia, or jaundice occurs.
Fluvastatin may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including fluvastatin. Inform individuals of the risk of myopathy and rhabdomyolysis when initiating treatment. Instruct them to promptly report unexplained muscle pain, tenderness or weakness, especially if accompanied by malaise or fever. Temporarily discontinue fluvastatin in those experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., acute infection, including sepsis, shock, severe hypovolemia, hypotension major surgery, trauma, severe metabolic disorders, severe endocrine disease, severe electrolyte imbalance, or uncontrolled seizure disorder). Discontinue fluvastatin if myopathy is suspected or diagnosed and if markedly elevated CK concentrations occur. Risk factors for myopathy include age 65 years and older, uncontrolled hypothyroidism, renal impairment, concomitant use of certain drugs, and higher statin dosage. Fluvastatin has not been evaluated at doses greater than 40 mg/day in adults with severe renal impairment.
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred rarely (1 to 3 of every 100,000 patients) with HMG-CoA reductase inhibitors, such as fluvastatin. Recurrence of IMNM has been reported following administration of the same or a different statin. IMNM is characterized by myalgia with symmetrical and proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment. Some cases have occurred months to years after starting HMG-CoA reductase therapy and the myopathy progressed following therapy discontinuation. Other characteristics include positive anti-HMG-CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. 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.
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. Optimization of lifestyle measures, including regular exercise, maintaining a healthy body weight and making healthy food choices are recommended. 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.
Advanced age (65 years or more) is a predisposing risk factor for myopathy and rhabdomyolysis; use fluvastatin with caution in geriatric adults. Monitor geriatric patients receiving fluvastatin for the increased risk of myopathy. Fluvastatin concentrations were not significantly different between non-elderly and elderly individuals. Dose selection for geriatric persons should be cautious due to greater frequency of decreased hepatic, renal, or cardiac function and concomitant disease or other medication therapy in addition to the higher risk of myopathy.
Fluvastatin therapy should be discontinued once pregnancy is identified in most patients. Alternatively, consider the ongoing therapeutic needs of the individual patient, particularly those at very high risk for cardiovascular events during pregnancy, such as those with homozygous familial hypercholesterolemia or with established cardiovascular disease. Based on the mechanism of action, fluvastatin may cause fetal harm when administered to pregnant patients due to decreases in the synthesis of cholesterol and possibly other biologically active substances derived from cholesterol. Cholesterol and other products of cholesterol biosynthesis are important for fetal development including synthesis of steroids and cell membranes. The U.S. Food and Drug Administration (FDA) completed a review of data from case series, prospective and retrospective observational cohort studies over decades of statin use in pregnant patients and concluded that these studies have not identified a drug-associated risk of major congenital malformations associated with statin use during pregnancy. In a Medicaid cohort linkage study of 1,152 statin-exposed pregnant women, no significant teratogenic effects were observed following maternal statin use during the first trimester of pregnancy after adjusting for potential confounders (i.e., maternal age, diabetes mellitus, hypertension, obesity, alcohol use, and tobacco); the relative risk (RR) of congenital malformations was 1.07 (95% confidence interval (CI), 0.85 to 1.37). In addition, after accounting for confounders, there were no statistically significant increases in organ-specific malformations. In the study, statin treatment was started prior to pregnancy and was discontinued within the first trimester after pregnancy was detected in a majority of patients. In another cohort study of 469 patients who were dispensed statins during pregnancy, it was determined that there was no increase in congenital anomalies after adjustment for maternal age and comorbidities; however, statin use was associated with an increased risk of preterm labor (RR, 1.99 [95% CI, 1.46 to 2.71]) and low birth weight (RR, 1.51 [95% CI 1.05 to 2.16]). In a published, retrospective cohort study of 281 statin-exposed pregnant women, patients on statin therapy had a miscarriage rate of 25% compared to 21% for pregnant women not on statin therapy (n = 2,643); adjusted hazard ratio was 1.64 (95% CI, 1.1 to 2.46). The FDA also re-reviewed non-clinical, animal data statin development programs and concluded that statins have limited potential to cause malformations or embryofetal lethality, and limited potential to affect nervous system development during embryofetal development in the pre- and post-natal periods. While maternal toxicity was observed, no embryotoxic or teratogenic effects were observed in rabbit and rat studies at doses of 2 to 24 mg/kg/day. Overall, available data have not identified a drug-associated risk of major congenital malformations, but published data are insufficient to determine if there is a drug-associated risk of miscarriage. Temporary discontinuation of lipid-lowering therapy, such as fluvastatin, should have minimal impact on the long-term therapy of primary hyperlipidemia, as atherosclerosis is a chronic process. Advise pregnant patients and patients of child-bearing potential of the potential risk of statin therapy to the fetus and the importance of informing their health care provider of known or suspected pregnancy.
