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Fluvastatin sodium is a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3methylglutaryl- coenzyme A (HMG-CoA) reductase.
Fluvastatin sodium is [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt. The empirical formula of fluvastatin sodium is C24H25FNO4•Na, its molecular weight is 433.46 and its structural formula is:
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This molecular entity is the first entirely synthetic HMG-CoA reductase inhibitor, and is in part structurally distinct from the fungal derivatives of this therapeutic class.
Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. LESCOL XL is supplied as extended-release tablets containing fluvastatin sodium, equivalent to 80 mg of fluvastatin, for oral administration.
Active Ingredient: fluvastatin sodium
Inactive Ingredients in extended-release tablets: microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, potassium bicarbonate, povidone, magnesium stearate, yellow iron oxide, titanium dioxide and polyethylene glycol 8000.
LESCOL XL is indicated:
The recommended dosage for LESCOL XL is 80 mg once daily.
LESCOL XL is not recommended for dosage initiation in pediatric patients because the recommended starting dosage cannot be achieved with the available strength of 80 mg. Recommend use of another fluvastatin product to initiate dosing in pediatric patients.
The recommended dosage of LESCOL XL is 80 mg once daily in pediatric patients 10 years of age and older who require 80 mg of fluvastatin.
Extended-release tablets: 80 mg of fluvastatin: yellow, round, slightly biconvex film-coated tablets with beveled edges debossed with “LESCOL XL” on one side and “80” on the other.
LESCOL XL extended-release tablets supplied as:
| Strength | How supplied | NDC | Tablet description |
| 80 mg of fluvastatin | bottles of 30 | 0078-0354-15 | Yellow, round, slightly biconvex film-coated tablet with beveled edges debossed with “LESCOL XL” on one side and “80” on the other |
| bottles of 100 | 0078-0354-05 |
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight container. Protect from light.
Manufactured by: Pfizer Ireland Pharmaceuticals Newbridge, Ireland for Sandoz Inc., Princeton, NJ 08540. Revised: Nov 2023
The following serious adverse reactions are discussed in greater detail in other sections of the label:
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 | Placeboa N = 960 (%) |
Fluvastatin capsulesa N = 2326 (%) |
LESCOL XLb 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 |
| aControlled trials with fluvastatin capsules (20 mg and 40 mg daily and 40 mg twice daily) compared to placebo. bControlled trials with LESCOL XL 80 mg Tablets as compared to fluvastatin capsules. |
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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].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 | 4.4 |
| Pain 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 | 2.1 |
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.
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].
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 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, lichen planus, 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.
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, CLINICAL PHARMACOLOGY].
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. |
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]. |
| 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]. |
| Intervention | Monitor plasma phenytoin levels when LESCOL XL is initiated. |
Included as part of the "PRECAUTIONS" Section
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].
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].
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].
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.
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.
Increases in serum transaminases have been reported with use of LESCOL XL [see ADVERSE REACTIONS]. 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]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LESCOL XL.
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.
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Advise patients that LESCOL XL may cause myopathy and rhabdomyolysis. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Inform patients that LESCOL XL may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see WARNINGS AND PRECAUTIONS].
Inform patients that increases in HbA1c and fasting serum glucose levels may occur with LESCOL XL. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see WARNINGS AND PRECAUTIONS].
Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if LESCOL XL should be discontinued [see Use In Specific Populations].
Advise patients that breastfeeding is not recommended during treatment with LESCOL XL [see Use In Specific Populations].
In a 2-year carcinogenicity study in rats at doses of 6, 9, and 18 to 24 (escalated after 1 year) mg/kg/day, there was an increased incidence of thyroid follicular cell adenomas and carcinomas in males treated with 18 to 4 mg/kg/day. Additionally, a low incidence of forestomach squamous papillomas and one forestomach carcinoma were observed at the 18 to 24 mg/kg/day dose, likely due to prolonged direct contact exposure rather than a systemic effect. This dose represents a plasma AUC exposure approximately 26 to 35 times the mean human plasma drug concentration after a 40 mg oral dose.
A carcinogenicity study conducted in mice at doses of 0.3, 15 and 30 mg/kg/day revealed a statistically significant increase in forestomach squamous cell papillomas in females at 15 mg/kg/day and in males and females at 30 mg/kg/day. These doses represent plasma AUC exposures approximately 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 genotoxicity in vivo in either a rat chromosome aberration study or mouse micronucleus test.
In a fertility study in rats with daily doses up to 6 mg/kg/day for females and 20 mg/kg/day for males, fluvastatin sodium had no adverse effects on the fertility or reproductive performance.
