ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed in greater detail in other sections of the label: oMyopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)]oImmune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2)]oHepatic Dysfunction [see Warnings and Precautions (5.3)]oIncreases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4)]. oMyopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)]. oImmune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2)]. oHepatic Dysfunction [see Warnings and Precautions (5.3)]. oIncreases 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.. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 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 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 DosagesAdverse reactionPlaceboa = 960(%)Fluvastatin capsulesa = 2326(%)LESCOL XLb = 912(%)Influenza-like symptoms5.75.17.1Headache7.88.94.7Myalgia4.55.03.8Abdominal pain3.84.93.7Dyspepsia3.27.93.5Sinusitis1.92.63.5Diarrhea4.24.93.3ArthropathyNANA3.2Urinary tract infection1.11.62.7Nausea2.03.22.5Bronchitis1.01.82.6Fatigue2.32.71.6Flatulence2.52.61.4Arthritis2.02.11.3Allergy2.22.31.0Insomnia1.42.70.8aControlled 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.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 percutaneous coronary intervention. This was 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 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 TrialTable 2. Adverse Reactions Reported in >= 2% in Patients Treated with Fluvastatin Capsules/LESCOL XL and at an Incidence Greater Than Placebo in the LIPS TrialAdverse reactionPlaceboN 818 (%)Fluvastatin Capsules40 mg twice dailyN 822 (%)Abdominal pain upper4.56.3Hypertension4.25.8Fatigue3.84.7Dyspepsia4.04.5Edema peripheral2.94.4Pain in extremity2.74.1Dizziness3.53.9Constipation2.13.3Nasopharyngitis2.12.8Dyspnea exertional2.42.8Gastric disorder2.12.7Nausea2.32.7Atrial fibrillation2.02.4Syncope2.22.4Bronchitis2.02.3Intermittent claudication2.12.3Myalgia1.62.2Arthralgia1.82.1Elevations in Liver Enzyme TestsApproximately 1.1% of patients treated with fluvastatin capsules in clinical trials developed dose-related, persistent elevations of serum transaminase levels to more than times the ULN. Fourteen of these patients (0.6%) were discontinued from therapy. In all clinical trials, 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 pooled analysis of all placebo-controlled studies in which LESCOL capsules were used, persistent transaminase elevations (> 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.. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fluvastatin. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 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 different statin was administered.Psychiatric: Anxiety, depression, psychic disturbancesRespiratory: Interstitial lung diseaseHypersensitivity 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, 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Fluvastatin is competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) to mevalonate, precursor of cholesterol.. 12.2Pharmacodynamics 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 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 weeks and is maintained after that.. 12.3 Pharmacokinetics. AbsorptionFluvastatin administered as LESCOL XL 80 mg tablets reaches peak concentration in approximately hours under fasting conditions, after low-fat meal, or 2.5 hours after 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 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 high-fat meal is less than the peak concentration following single dose or twice daily dose of the 40 mg fluvastatin capsule.DistributionFluvastatin 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.EliminationMetabolismFluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. N-dealkylation 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 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 much less extent, i.e., approximately 5% and approximately 20%, respectively.ExcretionFollowing oral administration, fluvastatin is primarily (about 90%) excreted in the feces as metabolites, with less than 2% present as unchanged drug. Approximately 5% of radiolabeled oral dose were recovered in urine. The elimination half-life (t1/2) of fluvastatin is approximately hours.Specific PopulationsGeriatric PatientsPlasma levels of fluvastatin are not significantly different in patients age 65 years compared to patients age 21 to 49 years. GenderIn 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.Pediatric PatientsPharmacokinetic data in the pediatric population are not available. Patients with Renal ImpairmentIn patients with