To reduce the risk of undergoing coronary revascularization procedures and slow the progression of coronary atherosclerosis in adults with clinically evident coronary heart disease.
As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia.
As an adjunct to diet to reduce LDL-C in adults and pediatric patients 10 years of age and older with heterozygous familial hypercholesterolemia (HeFH) who require 80 mg of fluvastatin daily. LESCOL XL is indicated ( 1 ):
To reduce the risk of undergoing coronary revascularization procedures and slow the progression of coronary atherosclerosis in adults with clinically evident coronary heart disease.
As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia.
As an adjunct to diet to reduce LDL-C in adults and pediatric patients 10 years of age and older with heterozygous familial hypercholesterolemia (HeFH) who require 80 mg
Contraindications
LESCOL XL is contraindicated in patients with:
Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3)] .
Hypersensitivity to fluvastatin or any of the excipients in LESCOL XL. Hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome have been reported [see Adverse Reactions (6.2)] .
Acute liver failure or decompensated cirrhosis ( 4 )
Hypersensitivity to fluvastatin or any excipient in LESCOL XL ( 4 )
Warnings and precautions
Myopathy and Rhabdomyolysis : Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs. Discontinue LESCOL XL if markedly elevated creatine kinase (CK) levels occur, or myopathy is diagnosed or suspected. Temporarily discontinue LESCOL XL in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing LESCOL XL dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. ( 5.1 )
Immune-Mediated Necrotizing Myopathy (IMNM) : Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue LESCOL XL if IMNM is suspected.( 5.2 )
Hepatic Dysfunction : Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzyme before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LESCOL XL ( 5.3 )
5.1Myopathy and Rhabdomyolysis
LESCOL XL may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis with statins, including LESCOL XL. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CK, values to greater than 10 times the upper limit of normal (ULN) was < 0.1% in fluvastatin clinical trials [see Adverse Reactions (6.1)] .
Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs (including other lipid-lowering therapies) [see Drug Interactions (7.1)] . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Avoid concomitant use of LESCOL XL with gemfibrozil, cyclosporin, and fluconazole. When used concomitantly with LESCOL XL, lipid modifying doses (≥ 1 g/day) of niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)] .
Discontinue LESCOL XL if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if LESCOL XL is discontinued. Temporarily discontinue LESCOL XL in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis, shock, severe hypovolemia, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, or uncontrolled epilepsy.
Inform patients of the risk of myopathy and rhabdomyolysis when starting LESCOL XL. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
5.2Immune-Mediated Necrotizing Myopathy
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum CK, 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. Discontinue LESCOL XL if IMNM is suspected.
5.3Hepatic Dysfunction Increases
in serum transaminases have been reported with use of LESCOL XL [see Adverse Reactions (6.1)] . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 1.1% of patients receiving fluvastatin in clinical trials.
Marked persistent increases of hepatic transaminases have also occurred with fluvastatin. There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including LESCOL XL. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before LESCOL XL initiation and thereafter, when clinically indicated.
LESCOL XL is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)] . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LESCOL XL.
5.4Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c
and fasting serum glucose levels have been reported with statins, including LESCOL XL. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.
Interactions
Gemfibrozil : Avoid use with LESCOL XL. ( 7.1 )
Cyclosporine and Fluconazole : Avoid use with LESCOL XL. ( 7.1 )
Fibrates, Lipid-modifying doses (≥ 1 g/day) of Niacin, and Colchicine : Consider if the benefit of concomitant use with LESCOL XL outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration. ( 7.1 )
Warfarin : Obtain an International Normalized Ratio (INR) before starting and frequently enough after initiation or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regular intervals. ( 7.2 )
Glyburide : Monitor blood glucose levels when LESCOL XL is initiated. ( 7.2 )
Phenytoin : Monitor plasma phenytoin levels when LESCOL XL treatment is initiated. ( 7.2 )
7.1Drug
Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with LESCOL XL Table 3 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with fluvastatin and instructions for preventing or managing them [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)] . Table 3. Drug Interactions That Increase the Risk of Myopathy and Rhabdomyolysis with LESCOL XL Gemfibrozil Clinical impact There is an increased risk of myopathy/rhabdomyolysis when LESCOL XL is administered with gemfibrozil Intervention Avoid concomitant use of gemfibrozil with LESCOL XL.
Cyclosporine Clinical impact Cyclosporine coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of cyclosporine with LESCOL XL. Intervention Avoid concomitant use of cyclosporine with LESCOL XL. Fluconazole Clinical impact Fluconazole coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of fluconazole with LESCOL XL.
Intervention Avoid concomitant use of fluconazole with LESCOL XL Niacin Clinical impact Risk of myopathy and rhabdomyolysis may be enhanced with concomitant use with lipid-modifying doses (≥ 1 g/day) of niacin with LESCOL XL. Intervention Consider if the benefit of using lipid-modifying doses (≥ 1 g/day) of niacin concomitantly with LESCOL XL outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration.
