TEVA-FLUVASTATIN

). TEVA-FLUVASTATIN (Fluvastatin Sodium) Page 22 of 52 Warfarin and other coumarin derivatives: In vitro protein binding studies demonstrated no interaction at therapeutic concentrations. In a drug interaction study, the concomitant use of fluvastatin sodium capsules and warfarin did not alter the plasma levels and prothrombin times compared to warfarin alone.

However, isolated incidences of bleeding episodes and/or increased prothrombin times have been reported very rarely in patients on fluvastatin receiving concomitant warfarin or other coumarin derivatives. It is recommended that prothrombin times are monitored when fluvastatin treatment is initiated, discontinued, or the dosage changed in patients receiving warfarin or other coumarin derivatives.

Cytochrome P450 Fluvastatin is predominantly metabolized by the hepatic microsomal CYP2C9 subclass of the P450 cytochromes. It is not metabolized to a significant extent by other cytochrome subclasses, including CYP3A4. The clearance of drugs which are also CYP2C9 substrates may decrease when co-administered with fluvastatin.

However, for those CYP2C9-metabolized drugs which have been studied directly, including diclofenac, tolbutamide, and warfarin, the effect on clearance is small and no clinically significant drug interactions of fluvastatin with other CYP2C9 substrates have been demonstrated.

g. g. g. diclofenac) (see 7 WARNINGS AND PRECAUTIONS, Muscle Effects). Since fluvastatin sodium is predominantly metabolized by the CYP2C9 subclass of the P450 cytochromes and not metabolized to a significant extent by other cytochrome subclasses, including CYP3A4, it is not expected to increase the risks of drug interactions when combined with drugs or common agents such as grapefruit juice that inhibit this enzyme (immunosuppressants, azole-type antifungal agents, macrolide antibiotics or antidepressants) (see 7 WARNINGS AND PRECAUTIONS, Pharmacokinetics Interactions and Muscle Effects).

Itraconazole and erythromycin Concomitant administration of fluvastatin with the potent cytochrome P450 (CYP) 3A4 inhibitors itraconazole and erythromycin has minimal effects on the bioavailability of fluvastatin. g. ketoconazole, cyclosporin) are unlikely to affect the bioavailability of fluvastatin (see 7 WARNINGS AND PRECAUTIONS, Muscle Effects).

Fluconazole Administration of fluvastatin to healthy volunteers pre-treated with fluconazole (CYP2C9 TEVA-FLUVASTATIN (Fluvastatin Sodium) Page 23 of 52 inhibitor) resulted in a significant increase in the exposure, elimination half life and peak concentration of fluvastatin by about 84%, 80% and 44%, respectively.

Although there was no clinical evidence that the safety profile of fluvastatin was altered in patients pre-treated with fluconazole for 4 days, caution should be exercised when fluvastatin is administered concomitantly with fluconazole.

Oral Antidiabetic Agents For patients receiving oral sulfonylureas (glibenclamide [glyburide], tolbutamide) for the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), addition of fluvastatin does not lead to clinically significant changes in glycemic control.

In glyburide-treated NIDDM patients (n=32), administration of fluvastatin (40 mg twice daily for 14 days) increased the mean Cmax, AUC, and t1/2 of glyburide approximately 50%, 69% and 121%, respectively. Glyburide (5 to 20 mg daily) increased the mean Cmax and AUC of fluvastatin by 44% and 51%, respectively.

In this study there were no changes in glucose, insulin and C-peptide levels. However, patients on concomitant therapy with glyburide (glibenclamide) and fluvastatin should continue to be monitored appropriately when their fluvastatin dose is increased to 80 mg per day.

Phenytoin The overall magnitude of the changes in phenytoin pharmacokinetics during co-administration with fluvastatin are relatively small and not clinically significant. Thus, routine monitoring of phenytoin plasma levels is sufficient during co-administration with fluvastatin.

The minimal effect of phenytoin on fluvastatin pharmacokinetics indicates that dosage adjustment of fluvastatin is not warranted when co-administered with phenytoin. Colchicines Myotoxicity, including muscle pain and weakness and rhabdomyolysis, has been reported anecdotally with concomitant administration of fluvastatin and colchicine during acute exacerbation of gouty arthritis.

