Fluvastatin capsules are indicated

The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature CVD is summarized below.

<div class="scrollingtable"><table> <colgroup> <col width="13%"/> <col width="19%"/> <col width="18%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Toprule" valign="top"> <p class="First"> <span class="Bold">Category</span> </p> </td><td class="Botrule Lrule Toprule" valign="top"> <p class="First"> <span class="Bold">Total-C (mg/dL)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">LDL-C (mg/dL)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Acceptable</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">&lt; 170</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">&lt; 110</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Borderline</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">170 to 199</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">110 to 129</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule" valign="top"> <p class="First">High</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">≥ 200</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">≥ 130</p> </td> </tr> </tbody> </table></div>

Children treated with fluvastatin in adolescence should be re-evaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult treatment goals.

In patients with clinically evident CHD, fluvastatin capsules are indicated to:

Fluvastatin capsules have not been studied in conditions where the major abnormality is elevation of chylomicrons, VLDL, or IDL (i.e., hyperlipoproteinemia Types I, III, IV, or V).

Dose range: 20 mg to 80 mg/day.

Fluvastatin capsules can be administered orally as a single dose, with or without food.

Do not open fluvastatin capsules prior to administration.

Do not take two fluvastatin capsules, 40 mg at one time.

Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines.

For patients requiring LDL-C reduction to a goal of ≥ 25%, the recommended starting dose is 40 mg as one capsule in the evening, or 80 mg in divided doses of the 40 mg capsule given twice daily. For patients requiring LDL-C reduction to a goal of < 25% a starting dose of 20 mg may be used.

Adult patients can be started on fluvastatin capsules. The recommended starting dose for fluvastatin capsules is one 40 mg capsule in the evening, or one fluvastatin capsule, 40 mg twice daily. Do not take two fluvastatin capsules, 40 mg at one time.

The recommended starting dose is one fluvastatin capsule, 20 mg. Dose adjustments, up to a maximum daily dose administered as fluvastatin capsules, 40 mg twice daily should be made at 6 week intervals. Doses should be individualized according to the goal of therapy [see NCEP Pediatric Panel Guidelines and CLINICAL STUDIES (14)]1.

1 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992.

Do not exceed a dose of 20 mg b.i.d. fluvastatin capsules in patients taking cyclosporine [see Drug Interactions (7.1)].

Do not exceed a dose of 20 mg b.i.d. fluvastatin capsules in patients taking fluconazole [see Drug Interactions (7.2)].

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Fluvastatin capsules are contraindicated in patients with hypersensitivity to any component of this medication.

Fluvastatin capsules are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases [see Warnings and Precautions (5.3)].

Fluvastatin capsules are contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Fluvastatin capsules may cause fetal harm when administered to pregnant women. 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 hypercholesterolemia.

Fluvastatin capsules should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, fluvastatin capsules should be discontinued and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

Fluvastatin is secreted into the breast milk of animals and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require treatment with fluvastatin capsules should be advised not to breastfeed their infants [see Use in Specific Populations (8.3)].

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

Fluvastatin capsules should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age (> 65 years), renal impairment, and inadequately treated hypothyroidism.

The risk of myopathy and/or rhabdomyolysis with statins is increased with concurrent therapy with cyclosporine, erythromycin, fibrates or niacin. Myopathy was not observed in a clinical trial in 74 patients involving patients who were treated with fluvastatin sodium together with niacin. Isolated cases of myopathy have been reported during postmarketing experience with concomitant administration of fluvastatin sodium and colchicine. No information is available on the pharmacokinetic interaction between fluvastatin sodium and colchicine.

Uncomplicated myalgia has also been reported in fluvastatin sodium-treated patients [see Adverse Reactions (6)]. In clinical trials, uncomplicated myalgia has been observed infrequently in patients treated with fluvastatin sodium at rates indistinguishable from placebo. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CPK values to greater than 10 times the upper limit of normal, was < 0.1% in fluvastatin clinical trials. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK.

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

Fluvastatin sodium therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Fluvastatin sodium therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

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

Increases in serum transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase, or alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors, including fluvastatin sodium. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy.

Approximately 1.1% of patients treated with fluvastatin capsules in worldwide trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the upper limit of normal. 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 sodium 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 fluvastatin capsules were used, persistent transaminase elevations (> 3 times the upper limit of normal [ULN] on two consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients treated with daily doses of 20, 40, and 80 mg (titrated to 40 mg twice daily) fluvastatin capsules, respectively. Ninety-one percent of the cases of persistent liver function test abnormalities (20 of 22 patients) occurred within 12 weeks of therapy and in all patients with persistent liver function test abnormalities there was an abnormal liver function test present at baseline or by Week 8.

In the pooled analysis of the 24 week controlled trials, persistent transaminase elevation occurred in 1.8% and 4.9% of patients treated with fluvastatin capsules, 40 mg and fluvastatin capsules, 40 mg twice daily, respectively.

It is recommended that liver enzyme tests be performed prior to the initiation of fluvastatin sodium, and if signs or symptoms of liver injury occur.

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with fluvastatin sodium, promptly interrupt therapy. If an alternate etiology is not found do not restart fluvastatin sodium.

In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment.1 Active liver disease or unexplained serum transaminase elevations are contraindications to the use of fluvastatin sodium [see Contraindications (4) and Warnings and Precautions (5.3)]. Caution should be exercised when fluvastatin sodium is administered to patients with a history of liver disease or heavy alcohol ingestion [see Clinical Pharmacology (12.3)]. Such patients should be closely monitored.

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

Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production.

Fluvastatin sodium exhibited no effect upon non-stimulated cortisol levels and demonstrated no effect upon thyroid metabolism as assessed by measurement of thyroid stimulating hormone (TSH). Small declines in total serum testosterone have been noted in treated groups, but no commensurate elevation in LH occurred, suggesting that the observation was not due to a direct effect upon testosterone production. No effect upon FSH in males was noted. Due to the limited number of premenopausal females studied to date, no conclusions regarding the effect of fluvastatin sodium upon female sex hormones may be made.

Two clinical studies in patients receiving fluvastatin at doses up to 80 mg daily for periods of 24 to 28 weeks demonstrated no effect of treatment upon the adrenal response to ACTH stimulation. A clinical study evaluated the effect of fluvastatin at doses up to 80 mg daily for 28 weeks upon the gonadal response to HCG stimulation. Although the mean total testosterone response was significantly reduced (p < 0.05) relative to baseline in the 80 mg group, it was not significant in comparison to the changes noted in groups receiving either 40 mg of fluvastatin or placebo.

Patients treated with fluvastatin sodium who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if a statin or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may decrease the levels of endogenous steroid hormones.

CNS effects, as evidenced by decreased activity, ataxia, loss of righting reflex, and ptosis were seen in the following animal studies: the 18 month mouse carcinogenicity study at 50 mg/kg/day, the 6 month dog study at 36 mg/kg/day, the 6 month hamster study at 40 mg/kg/day, and in acute, high-dose studies in rats and hamsters (50 mg/kg), rabbits (300 mg/kg) and mice (1500 mg/kg). CNS toxicity in the acute high-dose studies was characterized (in mice) by conspicuous vacuolation in the ventral white columns of the spinal cord at a dose of 5000 mg/kg and (in rats) by edema with separation of myelinated fibers of the ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS toxicity, characterized by periaxonal vacuolation, was observed in the medulla of dogs that died after treatment for 5 weeks with 48 mg/kg/day; this finding was not observed in the remaining dogs when the dose level was lowered to 36 mg/kg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this drug class. No CNS lesions have been observed after chronic treatment for up to 2 years with fluvastatin in the mouse (at doses up to 350 mg/kg/day), rat (up to 24 mg/kg/day), or dog (up to 16 mg/kg/day).

Prominent bilateral posterior Y suture lines in the ocular lens were seen in dogs after treatment with 1, 8, and 16 mg/kg/day for 2 years.

Because clinical studies on fluvastatin capsules are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of fluvastatin capsules cannot be directly compared with that in the clinical studies of other statins and may not reflect the frequency of adverse reactions observed in clinical practice.

In the fluvastatin capsules placebo-controlled clinical trials database of 2326 patients treated with fluvastatin capsules1 (age range 18 to 75 years, 44% women, 94% Caucasians, 4% Blacks, 2% other ethnicities) with a median treatment duration of 24 weeks, 3.4% of patients on fluvastatin capsules and 2.3% patients on placebo discontinued due to adverse reactions regardless of causality. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: transaminase increased (0.8%), upper abdominal pain (0.3%), dyspepsia (0.3%), fatigue (0.2%) and diarrhea (0.2%).

Clinically relevant adverse experiences occurring in the fluvastatin capsules controlled studies with a frequency ≥ 2%, regardless of causality, included the following:

<div class="scrollingtable"><table> <caption> <span>Table 1: Clinical Adverse Events Reported in &gt; 2% in Patients Treated With Fluvastatin Capsules and at an Incidence Greater Than Placebo in Placebo-Controlled Trials Regardless of Causality (% of Patients) Pooled Dosages </span> </caption> <col width="17%"/> <col width="25%"/> <col width="22%"/> <col width="10%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Toprule" valign="top"></td><td class="Botrule Lrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Toprule" valign="top"> <p class="First">Fluvastatin Capsules<span class="Italics"><span class="Sup">1</span></span> </p> <p>N = 2326</p> <p>(%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Placebo<span class="Italics"><span class="Sup">1</span></span> </p> <p>N = 960</p> <p>(%)</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Musculoskeletal</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Myalgia</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">5.0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4.5</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Arthritis</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">2.1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2.0</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Arthropathy</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">NA</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Respiratory</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Sinusitis</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">2.6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1.9</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Bronchitis</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">1.8</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1.0</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Gastrointestinal</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Dyspepsia</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">7.9</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3.2</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">4.9</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4.2</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Abdominal pain</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">4.9</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3.8</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">3.2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2.0</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Flatulence</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">2.6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2.5</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Tooth disorder</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">2.1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1.7</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Psychiatric</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Insomnia</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">2.7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1.4</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Genitourinary</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Urinary tract infection</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">1.6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Miscellaneous</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">8.9</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7.8</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Influenza-like symptoms</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">5.1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5.7</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Accidental Trauma</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">5.1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4.8</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Fatigue</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">2.7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2.3</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Allergy</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">2.3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2.2</p> </td> </tr> </tbody> </table></div>

1. Controlled trials with fluvastatin capsules (20 and 40 mg daily and 40 mg twice daily) compared to placebo

Fluvastatin Capsules Intervention Prevention Study

In the Fluvastatin Capsules Intervention Prevention Study, the effect of fluvastatin capsules, 40 mg, administered twice daily on the risk of recurrent cardiac events was assessed in 1677 patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure. This was a multicenter, randomized, double-blind, placebo-controlled study, patients were treated with dietary/lifestyle counseling and either fluvastatin capsules, 40 mg (n = 844) or placebo (n = 833) given twice daily for a median of 3.9 years [see Clinical Studies (14.3)].