Fibrates Clinical impact Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of fibrates with LESCOL XL. Intervention Consider if the benefit of using fibrates concomitantly with LESCOL XL outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration.
Colchicine Clinical impact Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with fluvastatin. Intervention Consider if the benefit of using colchicine concomitantly with LESCOL XL outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration.
7.2LESCOL XL Effects on Other Drugs Table
4 presents LESCOL XL’s effect on other drugs and instructions for preventing or managing them. Table 4. LESCOL XL Effects on Other Drugs Warfarin Clinical impact There are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins and warfarin. Intervention In patients taking warfarin, obtain an INR before starting LESCOL XL and frequently enough after initiation or discontinuation to ensure that no significant alteration in INR occurs.
Once the INR is stable, monitor INR at regularly recommended intervals. Glyburide Clinical impact Concomitant administration of fluvastatin and glyburide increased glyburide exposures [see Clinical Pharmacology (12.3)] . Intervention Monitor blood glucose levels when LESCOL XL is initiated. Phenytoin Clinical impact Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures [see Clinical Pharmacology (12.3)] .
Intervention Monitor plasma phenytoin levels when LESCOL XL is initiated.
Adverse reactions
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)]
Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2)]
Hepatic Dysfunction [see Warnings and Precautions (5.3)]
Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4)] Most frequent adverse reactions occurring in ≥ 2.5% of subjects treated with LESCOL XL and more than placebo are: influenza-like symptoms, sinusitis, dyspepsia, urinary tract infection, bronchitis, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the fluvastatin capsule, clinical trials there were 2326 patients treated with fluvastatin (age range, 18 to 75 years, 44% women, 94% White, 4% Black or African American, 2% other ethnicities) with a median treatment duration of 24 weeks.
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 clinical trials there were 912 patients treated with LESCOL XL (age range, 21 to 87 years, 52% women, 91% White, 4% Black of African American, 5% other ethnicities) with a median treatment duration of 24 weeks.
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%). Adverse reactions occurring in the fluvastatin capsules and LESCOL XL controlled trials with a frequency ≥ 2% included the following: Table 1. Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/LESCOL XL and at an Incidence Greater Than Placebo in Placebo-Controlled Trials Pooled Dosages Adverse reaction Placebo a N = 960 (%) Fluvastatin capsules a N = 2326 (%) LESCOL XL b N = 912 (%) Influenza-like symptoms 5.7 5.1
7.1 Headache 7.8 8.9
4.7 Myalgia 4.5 5.0
3.8 Abdominal pain 3.8 4.9
3.7 Dyspepsia 3.2 7.9
3.5 Sinusitis 1.9 2.6
3.5 Diarrhea 4.2 4.9
3.3 Arthropathy NA NA
3.2 Urinary tract infection 1.1 1.6
2.7 Nausea 2.0 3.2
2.5 Bronchitis 1.0 1.8
2.6 Fatigue 2.3 2.7
1.6 Flatulence 2.5 2.6
1.4 Arthritis 2.0 2.1
1.3 Allergy 2.2 2.3
1.0 Insomnia 1.4 2.7 0.8 a Controlled trials with fluvastatin capsules (20 mg and 40 mg daily and 40 mg twice daily) compared to placebo. b Controlled trials with LESCOL XL 80 mg Tablets as compared to fluvastatin capsules. 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 coronary heart disease who had undergone a percutaneous coronary intervention.
This was a multicenter, randomized, double-blind, placebo-controlled trial, 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. Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/LESCOL XL and at an Incidence Greater Than Placebo in the LIPS Trial Table 2.
Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/LESCOL XL and at an Incidence Greater Than Placebo in the LIPS Trial Adverse reaction Placebo N = 818 (%) Fluvastatin Capsules 40 mg twice daily N = 822 (%) Abdominal pain upper 4.5
6.3 Hypertension 4.2
5.8 Fatigue 3.8
4.7 Dyspepsia 4.0
4.5 Edema peripheral 2.9
4.4Pain
in extremity 2.7
4.1 Dizziness 3.5
3.9 Constipation 2.1
3.3 Nasopharyngitis 2.1
2.8 Dyspnea exertional 2.4
2.8 Gastric disorder 2.1
2.7 Nausea 2.3
2.7 Atrial fibrillation 2.0
2.4 Syncope 2.2
2.4 Bronchitis 2.0
2.3 Intermittent claudication 2.1
2.3 Myalgia 1.6
2.2 Arthralgia 1.8
2.1Elevations in Liver Enzyme Tests Approximately 1.1%
of patients treated with fluvastatin capsules in clinical trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the 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 ALT/AST increased 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 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.
6.2Postmarketing Experience
The following adverse reactions have been identified during postapproval use of fluvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal : Muscle cramps, myopathy, rhabdomyolysis, arthralgias, muscle spasms, muscle weakness, myositis. There have been rare reports of IMNM 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, 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 the use of 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). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Psychiatric : Anxiety, 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 ch
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
FLUVASTATIN SODIUM EQ 80MG BASE
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA021192.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
