Simvastatin Tablets USP 10mg Taj Pharma

1. Name of the medicinal product

Simvastatin Tablets USP 10mg Taj Pharma Ltd.
Simvastatin Tablets USP 20mg Taj Pharma Ltd.
Simvastatin Tablets USP 40mg Taj Pharma Ltd.

2. Qualitative and quantitative composition

a) Simvastatin Tablets USP 10mg Taj Pharma Ltd.
Each film-coated tablets contains:
Simvastatin USP 10mg
Excipients: Q.S.

b) Simvastatin Tablets USP 20mg Taj Pharma Ltd.
Each film-coated tablets contains:
Simvastatin USP 20mg
Excipients: Q.S.

c) Simvastatin Tablets USP 40mg Taj Pharma Ltd.
Each film-coated tablets contains:
Simvastatin USP 40mg
Excipients: Q.S.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

4. Clinical particulars

• Therapeutic indications

Hypercholesterolaemia

Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate. Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate.

Cardiovascular prevention

Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardio protective therapy (see section 5.1).

• Posology and method of administration

The dosage range is 5-80mg/day given orally as a single dose in the evening. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80mg/day given as a single dose in the evening. The 80-mg dose is only recommended in patients with severe hypercholesterolaemia and at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (sees sections 4.4 and 5.1).

Hypercholesterolaemia

The patient should be placed on a standard cholesterol-lowering diet, and should continue on this diet during treatment with Simvastatin Taj Pharma. The usual starting dose is 10-20mg/day given as a single dose in the evening. Patients who require a large reduction in LDL-C (more than 45 %) may be started at 20-40mg/day given as a single dose in the evening. Adjustments of dosage, if required, should be made as specified above.

Homozygous familial hypercholesterolaemia

Based on the results of a controlled clinical study, the recommended starting dosage is Simvastatin Taj Pharma 40mg/day in the evening. Simvastatin Taj Pharma should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Cardiovascular prevention

The usual dose of Simvastatin Taj Pharma is 20 to 40mg/day given as a single dose in the evening in patients at high risk of coronary heart disease (CHD, with or without hyperlipidaemia). Drug therapy can be initiated simultaneously with diet and exercise. Adjustments of dosage, if required, should be made as specified above.

Concomitant therapy

Simvastatin Taj Pharma is effective alone or in combination with bile acid sequestrants. Dosing should occur either > 2 hours before or > 4 hours after administration of a bile acid sequestrant.

In patients taking Simvastatin Taj Pharma concomitantly with fibrates other than gemfibrozil (see section 4.3) or fenofibrate, the dose of Simvastatin Taj Pharma should not exceed 10mg/day. In patients taking amiodarone, amlodipine, verapamil or diltiazem concomitantly with Simvastatin Taj Pharma, the dose of Simvastatin Taj Pharma should not exceed 20mg/day. (See sections 4.4 and 4.5.)

Dosage in renal insufficiency

No modification of dosage should be necessary in patients with moderate renal insufficiency.

In patients with severe renal insufficiency (creatinine clearance < 30 ml/min), dosages above 10mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Use in the elderly

No dosage adjustment is necessary.

Use in children and adolescents (10-17 years of age)

For children and adolescents (boys Tanner Stage II and above and girls who are at least one year post-menarche, 10-17 years of age) with heterozygous familial hypercholesterolaemia, the recommended usual starting dose is 10mg once a day in the evening. Children and adolescents should be placed on a standard cholesterol-lowering diet before Simvastatin Taj Pharma treatment initiation; this diet should be continued during Simvastatin Taj Pharma treatment.

The recommended dosing range is 10-40mg/day; the maximum recommended dose is 40mg/day. Doses should be individualized according to the recommended goal of therapy as recommended by the paediatric treatment recommendations (see sections 4.4 and 5.1). Adjustments should be made at intervals of 4 weeks or more.

The experience of Simvastatin Taj Pharma in pre-pubertal children is limited.

• Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Active liver disease or unexplained persistent elevations of serum transaminases
• Pregnancy and lactation (see section 4.6)
• Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin, clarithromycin, telithromycin and nefazodone) (see section 4.4 and 4.5).
• Concomitant administration of gemfibrozil, ciclosporin, or danazol (see sections 4.4 and 4.5).
  • Special warnings and precautions for use

Myopathy/Rhabdomyolysis

Simvastatin Taj Pharma, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with Simvastatin Taj Pharma, 24,747 patients (approximately 60 %) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03 %, 0.08 % and 0.61 % at 20, 40 and 80mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which patients with a history of myocardial infarction were treated with Simvastatin Taj Pharma 80mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0 % compared with 0.02 % for patients on 20mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %. (See sections 4.8 and 5.1.)