moderate to severe renal impairment (CLCr 10-40 mL/min), AUC and Cmax increased approximately 1.2-fold after administration of 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 (8.6)]. However, systemic exposures after administration of LESCOL XL are lower than after the 40 mg immediate release capsule.Patients with Hepatic ImpairmentIn patients with hepatic impairment due to liver cirrhosis, fluvastatin AUC and Cmax increased approximately 2.5-fold compared to healthy subjects after administration of single 40 mg dose [see Use in Specific Populations (8.7)]. The enantiomer ratios of the two isomers of fluvastatin in hepatic impairment patients were comparable to those observed in healthy subjects.Drug Interaction StudiesData 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 ExposureCoadministered drug and dosing regimenFluvastatinDose (mg)a Change in AUCb Change in Cmax Cyclosporine stable dose (twice daily)c 20 mg once daily for 14 weeks90%30% Fluconazole 400 mg once daily1,200 mg twice daily to 4c 40 mg once daily 84%44% Cholestyramine g once daily20 mg once daily administered hrs after meal plus cholestyramine51%83% Rifampicin 600 mg once daily for days20 mg once daily53% 42% Cimetidine 400 mg twice daily for days, once daily on Day 620 mg once daily30%40% Ranitidine 150 mg twice daily for days, once daily on Day 620 mg once daily10%50% Omeprazole 40 mg once daily for days20 mg once daily20%37%Phenytoin 300 mg once daily40 mg twice daily for days40%27%Propranolol 40 mg twice daily for 3.5 days40 mg once daily5%No changeDigoxin 0.1 to 0.5 mg once daily for weeks40 mg once daily No change11% Diclofenac 25 mg once daily40 mg once daily for days50%80%Glyburide mg to 20 mg once daily for 22 days40 mg twice daily for 14 days51% 44% Warfarin 30 mg once dailyClopidogrel 300 mg loading dose on Day 10, 75 mg once daily on Days 11 to 1940 mg once daily for days 80 mg XL once daily for 19 days30%2%67%27%Abbreviation: AUC, area under the curve.aSingle dose unless otherwise noted.bMean 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. cConsidered clinically significant [see Dosage and Administration (2.4), Drug Interactions (7.1)].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 DrugsCoadministered drugFluvastatin dosage regimenName and dose (mg)a Change in AUCb Change in Cmax 40 mg once daily for daysPhenytoin 300 mg once dailyc 20% 5%40 mg twice daily for 21 daysGlyburide to 20 mg once daily for 22 daysc 70%50% 40 mg once daily for daysDiclofenac 25 mg once daily25%60%40 mg once daily for daysWarfarin 30 mg once dailyS-warfarin: 7% R-warfarin: no changeS-warfarin: 10%R-warfarin: 6%Abbreviation: AUC, area under the curve.aSingle dose unless otherwise noted.bMean 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. cConsidered clinically significant [see Drug Interactions (7.2)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Secondary Prevention of Cardiovascular Disease 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 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 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 months of the initial procedure involving the originally instrumental site, treatment with fluvastatin capsules was associated with 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 EndpointsIn 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 below), percent diameter stenosis (Figure 4), and the formation of new lesions (13% of all fluvastatin patients versus 22% of all placebo patients). 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 range of baseline LDL-C levels.Figure 3. Change in Minimum Lumen Diameter (mm)Figure 4. Change in Diameter StenosisPrimary Hyperlipidemia in Adults 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 to 26 weeks in duration. In the three largest of these trials, LESCOL XL given as single daily dose of 80 mg significantly reduced Total-C, LDL-C, TG, and Apo (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 (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)Total CholTGLDLApo BHDLDoseN%N%N%N%N%All Patients LESCOL XL 80 mga 750-25750-19748-35745-27750+7Baseline TG >= 200 mg/dL LESCOL XL 80 mga 239-25239-25237-33235-27239+11aData for LESCOL XL 80 mg tablet from three 24- week controlled trials.HeFH in Pediatric Patients Aged 10 Years and Older Fluvastatin capsules were studied in two open-label, uncontrolled, dose-titration trials. The first trial enrolled 29 pre-pubertal males, to12 years of age, who had an LDL-C level 90th percentile for age and one parent with primary hypercholesterolemia and either 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 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 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 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 80 mga LESCOL XL 80 mga lescol-03. lescol-04. lescol-05. lescol-06.