Hamsters treated for 3 months at 20 mg/kg/day (approximately three times the 40 mg human daily dose based on body surface area, mg/m2) showed small seminal vesicles and testes, along with tubular degeneration and aspermatogenesis in the testes and vesiculitis in the seminal vesicles. Rats treated for 2 years at 18 mg/kg/day (approximately four times human exposure based on body surface area) exhibited vesiculitis in the seminal vesicles and edema in the testes.
Discontinue LESCOL XL when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. LESCOL XL decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, LESCOL XL may cause fetal harm when administered to pregnant patients based on the mechanism of action [see CLINICAL PHARMACOLOGY]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. 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 hyperlipidemia for most patients.
Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with LESCOL XL use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data).
In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered fluvastatin during the period of organogenesis at doses that resulted in 2 and 5 times, respectively, the human exposure at the maximum recommended human dosage of 40 mg/day, based on body surface area (mg/m2) (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Human Data
A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders, including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% CI: 0.85 to 1.37) after controlling for confounders, particularly preexisting diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.
Animal Data
Fluvastatin sodium given to rats during organogenesis at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day produced delays in skeletal development. 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. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced significant maternal toxicity. A study in which female rats were given fluvastatin 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. Rats were given fluvastatin from Gestation Day 15 to Lactation Day 21 at doses 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.
There is no information about the presence of fluvastatin in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Studies in rats have shown that fluvastatin and/or its metabolites are present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Statins, including LESCOL XL, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.
Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with LESCOL XL [see Pregnancy, CLINICAL PHARMACOLOGY].
Following a single oral administration of 1 mg/kg of radioactive fluvastatin to lactating rats, the concentration of total radioactivity was determined. Fluvastatin and/or its metabolites were measured in the breast milk at a 2:1 ratio (milk:plasma).
The safety and effectiveness of LESCOL XL as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of LESCOL XL for this indication is based on open-label, uncontrolled clinical trials in 114 pediatric patients 9 years of age and older with HeFH. In these limited uncontrolled studies, there was no significant effect on growth or sexual maturation in the males or females, or on menstrual cycle length in females.
The safety and effectiveness of LESCOL XL have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH).
Fluvastatin exposures were not significantly different between the nonelderly and elderly populations (age ≥ 65 years) [see CLINICAL PHARMACOLOGY].
Advanced age (≥ 65 years) is a risk factor for LESCOL XL-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving LESCOL XL for the increased risk of myopathy [see WARNINGS AND PRECAUTIONS].
Renal impairment is a risk factor for myopathy and rhabdomyolysis. 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, use LESCOL XL with caution in patients with severe renal impairment. Monitor all patients with renal impairment for development of myopathy [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].
LESCOL XL is contraindicated in patients with acute liver failure or decompensated cirrhosis [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
No specific antidotes for LESCOL XL are known. In the event of an overdose of LESCOL XL, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
LESCOL XL is contraindicated in patients with:
Fluvastatin is a competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of cholesterol.
Inhibition of HMG-CoA reductase by fluvastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of LESCOL XL is usually achieved by 4 weeks and is maintained after that.
Fluvastatin administered as LESCOL XL 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low-fat meal, or 2.5 hours after a low-fat meal. The mean relative bioavailability of the XL tablet is approximately 29% (range, 9% to 66%) compared to that of the fluvastatin immediate-release capsule administered under fasting conditions. Administration of a high-fat meal delayed the absorption (Tmax 6h) and increased the bioavailability of the XL tablet by approximately 50%. However, the maximum concentration of LESCOL XL seen after a high-fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg fluvastatin capsule.
Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide.
Metabolism
Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5-and 6-positions. Ndealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers. Both enantiomers of fluvastatin are metabolized in a similar manner.
In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e., approximately 5% and approximately 20%, respectively.
Excretion
Following oral administration, fluvastatin is primarily (about 90%) excreted in the feces as metabolites, with less than 2% present as unchanged drug. Approximately 5% of a radiolabeled oral dose were recovered in urine. The elimination half-life (t1/2) of fluvastatin is approximately 3 hours.
Plasma levels of fluvastatin are not significantly different in patients age > 65 years compared to patients age 21 to 49 years.
In a study evaluating the effect of age and gender on fluvastatin pharmacokinetics, there were no significant differences in fluvastatin exposures between males and females, except between younger females and younger males (both ages 21-49 years), where there was an approximate 30% increase in area under the curve (AUC) in females. Adjusting for body weight decreases the magnitude of the differences seen. For LESCOL XL, the AUC increases 67% and 77% for women compared to men under fasted and high-fat meal fed conditions, respectively.
