Fluvastatin Drug Information

General Dosing Information Dose range: 20 mg to 80 mg/day. Fluvastatin capsules

can be administered orally as a single dose, with or without food. Do not open fluvastatin capsules prior to administration. Do not take two fluvastatin capsules, 40 mg at one time.

Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines. For patients requiring LDL-C reduction to a goal of ≥ 25%, the recommended starting dose is 40 mg as one capsule in the evening, or 80 mg in divided doses of the 40 mg capsule given twice daily. For patients requiring LDL-C reduction to a goal of < 25% a starting dose of 20 mg may be used.

Adult Patients With Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia Adult

patients can be started on fluvastatin capsules. The recommended starting dose for fluvastatin capsules is one 40 mg capsule in the evening, or one fluvastatin capsule, 40 mg twice daily. Do not take two fluvastatin capsules, 40 mg at one time.

Pediatric Patients (10 to 16 Years of Age) With Heterozygous Familial Hypercholesterolemia

The recommended starting dose is one fluvastatin capsule, 20 mg. Dose adjustments, up to a maximum daily dose administered as fluvastatin capsules, 40 mg twice daily should be made at 6 week intervals. Doses should be individualized according to the goal of therapy 1. 1 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents.

Pediatrics. 89:495-501. 1992.

Use With Cyclosporine Do not exceed a dose of 20 mg b.i.d.

fluvastatin capsules in patients taking cyclosporine .

Use With Fluconazole Do not exceed a dose of 20 mg b.i.d.

fluvastatin capsules in patients taking fluconazole .

Clinical Studies Experience in Adult Patients

Because clinical studies on fluvastatin capsules are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of fluvastatin capsules cannot be directly compared with that in the clinical studies of other statins and may not reflect the frequency of adverse reactions observed in clinical practice. In the fluvastatin capsules placebo-controlled clinical trials database of 2326 patients treated with fluvastatin capsules 1 (age range 18 to 75 years, 44% women, 94% Caucasians, 4% Blacks, 2% other ethnicities) with a median treatment duration of 24 weeks, 3.4% of patients on fluvastatin capsules and 2.3% patients on placebo discontinued due to adverse reactions regardless of causality. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: transaminase increased (0.8%), upper abdominal pain (0.3%), dyspepsia (0.3%), fatigue (0.2%) and diarrhea (0.2%). Clinically relevant adverse experiences occurring in the fluvastatin capsules controlled studies with a frequency ≥ 2%, regardless of causality, included the following: Table 1: Clinical Adverse Events Reported in > 2% in Patients Treated With Fluvastatin Capsules and at an Incidence Greater Than Placebo in Placebo-Controlled Trials Regardless of Causality (% of Patients) Pooled Dosages Fluvastatin Capsules 1 N = 2326 (%) Placebo 1 N = 960 (%) Musculoskeletal Myalgia 5.0

Gastrointestinal Dyspepsia 7.9 3.2 Diarrhea 4.9 4.2 Abdominal pain 4.9 3.8 Nausea

3.2

Flatulence 2.6 2.5 Tooth disorder 2.1 1.7 Psychiatric Insomnia 2.7 1.4 Genitourinary

Urinary tract infection 1.6

Miscellaneous Headache 8.9 7.8 Influenza-like symptoms 5.1 5.7 Accidental Trauma 5.1 4.8

Fatigue 2.7

Allergy 2.3 2.2 1. Controlled trials with fluvastatin capsules (20 and 40

mg daily and 40 mg twice daily) compared to placebo Fluvastatin Capsules Intervention Prevention Study In the Fluvastatin Capsules Intervention Prevention Study, the effect of fluvastatin capsules, 40 mg, administered twice daily on the risk of recurrent cardiac events was assessed in 1677 patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure. This was a multicenter, randomized, double-blind, placebo-controlled study, patients were treated with dietary/lifestyle counseling and either fluvastatin capsules, 40 mg (n = 844) or placebo (n = 833) given twice daily for a median of 3.9 years. Table 2: Clinical Adverse Events Reported in ≥ 2% in Patients Treated With Fluvastatin Sodium and at an Incidence Greater Than Placebo in the Trial Regardless of Causality (% of Patients) Fluvastatin Capsules, 40 mg b.i.d.

N = 822 (%) Placebo N = 818 (%) Cardiac disorders Atrial fibrillation 2.4

Gastric disorder 2.7 2.1 Nausea 2.7 2.3 General disorders Fatigue 4.7 3.8

Edema peripheral 4.4

Infections and infestations Bronchitis 2.3 2.0 Nasopharyngitis 2.8 2.1 Musculoskeletal and connective

tissue disorders Arthralgia 2.1

Myalgia 2.2 1.6 Pain in extremity 4.1 2.7 Nervous system disorders Dizziness

3.9

Syncope 2.4 2.2 Respiratory disorders Dyspnea exertional 2.8 2.4 Vascular disorders Hypertension

5.8

Intermittent claudication 2.3 2.1 6.2 Clinical Studies Experience in Pediatric Patients

In patients aged < 18 years, efficacy and safety have not been studied for treatment periods longer than two years. In two open-label, uncontrolled studies, 66 boys and 48 girls with heterozygous familial hypercholesterolemia (9 to 16 years of age, 80% Caucasian, 19% Other, 1% Asians) were treated with fluvastatin sodium administered as fluvastatin capsules, 20 mg to 40 mg twice daily, or fluvastatin sodium extended-release tablets, 80 mg.