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oLESCOL XL can be taken with or without food and may be taken at any time of the day. (2.1)oDo not break, crush or chew LESCOL XL tablets prior to administration. (2.1)oAdults: The recommended starting dose is 80 mg (administered as one 80 mg LESCOL XL once daily). (2.2) Children: The recommended dose is 80 mg once daily in pediatric patients 10 years of age and older who require 80 mg of fluvastatin. 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. (2.3). oLESCOL XL can be taken with or without food and may be taken at any time of the day. (2.1). oDo not break, crush or chew LESCOL XL tablets prior to administration. (2.1). oAdults: The recommended starting dose is 80 mg (administered as one 80 mg LESCOL XL once daily). (2.2). Children: The recommended dose is 80 mg once daily in pediatric patients 10 years of age and older who require 80 mg of fluvastatin. 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. (2.3). 2.1 Important Dosage Information. oTake LESCOL XL tablets orally once daily as single dose, with or without food. oDo not break, crush, or chew LESCOL XL tablets. oLESCOL XL is only available as an 80 mg tablet. LESCOL XL cannot be titrated [see Dosage and Administration (2.2, 2.3)]. oFor patients that require high-intensity statin or are unable to achieve their LDL-C goal receiving LESCOL XL 80 mg daily, prescribe alternative LDL-C-lowering treatment.oAssess LDL-C when clinically appropriate, as early as weeks after initiating LESCOL XL.. oTake LESCOL XL tablets orally once daily as single dose, with or without food. oDo not break, crush, or chew LESCOL XL tablets. oLESCOL XL is only available as an 80 mg tablet. LESCOL XL cannot be titrated [see Dosage and Administration (2.2, 2.3)]. oFor patients that require high-intensity statin or are unable to achieve their LDL-C goal receiving LESCOL XL 80 mg daily, prescribe alternative LDL-C-lowering treatment.. oAssess LDL-C when clinically appropriate, as early as weeks after initiating LESCOL XL.. 2.2 Recommended Dosage in Adult Patients. The recommended dosage for LESCOL XL is 80 mg once daily.. 2.3 Recommended Dosage in Pediatric Patients Aged 10 Years of Age and Older with HeFH 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.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oGemfibrozil: Avoid use with LESCOL XL. (7.1)oCyclosporine and Fluconazole: Avoid use with LESCOL XL. (7.1)oFibrates, Lipid-modifying doses (>= 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)oWarfarin: 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)oGlyburide: Monitor blood glucose levels when LESCOL XL is initiated. (7.2)oPhenytoin: Monitor plasma phenytoin levels when LESCOL XL treatment is initiated. (7.2). oGemfibrozil: Avoid use with LESCOL XL. (7.1). oCyclosporine and Fluconazole: Avoid use with LESCOL XL. (7.1). oFibrates, Lipid-modifying doses (>= 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). oWarfarin: 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). oGlyburide: Monitor blood glucose levels when LESCOL XL is initiated. (7.2). oPhenytoin: Monitor plasma phenytoin levels when LESCOL XL treatment is initiated. (7.2). 7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with LESCOL XL Table includes 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 XLGemfibrozilClinical impactThere is an increased risk of myopathy/rhabdomyolysis when LESCOL XL is administered with gemfibrozilInterventionAvoid concomitant use of gemfibrozil with LESCOL XL.CyclosporineClinical impact Cyclosporine coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of cyclosporine with LESCOL XL. InterventionAvoid concomitant use of cyclosporine with LESCOL XL.FluconazoleClinical impact Fluconazole coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of fluconazole with LESCOL XL. InterventionAvoid concomitant use of fluconazole with LESCOL XL Niacin Clinical impactRisk of myopathy and rhabdomyolysis may be enhanced with concomitant use with lipid-modifying doses (>= g/day) of niacin with LESCOL XL. InterventionConsider if the benefit of using lipid-modifying doses (>= 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.FibratesClinical impactFibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of fibrates with LESCOL XL. InterventionConsider 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.ColchicineClinical impactCases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with fluvastatin.InterventionConsider 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.. Cyclosporine coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of cyclosporine with LESCOL XL. Fluconazole coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of fluconazole with LESCOL XL. 7.2 LESCOL XL Effects on Other Drugs Table presents LESCOL XLs effect on other drugs and instructions for preventing or managing them.Table 4. LESCOL XL Effects on Other DrugsWarfarin Clinical impactThere are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins and warfarin. InterventionIn 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. GlyburideClinical impactConcomitant administration of fluvastatin and glyburide increased glyburide exposures [see Clinical Pharmacology (12.3)].InterventionMonitor blood glucose levels when LESCOL XL is initiated.PhenytoinClinical impactConcomitant administration of fluvastatin and phenytoin increased phenytoin exposures [see Clinical Pharmacology (12.3)].InterventionMonitor plasma phenytoin levels when LESCOL XL is initiated.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFluvastatin administered as LESCOL XL 80 mg tablets reaches peak concentration in approximately hours under fasting conditions, after low-fat meal, or 2.5 hours after 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 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 high-fat meal is less than the peak concentration following single dose or twice daily dose of the 40 mg fluvastatin capsule.DistributionFluvastatin 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.EliminationMetabolismFluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. N-dealkylation 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 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 much less extent, i.e., approximately 5% and approximately 20%, respectively.ExcretionFollowing oral administration, fluvastatin is primarily (about 90%) excreted in the feces as metabolites, with less than 2% present as unchanged drug. Approximately 5% of radiolabeled oral dose were recovered in urine. The elimination half-life (t1/2) of fluvastatin is approximately hours.Specific PopulationsGeriatric PatientsPlasma levels of fluvastatin are not significantly different in patients age 65 years compared to patients age 21 to 49 years. GenderIn 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.Pediatric PatientsPharmacokinetic data in the pediatric population are not available. Patients with Renal ImpairmentIn patients with moderate to severe renal impairment (CLCr 10-40 mL/min), AUC and Cmax increased approximately 1.2-fold after administration of 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 (8.6)]. However, systemic exposures after administration of LESCOL XL are lower than after the 40 mg immediate release capsule.Patients with Hepatic ImpairmentIn patients with hepatic impairment due to liver cirrhosis, fluvastatin AUC and Cmax increased approximately 2.5-fold compared to healthy subjects after administration of single 40 mg dose [see Use in Specific Populations (8.7)]. The enantiomer ratios of the two isomers of fluvastatin in hepatic impairment patients were comparable to those observed in healthy subjects.Drug Interaction StudiesData 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 ExposureCoadministered drug and dosing regimenFluvastatinDose (mg)a Change in AUCb Change in Cmax Cyclosporine stable dose (twice daily)c 20 mg once daily for 14 weeks90%30% Fluconazole 400 mg once daily1,200 mg twice daily to 4c 40 mg once daily 84%44% Cholestyramine g once daily20 mg once daily administered hrs after meal plus cholestyramine51%83% Rifampicin 600 mg once daily for days20 mg once daily53% 42% Cimetidine 400 mg twice daily for days, once daily on Day 620 mg once daily30%40% Ranitidine 150 mg twice daily for days, once daily on Day 620 mg once daily10%50% Omeprazole 40 mg once daily for days20 mg once daily20%37%Phenytoin 300 mg once daily40 mg twice daily for days40%27%Propranolol 40 mg twice daily for 3.5 days40 mg once daily5%No changeDigoxin 0.1 to 0.5 mg once daily for weeks40 mg once daily No change11% Diclofenac 25 mg once daily40 mg once daily for days50%80%Glyburide mg to 20 mg once daily for 22 days40 mg twice daily for 14 days51% 44% Warfarin 30 mg once dailyClopidogrel 300 mg loading dose on Day 10, 75 mg once daily on Days 11 to 1940 mg once daily for days 80 mg XL once daily for 19 days30%2%67%27%Abbreviation: AUC, area under the curve.aSingle dose unless otherwise noted.bMean 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. cConsidered clinically significant [see Dosage and Administration (2.4), Drug Interactions (7.1)].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 DrugsCoadministered drugFluvastatin dosage regimenName and dose (mg)a Change in AUCb Change in Cmax 40 mg once daily for daysPhenytoin 300 mg once dailyc 20% 5%40 mg twice daily for 21 daysGlyburide to 20 mg once daily for 22 daysc 70%50% 40 mg once daily for daysDiclofenac 25 mg once daily25%60%40 mg once daily for daysWarfarin 30 mg once dailyS-warfarin: 7% R-warfarin: no changeS-warfarin: 10%R-warfarin: 6%Abbreviation: AUC, area under the curve.aSingle dose unless otherwise noted.bMean 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. cConsidered clinically significant [see Drug Interactions (7.2)].