Pharmacokinetic data in the pediatric population are not available.
In patients with moderate to severe renal impairment (CLCr 10-40 mL/min), AUC and Cmax increased approximately 1.2fold after administration of a single dose of 40 mg fluvastatin compared to healthy volunteers. In patients with end-stage renal disease on hemodialysis, the AUC increased by approximately 1.5-fold. LESCOL XL was not evaluated in patients with renal impairment [see Use In Specific Populations]. However, systemic exposures after administration of LESCOL XL are lower than after the 40 mg immediate release capsule.
In patients with hepatic impairment due to liver cirrhosis, fluvastatin AUC and Cmax increased approximately 2.5-fold compared to healthy subjects after administration of a single 40 mg dose [see Use In Specific Populations]. The enantiomer ratios of the two isomers of fluvastatin in hepatic impairment patients were comparable to those observed in healthy subjects.
Data from drug-drug interactions studies involving coadministration of gemfibrozil, niacin, itraconazole, erythromycin, tolbutamide or clopidogrel indicate that the PK disposition of fluvastatin is not significantly altered when fluvastatin is coadministered with any of these drugs.
The below listed drug interaction information is derived from studies using fluvastatin capsules. Similar studies have not been conducted using the LESCOL XL tablet.
Table 5. Effect of Coadministered Drugs on Fluvastatin Systemic Exposure
| Coadministered drug and dosing regimen | Fluvastatin | ||
| Dose (mg)a | Change in AUCb | Change in Cmaxb | |
| Cyclosporine – stable dose (twice daily)c | 20 mg once daily for 14 weeks | ↑90% | ↑30% |
| Fluconazole 400 mg once daily 1,200 mg twice daily 2 to 4c | 40 mg once daily | ↑84% | ↑44% |
| Cholestyramine 8 g once daily | 20 mg once daily administered 4 hrs after a meal plus cholestyramine | ↓51% | ↓83% |
| Rifampicin 600 mg once daily for 6 days | 20 mg once daily | ↓53% | ↓42% |
| Cimetidine 400 mg twice daily for 5 days, once daily on Day 6 | 20 mg once daily | ↑30% | ↑40% |
| Ranitidine 150 mg twice daily for 5 days, once daily on Day 6 | 20 mg once daily | ↑10% | ↑50% |
| Omeprazole 40 mg once daily for 6 days | 20 mg once daily | ↑20% | ↑37% |
| Phenytoin 300 mg once daily | 40 mg twice daily for 5 days | ↑40% | ↑27% |
| Propranolol 40 mg twice daily for 3.5 days | 40 mg once daily | ↓5% | No change |
| Digoxin 0.1 to 0.5 mg once daily for 3 weeks | 40 mg once daily | No change | ↑11% |
| Diclofenac 25 mg once daily | 40 mg once daily for 8 days | ↑50% | ↑80% |
| Glyburide 5 mg to 20 mg once daily for 22 days | 40 mg twice daily for 14 days | ↑51% | ↑44% |
|
Warfarin 30 mg once daily Clopidogrel 300 mg loading dose on Day 10, 75 mg once daily on Days 11 to 19 |
40 mg once daily for 8 days 80 mg XL once daily for 19 days |
↑30% ↓2% |
↑67% |
| Abbreviation: AUC, area under the curve. a Single dose unless otherwise noted. b Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively. c Considered clinically significant [seeDOSAGE AND ADMINISTRATION, DRUG INTERACTIONS]. |
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Data from drug-drug interaction studies involving fluvastatin and coadministration of either gemfibrozil, tolbutamide or losartan indicate that the PK disposition of either gemfibrozil, tolbutamide or losartan is not significantly altered when coadministered with fluvastatin.