<div class="scrollingtable"><table> <caption> <span>Table 2: Clinical Adverse Events Reported in ≥ 2% in Patients Treated With Fluvastatin Sodium and at an Incidence Greater Than Placebo in the Trial Regardless of Causality (% of Patients) </span> </caption> <col width="45%"/> <col width="24%"/> <col width="21%"/> <col width="10%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Toprule" valign="top"></td><td class="Botrule Lrule Toprule" valign="top"></td><td class="Botrule Lrule Toprule" valign="top"> <p class="First">Fluvastatin Capsules, </p> <p>40 mg b.i.d.</p> <p>N = 822</p> <p>(%)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Placebo</p> <p>N = 818</p> <p>(%)</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Cardiac disorders</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Atrial fibrillation</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">2.4</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">2.0</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Gastrointestinal disorders</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Abdominal pain upper</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">6.3</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">4.5</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Constipation</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">3.3</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">2.1</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Dyspepsia</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">4.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">4.0</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Gastric disorder</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">2.7</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">2.1</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Nausea</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">2.7</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">General disorders</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Fatigue</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">4.7</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">3.8</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Edema peripheral</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">4.4</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">2.9</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Infections and infestations</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Bronchitis</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">2.3</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">2.0</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Nasopharyngitis</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">2.8</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">2.1</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Musculoskeletal and connective tissue disorders</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Arthralgia</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">2.1</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">1.8</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Myalgia</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">2.2</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">1.6</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Pain in extremity</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">4.1</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">2.7</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Nervous system disorders</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Dizziness</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">3.9</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">3.5</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Syncope</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">2.4</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">2.2</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Respiratory disorders</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Dyspnea exertional</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">2.8</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">2.4</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Vascular disorders</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Hypertension</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">5.8</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">4.2</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">Intermittent claudication</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">2.3</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">2.1</p> </td> </tr> </tbody> </table></div>

In patients aged < 18 years, efficacy and safety have not been studied for treatment periods longer than two years.

In two open-label, uncontrolled studies, 66 boys and 48 girls with heterozygous familial hypercholesterolemia (9 to 16 years of age, 80% Caucasian, 19% Other [mixed ethnicity], 1% Asians) were treated with fluvastatin sodium administered as fluvastatin capsules, 20 mg to 40 mg twice daily, or fluvastatin sodium extended-release tablets, 80 mg [see Clinical Studies (14.2) and Use in Specific Populations (8.4)].

Because adverse reactions from spontaneous reports are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with fluvastatin sodium therapy.

Musculoskeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias, muscle spasms, muscle weakness, myositis.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)].

Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, hypoesthesia, dysesthesia, peripheral neuropathy, peripheral nerve palsy.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Psychiatric: anxiety, insomnia, depression, psychic disturbances

Respiratory: interstitial lung disease

Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR (erythrocyte sedimentation rate) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity reaction, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, anorexia, vomiting, fatal and non-fatal hepatic failure.

Skin: rash, dermatitis, including bullous dermatitis, eczema, alopecia, pruritus, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails).

Reproductive: gynecomastia, loss of libido, erectile dysfunction.

Eye: progression of cataracts (lens opacities), ophthalmoplegia.

Laboratory abnormalities: elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase and bilirubin; thyroid function abnormalities.

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

Administration of fluvastatin 40 mg single dose to healthy volunteers pre-treated with fluconazole for 4 days results in an increase of fluvastatin exposure. Therefore, in patients taking fluconazole, therapy should be limited to fluvastatin 20 mg twice daily [see Clinical Pharmacology (12.3)].

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

Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, fluvastatin sodium should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

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

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

Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures. Patients should continue to be monitored appropriately when fluvastatin therapy is initiated or when fluvastatin dose is changed [see Clinical Pharmacology (12.3)].

Bleeding and/or increased prothrombin times have been reported in patients taking coumarin anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients receiving warfarin-type anticoagulants should have their prothrombin times closely monitored when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed.

Cases of myopathy, including rhabdomyolysis, have been reported with fluvastatin coadministered with colchicine, and caution should be exercised when prescribing fluvastatin with colchicine.

Fluvastatin sodium is contraindicated in women who are or may become pregnant [see Contraindications (4)].

Lipid lowering drugs are contraindicated during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Serum cholesterol and triglycerides increase during normal pregnancy. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.

There are no adequate and well-controlled studies of use with fluvastatin sodium during pregnancy. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review2 of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. The number of cases is adequate only to exclude a 3 to 4 fold increase in congenital anomalies over background incidence. In 89% of prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Teratology studies with fluvastatin in rats and rabbits showed maternal toxicity at high dose levels, but there was no evidence of embryotoxic or teratogenic potential [see Nonclinical Toxicology (13)].

Fluvastatin sodium should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If a woman becomes pregnant while taking fluvastatin sodium, the drug should be discontinued and the patient advised again as to the potential hazards to the fetus.

Based on animal data, fluvastatin is present in breast milk in a 2:1 ratio (milk:plasma). Because of the potential for serious adverse reactions in nursing infants, nursing women should not take fluvastatin sodium [see Contraindications (4)].

The safety and efficacy of fluvastatin sodium in children and adolescent patients 9 to 16 years of age with heterozygous familial hypercholesterolemia have been evaluated in open-label, uncontrolled clinical trials for a duration of two years. The most common adverse events observed were influenza and infections. In these limited uncontrolled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls [see Clinical Studies (14.2), Adverse Reactions (6.3), and Dosage and Administration (2.2)]. Adolescent females should be counseled on appropriate contraceptive methods while on fluvastatin sodium therapy [see Contraindications (4)].

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

Fluvastatin sodium is contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases [see Clinical Pharmacology (12.3)].

Dose adjustments for mild to moderate renal impairment are not necessary. Fluvastatin has not been studied at doses greater than 40 mg in patients with severe renal impairment; therefore caution should be exercised when treating such patients at higher doses [see Clinical Pharmacology (12.3)].

To date, there has been limited experience with overdosage of fluvastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required. The dialyzability of fluvastatin sodium and of its metabolites in humans is not known at present [see Warnings and Precautions (5)].

{ "type": "p", "children": [], "text": "To date, there has been limited experience with overdosage of fluvastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required. The dialyzability of fluvastatin sodium and of its metabolites in humans is not known at present [see Warnings and Precautions (5)]. " }

In the pediatric population, there have been reports of overdosage with fluvastatin sodium in children including a 2-year-old and the other 3 years of age, either of whom may have possibly ingested fluvastatin sodium. The maximum amount of fluvastatin sodium that could have been ingested was 80 mg (4 x 20 mg capsules). Vomiting was induced by ipecac in both children and no capsules were noted in their emesis. Neither child experienced any adverse symptoms and both recovered from the incident without problems.

{ "type": "p", "children": [], "text": "In the pediatric population, there have been reports of overdosage with fluvastatin sodium in children including a 2-year-old and the other 3 years of age, either of whom may have possibly ingested fluvastatin sodium. The maximum amount of fluvastatin sodium that could have been ingested was 80 mg (4 x 20 mg capsules). Vomiting was induced by ipecac in both children and no capsules were noted in their emesis. Neither child experienced any adverse symptoms and both recovered from the incident without problems. " }

In the postmarketing experience there have been reports of accidental ingestion of fluvastatin tablets in infants up to 3 years of age. In one case, increased serum CPK values were noted. There have been reports of intentional overdose in adolescents with the development of hepatic enzyme elevations, convulsions and gastroenteritis/vomiting/diarrhea.

{ "type": "p", "children": [], "text": "In the postmarketing experience there have been reports of accidental ingestion of fluvastatin tablets in infants up to 3 years of age. In one case, increased serum CPK values were noted. There have been reports of intentional overdose in adolescents with the development of hepatic enzyme elevations, convulsions and gastroenteritis/vomiting/diarrhea. " }

Fluvastatin sodium, USP is a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.

{ "type": "p", "children": [], "text": "Fluvastatin sodium, USP is a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. " }

Fluvastatin sodium, USP is [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt. Its structural formula is:

{ "type": "p", "children": [], "text": "Fluvastatin sodium, USP is [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt. Its structural formula is:" }

C24H25FNNaO4 M.W. 433.45

{ "type": "p", "children": [], "text": "C24H25FNNaO4 M.W. 433.45" }

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.

{ "type": "p", "children": [], "text": "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, USP (hydrated form) is a white to pale yellow, brownish-pale yellow, or reddish-pale yellow, hygroscopic powder soluble in water, ethanol, and methanol. Fluvastatin Capsules, USP contain fluvastatin sodium, USP (hydrated form), equivalent to 20 mg or 40 mg of fluvastatin, for oral administration.

{ "type": "p", "children": [], "text": "Fluvastatin sodium, USP (hydrated form) is a white to pale yellow, brownish-pale yellow, or reddish-pale yellow, hygroscopic powder soluble in water, ethanol, and methanol. Fluvastatin Capsules, USP contain fluvastatin sodium, USP (hydrated form), equivalent to 20 mg or 40 mg of fluvastatin, for oral administration." }

Active Ingredient: fluvastatin sodium, USP (hydrated form)

{ "type": "p", "children": [], "text": "\nActive Ingredient: fluvastatin sodium, USP (hydrated form) " }

Inactive Ingredients: black iron oxide, colloidal silicon dioxide, crospovidone, gelatin, lactose monohydrate, magnesium stearate, propylene glycol, red iron oxide, shellac, titanium dioxide, and yellow iron oxide. The imprinting ink may contain potassium hydroxide.

{ "type": "p", "children": [], "text": "\nInactive Ingredients: black iron oxide, colloidal silicon dioxide, crospovidone, gelatin, lactose monohydrate, magnesium stearate, propylene glycol, red iron oxide, shellac, titanium dioxide, and yellow iron oxide. The imprinting ink may contain potassium hydroxide." }

Fluvastatin sodium is a competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles. The end result of these biochemical processes is a reduction of the plasma cholesterol concentration.

Absorption:

Following oral administration of the capsule, fluvastatin reaches peak concentrations in less than 1 hour. The absolute bioavailability is 24% (range 9% to 50%) after administration of a 10 mg dose.

At steady state, administration of fluvastatin with the evening meal results in a 50% decrease in Cmax, an 11% decrease in AUC, and a more than two-fold increase in tmax as compared to administration 4 hours after the evening meal. No significant differences in the lipid-lowering effects were observed between the two administrations. After single or multiple doses above 20 mg, fluvastatin exhibits saturable first-pass metabolism resulting in more than dose proportional plasma fluvastatin concentrations.

Fluvastatin administered as fluvastatin sodium extended-release 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 extended-release 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 extended-release tablet by approximately 50%. However, the maximum concentration of fluvastatin sodium extended-release tablets 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.

Distribution:

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. 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 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.

Specific Populations

Renal Impairment:

In patients with moderate to severe renal impairment (CLCr 10 to 40 mL/min), AUC and Cmax increased approximately 1.2 fold 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. Fluvastatin sodium extended-release tablets were not evaluated in patients with renal impairment. However, systemic exposures after administration of fluvastatin sodium extended-release tablets are lower than after the 40 mg immediate-release capsule.

Hepatic Impairment:

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. The enantiomer ratios of the two isomers of fluvastatin in hepatic impairment patients were comparable to those observed in healthy subjects.

Geriatric:

Plasma levels of fluvastatin are not significantly different in patients age > 65 years compared to patients age 21 to 49 years.

Gender:

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 to 49 years), where there was an approximate 30% increase in AUC in females. Adjusting for body weight decreases the magnitude of the differences seen.

Pediatric:

Pharmacokinetic data in the pediatric population are not available.

Drug-Drug Interactions:

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.