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION LESCOL(R) XL(les-col)(fluvastatin)extended-release tablets, for oral useYou 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 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 XLLESCOL XL is prescription medicine that contains the cholesterol lowering medicine, fluvastatin.LESCOL XL is used in adults with heart disease (coronary artery disease) to:olower the need for heart and blood vessel procedures to improve flow to the heart, called coronary revascularization.oslow the buildup of too much cholesterol in the arteries of the heart.LESCOL XL is used along with diet to lower the level of:olow-density lipoprotein cholesterol (LDL-C) or bad cholesterol in adults with hyperlipidemia (high levels of fat in the blood)oLDL-C in adults and children 10 years of age and older with heterozygous familial hypercholesterolemia (HeFH), an inherited condition that causes high levels of LDL, who require 80 mg of fluvastatin daily.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:ohave liver problems (acute liver failure or decompensated cirrhosis)oare allergic to fluvastatin or any of the ingredients in LESCOL XL. See the end of this Patient Information leaflet for complete list of ingredients in LESCOL XL.Before you take LESCOL XL, tell your healthcare provider about all of your medical conditions, including if you:ohave muscle aches or weaknessodrink more than glasses of alcohol dailyohave diabetesohave thyroid problemohave kidney problemsoare pregnant or plan to become pregnant. If you become pregnant while taking LESCOL XL, stop taking LESCOL XL and call your healthcare provider.oare breastfeeding or plan to breastfeed. It is not known if LESCOL XL passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take LESCOL XL. You should not breastfeed while taking LESCOL XLTell your healthcare provider about all the medicines you take, including prescription and over-the-counter 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:owarfarin (a medicine used to reduce blood clotting)oglyburide (a medicine used to treat diabetes)ophenytoin (a medicine used to treat epilepsy)Taking LESCOL XL with certain medicines can also increase the risk of muscle problems. Especially tell your healthcare provider if you take: ogemfibrozil (a medicine used to lower triglycerides)ocyclosporine (a medicine used to suppress the immune system)ofluconazole (a medicine used to treat fungal infections)ofibrates or niacin ocolchicine Ask your healthcare provider or pharmacist for list of medicines if you are not sure. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take LESCOL XLoTake LESCOL XL exactly as your healthcare provides tells you to take it.oDo not change your dose or stop taking LESCOL XL without talking to your healthcare provider.oTake LESCOL XL tablets time each day, at any time of the day. LESCOL XL can be taken with or without food.oLESCOL XL tablets must be swallowed whole with liquid. Do not break, crush or chew LESCOL XL tablets. Tell your healthcare provider if you cannot swallow tablets whole. You may need fluvastatin capsules or different medicine instead of LESCOL XL tablets. oWhile taking LESCOL XL, continue to follow your cholesterol-lowing diet and exercise as your healthcare provider told you to. oIn case of overdose, get medical help or contact Poison Center expert right away at 1-800-222-1222. Advice is also available online at poisonhelp.org.What are the possible side effects of LESCOL XLLESCOL XL may cause serious side effects, including:oMuscle pain, tenderness, and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and rarely cause kidney damage that can lead to death.Tell your healthcare provider right away if you have: ounexplained muscle pain, tenderness, or weakness, especially if you have fever or feel more tired than usual, while you take LESCOL XL.omuscle problems that do not go away even after your healthcare provider has advised you to stop taking LESCOL XL. Your healthcare provider may do further tests to diagnose the cause of your muscle problems. Your chances of getting muscle problems are higher if you:oare taking certain other medicines while you take