Patients with severe hypercholesterolemia Higher dosages (80 mg/day) required for some patients with severe hypercholesterolemia are associated with increased plasma levels of fluvastatin. Caution should be exercised in such patients who are also significantly renally impaired, elderly, or are also concomitantly being administered digoxin, or CYP 450 inhibitors (see 7 WARNINGS AND PRECAUTIONS, Pharmacokinetic Interactions and Muscle Effects and

, Muscle Effects – Pre-disposing Factors for Myopathy/Rhabdomyolysis). 2. Contraindications TEVA-FLUVASTATIN is contraindicated under the following conditions:  TEVA-FLUVASTATIN is contraindicated in patients with known hypersensitivity to any component of this medication (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).

 TEVA-FLUVASTATIN is contraindicated in patients with active liver disease or unexplained, persistent clinically relevant elevations in serum transaminases (see 7 WARNINGS AND PRECAUTIONS, Hepatic). 2 Breast-feeding). Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes).

TEVA-FLUVASTATIN should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the possible harm. If the patient becomes pregnant while taking TEVA-FLUVASTATIN, the drug should be discontinued immediately and the patient apprised of the potential harm to the fetus.

2 Breast-feeding). TEVA-FLUVASTATIN (Fluvastatin Sodium) Page 6 of 52 4. 1. Dosing Considerations Patients should be placed on a standard cholesterol-lowering diet [at least equivalent to the Adult Treatment Panel III (ATP III TLC diet)] before receiving TEVA-FLUVASTATIN and should continue on this diet during treatment with TEVA-FLUVASTATIN.

If appropriate, a program of weight control and physical exercise should be implemented. Prior to initiating therapy with TEVA-FLUVASTATIN, secondary causes for elevations in plasma lipid levels should be excluded. A lipid profile should also be performed.

Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of TEVA-FLUVASTATIN capsule, if cholesterol levels fall below the desired range. 2. Recommended Dose and Dosage Adjustment Adults Hypercholesterolemia and Mixed Hyperlipidemia For patients requiring LDL-C reduction of less than 25%, a starting dose of 20 mg TEVA- FLUVASTATIN capsule taken once daily is recommended.

For patients requiring LDL-C reduction of at least 25%, the recommended starting dose is 40 mg daily of TEVA-FLUVASTATIN capsule taken once daily. If necessary, the dosage of TEVA- FLUVASTATIN may then be increased to 80 mg of TEVA-FLUVASTATIN taken in divided doses of 40 mg twice daily.

TEVA-FLUVASTATIN capsules may be taken consistently with or without food, in the evening or at bedtime. TEVA-FLUVASTATIN capsules must be swallowed whole with a glass of water. Since maximal reduction in LDL-C is seen within 4 weeks of administration of a given dose of TEVA-FLUVASTATIN capsule, periodic lipid level determination should be performed with dosage adjusted to a maximum of 80 mg of fluvastatin daily, according to patient response.

Severe Hypercholesterolemia In patients with severe hypercholesterolemia, higher dosages (up to 80 mg/day) may be required (see 7 WARNINGS AND PRECAUTIONS, Pharmacokinetic Interactions and Muscle Effects and 9 DRUG INTERACTIONS). The maximum recommended daily dosage is 80 mg/day.

TEVA-FLUVASTATIN (Fluvastatin Sodium) Page 7 of 52 Secondary Prevention of Cardiovascular Events (See Hypercholesterolemia and Mixed Hypercholesterolemia) During the Fluvastatin Sodium Intervention Prevention Study, patients were initiated on fluvastatin treatment at 40 mg twice a day with no titration from a lower dose level.

This daily dose was proven to be as well tolerated as placebo. Therefore, in patients with coronary heart disease who have undergone a percutaneous intervention procedure, the appropriate dose of TEVA-FLUVASTATIN is 40 mg twice a day.

3 Pediatrics The dosage of TEVA-FLUVASTATIN should be individualized according to baseline LDL-C, total- C/HDL-C ratio and/or TG levels to achieve the desired lipid values at the lowest possible dose. Lipid levels should be monitored periodically and, if necessary, the dose of TEVA-FLUVASTATIN adjusted accordingly.

5. Overdosage For management of a suspected drug overdose, contact your regional Poison Control Centre. The maximum single oral dose of fluvastatin sodium received by healthy volunteers was 80 mg. No clinically significant adverse experiences were seen at this dose.

The maximum dose administered with an extended release formulation was 640 mg for two weeks. , ALT and AST). There has been a single report of two children, one 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 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.

