LESCOL XL Extended-release tablet Ref.[10581] Active ingredients: Fluvastatin

5.1 Skeletal Muscle

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

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 XL together with niacin. Isolated cases of myopathy have been reported during postmarketing experience with concomitant administration of LESCOL XL and colchicine. No information is available on the pharmacokinetic interaction between LESCOL XL and colchicine.

Uncomplicated myalgia has also been reported in fluvastatin-treated patients [see Adverse Reactions (6)]. In clinical trials, uncomplicated myalgia has been observed infrequently in patients treated with fluvastatin 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.

All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing LESCOL XL.

LESCOL XL therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. 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.

5.2 Immune-Mediated Necrotizing Myopathy

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

5.3 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 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 fluvastatin capsules in worldwide trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the upper limit of normal (ULN). 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 fluvastatin 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 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) fluvastatin 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, fluvastatin capsules 40 mg and fluvastatin capsules 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 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 XL, promptly interrupt therapy. If an alternate etiology is not found, do not restart 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 XL [see Contraindications (4.2) and Warnings and Precautions (5.3)]. Caution should be exercised when fluvastatin is administered to patients with a history of liver disease or heavy alcohol ingestion [see Clinical Pharmacology (12.3)]. Such patients should be closely monitored.

5.4 Endocrine Effects

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including 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 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 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 fluvastatin 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 fluvastatin or placebo.

Patients treated with 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.

5.5 Central Nervous System Toxicity

Central Nervous System (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 (1,500 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 5,000 mg/kg and (in rats) by edema with separation of myelinated fibers of the ventral spinal tracts and sciatic nerve at a dose of 1,500 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.

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis) [see Warnings and Precautions (5.1)].
• Liver Enzyme Abnormalities [see Warnings and Precautions (5.3)].

6.1 Clinical Studies Experience in Adult Patients

Because clinical studies on fluvastatin capsules/LESCOL XL are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of fluvastatin capsules/LESCOL XL 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 capsule placebo-controlled clinical trials database of 2326 patients treated with fluvastatin 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%).

In the LESCOL XL database of controlled clinical trials of 912 patients treated with LESCOL XL (age range 21 to 87 years, 52% women, 91% Caucasians, 4% Blacks, 5% other ethnicities) with a median treatment duration of 24 weeks, 3.9% of patients on LESCOL XL discontinued due to adverse reactions regardless of causality. The most common adverse reactions that led to treatment discontinuation were abdominal pain (0.7%), diarrhea (0.5%), nausea (0.4%), dyspepsia (0.4%), and chest pain (0.3%).

Clinically relevant adverse experiences occurring in the fluvastatin capsules and LESCOL XL 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/LESCOL XL and at an Incidence Greater Than Placebo in Placebo-Controlled Trials Regardless of Causality (% of patients) Pooled Dosages:

¹ Controlled trials with fluvastatin capsules (20 and 40 mg daily and 40 mg twice daily) compared to placebo.
² Controlled trials with LESCOL XL 80 mg Tablets as compared to fluvastatin capsules.

LESCOL Intervention Prevention Study

In the LESCOL Intervention Prevention Study (LIPS), the effect of LESCOL (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 [see Clinical Studies (14.3)].

Table 2. Clinical Adverse Events Reported in ≥2% in Patients Treated With Fluvastatin Capsules/LESCOL XL and at an Incidence Greater Than Placebo in the LIPS Trial Regardless of Causality (% of patients):

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 [mixed ethnicity], 1% Asians) were treated with fluvastatin sodium administered as fluvastatin capsules 20 mg to 40 mg twice daily, or LESCOL XL 80 mg extended-release tablet [see Clinical Studies (14.2) and Use in Specific Populations (8.4)].

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 [see Warnings and Precautions (5.2)].

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

7.1 Cyclosporine

Cyclosporine coadministration increases fluvastatin exposure. Therefore, in patients taking cyclosporine, therapy should be limited to fluvastatin 20 mg twice daily [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

7.2 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 [see Clinical Pharmacology (12.3)].

7.3 Gemfibrozil

Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of LESCOL XL with gemfibrozil should be avoided.

7.4 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, LESCOL XL should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

7.5 Niacin

The risk of skeletal muscle effects may be enhanced when fluvastatin is used in combination with lipid-modifying doses (≥1 g/day) of niacin; a reduction in fluvastatin dosage should be considered in this setting [see Warnings and Precautions (5.1)].

7.6 Glyburide

Concomitant administration of fluvastatin and glyburide increased glyburide exposures. Patients on concomitant therapy of glyburide and fluvastatin should continue to be monitored appropriately [see Clinical Pharmacology (12.3)].

7.7 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 [see Clinical Pharmacology (12.3)].

7.8 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.

7.9 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 Category X

LESCOL XL is contraindicated in women who are or may become pregnant [see Contraindications (4.3)].

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 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 Nonclinical Toxicology (13)].

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

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 XL [see Contraindications (4.4)].

The safety and efficacy of LESCOL XL 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 [see Clinical Studies (14.2), Adverse Reactions (6.3), and Dosage and Administration (2.2)]. Adolescent females should be counseled on appropriate contraceptive methods while on fluvastatin therapy [see Contraindications (4)].

Fluvastatin exposures were not significantly different between the nonelderly and elderly populations (age ≥65 years) [see Clinical Pharmacology (12.3)]. Since advanced age (>65 years) is a predisposing factor for myopathy, LESCOL XL should be prescribed with caution in the elderly.

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 (12.3)].

LESCOL XL are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases [see Clinical Pharmacology (12.3)].