LESCOL XLoare 65 years of age or olderohave thyroid problems (hypothyroidism) that are not controlledohave kidney problemsoLiver problems. Your healthcare provider should do blood tests to check your liver before you start taking LESCOL XL, and if you have symptoms of liver problems while you take LESCOL XL. Call your healthcare provider right away if you have the following symptoms of liver problems:ofeel tired or weakoloss of appetiteoright sided upper belly painodark amber colored urineoyellowing of your skin or the whites of your eyeoIncrease in blood sugar (glucose) levels. LESCOL XL may cause an increase in your blood sugar levels.The most common side effects of LESCOL XL include:oflu-like symptoms osinus infection oupset stomach and stomach pain ourinary tract infectionsobronchitisonauseaThese side effects are usually mild and may go away. The following additional side effects have been reported with LESCOL XL:omemory loss and confusionTalk 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 store LESCOL XLoStore LESCOL XL at room temperature 68F to 77F (20C to 25C). Protect from light. oKeep LESCOL XL out of the reach of children. Be sure that if you throw medicines away, it is out of the reach of children.General information about safe and effective use of LESCOL XL.Medicines are sometimes prescribed for purposes other than those listed in Patient Information Leaflet. Do not use LESCOL XL for 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 XLActive 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.For more information go to www.sandoz.com or call 1-800-525-8747.Manufactured byPfizer Ireland PharmaceuticalsNewbridge, Ireland forSandoz Inc., Princeton, NJ 08540This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 12/2023. olower the need for heart and blood vessel procedures to improve flow to the heart, called coronary revascularization.. oslow the buildup of too much cholesterol in the arteries of the heart.. olow-density lipoprotein cholesterol (LDL-C) or bad cholesterol in adults with hyperlipidemia (high levels of fat in the blood). oLDL-C in adults and children 10 years of age and older with heterozygous familial hypercholesterolemia (HeFH), an inherited condition that causes high levels of LDL, who require 80 mg of fluvastatin daily.. ohave liver problems (acute liver failure or decompensated cirrhosis). oare allergic to fluvastatin or any of the ingredients in LESCOL XL. See the end of this Patient Information leaflet for complete list of ingredients in LESCOL XL.. ohave muscle aches or weakness. odrink more than glasses of alcohol daily. ohave diabetes. ohave thyroid problem. ohave kidney problems. oare pregnant or plan to become pregnant. If you become pregnant while taking LESCOL XL, stop taking LESCOL XL and call your healthcare provider.. oare breastfeeding or plan to breastfeed. It is not known if LESCOL XL passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take LESCOL XL. You should not breastfeed while taking LESCOL XL. owarfarin (a medicine used to reduce blood clotting). oglyburide (a medicine used to treat diabetes). ophenytoin (a medicine used to treat epilepsy). ogemfibrozil (a medicine used to lower triglycerides). ocyclosporine (a medicine used to suppress the immune system). ofluconazole (a medicine used to treat fungal infections). ofibrates or niacin ocolchicine oTake LESCOL XL exactly as your healthcare provides tells you to take it.. oDo not change your dose or stop taking LESCOL XL without talking to your healthcare provider.. oTake LESCOL XL tablets time each day, at any time of the day. LESCOL XL can be taken with or without food.. oLESCOL XL tablets must be swallowed whole with liquid. Do not break, crush or chew LESCOL XL tablets. Tell your healthcare provider if you cannot swallow tablets whole. You may need fluvastatin capsules or different medicine instead of LESCOL XL tablets. oWhile taking LESCOL XL, continue to follow your cholesterol-lowing diet and exercise as your healthcare provider told you to. oIn case of overdose, get medical help or contact Poison Center expert right away at 1-800-222-1222. Advice is also available online at poisonhelp.org.. oMuscle pain, tenderness, and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and rarely cause kidney damage that can lead to death.. ounexplained muscle pain, tenderness, or weakness, especially if you have fever or feel more tired than usual, while you take LESCOL XL.. omuscle problems that do not go away even after your healthcare provider has advised you to stop taking LESCOL XL. Your healthcare provider may do further tests to diagnose the cause of your muscle problems. Your chances of getting muscle problems are higher if