Fluvastatin is not recommended for use during breast-feeding. There is no information about the presence of fluvastatin in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. 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. Based on the mechanism of action of fluvastatin, there is potential for development of serious adverse reactions in a breastfed infant. Advise patients that breast-feeding is not recommended during treatment with fluvastatin. If pharmacotherapy for hypercholesterolemia is necessary in the nursing mother, an alternative agent such as a nonabsorbable resin (cholestyramine, colesevelam, or colestipol) may 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.
Safety and efficacy of fluvastatin have not been established in infants and children younger than 10 years of age with heterozygous familial hypercholesterolemia (HeFH) or in pediatric patients with other types of hyperlipidemia. 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. Due to 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. In limited uncontrolled clinical trials with fluvastatin in pediatric patients 9 years of age and older with HeFH, there was no significant effect on growth or sexual maturation in males or females or on menstrual cycle length in females.
Statin therapy, including fluvastatin, has been associated with rare reports of new-onset or exacerbation of myasthenia gravis (including ocular myasthenia) and reports of recurrence when the same or different statin was administered. 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.
-Immediate-release fluvastatin 40 mg twice daily or extended-release fluvastatin 80 mg once daily is considered to be a moderate-intensity statin (expected to lower low-density lipoprotein cholesterol (LDL-C) by 30% to 49%), while immediate-release fluvastatin 20 or 40 mg once daily is considered low-intensity (expected to lower LDL-C by less than 30%).
-Choice of moderate- or low-intensity statin therapy is dependent on patient age, baseline LDL-C, ASCVD risk factors, and concomitant diseases. High-intensity therapy provides greatest LDL-C reductions and is associated with a significantly greater reduction in ASCVD events vs. moderate- or low-intensity therapy.
-Guidelines recommend assessment of liver function at baseline and if signs or symptoms of hepatic injury occur.
-Monitor lipid concentrations at 4 to 12 weeks after initiation or dose adjustment, and then every 3 to 12 months as necessary.
For general dosing information in persons requiring moderate-intensity statin therapy:
Oral dosage (immediate-release):
Adults: 40 mg PO twice daily.
Oral dosage (extended-release):
Adults: 80 mg PO once daily.
For general dosing information in persons requiring low-intensity statin therapy:
Oral dosage (immediate-release):
Adults: 20 or 40 mg PO once daily.
For the treatment of primary hyperlipidemia, including hypercholesterolemia, hyperlipoproteinemia, and mixed dyslipidemia, as an adjunct to dietary control:
Oral dosage (immediate-release capsules):
Adults: 20 mg PO once daily to 40 mg PO twice daily. Dose depends on patient-specific factors and goals of therapy. Maximum is 40 mg PO twice daily. Monitor lipid concentrations as early as 4 weeks after starting therapy and as clinically appropriate and adjust dose if needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 10 to 17 years (at least 1 year post-menarche)*: 20 mg PO once daily initially. Adjust dosage at 6-week intervals to attain individual goals of therapy. Maximum is 40 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (extended-release tablets):
Adults: 80 mg PO once daily. Dose depends on patient-specific factors and goals of therapy. Maximum is 80 mg/day. Monitor lipid concentrations as early as 4 weeks after starting therapy and as clinically appropriate and adjust dose if needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 10 to 17 years (at least 1 year post-menarche)*: 80 mg PO once daily of the extended-release formulation may be used in individuals who have been titrated up to 40 mg PO twice daily of the immediate-release formulation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the treatment of heterozygous familial hypercholesterolemia as an adjunct to dietary control:
Oral dosage (immediate-release capsules):
Adults: 20 mg PO once daily to 40 mg PO twice daily. Dose depends on patient-specific factors and goals of therapy. Maximum is 40 mg PO twice daily. Monitor lipid concentrations as early as 4 weeks after starting therapy and as clinically appropriate and adjust dose if needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 10 to 17 years (at least 1 year post-menarche): 20 mg PO once daily initially. Adjust dosage at 6-week intervals to attain individual goals of therapy. Maximum is 40 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (extended-release tablets):
Adults: 80 mg PO once daily. Dose depends on patient-specific factors and goals of therapy. Maximum is 80 mg/day. Monitor lipid concentrations as early as 4 weeks after starting therapy and as clinically appropriate and adjust dose if needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 10 to 17 years (at least 1 year post-menarche): 80 mg PO once daily of the extended-release formulation may be used in individuals who have been titrated up to 40 mg PO twice daily of the immediate-release formulation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For slowing the progression of coronary atherosclerosis and reducing the risk of coronary revascularization procedures in patients with coronary heart disease:
Oral dosage (immediate-release capsules):
Adults: 20 mg PO once daily to 40 mg PO twice daily. Dose depends on patient-specific factors and goals of therapy. Maximum is 40 mg PO twice daily. Monitor lipid concentrations as early as 4 weeks after starting therapy and as clinically appropriate and adjust dose if needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (extended-release tablets):
Adults: 80 mg PO once daily. Dose depends on patient-specific factors and goals of therapy. Maximum is 80 mg/day. Monitor lipid concentrations as early as 4 weeks after starting therapy and as clinically appropriate and adjust dose if needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
Contraindicated in patients with active hepatic disease or with unexplained or persistent hepatic transaminase elevations.
