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Lescol

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Lescol

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Skeletal Muscle

Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with LESCOL/LESCOL XL and other drugs in this class.

LESCOL/LESCOL XL should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age ( > 65 years), renal impairment, and inadequately treated hypothyroidism.

The risk of myopathy and/or rhabdomyolysis with statins is increased with concurrent therapy with cyclosporine, erythromycin, fibrates or niacin. Myopathy was not observed in a clinical trial in 74 patients involving patients who were treated with LESCOL/LESCOL XL together with niacin. Isolated cases of myopathy have been reported during post-marketing experience with concomitant administration of LESCOL/LESCOL XL and colchicine. No information is available on the pharmacokinetic interaction between LESCOL/LESCOL XL and colchicine.

Uncomplicated myalgia has also been reported in LESCOL-treated patients [see ADVERSE REACTIONS]. In clinical trials, uncomplicated myalgia has been observed infrequently in patients treated with LESCOL at rates indistinguishable from placebo. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CPK values to greater than 10 times the upper limit of normal, was < 0.1% in fluvastatin clinical trials. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

LESCOL/LESCOL XL therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. LESCOL/LESCOL XL therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

Liver Enzymes

Increases in serum transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase, or alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors, including LESCOL/LESCOL XL. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy.

Approximately 1.1% of patients treated with LESCOL capsules in worldwide trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the upper limit of normal. Fourteen of these patients (0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase elevations with an average LESCOL exposure of approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The majority of patients with these abnormal biochemical findings were asymptomatic.

In a pooled analysis of all placebo-controlled studies in which LESCOL capsules were used, persistent transaminase elevations ( > 3 times the upper limit of normal [ULN] on two consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients treated with daily doses of 20, 40, and 80 mg (titrated to 40 mg twice daily) LESCOL capsules, respectively. Ninety-one percent of the cases of persistent liver function test abnormalities (20 of 22 patients) occurred within 12 weeks of therapy and in all patients with persistent liver function test abnormalities there was an abnormal liver function test present at baseline or by Week 8.

In the pooled analysis of the 24-week controlled trials, persistent transaminase elevation occurred in 1.9%, 1.8% and 4.9% of patients treated with LESCOL XL 80 mg, LESCOL 40 mg and LESCOL 40 mg twice daily, respectively. In 13 of 16 patients treated with LESCOL XL the abnormality occurred within 12 weeks of initiation of treatment with LESCOL XL 80 mg.

It is recommended that liver enzyme tests be performed prior to the initiation of LESCOL/LESCOL XL, and if signs or symptoms of liver injury occur.

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with LESCOL/LESCOL XL, promptly interrupt therapy. If an alternate etiology is not found do not restart LESCOL/LESCOL XL.

In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment.1 Active liver disease or unexplained serum transaminase elevations are contraindications to the use of LESCOL and LESCOL XL [see CONTRAINDICATIONS. Caution should be exercised when LESCOL is administered to patients with a history of liver disease or heavy alcohol ingestion [see CLINICAL PHARMACOLOGY]. Such patients should be closely monitored.

Endocrine Effects

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including LESCOL/LESCOL XL.

Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production.

LESCOL/LESCOL XL exhibited no effect upon non-stimulated cortisol levels and demonstrated no effect upon thyroid metabolism as assessed by measurement of thyroid stimulating hormone (TSH). Small declines in total serum testosterone have been noted in treated groups, but no commensurate elevation in LH occurred, suggesting that the observation was not due to a direct effect upon testosterone production. No effect upon FSH in males was noted. Due to the limited number of premenopausal females studied to date, no conclusions regarding the effect of LESCOL/LESCOL XL upon female sex hormones may be made.

Two clinical studies in patients receiving fluvastatin at doses up to 80 mg daily for periods of 24 to 28 weeks demonstrated no effect of treatment upon the adrenal response to ACTH stimulation. A clinical study evaluated the effect of LESCOL at doses up to 80 mg daily for 28 weeks upon the gonadal response to HCG stimulation. Although the mean total testosterone response was significantly reduced (p < 0.05) relative to baseline in the 80 mg group, it was not significant in comparison to the changes noted in groups receiving either 40 mg of LESCOL or placebo.

Patients treated with LESCOL/LESCOL XL who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if a statin or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone, cimetidine) that may decrease the levels of endogenous steroid hormones.

CNS Toxicity

CNS effects, as evidenced by decreased activity, ataxia, loss of righting reflex, and ptosis were seen in the following animal studies: the 18-month mouse carcinogenicity study at 50 mg/kg/day, the 6-month dog study at 36 mg/kg/day, the 6-month hamster study at 40 mg/kg/day, and in acute, high-dose studies in rats and hamsters (50 mg/kg), rabbits (300 mg/kg) and mice (1500 mg/kg). CNS toxicity in the acute high-dose studies was characterized (in mice) by conspicuous vacuolation in the ventral white columns of the spinal cord at a dose of 5000 mg/kg and (in rats) by edema with separation of myelinated fibers of the ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS toxicity, characterized by periaxonal vacuolation, was observed in the medulla of dogs that died after treatment for 5 weeks with 48 mg/kg/day; this finding was not observed in the remaining dogs when the dose level was lowered to 36 mg/kg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this drug class. No CNS lesions have been observed after chronic treatment for up to 2 years with fluvastatin in the mouse (at doses up to 350 mg/kg/day), rat (up to 24 mg/kg/day), or dog (up to 16 mg/kg/day).