you:. oare taking certain other medicines while you take LESCOL XL. oare 65 years of age or older. ohave thyroid problems (hypothyroidism) that are not controlled. ohave kidney problems. oLiver problems. Your healthcare provider should do blood tests to check your liver before you start taking LESCOL XL, and if you have symptoms of liver problems while you take LESCOL XL. Call your healthcare provider right away if you have the following symptoms of liver problems:. ofeel tired or weak. oloss of appetite. oright sided upper belly pain. odark amber colored urine. oyellowing of your skin or the whites of your eye. oIncrease in blood sugar (glucose) levels. LESCOL XL may cause an increase in your blood sugar levels.. oflu-like symptoms osinus infection oupset stomach and stomach pain ourinary tract infections. obronchitis. onausea. omemory loss and confusion. oStore LESCOL XL at room temperature 68F to 77F (20C to 25C). Protect from light. oKeep LESCOL XL out of the reach of children. Be sure that if you throw medicines away, it is out of the reach of children.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oPregnancy: May cause fetal harm (8.1)oLactation: Breastfeeding not recommended during treatment with LESCOL XL (8.2). oPregnancy: May cause fetal harm (8.1). oLactation: Breastfeeding not recommended during treatment with LESCOL XL (8.2). 8.1Pregnancy Risk SummaryDiscontinue 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 (12.1)]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is 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 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 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 and 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.DataHuman DataA Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find 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 malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of statin, and lack of information on non-live births.Animal DataFluvastatin 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 times (rat at 12 mg/kg) or 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, dose that produced significant maternal toxicity. 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 mg/kg/day. 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 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, 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 and postpartum.. 8.2Lactation Risk SummaryThere 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 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 breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with LESCOL XL [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].DataFollowing single oral administration of 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 2:1 ratio (milk:plasma).. 8.4Pediatric Use 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 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).. 8.5Geriatric Use Fluvastatin exposures were not significantly different between the nonelderly and elderly populations (age >= 65 years) [see Clinical Pharmacology (12.3)]. Advanced age (>= 65 years) is 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 (5.1)].. 8.6Renal Impairment Renal impairment is 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 (5.1), Clinical Pharmacology (12.3)].. 8.7Hepatic Impairment LESCOL XL is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4), Warnings and Precautions (5.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oMyopathy 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)oImmune-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)oHepatic 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). oMyopathy 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). oImmune-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). oHepatic 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). 5.1 Myopathy 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 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 MyopathyRisk 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 RhabdomyolysisAvoid concomitant use of LESCOL XL with gemfibrozil, cyclosporin, and fluconazole. When used concomitantly with LESCOL XL, lipid modifying doses (>= 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.. 5.2 Immune-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 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.. 5.3 Hepatic 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 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 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.. 5.4 Increases 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 healthy body weight, and making healthy food choices.