<div class="scrollingtable"><table> <caption> <span>Table 3: Effect of Coadministered Drugs on Fluvastatin Systemic Exposure </span> </caption> <col width="39%"/> <col width="36%"/> <col width="13%"/> <col width="12%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule" valign="top"> <p class="First">Coadministered drug and dosing regimen</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Fluvastatin </p> </td><td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Dose (mg)</span><span class="Italics"><span class="Sup">1</span></span> </p> </td><td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Change in AUC</span><span class="Italics"><span class="Sup">2</span></span> </p> </td><td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Change in C</span><span class="Bold"><span class="Sub">max</span></span><span class="Italics"><span class="Sup">2</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Cyclosporine - stable dose (b.i.d.)<span class="Italics"><span class="Sup">3</span></span> </p> </td><td class="Botrule Lrule" valign="top"> <p class="First">20 mg QD for 14 weeks</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑90%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑30%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Fluconazole 400 mg QD day 1,200 mg b.i.d. day 2 to 4<span class="Italics"><span class="Sup">3</span></span> </p> </td><td class="Botrule Lrule" valign="top"> <p class="First">40 mg QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑84%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑44%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Cholestyramine 8 g QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">20 mg QD administered 4 hrs after a meal plus cholestyramine</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↓51%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↓83%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Rifampicin 600 mg QD for 6 days</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">20 mg QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↓53%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↓42%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Cimetidine 400 mg b.i.d. for 5 days, QD on Day 6</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">20 mg QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑30%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑40%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Ranitidine 150 mg b.i.d. for 5 days, QD on Day 6</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">20 mg QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑10%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑50%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Omeprazole 40 mg QD for 6 days</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">20 mg QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑20%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑37%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Phenytoin 300 mg QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">40 mg b.i.d. for 5 days</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑40%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑27%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Propranolol 40 mg b.i.d. for 3.5 days</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">40 mg QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↓5%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">No change</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Digoxin 0.1 to 0.5 mg QD for 3 weeks</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">40 mg QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">No change</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑11%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Diclofenac 25 mg QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">40 mg QD for 8 days</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑50%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑80%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Glyburide 5 to 20 mg QD for 22 days</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">40 mg b.i.d. for 14 days</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑51%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑44%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Warfarin 30 mg QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">40 mg QD for 8 days</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑30%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑67%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule" valign="top"> <p class="First">Clopidogrel 300 mg loading dose on day 10, 75 mg QD on days 11 to 19</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">fluvastatin sodium extended-release tablets, 80 mg QD for 19 days </p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↓2%</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑27%</p> </td> </tr> </tbody> </table></div>

1. Single dose unless otherwise noted2. 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.3. Considered clinically significant [see Dosage and Administration (2) and Drug Interactions (7)]

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.

<div class="scrollingtable"><table> <caption> <span>Table 4: Effect of Fluvastatin Coadministration on Systemic Exposure of Other Drugs </span> </caption> <col width="26%"/> <col width="35%"/> <col width="21%"/> <col width="17%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Toprule" valign="top"> <p class="First">Fluvastatin dosage regimen</p> </td><td class="Botrule Lrule Toprule" valign="top"> <p class="First">Coadministered drug</p> </td><td class="Botrule Lrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Name and Dose (mg)</span><span class="Italics"><span class="Sup">1</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Change in AUC</span><span class="Italics"><span class="Sup">2</span></span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Change in C<span class="Sub">max</span></span><span class="Italics"><span class="Sup">2</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">40 mg QD for 5 days</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Phenytoin 300 mg QD<span class="Italics"><span class="Sup">3</span></span> </p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑20%</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">↑5%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">40 mg b.i.d. for 21 days</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Glyburide 5 to 20 mg QD for 22 days<span class="Italics"><span class="Sup">3</span></span> </p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑70%</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">↑50%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">40 mg QD for 8 days</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Diclofenac 25 mg QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">↑25%</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">↑60%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">40 mg QD for 8 days</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">Warfarin 30 mg QD</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">S-warfarin: ↑7%</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">S-warfarin: ↑10%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td><td class="Botrule Lrule" valign="top"> <p class="First">R-warfarin: no change</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">R-warfarin: ↑6%</p> </td> </tr> </tbody> </table></div>

1. Single dose unless otherwise noted2. 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.3. Considered clinically significant [see Dosage and Administration (2) and Drug Interactions (7)]

A 2 year study was performed in rats at dose levels of 6, 9, and 18 to 24 (escalated after 1 year) mg/kg/day. These treatment levels represented plasma drug levels of approximately 9, 13, and 26 to 35 times the mean human plasma drug concentration after a 40 mg oral dose. A low incidence of forestomach squamous papillomas and 1 carcinoma of the forestomach at the 24 mg/kg/day dose level was considered to reflect the prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium rather than to a systemic effect of the drug. In addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was recorded for males treated with 18 to 24 mg/kg/day. The increased incidence of thyroid follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with findings from other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas were observed.

The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. These treatment levels represented plasma drug levels of approximately 0.05, 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 mutagenicity in vivo in either a rat or mouse micronucleus test.

In a study in rats at dose levels for females of 0.6, 2, and 6 mg/kg/day and at dose levels for males of 2, 10 and 20 mg/kg/day, fluvastatin sodium had no adverse effects on the fertility or reproductive performance.

Seminal vesicles and testes were small in hamsters treated for 3 months at 20 mg/kg/day (approximately three times the 40 mg human daily dose based on surface area, mg/m2). There was tubular degeneration and aspermatogenesis in testes as well as vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were also seen in rats treated for 2 years at 18 mg/kg/day (approximately 4 times the human Cmax achieved with a 40 mg daily dose).

Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced maternal toxicity. 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. A study in which female rats were dosed 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. A modified Segment III study was performed at dose levels 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.

In 12 placebo-controlled studies in patients with primary hypercholesterolemia and mixed dyslipidemia, fluvastatin capsules were administered to 1621 patients in daily dose regimens of 20 mg, 40 mg, and 80 mg (40 mg twice daily) for at least 6 weeks duration (Table 5). After 24 weeks of treatment, treatment with fluvastatin capsules resulted in significantly reduced plasma LDL-C, TC, TG, and Apo B compared to placebo and was associated with variable increases in HDL-C across the dose range.

In patients with primary mixed dyslipidemia as defined by baseline plasma TG levels ≥ 200 mg/dL and < 400 mg/dL, treatment with fluvastatin capsules produced significant decreases in Total-C, LDL-C, TG and Apo B and variable increases in HDL-C (Table 5).

<div class="scrollingtable"><table> <caption> <span>Table 5: Median Percent Change in Lipid Parameters From Baseline to Week 24 Endpoint All Placebo-Controlled Studies (Fluvastatin Capsules)  </span> </caption> <colgroup> <col/> <col/> <col/> <col/> <col/> <col/> </colgroup> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"></td><td align="center" class="Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Total Chol </span> </p> </td><td align="center" class="Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">TG </span> </p> </td><td align="center" class="Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">LDL </span> </p> </td><td align="center" class="Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Apo B </span> </p> </td><td align="center" class="Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">HDL </span> </p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Dose </span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">N </span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">% Δ</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">% Δ</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold"> N </span> </p> </td><td class="Botrule" valign="top"> <p class="First"> <span class="Bold">% Δ</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">% Δ</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">N</span> </p> </td><td class="Botrule" valign="top"> <p class="First"> <span class="Bold">% Δ</span> </p> </td> </tr> <tr> <td valign="bottom"> <p class="First">All Patients  </p> <p>fluvastatin capsules 20 mg<span class="Italics"><span class="Sup">1</span></span> </p> </td><td align="center" valign="top"> <p class="First">747</p> </td><td align="center" valign="top"> <p class="First">-17</p> </td><td align="center" valign="top"> <p class="First">747</p> </td><td align="center" valign="top"> <p class="First">-12</p> </td><td align="center" valign="top"> <p class="First">747</p> </td><td align="center" valign="top"> <p class="First">-22</p> </td><td align="center" valign="top"> <p class="First">114</p> </td><td align="center" valign="top"> <p class="First">-19</p> </td><td align="center" valign="top"> <p class="First">747</p> </td><td align="center" valign="top"> <p class="First">+3</p> </td> </tr> <tr> <td valign="top"> <p class="First">fluvastatin capsules 40 mg<span class="Italics"><span class="Sup">1 </span></span> </p> </td><td align="center" valign="top"> <p class="First">748</p> </td><td align="center" valign="top"> <p class="First">-19</p> </td><td align="center" valign="top"> <p class="First">748</p> </td><td align="center" valign="top"> <p class="First">-14</p> </td><td align="center" valign="top"> <p class="First">748</p> </td><td align="center" valign="top"> <p class="First">-25</p> </td><td align="center" valign="top"> <p class="First">125</p> </td><td align="center" valign="top"> <p class="First">-18</p> </td><td align="center" valign="top"> <p class="First">748</p> </td><td align="center" valign="top"> <p class="First">+4</p> </td> </tr> <tr> <td valign="top"> <p class="First">fluvastatin capsules 40 mg twice daily<span class="Italics"><span class="Sup">1 </span></span> </p> </td><td align="center" valign="top"> <p class="First">257</p> </td><td align="center" valign="top"> <p class="First">-27</p> </td><td align="center" valign="top"> <p class="First">257</p> </td><td align="center" valign="top"> <p class="First">-18</p> </td><td align="center" valign="top"> <p class="First">257</p> </td><td align="center" valign="top"> <p class="First">-36</p> </td><td align="center" valign="top"> <p class="First">232</p> </td><td align="center" valign="top"> <p class="First">-28</p> </td><td align="center" valign="top"> <p class="First">257</p> </td><td align="center" valign="top"> <p class="First">+6</p> </td> </tr> <tr> <td valign="top"> <p class="First">Baseline TG ≥ 200 mg/dL </p> <p>fluvastatin capsules 20 mg<span class="Italics"><span class="Sup">1 </span></span> </p> </td><td align="center" valign="top"> <p class="First">148</p> </td><td align="center" valign="top"> <p class="First">-16</p> </td><td align="center" valign="top"> <p class="First">148</p> </td><td align="center" valign="top"> <p class="First">-17</p> </td><td align="center" valign="top"> <p class="First">148</p> </td><td align="center" valign="top"> <p class="First">-22</p> </td><td align="center" valign="top"> <p class="First">23</p> </td><td align="center" valign="top"> <p class="First">-19</p> </td><td align="center" valign="top"> <p class="First">148</p> </td><td align="center" valign="top"> <p class="First">+6</p> </td> </tr> <tr> <td valign="top"> <p class="First">fluvastatin capsules 40 mg<span class="Italics"><span class="Sup">1 </span></span> </p> </td><td align="center" valign="top"> <p class="First">179 </p> </td><td align="center" valign="top"> <p class="First">-18</p> </td><td align="center" valign="top"> <p class="First">179</p> </td><td align="center" valign="top"> <p class="First">-20</p> </td><td align="center" valign="top"> <p class="First">179</p> </td><td align="center" valign="top"> <p class="First">-24</p> </td><td align="center" valign="top"> <p class="First">47</p> </td><td align="center" valign="top"> <p class="First">-18</p> </td><td align="center" valign="top"> <p class="First">179</p> </td><td align="center" valign="top"> <p class="First">+7</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">fluvastatin capsules 40 mg twice daily<span class="Italics"><span class="Sup">1 </span></span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">76 </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">-27</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">76</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">-23</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">76</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">-35</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">69</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">-28</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">76</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">+9</p> </td> </tr> </tbody> </table></div>

1. Data for fluvastatin capsules from 12 placebo-controlled trials

Fluvastatin capsules were studied in two open-label, uncontrolled, dose-titration studies. The first study enrolled 29 pre-pubertal boys, 9 to 12 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 b.i.d.) to achieve an LDL-C goal between 96.7 to 123.7 mg/dL. Endpoint analyses were performed at Year 2. Fluvastatin capsules 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 study 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 (fluvastatin sodium extended-release tablets, 80 mg) to achieve an LDL-C goal of < 130 mg/dL. Endpoint analyses were performed at Week 114. Fluvastatin sodium 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 studies (83% in the first study and 89% in the second study) were titrated to the maximum daily dose of 80 mg. At study endpoint, 26% to 30% of patients in both studies achieved a targeted LDL-C goal of < 130 mg/dL. The long-term efficacy of fluvastatin sodium therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

In the Fluvastatin Capsules Intervention Prevention Study, 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 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 study, patients were treated with dietary/lifestyle counseling and either fluvastatin capsules, 40 mg (n = 844) or placebo (n = 833) given twice daily for a median of 3.9 years. The study population was 84% male, 98% Caucasian, 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 vs. 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 Fluvastatin Capsules 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: Fluvastatin Capsules 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 capsules, 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, fluvasatin 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

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Fluvastatin Capsules, USP are available as follows:

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40 mg - Hard gelatin capsules with yellow opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates, cap imprinted with “TEVA” and body imprinted with “7443”, in bottles 100 (NDC: 63629-8737-1).