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
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.
Asciminib: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with asciminib is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; asciminib is an inhibitor of OATP1B3.
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: (Moderate) Use HMG-CoA reductase inhibitors with caution with concomitant drugs that may decrease the levels or activity of endogenous steroids, such as cimetidine. Evaluate patients with signs and symptoms of endocrine dysfunction appropriately. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production.
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: (Moderate) Concomitant use of colchicine and HMG-CoA reductase inhibitors (statins) may increase the risk for myopathy and rhabdomyolysis. If concomitant use is necessary, monitor for signs and symptoms of muscle pain, tenderness, or weakness especially following therapy initiation and upward dose titration. The use of low dose colchicine may further reduce the risk for myopathy.
Cyclosporine: (Major) Avoid coadministration of fluvastatin extended release (ER) and cyclosporine. Limit the fluvastatin immediate release (IR) dose to 20 mg twice daily and monitor for signs of myopathy and rhabdomyolysis if concomitant use with cyclosporine is necessary. Concomitant use may increase fluvastatin exposure and the risk for fluvastatin-related adverse effects. Concomitant use with cyclosporine increased fluvastatin exposure by 90%.
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.
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 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.
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 an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with elexacaftor is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; elexacaftor is an inhibitor of OATP1B3. (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.
Encorafenib: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; encorafenib 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.
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.
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) Avoid coadministration of fluvastatin extended release (ER) and fluconazole. Limit the fluvastatin immediate release (IR) dose to 20 mg twice daily and monitor for signs of myopathy and rhabdomyolysis if concomitant use with fluconazole is necessary. Concomitant use may increase fluvastatin exposure and the risk for fluvastatin-related adverse effects. Fluvastatin is a CYP2C9 substrate and fluconazole is a CYP2C9 inhibitor. Concomitant use with fluconazole increased fluvastatin exposure by 84%.
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.
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.
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.
Leniolisib: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with leniolisib is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; leniolisib is an inhibitor of OATP1B3.
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.
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.
Mafenide: (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.
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.
Nateglinide: (Moderate) Monitor for an increase in nateglinide-related adverse effects, such as hypoglycemia, if concomitant use with fluvastatin is necessary; a nateglinide dosage reduction may be required. Concomitant use may increase nateglinide exposure. Nateglinide is a CYP2C9 substrate and fluvastatin is a CYP2C9 inhibitor.
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.
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.
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: (Moderate) Concomitant use of colchicine and HMG-CoA reductase inhibitors (statins) may increase the risk for myopathy and rhabdomyolysis. If concomitant use is necessary, monitor for signs and symptoms of muscle pain, tenderness, or weakness especially following therapy initiation and upward dose titration. The use of low dose colchicine may further reduce the risk for myopathy.
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.
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.
Sulfacetamide; Sulfur: (Moderate) HMG-CoA reductase inhibitors have been administered safely with niacin (nicotinic acid) in some patients; however the risk of potential myopathy should be considered. Rare cases of rhabdomyolysis have been reported in patients taking niacin (nicotinic acid) in lipid-altering doses (i.e., >=1 g/day) and HMG-CoA reductase inhibitors (Statins) concurrently. The serious risk of myopathy or rhabdomyolysis should be carefully weighed against the potential risks. Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy.
Sulfadiazine: (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.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (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.