Table 6. Effect of Fluvastatin Coadministration on Systemic Exposure of Other Drugs
| Coadministered drug | |||
| Fluvastatin dosage regimen | Name and dose (mg)a | Change in AUCb | Change in Cmaxb |
| 40 mg once daily for 5 days | Phenytoin 300 mg once dailyc | ↑20% | ↑5% |
| 40 mg twice daily for 21 days | Glyburide 5 to 20 mg once daily for 22 daysc | ↑70% | ↑50% |
| 40 mg once daily for 8 days | Diclofenac 25 mg once daily | ↑25% | ↑60% |
| 40 mg once daily for 8 days | Warfarin 30 mg once daily | S-warfarin: ↑7% R-warfarin: no change |
S-warfarin: ↑10% R-warfarin: ↑6% |
| Abbreviation: AUC, area under the curve. a Single dose unless otherwise noted. b Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively. c Considered clinically significant [see DRUG INTERACTIONS]. |
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In the LESCOL Intervention Prevention Study (LIPS), the effect of fluvastatin capsules 40 mg administered twice daily on the risk of recurrent cardiac events (time to first occurrence of cardiac death, nonfatal myocardial infarction, or revascularization) was assessed in 1677 adult patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure (mean time from PCI to randomization = 3 days). In this multicenter, randomized, double-blind, placebo-controlled trial, patients were treated with dietary/lifestyle counseling and either fluvastatin 40 mg (n = 844)or placebo (n = 833) given twice daily for a median of 3.9 years. The study population was 84% male, 98% White, with 37% > 65 years of age. Mean baseline lipid concentrations were: total cholesterol 201 mg/dL, LDL-C 132 mg/dL, triglycerides 70 mg/dL, and HDL-C 39 mg/dL.
Fluvastatin capsules significantly reduced the risk of recurrent cardiac events (Figure 1) by 22% (p = 0.013, 181 patients in the fluvastatin capsules group versus 222 patients in the placebo group). Revascularization procedures comprised the majority of the initial recurrent cardiac events (143 revascularization procedures in the fluvastatin capsules group and 171 in the placebo group). Consistent trends in risk reduction were observed in patients > 65 years of age.
Figure 1. Primary Endpoint – Recurrent Cardiac Events (Cardiac Death, Nonfatal MI or Revascularization Procedure) (ITT Population)
 |
Outcome data for the LESCOL Intervention Prevention Study are shown in Figure 2. After exclusion of revascularization procedures (CABG and repeat PCI) occurring within the first 6 months of the initial procedure involving the originally instrumental site, treatment with fluvastatin capsules was associated with a 32% (p = 0.002) reduction in risk of late revascularization procedures (CABG or PCI occurring at the original site > 6 months after the initial procedure, or at another site).
Figure 2. LESCOL Intervention Prevention Study–-Primary and Secondary Endpoints
 |
In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of fluvastatin capsule therapy on coronary atherosclerosis was assessed by quantitative coronary angiography (QCA) in patients with CAD and mild to moderate hypercholesterolemia (baseline LDL-C range 115 to 190 mg/dL). In this randomized double-blind, placebo-controlled trial, 429 patients were treated with conventional measures (Step 1, AHA Diet) and either fluvastatin 40 mg/day or placebo. In order to provide treatment to patients receiving placebo with LDL-C levels ≥160 mg/dL at baseline, adjunctive therapy with cholestyramine was added after Week 12 to all patients in the study with baseline LDL-C values of ≥ 160 mg/dL, which were present in 25% of the study population. Quantitative coronary angiograms were evaluated at baseline and 2.5 years in 340 (79%) angiographic evaluable patients.
Compared to placebo, fluvastatin capsules significantly slowed the progression of coronary atherosclerosis as measured by within-patient per-lesion change in minimum lumen diameter (MLD), the primary endpoint (Figure 3 below), percent diameter stenosis (Figure 4), and the formation of new lesions (13% of all fluvastatin patients versus 22% of all placebo patients). A significant difference in favor of fluvastatin capsules was found between all fluvastatin and all placebo patients in the distribution among the three categories of definite progression, definite regression, and mixed or no change. Beneficial angiographic results (change in MLD) were independent of patients’ gender and consistent across a range of baseline LDL-C levels.
Figure 3. Change in Minimum Lumen Diameter (mm)
 |
Figure 4. Change in % Diameter Stenosis
 |
LESCOL XL has been studied in five controlled trials of adult patients with primary hyperlipidemia and mixed dyslipidemia. LESCOL XL was administered to over 900 patients in trials from 4 to 26 weeks in duration. In the three largest of these trials, LESCOL XL given as a single daily dose of 80 mg significantly reduced Total-C, LDL-C, TG, and Apo B (Table 5).
In patients with primary mixed dyslipidemia as defined by baseline plasma TG levels ≥ 200 mg/dL and < 400 mg/dL, treatment with LESCOL XL produced significant decreases in Total-C, LDL-C, TG, and Apo B (see Table 7).