{ "type": "p", "children": [], "text": "40 mg - Hard gelatin capsules with yellow opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates, cap imprinted with “TEVA” and body imprinted with “7443”, in bottles 100 (NDC: 63629-8737-1)." }

Store and Dispense

{ "type": "p", "children": [], "text": "Store and Dispense" }

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]." }

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Protect from light.

{ "type": "p", "children": [], "text": "Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Protect from light." }

Repackaged/Relabeled by:

{ "type": "p", "children": [], "text": "Repackaged/Relabeled by:" }

Bryant Ranch Prepack, Inc.

{ "type": "p", "children": [], "text": "Bryant Ranch Prepack, Inc." }

Burbank, CA 91504

{ "type": "p", "children": [], "text": "Burbank, CA 91504" }

Patients starting therapy with fluvastatin capsules should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing fluvastatin.

It is recommended that liver enzyme tests be performed before the initiation of fluvastatin capsules and if signs or symptoms of liver injury occur. All patients treated with fluvastatin capsules should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using fluvastatin capsules. Discuss future pregnancy plans with your patients, and discuss when to stop taking fluvastatin capsules if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking fluvastatin capsules and call their healthcare professional.

Women who are breastfeeding should not use fluvastatin capsules. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional.

Manufactured In Israel By:

Teva Pharmaceutical Ind. Ltd.

Kfar Saba, 4410202, Israel

Manufactured For:

Teva Pharmaceuticals USA, Inc.

Parsippany, NJ 07054

Rev. I 8/2020

FDA-Approved Patient Labeling

{ "type": "p", "children": [], "text": "\nFDA-Approved Patient Labeling \n" }

Fluvastatin (floo'' va stat' in) Capsules

{ "type": "p", "children": [], "text": "\nFluvastatin (floo'' va stat' in) Capsules\n" }

20 mg, 40 mg

{ "type": "p", "children": [], "text": "\n20 mg, 40 mg\n" }

You must read and follow all instructions before using fluvastatin capsules.

{ "type": "p", "children": [], "text": "\nYou must read and follow all instructions before using fluvastatin capsules. \n" }

Read the Patient Information every time you or a family member gets fluvastatin capsules. There may be new information. This Patient Information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about fluvastatin capsules, ask your doctor or pharmacist.

{ "type": "p", "children": [], "text": "Read the Patient Information every time you or a family member gets fluvastatin capsules. There may be new information. This Patient Information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about fluvastatin capsules, ask your doctor or pharmacist." }

What are fluvastatin capsules?

{ "type": "p", "children": [], "text": "\nWhat are fluvastatin capsules? \n" }

Fluvastatin capsules are a prescription medicine called "statins" that lower cholesterol in your blood. They lower the "bad" cholesterol and triglycerides in your blood. They can raise your "good" cholesterol as well.

{ "type": "p", "children": [], "text": "Fluvastatin capsules are a prescription medicine called \"statins\" that lower cholesterol in your blood. They lower the \"bad\" cholesterol and triglycerides in your blood. They can raise your \"good\" cholesterol as well. " }

Fluvastatin capsules are for people whose cholesterol does not come down enough with exercise and a low-fat diet alone.

{ "type": "p", "children": [], "text": "Fluvastatin capsules are for people whose cholesterol does not come down enough with exercise and a low-fat diet alone. " }

Fluvastatin capsules may be used in patients with heart disease (coronary artery disease) to:

{ "type": "p", "children": [], "text": "Fluvastatin capsules may be used in patients with heart disease (coronary artery disease) to: " }

{ "type": "ul", "children": [ "lower the chances of heart problems which would require procedures to help restore blood flow to the heart. ", "slow the buildup of too much cholesterol in the arteries of the heart. " ], "text": "" }

Treatment with fluvastatin capsules has not been shown to prevent heart attacks or stroke.

{ "type": "p", "children": [], "text": "Treatment with fluvastatin capsules has not been shown to prevent heart attacks or stroke." }

Fluvastatin capsules are taken one or two times a day.

{ "type": "p", "children": [], "text": "Fluvastatin capsules are taken one or two times a day. " }

Who should not take fluvastatin capsules?

{ "type": "p", "children": [], "text": "\nWho should not take fluvastatin capsules? \n" }

Do not take fluvastatin capsules if you:

{ "type": "p", "children": [], "text": "\nDo not take fluvastatin capsules if you: \n" }

{ "type": "ul", "children": [ "are pregnant or think you may be pregnant, or are planning to become pregnant. Fluvastatin capsules may harm your unborn baby. If you get pregnant, stop taking fluvastatin capsules and call your doctor right away. ", "are breast-feeding. Fluvastatin sodium can pass into your breast milk and may harm your baby ", "have liver problems ", "are allergic to fluvastatin capsules or any of their ingredients. The active ingredient in fluvastatin capsules is fluvastatin. See the end of this leaflet for a complete list of ingredients in fluvastatin capsules. " ], "text": "" }

Fluvastatin capsules have not been studied in children under 9 years of age.

{ "type": "p", "children": [], "text": "Fluvastatin capsules have not been studied in children under 9 years of age. " }

Before taking fluvastatin capsules, tell your doctor if you:

{ "type": "p", "children": [], "text": "\nBefore taking fluvastatin capsules, tell your doctor if you: \n" }

{ "type": "ul", "children": [ "have muscle aches or weakness ", "drink more than 2 glasses of alcohol daily ", "have diabetes", "have a thyroid problem ", "have kidney problems " ], "text": "" }

Some medicines should not be taken with fluvastatin capsules. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Fluvastatin capsules and certain other medicines can interact causing serious side effects. Especially tell your doctor if you take medicines for:

{ "type": "p", "children": [], "text": "Some medicines should not be taken with fluvastatin capsules. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Fluvastatin capsules and certain other medicines can interact causing serious side effects. Especially tell your doctor if you take medicines for: " }

{ "type": "ul", "children": [ "your immune system", "cholesterol", "infections", "heart failure", "seizures", "diabetes", "heartburn or stomach ulcers" ], "text": "" }

Know all the medicines you take. Keep a list of all the medicines you take with you to show your doctor and pharmacist.

{ "type": "p", "children": [], "text": "Know all the medicines you take. Keep a list of all the medicines you take with you to show your doctor and pharmacist. " }

How should I take fluvastatin capsules?

{ "type": "p", "children": [], "text": "\nHow should I take fluvastatin capsules? \n" }

{ "type": "ul", "children": [ "Your doctor will prescribe the medicine that is right for you. Take fluvastatin capsules exactly as prescribed. Do not change your dose or stop fluvastatin capsules without talking to your doctor. Your doctor may do blood tests to check your cholesterol levels during treatment with fluvastatin capsules. Your dose of fluvastatin capsules may be changed based on these blood test results. ", "Take fluvastatin capsules at the same time every evening. When fluvastatin capsules are taken twice daily, the capsules may be taken once in the morning and once in the evening. Fluvastatin capsules can be taken with or without food. ", "Do not open fluvastatin capsules. ", "Your doctor should start you on a low-fat and low-cholesterol diet before giving you fluvastatin capsules. Stay on this low-fat and low-cholesterol diet while taking fluvastatin capsules. ", "If you miss a dose of fluvastatin capsules, take it as soon as you remember. Do not take fluvastatin capsules if it has been more than 12 hours since your last dose. Wait and take the next dose at your regular time. Do not take 2 doses of fluvastatin capsules at the same time. ", "If you take too many fluvastatin capsules or overdose, call your doctor or Poison Control Center right away. Or, go to the nearest emergency room. " ], "text": "" }

What should I avoid while taking fluvastatin capsules?

{ "type": "p", "children": [], "text": "\nWhat should I avoid while taking fluvastatin capsules? \n" }

{ "type": "ul", "children": [ "Talk to your doctor before you start any new medicines. This includes prescription and nonprescription medicines, vitamins and herbal supplements. Fluvastatin capsules and certain other medicines can interact causing serious side effects. ", "Do not get pregnant. If you get pregnant, stop taking fluvastatin capsules right away and call your doctor. " ], "text": "" }

What are the possible side effects of fluvastatin capsules?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of fluvastatin capsules? \n" }

When taking fluvastatin capsules, some patients may develop serious side effects, including:

{ "type": "p", "children": [], "text": "When taking fluvastatin capsules, some patients may develop serious side effects, including: " }

muscle problems. Call your health care professional right away if you experience unexplained muscle pain, tenderness, or weakness especially with fever. This may be an early sign of a rare muscle problem that could lead to serious kidney problems.

{ "type": "p", "children": [], "text": "\nmuscle problems. Call your health care professional right away if you experience unexplained muscle pain, tenderness, or weakness especially with fever. This may be an early sign of a rare muscle problem that could lead to serious kidney problems. " }

The risk of muscle problems is greater in people who are 65 years of age or older, or who already have thyroid or kidney problems. The chance of muscle problems may be increased if you are taking certain other medicines with fluvastatin capsules.

{ "type": "p", "children": [], "text": "The risk of muscle problems is greater in people who are 65 years of age or older, or who already have thyroid or kidney problems. The chance of muscle problems may be increased if you are taking certain other medicines with fluvastatin capsules. " }

If you have muscle problems that do not go away even after your health care professional has advised you to stop taking fluvastatin capsules, notify your health care professional. Your health care professional may do further tests to diagnose the cause of your muscle problems.

{ "type": "p", "children": [], "text": "If you have muscle problems that do not go away even after your health care professional has advised you to stop taking fluvastatin capsules, notify your health care professional. Your health care professional may do further tests to diagnose the cause of your muscle problems." }

liver problems. Your doctor should do blood tests to check your liver before you start taking fluvastatin capsules, and if you have symptoms of liver problems while you take fluvastatin capsules. Call your doctor right away if you have the following symptoms of liver problems:

{ "type": "p", "children": [], "text": "\nliver problems. Your doctor should do blood tests to check your liver before you start taking fluvastatin capsules, and if you have symptoms of liver problems while you take fluvastatin capsules. Call your doctor right away if you have the following symptoms of liver problems: " }

{ "type": "", "children": [], "text": "" }

The most common side effects of fluvastatin capsules are headache, upset stomach and stomach pain, diarrhea, flu-like symptoms, muscle pain, sinus infection, tiredness, or trouble sleeping. These side effects are usually mild and may go away. The following additional side effects have been reported with fluvastatin capsules: memory loss, and confusion.

{ "type": "p", "children": [], "text": "The most common side effects of fluvastatin capsules are headache, upset stomach and stomach pain, diarrhea, flu-like symptoms, muscle pain, sinus infection, tiredness, or trouble sleeping. These side effects are usually mild and may go away. The following additional side effects have been reported with fluvastatin capsules: memory loss, and confusion." }

Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away.

{ "type": "p", "children": [], "text": "Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away. " }

These are not all the side effects of fluvastatin capsules. Ask your doctor or pharmacist for a complete list.

{ "type": "p", "children": [], "text": "These are not all the side effects of fluvastatin capsules. Ask your doctor or pharmacist for a complete list. " }

How should I store fluvastatin capsules?

{ "type": "p", "children": [], "text": "\nHow should I store fluvastatin capsules? \n" }

{ "type": "", "children": [], "text": "" }

General information about fluvastatin capsules

{ "type": "p", "children": [], "text": "\nGeneral information about fluvastatin capsules \n" }

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use fluvastatin capsules for a condition for which they were not prescribed. Do not give fluvastatin capsules to other people, even if they have the same problem you have; they may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use fluvastatin capsules for a condition for which they were not prescribed. Do not give fluvastatin capsules to other people, even if they have the same problem you have; they may harm them. " }

For more information, call 1-888-838-2872.