Prominent bilateral posterior Y suture lines in the ocular lens were seen in dogs after treatment with 1, 8, and 16 mg/kg/day for 2 years.

Patient Counseling Information

Information For Patients

Patients taking LESCOL/LESCOL XL should be advised that high cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel to determine goal attainment.

Patients should be advised about substances they should not take concomitantly with LESCOL/LESCOL XL [see WARNINGS AND PRECAUTIONS]. Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking LESCOL/LESCOL XL.

Muscle Pain

Patients starting therapy with LESCOL/LESCOL XL should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

Liver Enzymes

It is recommended that liver enzyme tests be performed before the initiation of LESCOL/LESCOL XL and if signs or symptoms of liver injury occur. All patients treated with LESCOL/LESCOL XL should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

Pregnancy

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using LESCOL/LESCOL XL. Discuss future pregnancy plans with your patients, and discuss when to stop taking LESCOL/LESCOL XL if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking LESCOL/LESCOL XL and call their healthcare professional.

Breastfeeding

Women who are breastfeeding should not use LESCOL/LESCOL XL. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year) mg/kg/day. These treatment levels represented plasma drug levels of approximately 9, 13, and 26-35 times the mean human plasma drug concentration after a 40 mg oral dose. A low incidence of forestomach squamous papillomas and 1 carcinoma of the forestomach at the 24 mg/kg/day dose level was considered to reflect the prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium rather than to a systemic effect of the drug. In addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was recorded for males treated with 18-24 mg/kg/day. The increased incidence of thyroid follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with findings from other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas were observed.

The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. These treatment levels represented plasma drug levels of approximately 0.05, 2, and 7 times the mean human plasma drug concentration after a 40 mg oral dose.

No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of mutagenicity in vivo in either a rat or mouse micronucleus test.

In a study in rats at dose levels for females of 0.6, 2 and 6 mg/kg/day and at dose levels for males of 2, 10 and 20 mg/kg/day, fluvastatin sodium had no adverse effects on the fertility or reproductive performance.

Seminal vesicles and testes were small in hamsters treated for 3 months at 20 mg/kg/day (approximately three times the 40 mg human daily dose based on surface area, mg/m²). There was tubular degeneration and aspermatogenesis in testes as well as vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were also seen in rats treated for 2 years at 18 mg/kg/day (approximately 4 times the human Cmax achieved with a 40 mg daily dose).

Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced maternal toxicity. These doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m2 surface area. A study in which female rats were dosed during the third trimester at 12 and 24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on the dam or fetus occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study with neonatal mortality beginning at 6 mg/kg. A modified Segment III study was performed at dose levels of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol biosynthesis. The concurrent administration of mevalonic acid completely prevented the maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on days 0 and 7 postpartum.

Use In Specific Populations

Pregnancy

Pregnancy Category X

LESCOL/LESCOL XL is contraindicated in women who are or may become pregnant [see CONTRAINDICATIONS].

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 LESCOL/LESCOL XL during pregnancy. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review2 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 [see Non-Clinical Toxicology].

LESCOL or LESCOL XL 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 LESCOL or LESCOL XL, the drug should be discontinued and the patient advised again as to the potential hazards to the fetus.

Nursing Mothers

Based on animal data, fluvastatin is present in breast milk in a 2:1 ratio (milk:plasma). Because of the potential for serious adverse reactions in nursing infants, nursing women should not take LESCOL or LESCOL XL [see CONTRAINDICATIONS].

Pediatric Use

The safety and efficacy of LESCOL and LESCOL XL in children and adolescent patients 9-16 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 [see Clinical Studies, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION]. Adolescent females should be counseled on appropriate contraceptive methods while on LESCOL therapy [see CONTRAINDICATIONS].

Geriatric Use

Fluvastatin exposures were not significantly different between the nonelderly and elderly populations (age ≥ 65 years) [see CLINICAL PHARMACOLOGY]. Since advanced age ( > 65 years) is a predisposing factor for myopathy, LESCOL/LESCOL XL should be prescribed with caution in the elderly.

Hepatic Impairment

LESCOL and LESCOL XL are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases [see CLINICAL PHARMACOLOGY].

Renal Impairment

Dose adjustments for mild to moderate renal impairment are not necessary. Fluvastatin has not been studied at doses greater than 40 mg in patients with severe renal impairment; therefore caution should be exercised when treating such patients at higher doses [see CLINICAL PHARMACOLOGY].

REFERENCES

1. National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501.1992.

2. Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6): 439-446, 1996.

Last reviewed on RxList: 3/12/2012
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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