Lescol XL (Page 2 of 7)

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.

6 ADVERSE REACTIONS

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 fluvastatin1 (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
Fluvastatin capsules 1 N = 2326(%) Placebo 1 N = 960(%) LESCOL XL 2 N = 912(%)
Musculoskeletal Myalgia 5.0 4.5 3.8
Arthritis 2.1 2.0 1.3
Arthropathy NA NA 3.2
Respiratory Sinusitis 2.6 1.9 3.5
Bronchitis 1.8 1.0 2.6
Gastrointestinal Dyspepsia 7.9 3.2 3.5
Diarrhea 4.9 4.2 3.3
Abdominal pain 4.9 3.8 3.7
Nausea 3.2 2.0 2.5
Flatulence 2.6 2.5 1.4
Tooth disorder 2.1 1.7 1.4
Psychiatric Insomnia 2.7 1.4 0.8
Genitourinary Urinary tract infection 1.6 1.1 2.7
Miscellaneous Headache 8.9 7.8 4.7
Influenza-like symptoms 5.1 5.7 7.1
Accidental trauma 5.1 4.8 4.2
Fatigue 2.7 2.3 1.6
Allergy 2.3 2.2 1.0
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)
Fluvastatin Capsules 40 mg twice dailyN = 822(%) Placebo N = 818(%)
Cardiac disorders Atrial fibrillation 2.4 2.0
Gastrointestinal disorders Abdominal pain upper 6.3 4.5
Constipation 3.3 2.1
Dyspepsia 4.5 4.0
Gastric disorder 2.7 2.1
Nausea 2.7 2.3
General disorders Fatigue 4.7 3.8
Edema peripheral 4.4 2.9
Infections and infestations Bronchitis 2.3 2.0
Nasopharyngitis 2.8 2.1
Musculoskeletal and connective tissue disorders Arthralgia 2.1 1.8
Myalgia 2.2 1.6
Pain in extremity 4.1 2.7
Nervous system disorders Dizziness 3.9 3.5
Syncope 2.4 2.2
Respiratory disorders Dyspnea exertional 2.8 2.4
Vascular disorders Hypertension 5.8 4.2
Intermittent claudication 2.3 2.1

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