Sulfasalazine: (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.
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.
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.
Trofinetide: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with trofinetide is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; trofinetide is an inhibitor of OATP1B3.
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.
Vitamin B Complex Supplements: (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.
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.
Vonoprazan; 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.
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.
Fluvastatin is a competitive inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, a hepatic enzyme responsible for the intracellular synthesis of cholesterol. HMG-CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis and responsible for converting HMG-CoA to mevalonate, a precursor of sterols including cholesterol. Inhibition of HMG-CoA reductase decreases cholesterol concentrations within the hepatic cells, which induces expression of low-density lipoprotein receptors stimulating low-density lipoprotein cholesterol (LDL-C) uptake from the blood to the liver. Increased hepatic LDL-C uptake results in a reduction in plasma LDL-C and total cholesterol. Fluvastatin reduces plasma total cholesterol, LDL-C, and serum triglycerides; and it raises plasma high-density lipoprotein cholesterol (HDL-C) concentrations.
Fluvastatin is administered orally. The volume of distribution of fluvastatin is 0.35 L/kg and it is highly protein bound (more than 98%). Fluvastatin is hepatically metabolized, primarily via hydroxylation of the indole ring at the 5- and 6-positions. N-dealkylation and beta-oxidation of the side chain also occur. The active hydroxylated metabolites do not circulate systemically. Fluvastatin has 2 enantiomers; both are metabolized in a similar manner. Approximately 90% of an oral fluvastatin dose is excreted in the feces as metabolites, with less than 2% present as unchanged drug and approximately 5% excreted in the urine. The reported half-life of fluvastatin immediate-release is 1 to 3 hours compared to 7.3 to 10.5 hours for fluvastatin extended-release.
Affected cytochrome P450 isoenzymes: CYP2C8, CYP2C9, CYP3A4
Hepatic metabolism occurs primarily (75%) via CYP2C9 isoenzymes; other metabolic pathways include CYP2C8 (5%) and CYP3A4 (20%). Drugs that are CYP2C9 inhibitors or inducers have greater potential to alter fluvastatin plasma concentrations and cause potential toxicity relative to drugs that affect the CYP3A4 pathway. Fluvastatin also is a CYP2C9 inhibitor.
-Route-Specific Pharmacokinetics
Oral Route
Immediate-release formulation
Absorption of fluvastatin immediate-release is rapid reaching peak concentrations in less than 1 hour under fasting conditions. Due to a significant first-pass effect, the mean absolute bioavailability is only 24% after a 10 mg dose (range 9% to 50%). Fluvastatin immediate release exhibits saturable first-pass metabolism resulting in more than dose proportional plasma fluvastatin concentrations as the dosage increases. At steady state, administration with the evening meal results in a 50% lower Cmax, 11% lower AUC, and more than a 2-fold increase in the time to peak concentration compared to administration 4 hours after the evening meal. However, no clinically significant differences in lipid-lowering effects have been noted between the 2 administration techniques.
Extended-release formulation
Following administration of the fluvastatin extended-release formulation, peak concentrations are reached in approximately 3 hours in the fasting state or 2.5 hours after a low-fat meal. The mean relative bioavailability of fluvastatin extended-release is 29% (range 9% to 66%). Administration of fluvastatin extended-release with a high-fat meal delayed the absorption (Tmax 6 hours) and increased the bioavailability by approximately 50%.
-Special Populations
Hepatic Impairment
After a single 40 mg dose, adults with hepatic impairment due to liver cirrhosis experience AUC and Cmax values approximately 2.5-fold higher than those of healthy subjects.
Renal Impairment
The AUC and Cmax increased approximately 1.2-fold after administration of a single 40 mg oral dose of fluvastatin immediate-release to adults with moderate to severe renal impairment (CrCl 10 to 40 mL/minute). The AUC increased approximately 1.5-fold in persons with end-stage renal disease on hemodialysis. The pharmacokinetics of extended-release fluvastatin have not been studied in persons with renal impairment.
Geriatric
Plasma concentrations of fluvastatin are not significantly different in people older than 65 years compared to those 21 to 49 years of age.
Gender Differences
Among females and males aged 21 to 49 years, an approximate 30% increase in fluvastatin immediate-release exposure was observed in younger females compared to younger males; however, adjusting for body weight decreases the magnitude of the observed differences. No other significant differences were observed between females and males. The systemic availability of fluvastatin extended-release is approximately 67% and 77% higher in women compared to men for fasting and high-fat meal conditions, respectively.