{ "type": "p", "children": [], "text": "For more information, call 1-888-838-2872. " }

What are the ingredients in fluvastatin capsules?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in fluvastatin capsules? \n" }

Active Ingredient: fluvastatin sodium (hydrated form)

{ "type": "p", "children": [], "text": "\nActive Ingredient: fluvastatin sodium (hydrated form)" }

Inactive Ingredients: black iron oxide, colloidal silicon dioxide, crospovidone, gelatin, lactose monohydrate, magnesium stearate, propylene glycol, red iron oxide, shellac, titanium dioxide, and yellow iron oxide. The imprinting ink may contain potassium hydroxide.

{ "type": "p", "children": [], "text": "\nInactive Ingredients: black iron oxide, colloidal silicon dioxide, crospovidone, gelatin, lactose monohydrate, magnesium stearate, propylene glycol, red iron oxide, shellac, titanium dioxide, and yellow iron oxide. The imprinting ink may contain potassium hydroxide." }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

Manufactured In Israel By:

{ "type": "p", "children": [], "text": "Manufactured In Israel By:" }

Teva Pharmaceutical Ind. Ltd.

{ "type": "p", "children": [], "text": "\nTeva Pharmaceutical Ind. Ltd.\n" }

Kfar Saba, 4410202, Israel

{ "type": "p", "children": [], "text": "Kfar Saba, 4410202, Israel" }

Manufactured For:

{ "type": "p", "children": [], "text": "Manufactured For:" }

Teva Pharmaceuticals USA, Inc.

{ "type": "p", "children": [], "text": "\nTeva Pharmaceuticals USA, Inc.\n" }

Parsippany, NJ 07054

{ "type": "p", "children": [], "text": "Parsippany, NJ 07054" }

Rev. E 7/2020

{ "type": "p", "children": [], "text": " Rev. E 7/2020" }

Fluvastatin Sodium 40 mg Capsule #100

{ "type": "p", "children": [], "text": "Fluvastatin Sodium 40 mg Capsule #100" }

Fluvastatin sodium extended-release tablets are indicated:

{ "type": "p", "children": [], "text": "Fluvastatin sodium extended-release tablets are indicated: " }

{ "type": "", "children": [], "text": "" }

The recommended dosage for fluvastatin sodium extended-release tablets is 80 mg once daily.

Fluvastatin sodium extended-release tablets are 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 fluvastatin sodium extended-release tablets 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.

{ "type": "p", "children": [], "text": "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." }

Fluvastatin sodium extended-release tablets are contraindicated in patients with:

{ "type": "p", "children": [], "text": "Fluvastatin sodium extended-release tablets are contraindicated in patients with:" }

{ "type": "", "children": [], "text": "" }

Fluvastatin sodium extended-release tablets 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 fluvastatin sodium extended-release tablets .

Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CK, values to greater than 10 times the upper limit of normal (ULN) was < 0.1% in fluvastatin clinical trials [see Adverse Reactions (6.1)].

Risk Factors for Myopathy

Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs (including other lipid-lowering therapies) [see Drug Interactions (7.1)].

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

Avoid concomitant use of fluvastatin sodium extended-release tablets with gemfibrozil, cyclosporin, and fluconazole. When used concomitantly with fluvastatin sodium extended-release tablets, lipid modifying doses (≥ 1 g/day) of niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)].

Discontinue fluvastatin sodium extended-release tablets if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if fluvastatin sodium extended-release tablets are discontinued. Temporarily discontinue fluvastatin sodium extended-release tablets 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 fluvastatin sodium extended-release tablets. 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 fluvastatin sodium extended-release tablets if IMNM is suspected.

Increases in serum transaminases have been reported with use of fluvastatin sodium extended-release tablets [see Adverse Reactions (6.1)]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 1.1% of patients receiving fluvastatin in clinical trials. Marked persistent increases of hepatic transaminases have also occurred with fluvastatin. There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin sodium extended-release tablets.

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 fluvastatin sodium extended-release tablets initiation and thereafter, when clinically indicated. Fluvastatin sodium extended-release tablets are 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 fluvastatin sodium extended-release tablets.

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including fluvastatin sodium extended-release tablets. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

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 fluvastatin sodium extended-release tablets clinical trials there were 912 patients treated with fluvastatin sodium extended-release tablets (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 fluvastatin sodium extended-release tablets controlled trials with a frequency ≥ 2% included the following:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1. Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/ Fluvastatin Sodium Extended-Release Tablets and at an Incidence Greater Than Placebo in Placebo-Controlled Trials Pooled Dosages</span> </caption> <col width="30%"/> <col width="20%"/> <col width="25%"/> <col width="25%"/> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Adverse reaction</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Placebo<span class="Sup">a</span></span> </p> <p> <span class="Bold">N = 960</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Fluvastatin capsules<span class="Sup">a</span></span> </p> <p> <span class="Bold">N = 2326</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Fluvastatin sodium extended-release tablets<span class="Sup">b</span></span> </p> <p> <span class="Bold">N = 912</span> </p> <p> <span class="Bold">(%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Influenza-like symptoms</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5.7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5.1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Myalgia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3.8</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Abdominal pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Dyspepsia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Sinusitis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Arthropathy</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NA</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Urinary tract infection</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Bronchitis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Fatigue</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Flatulence</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Arthritis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Allergy</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.8</p> </td> </tr> <tr class="Botrule Last"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"> <p class="First"> <span class="Sup">a</span>Controlled trials with fluvastatin capsules (20 mg and 40 mg daily and 40 mg twice daily) compared to placebo.</p> <p> <span class="Sup">b</span>Controlled trials with fluvastatin sodium extended-release 80 mg tablets as compared to fluvastatin capsules.</p> </td> </tr> </tbody> </table></div>

In the Fluvastatin Capsules Intervention Prevention Study (LIPS), the effect of fluvastatin capsules 40 mg, administered twice daily on the risk of recurrent cardiac events was assessed in 1677 patients with coronary heart disease who had undergone a percutaneous coronary intervention. This was a multicenter, randomized, double-blind, placebo-controlled trial, patients were treated with dietary/lifestyle counseling and either fluvastatin capsules 40 mg (n = 844) or placebo (n = 833) given twice daily for a median of 3.9 years [see Clinical Studies (14.3)]. Table 2. Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/ Fluvastatin Sodium Extended-Release Tablets and at an Incidence Greater Than Placebo in the LIPS Trial

<div class="scrollingtable"><table width="90.84%"> <caption> <span>Table 2. Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/ Fluvastatin Sodium Extended-Release Tablets and at an Incidence Greater Than Placebo in the LIPS Trial</span> </caption> <col width="33%"/> <col width="41%"/> <col width="26%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Adverse reaction</span></th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Placebo<br/>N = 818 (%)</span></th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Fluvastatin Capsules<br/>40 mg twice daily</span> <br/> <span class="Bold">N = 822 (%)</span></th> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" valign="top">Abdominal pain upper</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">4.5</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">6.3</th> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" valign="top">Hypertension</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">4.2</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">5.8</th> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" valign="top">Fatigue</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">3.8</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">4.7</th> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" valign="top">Dyspepsia</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">4.0</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">4.5</th> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" valign="top">Edema peripheral</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">2.9</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">4.4</th> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" valign="top">Pain in extremity</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">2.7</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">4.1</th> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" valign="top">Dizziness</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">3.5</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">3.9</th> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" valign="top">Constipation</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">2.1</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">3.3</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" valign="top">Nasopharyngitis</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">2.1</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">2.8</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dyspnea exertional</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.8</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Gastric disorder</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Atrial fibrillation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Syncope</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Bronchitis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Intermittent claudication</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Myalgia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.2</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Arthralgia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.1</p> </td> </tr> </tbody> </table></div>

Elevations in Liver Enzyme Tests

Approximately 1.1% of patients treated with fluvastatin capsules in clinical trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the ULN. Fourteen of these patients (0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase elevations with an average fluvastatin exposure of approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The majority of patients with these abnormal biochemical findings were asymptomatic.

In a pooled analysis of all placebo-controlled studies in which fluvastatin 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 fluvastatin sodium extended-release tablets 80 mg, fluvastatin capsules 40 mg and fluvastatin capsules 40 mg twice daily, respectively. In 13 of 16 patients treated with fluvastatin sodium extended-release tablets the abnormality occurred within 12 weeks of initiation of treatment with fluvastatin sodium extended-release tablets 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 (5.2)].

Neurological: Dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, vertigo, paresthesia, hypoesthesia, dysesthesia, peripheral neuropathy, peripheral nerve palsy. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered.

Psychiatric: Anxiety, depression, psychic disturbances

Respiratory: Interstitial lung disease

Hypersensitivity reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR (erythrocyte sedimentation rate) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity reaction, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

Gastrointestinal: Pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty 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 (5.1), Clinical Pharmacology (12.3)].

Table 3. Drug Interactions That Increase the Risk of Myopathy and Rhabdomyolysis with Fluvastatin Sodium Extended-Release Tablets

<div class="scrollingtable"><table width="518.65pt"> <col width="22%"/> <col width="78%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Gemfibrozil</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Clinical impact</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">There is an increased risk of myopathy/rhabdomyolysis when fluvastatin sodium extended-release tablets are administered with gemfibrozil</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Intervention</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Avoid concomitant use of gemfibrozil with fluvastatin sodium extended-release tablets.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Cyclosporine</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Clinical impact</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd>Cyclosporine coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of cyclosporine with fluvastatin sodium extended-release tablets. </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Intervention</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Avoid concomitant use of cyclosporine with fluvastatin sodium extended-release tablets.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Fluconazole</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Clinical impact</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd>Fluconazole coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of fluconazole with fluvastatin sodium extended-release tablets. </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Intervention</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Avoid concomitant use of fluconazole with fluvastatin sodium extended-release tablets. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Niacin </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Clinical impact</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Risk of myopathy and rhabdomyolysis may be enhanced with concomitant use with lipid-modifying doses (≥ 1 g/day) of niacin with fluvastatin sodium extended-release tablets. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Intervention</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Consider if the benefit of using lipid-modifying doses (≥ 1 g/day) of niacin concomitantly with fluvastatin sodium extended-release tablets 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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Fibrates</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Clinical impact</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of fibrates with fluvastatin sodium extended-release tablets. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Intervention</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Consider if the benefit of using fibrates concomitantly with fluvastatin sodium extended-release tablets 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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Colchicine</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Clinical impact</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with fluvastatin.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Intervention</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Consider if the benefit of using colchicine concomitantly with fluvastatin sodium extended-release tablets 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.</p> </td> </tr> </tbody> </table></div>

Table 4 presents fluvastatin sodium extended-release tablets’ effects on other drugs and instructions for preventing or managing them.

Table 4. Fluvastatin Sodium Extended-Release Tablets’ Effects on Other Drugs

<div class="scrollingtable"><table width="513pt"> <col width="21%"/> <col width="79%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Warfarin </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Clinical impact</p> </td><td align="justify" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">There are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins and warfarin. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Intervention</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">In patients taking warfarin, obtain an INR before starting fluvastatin sodium extended-release tablets 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. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Glyburide</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Clinical impact</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Concomitant administration of fluvastatin and glyburide increased glyburide exposures <span class="Italics">[see Clinical Pharmacology (<a href="#s12p3">12.3</a>)]</span>.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Intervention</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Monitor blood glucose levels when fluvastatin sodium extended-release tablets are initiated.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Phenytoin</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Clinical impact</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures <span class="Italics">[see Clinical Pharmacology (<a href="#s12p3">12.3</a>)]</span>.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Intervention</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Monitor plasma phenytoin levels when fluvastatin sodium extended-release tablets are initiated.</p> </td> </tr> </tbody> </table></div>

Risk Summary

Discontinue fluvastatin sodium extended-release tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Fluvastatin sodium extended-release tablets decrease synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, fluvastatin sodium extended-release tablets 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 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 fluvastatin sodium extended-release tablets’ 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.