Postmarketing Experience

Because adverse reactions from spontaneous reports are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with fluvastatin sodium therapy.

Musculoskeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias, muscle spasms, muscle weakness, myositis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use. Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, hypoesthesia, dysesthesia, peripheral neuropathy, peripheral nerve palsy.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Psychiatric: anxiety, insomnia, depression, psychic disturbances Respiratory: interstitial lung disease Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR (erythrocyte sedimentation rate) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity reaction, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, anorexia, vomiting, fatal and non-fatal hepatic failure. Skin: rash, dermatitis, including bullous dermatitis, eczema, alopecia, pruritus, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails). Reproductive: gynecomastia, loss of libido, erectile dysfunction. Eye: progression of cataracts (lens opacities), ophthalmoplegia.

Laboratory abnormalities: elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase and bilirubin; thyroid function abnormalities.

Cyclosporine Cyclosporine coadministration increases fluvastatin exposure. Therefore, in patients taking cyclosporine, therapy

should be limited to fluvastatin 20 mg twice daily.

Fluconazole

Administration of fluvastatin 40 mg single dose to healthy volunteers pre-treated with fluconazole for 4 days results in an increase of fluvastatin exposure. Therefore, in patients taking fluconazole, therapy should be limited to fluvastatin 20 mg twice daily.

Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when

HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of fluvastatin sodium with gemfibrozil should be avoided.

Other Fibrates

Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, fluvastatin sodium should be administered with caution when used concomitantly with other fibrates.

Niacin

The risk of skeletal muscle effects may be enhanced when fluvastatin sodium is used in combination with lipid-modifying doses (≥ 1 g/day) of niacin; a reduction in fluvastatin sodium dosage should be considered in this setting.

Glyburide

Concomitant administration of fluvastatin and glyburide increased glyburide exposures. Patients on concomitant therapy of glyburide and fluvastatin should continue to be monitored appropriately.

Phenytoin

Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures. Patients should continue to be monitored appropriately when fluvastatin therapy is initiated or when fluvastatin dose is changed.

Warfarin Bleeding and/or increased prothrombin times have been reported in patients taking

coumarin anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients receiving warfarin-type anticoagulants should have their prothrombin times closely monitored when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed.

Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with fluvastatin coadministered

with colchicine, and caution should be exercised when prescribing fluvastatin with colchicine.

Pregnancy Pregnancy Category X Fluvastatin sodium is contraindicated in women who are or may become pregnant. Lipid lowering drugs are contraindicated during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Serum cholesterol and triglycerides increase during normal pregnancy.

Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of use with fluvastatin sodium during pregnancy. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins.

In a review 2 of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. The number of cases is adequate only to exclude a 3 to 4 fold increase in congenital anomalies over background incidence. In 89% of prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Teratology studies with fluvastatin in rats and rabbits showed maternal toxicity at high dose levels, but there was no evidence of embryotoxic or teratogenic potential. Fluvastatin sodium should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If a woman becomes pregnant while taking fluvastatin sodium, the drug should be discontinued and the patient advised again as to the potential hazards to the fetus.

Pediatric Use The safety and efficacy of fluvastatin sodium in children and adolescent patients 9 to 16 years of age with heterozygous familial hypercholesterolemia have been evaluated in open-label, uncontrolled clinical trials for a duration of two years. The most common adverse events observed were influenza and infections. In these limited uncontrolled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls . Adolescent females should be counseled on appropriate contraceptive methods while on fluvastatin sodium therapy.

Hypersensitivity to any Component of

This Medication Fluvastatin capsules are contraindicated in patients with hypersensitivity to any component of this medication.

Active Liver Disease Fluvastatin capsules are contraindicated in patients with active liver

disease or unexplained, persistent elevations in serum transaminases .

Pregnancy Fluvastatin capsules are contraindicated in women who are pregnant or may

become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Fluvastatin capsules may cause fetal harm when administered to pregnant women.

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. Fluvastatin capsules should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, fluvastatin capsules should be discontinued and the patient should be apprised of the potential hazard to the fetus .

Nursing Mothers Fluvastatin is secreted into the breast milk of animals and

because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require treatment with fluvastatin capsules should be advised not to breastfeed their infants .

To date, there has been limited experience with overdosage of fluvastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required. The dialyzability of fluvastatin sodium and of its metabolites in humans is not known at present.

In the pediatric population, there have been reports of overdosage with fluvastatin sodium in children including a 2-year-old and the other 3 years of age, either of whom may have possibly ingested fluvastatin sodium. The maximum amount of fluvastatin sodium that could have been ingested was 80 mg (4 x 20 mg capsules). Vomiting was induced by ipecac in both children and no capsules were noted in their emesis. Neither child experienced any adverse symptoms and both recovered from the incident without problems.

In the postmarketing experience there have been reports of accidental ingestion of fluvastatin tablets in infants up to 3 years of age. In one case, increased serum CPK values were noted. There have been reports of intentional overdose in adolescents with the development of hepatic enzyme elevations, convulsions and gastroenteritis/vomiting/diarrhea.