Table 7. Median Percent Change in Lipid Levels in Adult Patients with Primary Hyperlipidemia and Mixed Dyslipidemia From Baseline to Week 24 Endpoint All Active Controlled Trials (LESCOL XL)
| Dose | Total Chol | TG | LDL | Apo B | HDL | |||||
| N | % Δ |
N | % Δ | N | % Δ |
N | % Δ |
N | % Δ |
|
| All Patients | ||||||||||
| LESCOL XL 80 mga | 75 0 | - 25 | 75 0 | - 19 | 74 8 | - 35 | 74 5 | - 27 | 75 0 | +7 |
| Baseline TG ≥ 200 mg/dL | ||||||||||
| LESCOL XL 80 mga | 23 9 | - 25 | 23 9 | - 25 | 23 7 | - 33 | 23 5 | - 27 | 23 9 | +1 1 |
| aData for LESCOL XL 80 mg tablet from three 24-week controlled trials. | ||||||||||
Fluvastatin capsules were studied in two open-label, uncontrolled, dose-titration trials. The first trial enrolled 29 prepubertal males, 9 to12 years of age, who had an LDL-C level > 90th percentile for age and one parent with primary hypercholesterolemia and either a family history of premature ischemic heart disease or tendon xanthomas. The mean baseline LDL-C was 226 mg/dL (range, 137 to 354 mg/dL). All patients were started on fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (40 mg twice daily) to achieve an LDL-C goal between 97 to 124 mg/dL. Endpoint analyses were performed at Year 2. Fluvastatin decreased plasma levels of Total-C and LDL-C by 21% and 27%, respectively. The mean achieved LDL-C was 161 mg/dL (range, 74 to 336 mg/dL).
The second trial enrolled 85 male and female patients, 10 to 16 years of age, who had an LDL-C > 190 mg/dL or LDL-C > 160 mg/dL and one or more risk factors for coronary heart disease, or LDL-C > 160 mg/dL and a proven LDL-receptor defect. The mean baseline LDL-C was 225 mg/dL (range, 148 to 343 mg/dL). All patients were started on fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (LESCOL XL tablet) to achieve an LDL-C goal of < 130 mg/dL. Endpoint analyses were performed at Week 114. Fluvastatin decreased plasma levels of Total-C and LDL-C by 22% and 28%, respectively. The mean achieved LDL-C was 159 mg/dL (range, 90 to 295 mg/dL).
The majority of patients in both trials (83% in the first trial and 89% in the second trial) were titrated to the maximum daily dose of 80 mg.
LESCOL® XL
(les-col)
(fluvastatin) extended-release tablets, for oral use
You must read and follow all instructions before using LESCOL XL.
Read this Patient Information before you start taking LESCOL XL and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about LESCOL XL, ask your doctor or pharmacist.
What is LESCOL XL?
LESCOL XL is a prescription medicine “that contains the cholesterol lowering medicine, fluvastatin.”
LESCOL XL is used in adults with heart disease (coronary artery disease) to:
LESCOL XL is used along with diet to lower the level of:
The safety and effectiveness of LESCOL XL has not been established in children younger than 10 years of age with heterozygous familial hypercholesterolemia (HeFH) or in children with other types of hyperlipidemia (high levels in fat in the blood) other than HeFH.
Do not take LESCOL XL if you:
Before you take LESCOL XL, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. Talk to your healthcare provider before you start taking any new medicines. Tell your healthcare provider who prescribes LESCOL XL if another healthcare provider increases the dose of another medicine you are taking.
LESCOL XL may affect the way other medicines work, and other medicines may affect how LESCOL XL works. Especially tell your healthcare provider if you take:
Taking LESCOL XL with certain medicines can also increase the risk of muscle problems. Especially tell your healthcare provider if you take:
Ask your healthcare provider or pharmacist for a list of medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take LESCOL XL?
What are the possible side effects of LESCOL XL?
LESCOL XL may cause serious side effects, including:
Tell your healthcare provider right away if you have:
The most common side effects of LESCOL XL include:
These side effects are usually mild and may go away. The following additional side effects have been reported with LESCOL XL:
Talk to your healthcare provider or pharmacist if you have side effects that bother you or does not go away.
These are not all the possible side effects of LESCOL XL. Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
How should I store LESCOL XL?
General information about safe and effective use of LESCOL XL.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use LESCOL XL for a condition for which it was not prescribed. Do not give LESCOL XL to other people, even if they have the same medical condition you have; it may harm them.
You can ask your pharmacist or healthcare provider for information about LESCOL XL that is written for health professionals.
What are the ingredients in LESCOL XL?
Active Ingredient: fluvastatin
Inactive Ingredients: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 8000, potassium bicarbonate, povidone, titanium dioxide, and yellow iron oxide.
This Patient Information has been approved by the U.S. Food and Drug Administration.