Data

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.

Risk Summary

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 fluvastatin sodium extended-release tablets, 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 fluvastatin sodium extended-release tablets [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].

Data

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 fluvastatin sodium extended-release tablets 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 fluvastatin sodium extended-release tablets 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 fluvastatin sodium extended-release tablets 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 (12.3)].

Advanced age (≥ 65 years) is a risk factor for fluvastatin sodium extended-release tablets -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 fluvastatin sodium extended-release tablets for the increased risk of myopathy [see Warnings and Precautions (5.1)].

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 fluvastatin sodium extended-release tablets 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)].

Fluvastatin sodium extended-release tablets are contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4), Warnings and Precautions (5.3)].

No specific antidotes for fluvastatin sodium extended-release tablets are known. In the event of an overdose of fluvastatin sodium extended-release tablets, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

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Fluvastatin sodium inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.

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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 g/mol and its structural formula is:

{ "type": "p", "children": [], "text": "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 g/mol and its structural formula is:" }

Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. Fluvastatin sodium is supplied as extended-release tablets containing 84.24 mg of fluvastatin sodium, equivalent to 80 mg of fluvastatin, for oral use. Fluvastatin sodium extended-release tablets contain the following inactive ingredients: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 8000, potassium bicarbonate, povidone, titanium dioxide, and yellow iron oxide.

{ "type": "p", "children": [], "text": "Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. Fluvastatin sodium is supplied as extended-release tablets containing 84.24 mg of fluvastatin sodium, equivalent to 80 mg of fluvastatin, for oral use. Fluvastatin sodium extended-release tablets contain the following inactive ingredients: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 8000, potassium bicarbonate, povidone, titanium dioxide, and yellow iron oxide." }

Fluvastatin is a competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methylglutaryl-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 fluvastatin sodium extended-release tablets is usually achieved by 4 weeks and is maintained after that.

Absorption

Fluvastatin administered as fluvastatin sodium extended-release 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 extended-release 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 extended-release tablet by approximately 50%. However, the maximum concentration of fluvastatin sodium extended-release tablet 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.

Distribution

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.

Elimination

Metabolism

Fluvastatin 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 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.

Specific Populations

Geriatric Patients

Plasma levels of fluvastatin are not significantly different in patients age > 65 years compared to patients age 21 to 49 years.

Gender

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 fluvastatin sodium extended-release tablets, the AUC increases 67% and 77% for women compared to men under fasted and high- fat meal fed conditions, respectively.

Pediatric Patients

Pharmacokinetic data in the pediatric population are not available.

Patients with Renal Impairment

In patients with moderate to severe renal impairment (CLCr 10-40 mL/min), AUC and Cmax increased approximately 1.2-fold 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. Fluvastatin sodium extended-release tablets were not evaluated in patients with renal impairment [see Use in Specific Populations (8.6)]. However, systemic exposures after administration of fluvastatin sodium extended-release tablets are lower than after the 40 mg immediate release capsule.

Patients with Hepatic Impairment

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 (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 Studies

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 fluvastatin sodium extended-release tablet.

Table 5. Effect of Coadministered Drugs on Fluvastatin Systemic Exposure

<div class="scrollingtable"><table width="100%"> <col width="54%"/> <col width="19%"/> <col width="14%"/> <col width="14%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Coadministered drug and dosing regimen</span> </p> </td><td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Fluvastatin</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Dose (mg)<span class="Sup">a</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Change in AUC<span class="Sup">b</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Change in C<span class="Sub">max</span><span class="Sup">b</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cyclosporine – stable dose (twice daily)<span class="Bold"><span class="Sup">c</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20 mg once daily for 14 weeks</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑90%</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑30% </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fluconazole 400 mg once daily</p> <p>1,200 mg twice daily 2 to 4<span class="Bold"><span class="Sup">c</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">40 mg once daily </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑84%</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑44% </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cholestyramine 8 g once daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20 mg once daily administered 4 hrs after a meal plus cholestyramine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓51%</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓83% </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rifampicin 600 mg once daily for 6 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20 mg once daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓53% </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓42% </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cimetidine 400 mg twice daily for 5 days, once daily on Day 6</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20 mg once daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑30%</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑40% </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Ranitidine 150 mg twice daily for 5 days, once daily on Day 6</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20 mg once daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑10%</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑50% </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Omeprazole 40 mg once daily for 6 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20 mg once daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑20%</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑37%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Phenytoin 300 mg once daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">40 mg twice daily for 5 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑40%</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑27%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Propranolol 40 mg twice daily for 3.5 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">40 mg once daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓5%</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">No change</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Digoxin 0.1 to 0.5 mg once daily for 3 weeks</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">40 mg once daily </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">No change</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑11% </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diclofenac 25 mg once daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">40 mg once daily for 8 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑50%</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑80%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Glyburide 5 mg to 20 mg once daily for 22 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">40 mg twice daily for 14 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑51% </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑44% </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Warfarin 30 mg once daily</p> <p>Clopidogrel 300 mg loading dose on Day 10, 75 mg once daily on Days 11 to 19</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">40 mg once daily for 8 days </p> <p>80 mg extended-release once daily for 19 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑30%</p> <p>↓2%</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑67%</p> <p>↑27%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"> <p class="First">Abbreviation: AUC, area under the curve.</p> <p> <span class="Sup">a</span>Single dose unless otherwise noted.</p> <p> <span class="Sup">b</span>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. </p> <p> <span class="Sup">c</span>Considered clinically significant <span class="Italics">[see Dosage and Administration (2.4), Drug Interactions (7.1)].</span> </p> </td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 6. Effect of Fluvastatin Coadministration on Systemic Exposure of Other Drugs</span> </caption> <col width="52%"/> <col width="19%"/> <col width="14%"/> <col width="14%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Coadministered drug</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Fluvastatin dosage regimen</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Name and dose (mg)<span class="Sup">a</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Change in AUC<span class="Sup">b</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Change in C<span class="Sub">max</span><span class="Sup">b</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">40 mg once daily for 5 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Phenytoin 300 mg once daily<span class="Sup">c</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑20%<span class="Sup"></span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑5%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">40 mg twice daily for 21 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Glyburide 5 to 20 mg once daily for 22 days<span class="Sup">c</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑70%</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑50% </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">40 mg once daily for 8 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Diclofenac 25 mg once daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑25%</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑60%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">40 mg once daily for 8 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Warfarin 30 mg once daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">S-warfarin: ↑7% </p> <p>R-warfarin: no change</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">S-warfarin: ↑10%</p> <p>R-warfarin: ↑6%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"> <p class="First">Abbreviation: AUC, area under the curve.</p> <p> <span class="Sup">a</span>Single dose unless otherwise noted.</p> <p> <span class="Sup">b</span>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. </p> <p> <span class="Sup">c</span>Considered clinically significant <span class="Italics">[see Drug Interactions (7.2)]</span>.</p> </td> </tr> </tbody> </table></div>

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.

Secondary Prevention of Cardiovascular Disease

{ "type": "p", "children": [], "text": "\nSecondary Prevention of Cardiovascular Disease \n" }

In the Fluvastatin Capsules 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.

{ "type": "p", "children": [], "text": "In the Fluvastatin Capsules 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.

{ "type": "p", "children": [], "text": "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)

{ "type": "p", "children": [], "text": "\nFigure 1. Primary Endpoint – Recurrent Cardiac Events (Cardiac Death, Nonfatal MI or Revascularization Procedure) (ITT Population)\n" }

Outcome data for the Fluvastatin Capsules 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).

{ "type": "p", "children": [], "text": "Outcome data for the Fluvastatin Capsules 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. Fluvastatin Capsules Intervention Prevention Study–- Primary and Secondary Endpoints

{ "type": "p", "children": [], "text": "\nFigure 2. Fluvastatin Capsules Intervention Prevention Study–- Primary and Secondary Endpoints\n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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)

{ "type": "p", "children": [], "text": "\nFigure 3. Change in Minimum Lumen Diameter (mm)\n" }

Figure 4. Change in % Diameter Stenosis

{ "type": "p", "children": [], "text": "\nFigure 4. Change in % Diameter Stenosis\n" }

Primary Hyperlipidemia in Adults

{ "type": "p", "children": [], "text": "\nPrimary Hyperlipidemia in Adults \n" }

Fluvastatin sodium extended-release tablets have been studied in five controlled trials of adult patients with primary hyperlipidemia and mixed dyslipidemia. Fluvastatin sodium extended-release tablets were administered to over 900 patients in trials from 4 to 26 weeks in duration. In the three largest of these trials, fluvastatin sodium extended-release tablets given as a single daily dose of 80 mg significantly reduced Total-C, LDL-C, TG, and Apo B (Table 5).

{ "type": "p", "children": [], "text": "Fluvastatin sodium extended-release tablets have been studied in five controlled trials of adult patients with primary hyperlipidemia and mixed dyslipidemia. Fluvastatin sodium extended-release tablets were administered to over 900 patients in trials from 4 to 26 weeks in duration. In the three largest of these trials, fluvastatin sodium extended-release tablets 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 fluvastatin sodium extended-release tablets produced significant decreases in Total-C, LDL-C, TG, and Apo B (see Table 7).

{ "type": "p", "children": [], "text": "In patients with primary mixed dyslipidemia as defined by baseline plasma TG levels ≥ 200 mg/dL and < 400 mg/dL, treatment with fluvastatin sodium extended-release tablets 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 (Fluvastatin Sodium Extended-Release Tablets)

{ "type": "p", "children": [], "text": "\nTable 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 (Fluvastatin Sodium Extended-Release Tablets)\n" }

<div class="scrollingtable"><table width="537.25pt"> <col width="29%"/> <col width="8%"/> <col width="9%"/> <col width="7%"/> <col width="6%"/> <col width="7%"/> <col width="8%"/> <col width="8%"/> <col width="6%"/> <col width="7%"/> <col width="6%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Total Chol</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">TG</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">LDL</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Apo B</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">HDL</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Dose</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">%∆</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">%∆</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">%∆</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">%∆</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">%∆</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">All Patients</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Fluvastatin sodium extended-release tablets 80 mg<span class="Sup">a</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">750</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">-25</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">750</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">-19</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">748</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">-35</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">745</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">-27</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">750</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">+7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Baseline TG ≥ 200 mg/dL</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Fluvastatin sodium extended-release tablets 80 mg<span class="Sup">a</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">239</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">-25</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">239</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">-25</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">237</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">-33</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">235</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">-27</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">239</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">+11</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="11" valign="top"> <p class="First"> <span class="Sup">a</span>Data for fluvastatin sodium extended-release 80 mg tablet from three 24- week controlled trials.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"537.25pt\">\n<col width=\"29%\"/>\n<col width=\"8%\"/>\n<col width=\"9%\"/>\n<col width=\"7%\"/>\n<col width=\"6%\"/>\n<col width=\"7%\"/>\n<col width=\"8%\"/>\n<col width=\"8%\"/>\n<col width=\"6%\"/>\n<col width=\"7%\"/>\n<col width=\"6%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Total Chol</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">TG</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">LDL</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Apo B</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">HDL</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Dose</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">N</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">%∆</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">N</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">%∆</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">N</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">%∆</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">N</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">%∆</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">N</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">%∆</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">All Patients</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Fluvastatin sodium extended-release tablets 80 mg<span class=\"Sup\">a</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">750</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">-25</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">750</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">-19</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">748</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">-35</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">745</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">-27</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">750</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">+7</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Baseline TG ≥ 200 mg/dL</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Fluvastatin sodium extended-release tablets 80 mg<span class=\"Sup\">a</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">239</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">-25</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">239</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">-25</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">237</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">-33</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">235</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">-27</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">239</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">+11</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"11\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Sup\">a</span>Data for fluvastatin sodium extended-release 80 mg tablet from three 24- week controlled trials.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

HeFH in Pediatric Patients Aged 10 Years and Older

{ "type": "p", "children": [], "text": "\nHeFH in Pediatric Patients Aged 10 Years and Older \n" }

Fluvastatin capsules were studied in two open-label, uncontrolled, dose-titration trials. The first trial enrolled 29 pre-pubertal 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).