Specific treatment is not available for TEVA-FLUVASTATIN overdose. Should an overdose occur, the patient should be treated symptomatically and supporting measures should be […]

3 Pediatrics The dosage of TEVA-FLUVASTATIN should be individualized according to baseline LDL-C, total- C/HDL-C ratio and/or TG levels to achieve the desired lipid values at the lowest possible dose. Lipid levels should be monitored periodically and, if necessary, the dose of TEVA-FLUVASTATIN adjusted accordingly.

5. Overdosage For management of a suspected drug overdose, contact your regional Poison Control Centre. The maximum single oral dose of fluvastatin sodium received by healthy volunteers was 80 mg. No clinically significant adverse experiences were seen at this dose.

The maximum dose administered with an extended release formulation was 640 mg for two weeks. , ALT and AST). There has been a single report of two children, one 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 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.

Specific treatment is not available for TEVA-FLUVASTATIN overdose. Should an overdose occur, the patient should be treated symptomatically and supporting measures should be undertaken as required. Liver function tests and serum CK levels should be monitored.

The dialysability of fluvastatin sodium and its metabolites in man is not known at present. 6. Dosage Forms, Strengths, Composition and Packaging Table 1 – Dosage Forms, Strengths, Composition and Packaging Route of Administration Dosage Form / Strength Nonmedicinal Ingredients Oral Capsules / 20 mg and 40 mg Colloidal anhydrous silica, crospovidone lactose monohydrate, magnesium stearate.

Capsule shell and printing ink: antifoam DC 1510, black iron oxide, dehydrated alcohol, gelatin, industrial methylated spirit 74 OP BP, n-butyl alcohol, red iron oxide, SDA 3A alcohol, shellac, soya lecithin, titanium dioxide, yellow iron oxide.

Dosage Forms and Packaging:

TEVA-FLUVASTATIN Capsules 20 mg – Hard gelatin capsules with light yellow opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates. Body and cap imprint: 93 7442 Available in bottles of 100.

TEVA-FLUVASTATIN Capsules 40 mg - Hard gelatin capsules with yellow opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates. TEVA-FLUVASTATIN (Fluvastatin Sodium) Page 9 of 52 Body and cap imprint: 93 7443 Available in bottles of 100.

7. Warnings and Precautions General Before instituting therapy with TEVA-FLUVASTATIN, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in overweight and obese patients, and to treat other underlying medical problems (see 1 INDICATIONS).

The patient should be advised to inform subsequent physicians of the prior use of TEVA-FLUVASTATIN or any other lipid metabolism regulator. Endocrine and Metabolism Increases in fasting glucose and HbA1c levels have been reported with inhibitors of HMG-CoA reductase as a class.

For some patients, at high risk of diabetes mellitus, hyperglycemia was sufficient to shift them to the diabetes status. The benefit of treatment continues to outweigh the small increased risk. Periodic monitoring of these patients is recommended.

Muscle Effects Effects on skeletal muscle such as rare cases of myalgia, myopathy and, very rarely, rhabdomyolysis have been reported in patients treated with fluvastatin sodium. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with TEVA-FULVASTATIN and with other HMG-CoA reductase inhibitors.

Myopathy, defined as muscle pain or muscle weakness in conjunction with increases in creatine phosphokinase (CK) values to greater than ten times the upper limit of normal, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or a marked elevation of CK.

Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if associated with malaise or fever. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured.

TEVA-FLUVASTATIN therapy should be discontinued if markedly elevated CK levels are measured or myopathy is diagnosed or suspected.

CK measurement:

There is no current evidence to require routine monitoring of plasma total CK levels in asymptomatic patients on statins. If CK has to be measured it should not be done following TEVA-FLUVASTATIN (Fluvastatin Sodium) Page 10 of 52 strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes interpretation difficult.

Pre-disposing Factors for Myopathy/Rhabdomyolysis:

TEVA-FLUVASTATIN, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include: - Personal or family history of hereditary muscular disorders - Previous history of muscle toxicity with another HMG-CoA reductase inhibitor - Concomitant use of a fibrate or niacin - Hypothyroidism - Alcohol Abuse - Excessive physical exercise - Age >70 years - Renal impairment - Hepatic impairment - Diabetes with hepatic fatty change - Severe metabolic, endocrine or electrolyte disorders - Surgery and trauma - Frailty - Situations where an increase in plasma levels of active ingredient may occur - Sepsis - Hypotension - Uncontrolled epilepsy In such situations, the risk of treatment should be considered in relation to the possible […]