{ "type": "p", "children": [], "text": "Fluvastatin capsules were studied in two open-label, uncontrolled, dose-titration trials. The first trial enrolled 29 pre-pubertal 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 (fluvastatin sodium extended-release 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).

{ "type": "p", "children": [], "text": "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 (fluvastatin sodium extended-release 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.

{ "type": "p", "children": [], "text": "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." }

How Supplied

{ "type": "p", "children": [], "text": "\nHow Supplied\n" }

Fluvastatin sodium extended-release tablets supplied as:

{ "type": "p", "children": [], "text": "Fluvastatin sodium extended-release tablets supplied as:" }

<div class="scrollingtable"><table width="466.6pt"> <col width="23%"/> <col width="21%"/> <col width="22%"/> <col width="33%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Strength</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">How supplied </span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NDC</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Tablet description</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">80 mg of fluvastatin</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">bottles of 30</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0781-8017-31</p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">Yellow, round, slightly biconvex film-coated tablet with beveled edges debossed with “LESCOL XL” on one side and “80” on the other</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">bottles of 100</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0781-8017-01</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"466.6pt\">\n<col width=\"23%\"/>\n<col width=\"21%\"/>\n<col width=\"22%\"/>\n<col width=\"33%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Strength</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How supplied </span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NDC</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Tablet description</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" rowspan=\"2\" valign=\"top\">\n<p class=\"First\">80 mg of fluvastatin</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">bottles of 30</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0781-8017-31</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\" valign=\"top\">\n<p class=\"First\">Yellow, round, slightly biconvex film-coated tablet with beveled edges debossed with “LESCOL XL” on one side and “80” on the other</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">bottles of 100</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0781-8017-01</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Store and Dispense

{ "type": "p", "children": [], "text": "\nStore and Dispense\n" }

Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted between 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Dispense in a tight container. Protect from light.

{ "type": "p", "children": [], "text": "Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted between 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Dispense in a tight container. Protect from light." }

Advise the patient to read the FDA-approved patient labeling (Patient Information).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information)." }

Myopathy and Rhabdomyolysis

{ "type": "p", "children": [], "text": "\nMyopathy and Rhabdomyolysis\n" }

Advise patients that fluvastatin sodium extended-release tablets 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 (5.1), Drug Interactions (7.1)].

{ "type": "p", "children": [], "text": "Advise patients that fluvastatin sodium extended-release tablets 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 (5.1), Drug Interactions (7.1)]. " }

Hepatic Dysfunction

{ "type": "p", "children": [], "text": "\nHepatic Dysfunction\n" }

Inform patients that fluvastatin sodium extended-release tablets 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 (5.3)].

{ "type": "p", "children": [], "text": "Inform patients that fluvastatin sodium extended-release tablets 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 (5.3)]." }

Increases in HbA1c and Fasting Serum Glucose Levels

{ "type": "p", "children": [], "text": "\nIncreases in HbA1c and Fasting Serum Glucose Levels\n" }

Inform patients that increases in HbA1c and fasting serum glucose levels may occur with fluvastatin sodium extended-release tablets. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Inform patients that increases in HbA1c and fasting serum glucose levels may occur with fluvastatin sodium extended-release tablets. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)]." }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy\n" }

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 fluvastatin sodium extended-release tablets should be discontinued [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "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 fluvastatin sodium extended-release tablets should be discontinued [see Use in Specific Populations (8.1)]." }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise patients that breastfeeding is not recommended during treatment with fluvastatin sodium extended-release tablets [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise patients that breastfeeding is not recommended during treatment with fluvastatin sodium extended-release tablets [see Use in Specific Populations (8.2)]." }

Mfd. by: Pfizer Ireland Pharmaceuticals

{ "type": "p", "children": [], "text": "Mfd. by: Pfizer Ireland Pharmaceuticals" }

Newbridge, Ireland for

{ "type": "p", "children": [], "text": "Newbridge, Ireland for" }

Sandoz Inc., Princeton, NJ 08540

{ "type": "p", "children": [], "text": "Sandoz Inc., Princeton, NJ 08540" }

<div class="scrollingtable"><table width="100%"> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Fluvastatin (floo-vah-STA-tin )</span> </p> <p> <span class="Bold">Sodium Extended-Release Tablets, USP</span> </p> <p> <span class="Bold">for oral use</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">You must read and follow all instructions before using fluvastatin sodium extended-release tablets.</span> </p> <p>Read this Patient Information before you start taking fluvastatin sodium extended-release tablets 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 fluvastatin sodium extended-release tablets, ask your doctor or pharmacist. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What are fluvastatin sodium extended-release tablets?</span> </p> <p>Fluvastatin sodium extended-release tablets are a prescription medicine “that contains the cholesterol lowering medicine, fluvastatin.”</p> <p>Fluvastatin sodium extended-release tablets are used in adults with heart disease (coronary artery disease) to:</p> <dl> <dt>•</dt> <dd>lower the need for heart and blood vessel procedures to improve flow to the heart, called coronary revascularization.</dd> <dt>•</dt> <dd>slow the buildup of too much cholesterol in the arteries of the heart.</dd> </dl> <p>Fluvastatin sodium extended-release tablets are used along with diet to lower the level of:</p> <dl> <dt>•</dt> <dd>low-density lipoprotein cholesterol (LDL-C) or “bad” cholesterol in adults with hyperlipidemia (high levels of fat in the blood)</dd> <dt>•</dt> <dd>LDL-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.</dd> </dl> <p>The safety and effectiveness of fluvastatin sodium extended-release tablets have 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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Do not take fluvastatin sodium extended-release tablets if you:</span> </p> <dl> <dt>•</dt> <dd>have liver problems (acute liver failure or decompensated cirrhosis)</dd> <dt>•</dt> <dd>are allergic to fluvastatin or any of the ingredients in fluvastatin sodium extended-release tablets. See the end of this Patient Information leaflet for a complete list of ingredients in fluvastatin sodium extended-release tablets.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Before you take fluvastatin sodium extended-release tablets, tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <dl> <dt>•</dt> <dd>have muscle aches or weakness</dd> <dt>•</dt> <dd>drink more than 2 glasses of alcohol daily</dd> <dt>•</dt> <dd>have diabetes</dd> <dt>•</dt> <dd>have a thyroid problem</dd> <dt>•</dt> <dd>have kidney problems</dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. If you become pregnant while taking fluvastatin sodium extended-release tablets, stop taking fluvastatin sodium extended-release tablets and call your healthcare provider.</dd> <dt>•</dt> <dd>are breastfeeding or plan to breastfeed. It is not known if fluvastatin sodium passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take fluvastatin sodium extended-release tablets. You should not breastfeed while taking fluvastatin sodium extended-release tablets.</dd> </dl> <p> <span class="Bold">Tell your healthcare provider about all the medicines you take,</span> 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 fluvastatin sodium extended-release tablets if another healthcare provider increases the dose of another medicine you are taking.</p> <p>Fluvastatin sodium extended-release tablets may affect the way other medicines work, and other medicines may affect how fluvastatin sodium extended-release tablets work. Especially tell your healthcare provider if you take:</p> <dl> <dt>•</dt> <dd>warfarin (a medicine used to reduce blood clotting)</dd> <dt>•</dt> <dd>glyburide (a medicine used to treat diabetes)</dd> <dt>•</dt> <dd>phenytoin (a medicine used to treat epilepsy)</dd> </dl> <p>Taking fluvastatin sodium extended-release tablets with certain medicines can also increase the risk of muscle problems. Especially tell your healthcare provider if you take: </p> <dl> <dt>•</dt> <dd>gemfibrozil (a medicine used to lower triglycerides)</dd> <dt>•</dt> <dd>cyclosporine (a medicine used to suppress the immune system)</dd> <dt>•</dt> <dd>fluconazole (a medicine used to treat fungal infections)</dd> <dt>•</dt> <dd>fibrates or niacin </dd> <dt>•</dt> <dd>colchicine </dd> </dl> <p>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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I take fluvastatin sodium extended-release tablets?</span> </p> <dl> <dt>•</dt> <dd>Take fluvastatin sodium extended-release tablets exactly as your healthcare provides tells you to take it.</dd> <dt>•</dt> <dd> <span class="Bold">Do not</span> change your dose or stop taking fluvastatin sodium extended-release tablets without talking to your healthcare provider.</dd> <dt>•</dt> <dd>Take fluvastatin sodium extended-release tablets 1 time each day, at any time of the day. Fluvastatin sodium extended-release tablets can be taken with or without food.</dd> <dt>•</dt> <dd>Fluvastatin sodium extended-release tablets must be swallowed whole with a liquid. Do not break, crush or chew fluvastatin sodium extended-release tablets. Tell your healthcare provider if you cannot swallow tablets whole. You may need fluvastatin capsules or a different medicine instead of fluvastatin sodium extended-release tablets. </dd> <dt>•</dt> <dd>While taking fluvastatin sodium extended-release tablets, continue to follow your cholesterol-lowing diet and exercise as your healthcare provider told you to. </dd> <dt>•</dt> <dd>In case of overdose, get medical help or contact a Poison Center expert right away at 1-800-222-1222. Advice is also available online at poisonhelp.org.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of fluvastatin sodium extended-release tablets?</span> </p> <p> <span class="Bold">Fluvastatin sodium extended-release tablets may cause serious side effects, including:</span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">Muscle pain, tenderness, and weakness (myopathy).</span> Muscle problems, including muscle breakdown, can be serious in some people and rarely cause kidney damage that can lead to death.</dd> </dl> <p> <span class="Bold">Tell your healthcare provider right away if you have: </span> </p> <dl> <dt>•</dt> <dd>unexplained muscle pain, tenderness, or weakness, especially if you have a fever or feel more tired than usual, while you take fluvastatin sodium extended-release tablets.</dd> <dt>•</dt> <dd>muscle problems that do not go away even after your healthcare provider has advised you to stop taking fluvastatin sodium extended-release tablets. 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:</dd> <dt>o</dt> <dd>are taking certain other medicines while you take fluvastatin sodium extended-release tablets</dd> <dt>o</dt> <dd>are 65 years of age or older</dd> <dt>o</dt> <dd>have thyroid problems (hypothyroidism) that are not controlled</dd> <dt>o</dt> <dd>have kidney problems</dd> <dt>•</dt> <dd> <span class="Bold">Liver problems.</span> Your healthcare provider should do blood tests to check your liver before you start taking fluvastatin sodium extended-release tablets, and if you have symptoms of liver problems while you take fluvastatin sodium extended-release tablets. Call your healthcare provider right away if you have the following symptoms of liver problems:</dd> <dt>o</dt> <dd>feel tired or weak</dd> <dt>o</dt> <dd>loss of appetite</dd> <dt>o</dt> <dd>right sided upper belly pain</dd> <dt>o</dt> <dd>dark amber colored urine</dd> <dt>o</dt> <dd>yellowing of your skin or the whites of your eye</dd> <dt>•</dt> <dd> <span class="Bold">Increase in blood sugar (glucose) levels.</span> Fluvastatin sodium extended-release tablets may cause an increase in your blood sugar levels.</dd> </dl> <p> <span class="Bold">The most common side effects of fluvastatin sodium extended-release tablets include:</span> </p> <dl> <dt>•</dt> <dd>flu-like symptoms </dd> <dt>•</dt> <dd>sinus infection </dd> <dt>•</dt> <dd>upset stomach and stomach pain </dd> <dt>•</dt> <dd>urinary tract infections</dd> <dt>•</dt> <dd>bronchitis</dd> <dt>•</dt> <dd>nausea</dd> </dl> <p>These side effects are usually mild and may go away. The following additional side effects have been reported with fluvastatin sodium extended-release tablets:</p> <dl> <dt>•</dt> <dd>memory loss and confusion</dd> </dl> <p>Talk to your healthcare provider or pharmacist if you have side effects that bother you or does not go away.</p> <p>These are not all the possible side effects of fluvastatin sodium extended-release tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I store fluvastatin sodium extended-release tablets?</span> </p> <dl> <dt>•</dt> <dd>Store fluvastatin sodium extended-release tablets at room temperature 68°F to 77°F (20°C to 25°C). <span class="Bold">Protect from light.</span> </dd> <dt>•</dt> <dd> <span class="Bold">Keep fluvastatin sodium extended-release tablets out of the reach of children.</span> Be sure that if you throw medicines away, it is out of the reach of children.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General information about safe and effective use of fluvastatin sodium extended-release tablets.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use fluvastatin sodium extended-release tablets for a condition for which it was not prescribed. Do not give fluvastatin sodium extended-release tablets to other people, even if they have the same medical condition you have; it may harm them.</p> <p>You can ask your pharmacist or healthcare provider for information about fluvastatin sodium extended-release tablets that is written for health professionals.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in fluvastatin sodium extended-release tablets?</span> </p> <p>Active Ingredient: fluvastatin </p> <p>Inactive Ingredients: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 8000, potassium bicarbonate, povidone, titanium dioxide, and yellow iron oxide.</p> <p>For more information go to www.sandoz.com or call 1-800-525-8747.</p> <p>Mfd. by: Pfizer Ireland Pharmaceuticals</p> <p>Newbridge, Ireland for</p> <p>Sandoz Inc., Princeton, NJ 08540</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Fluvastatin (floo-vah-STA-tin )</span>\n</p>\n<p>\n<span class=\"Bold\">Sodium Extended-Release Tablets, USP</span>\n</p>\n<p>\n<span class=\"Bold\">for oral use</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">You must read and follow all instructions before using fluvastatin sodium extended-release tablets.</span>\n</p>\n<p>Read this Patient Information before you start taking fluvastatin sodium extended-release tablets 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 fluvastatin sodium extended-release tablets, ask your doctor or pharmacist. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are fluvastatin sodium extended-release tablets?</span>\n</p>\n<p>Fluvastatin sodium extended-release tablets are a prescription medicine “that contains the cholesterol lowering medicine, fluvastatin.”</p>\n<p>Fluvastatin sodium extended-release tablets are used in adults with heart disease (coronary artery disease) to:</p>\n<dl>\n<dt>•</dt>\n<dd>lower the need for heart and blood vessel procedures to improve flow to the heart, called coronary revascularization.</dd>\n<dt>•</dt>\n<dd>slow the buildup of too much cholesterol in the arteries of the heart.</dd>\n</dl>\n<p>Fluvastatin sodium extended-release tablets are used along with diet to lower the level of:</p>\n<dl>\n<dt>•</dt>\n<dd>low-density lipoprotein cholesterol (LDL-C) or “bad” cholesterol in adults with hyperlipidemia (high levels of fat in the blood)</dd>\n<dt>•</dt>\n<dd>LDL-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.</dd>\n</dl>\n<p>The safety and effectiveness of fluvastatin sodium extended-release tablets have 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.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Do not take fluvastatin sodium extended-release tablets if you:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>have liver problems (acute liver failure or decompensated cirrhosis)</dd>\n<dt>•</dt>\n<dd>are allergic to fluvastatin or any of the ingredients in fluvastatin sodium extended-release tablets. See the end of this Patient Information leaflet for a complete list of ingredients in fluvastatin sodium extended-release tablets.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Before you take fluvastatin sodium extended-release tablets, tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>have muscle aches or weakness</dd>\n<dt>•</dt>\n<dd>drink more than 2 glasses of alcohol daily</dd>\n<dt>•</dt>\n<dd>have diabetes</dd>\n<dt>•</dt>\n<dd>have a thyroid problem</dd>\n<dt>•</dt>\n<dd>have kidney problems</dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. If you become pregnant while taking fluvastatin sodium extended-release tablets, stop taking fluvastatin sodium extended-release tablets and call your healthcare provider.</dd>\n<dt>•</dt>\n<dd>are breastfeeding or plan to breastfeed. It is not known if fluvastatin sodium passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take fluvastatin sodium extended-release tablets. You should not breastfeed while taking fluvastatin sodium extended-release tablets.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take,</span> 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 fluvastatin sodium extended-release tablets if another healthcare provider increases the dose of another medicine you are taking.</p>\n<p>Fluvastatin sodium extended-release tablets may affect the way other medicines work, and other medicines may affect how fluvastatin sodium extended-release tablets work. Especially tell your healthcare provider if you take:</p>\n<dl>\n<dt>•</dt>\n<dd>warfarin (a medicine used to reduce blood clotting)</dd>\n<dt>•</dt>\n<dd>glyburide (a medicine used to treat diabetes)</dd>\n<dt>•</dt>\n<dd>phenytoin (a medicine used to treat epilepsy)</dd>\n</dl>\n<p>Taking fluvastatin sodium extended-release tablets with certain medicines can also increase the risk of muscle problems. Especially tell your healthcare provider if you take: </p>\n<dl>\n<dt>•</dt>\n<dd>gemfibrozil (a medicine used to lower triglycerides)</dd>\n<dt>•</dt>\n<dd>cyclosporine (a medicine used to suppress the immune system)</dd>\n<dt>•</dt>\n<dd>fluconazole (a medicine used to treat fungal infections)</dd>\n<dt>•</dt>\n<dd>fibrates or niacin </dd>\n<dt>•</dt>\n<dd>colchicine </dd>\n</dl>\n<p>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.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take fluvastatin sodium extended-release tablets?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Take fluvastatin sodium extended-release tablets exactly as your healthcare provides tells you to take it.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Do not</span> change your dose or stop taking fluvastatin sodium extended-release tablets without talking to your healthcare provider.</dd>\n<dt>•</dt>\n<dd>Take fluvastatin sodium extended-release tablets 1 time each day, at any time of the day. Fluvastatin sodium extended-release tablets can be taken with or without food.</dd>\n<dt>•</dt>\n<dd>Fluvastatin sodium extended-release tablets must be swallowed whole with a liquid. Do not break, crush or chew fluvastatin sodium extended-release tablets. Tell your healthcare provider if you cannot swallow tablets whole. You may need fluvastatin capsules or a different medicine instead of fluvastatin sodium extended-release tablets. </dd>\n<dt>•</dt>\n<dd>While taking fluvastatin sodium extended-release tablets, continue to follow your cholesterol-lowing diet and exercise as your healthcare provider told you to. </dd>\n<dt>•</dt>\n<dd>In case of overdose, get medical help or contact a Poison Center expert right away at 1-800-222-1222. Advice is also available online at poisonhelp.org.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of fluvastatin sodium extended-release tablets?</span>\n</p>\n<p>\n<span class=\"Bold\">Fluvastatin sodium extended-release tablets may cause serious side effects, including:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Muscle pain, tenderness, and weakness (myopathy).</span> Muscle problems, including muscle breakdown, can be serious in some people and rarely cause kidney damage that can lead to death.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your healthcare provider right away if you have: </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>unexplained muscle pain, tenderness, or weakness, especially if you have a fever or feel more tired than usual, while you take fluvastatin sodium extended-release tablets.</dd>\n<dt>•</dt>\n<dd>muscle problems that do not go away even after your healthcare provider has advised you to stop taking fluvastatin sodium extended-release tablets. 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:</dd>\n<dt>o</dt>\n<dd>are taking certain other medicines while you take fluvastatin sodium extended-release tablets</dd>\n<dt>o</dt>\n<dd>are 65 years of age or older</dd>\n<dt>o</dt>\n<dd>have thyroid problems (hypothyroidism) that are not controlled</dd>\n<dt>o</dt>\n<dd>have kidney problems</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Liver problems.</span> Your healthcare provider should do blood tests to check your liver before you start taking fluvastatin sodium extended-release tablets, and if you have symptoms of liver problems while you take fluvastatin sodium extended-release tablets. Call your healthcare provider right away if you have the following symptoms of liver problems:</dd>\n<dt>o</dt>\n<dd>feel tired or weak</dd>\n<dt>o</dt>\n<dd>loss of appetite</dd>\n<dt>o</dt>\n<dd>right sided upper belly pain</dd>\n<dt>o</dt>\n<dd>dark amber colored urine</dd>\n<dt>o</dt>\n<dd>yellowing of your skin or the whites of your eye</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increase in blood sugar (glucose) levels.</span> Fluvastatin sodium extended-release tablets may cause an increase in your blood sugar levels.</dd>\n</dl>\n<p>\n<span class=\"Bold\">The most common side effects of fluvastatin sodium extended-release tablets include:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>flu-like symptoms </dd>\n<dt>•</dt>\n<dd>sinus infection </dd>\n<dt>•</dt>\n<dd>upset stomach and stomach pain </dd>\n<dt>•</dt>\n<dd>urinary tract infections</dd>\n<dt>•</dt>\n<dd>bronchitis</dd>\n<dt>•</dt>\n<dd>nausea</dd>\n</dl>\n<p>These side effects are usually mild and may go away. The following additional side effects have been reported with fluvastatin sodium extended-release tablets:</p>\n<dl>\n<dt>•</dt>\n<dd>memory loss and confusion</dd>\n</dl>\n<p>Talk to your healthcare provider or pharmacist if you have side effects that bother you or does not go away.</p>\n<p>These are not all the possible side effects of fluvastatin sodium extended-release tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store fluvastatin sodium extended-release tablets?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store fluvastatin sodium extended-release tablets at room temperature 68°F to 77°F (20°C to 25°C). <span class=\"Bold\">Protect from light.</span>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Keep fluvastatin sodium extended-release tablets out of the reach of children.</span> Be sure that if you throw medicines away, it is out of the reach of children.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about safe and effective use of fluvastatin sodium extended-release tablets.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use fluvastatin sodium extended-release tablets for a condition for which it was not prescribed. Do not give fluvastatin sodium extended-release tablets to other people, even if they have the same medical condition you have; it may harm them.</p>\n<p>You can ask your pharmacist or healthcare provider for information about fluvastatin sodium extended-release tablets that is written for health professionals.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in fluvastatin sodium extended-release tablets?</span>\n</p>\n<p>Active Ingredient: fluvastatin </p>\n<p>Inactive Ingredients: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 8000, potassium bicarbonate, povidone, titanium dioxide, and yellow iron oxide.</p>\n<p>For more information go to www.sandoz.com or call 1-800-525-8747.</p>\n<p>Mfd. by: Pfizer Ireland Pharmaceuticals</p>\n<p>Newbridge, Ireland for</p>\n<p>Sandoz Inc., Princeton, NJ 08540</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 01/2024

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration.\tRevised: 01/2024" }

NDC 0781-8017-31

{ "type": "p", "children": [], "text": "NDC 0781-8017-31" }

Fluvastatin Sodium

{ "type": "p", "children": [], "text": "Fluvastatin Sodium" }

Extended-Release

{ "type": "p", "children": [], "text": "Extended-Release " }

Tablets, USP

{ "type": "p", "children": [], "text": "Tablets, USP" }

80 mg

{ "type": "p", "children": [], "text": "\n80 mg " }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

30 tablets

{ "type": "p", "children": [], "text": "30 tablets" }

Sandoz

{ "type": "p", "children": [], "text": "Sandoz" }