The risk of myopathy is greater in patients on Simvastatin Taj Pharma 80mg compared with other statin-based therapies with similar LDL-C-lowering efficacy. Therefore, the 80-mg dose of Simvastatin Taj Pharma should only be used in patients with severe hypercholesterolemia and at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks. In patients taking Simvastatin Taj Pharma 80mg for whom an interacting agent is needed, a lower dose of Simvastatin Taj Pharma or an alternative statin-based regimen with less potential for drug-drug interactions should be used (see below Measures to reduce the risk of myopathy caused by medicinal product interactions and sections 4.2, 4.3, and 4.5).

Creatine Kinase measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.

Before the treatment

All patients starting therapy with Simvastatin Taj Pharma, or whose dose of Simvastatin Taj Pharma is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations:

• Elderly (age > 65 years)
• Female gender
• Renal impairment
• Uncontrolled hypothyroidism
• Personal or familial history of hereditary muscular disorders
• Previous history of muscular toxicity with a statin or fibrate
• Alcohol abuse.

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated at baseline (> 5 x ULN), treatment should not be started.

Whilst on treatment

If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (> 5 x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.

A higher rate of myopathy has been observed in patients titrated to the 80mg dose (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

Therapy with Simvastatin Taj Pharma should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

Reduced function of transport proteins

Reduced function of hepatic OATP transport proteins can increase the systemic exposure of Simvastatin Taj Pharma and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (eg ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype.

Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of Simvastatin Taj Pharma and increased risk of myopathy. The risk of high dose (80mg) Simvastatin Taj Pharma related myopathy is about 1 % in general, without genetic testing. Based on the results of the SEARCH trial, homozygote C allele carriers (also called CC) treated with 80mg have a 15 % risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1.5 %. The corresponding risk is 0.3 % in patients having the most common genotype (TT) (See section 5.2). Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment prior to prescribing 80mg Simvastatin Taj Pharma for individual patients and high doses avoided in those found to carry the CC genotype. However, absence of this gene upon genotyping does not exclude that myopathy can still occur.

Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5)

The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of Simvastatin Taj Pharma with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir nefazodone), as well as gemfibrozil, ciclosporin and danazol. Use of these medicinal products is contraindicated (see section 4.3).

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of amiodarone, amlodipine, verapamil or diltiazem with certain doses of Simvastatin Taj Pharma (see sections 4.2 and section 4.5). The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of fusidic acid with statins (see section 4.5).

Consequently, regarding CYP3A4 inhibitors, the use of Simvastatin Taj Pharma concomitantly with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) is unavoidable, therapy with Simvastatin Taj Pharma must be suspended (and use of an alternative statin considered) during the course of treatment. Moreover, caution should be exercised when combining Simvastatin Taj Pharma with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and Simvastatin Taj Pharma should be avoided.

The use of Simvastatin Taj Pharma with gemfibrozil is contraindicated (see section 4.3). Due to the increased risk of myopathy and rhabdomyolysis, the dose of Simvastatin Taj Pharma should not exceed 10mg daily in patients taking Simvastatin Taj Pharma with other fibrates, except fenofibrate. (See sections 4.2 and section 4.5)

Caution should be used when prescribing fenofibrate with Simvastatin Taj Pharma, as either agent can cause myopathy when given alone.

Simvastatin Taj Pharma must not be co-administered with fusidic acid. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination (see section 4.5). In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be reintroduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Simvastatin Taj Pharma and fusidic acid should only be considered on a case by case basis and under close medical supervision.

The combined use of Simvastatin Taj Pharma at doses higher than 20mg daily with amiodarone, amlodipine, verapamil or diltiazem should be avoided (see sections 4.2 and 4.5).

Patients taking other medicines labelled as having a moderate inhibitory effect on CYP3A4 concomitantly with Simvastatin Taj Pharma, particularly higher Simvastatin Taj Pharma doses, may have an increased risk of myopathy. When coadministering Simvastatin Taj Pharma with a moderate inhibitor of CYP3A4 (agents that increase AUC approximately 2-5 fold), a dose adjustment of Simvastatin Taj Pharma may be necessary. For certain moderate CYP3A4 inhibitors e.g. diltiazem, a maximum dose of 20mg Simvastatin Taj Pharma is recommended (see section 4.2).

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid), either of which can cause myopathy when given alone.

Physicians contemplating combined therapy with Simvastatin Taj Pharma and lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or products containing niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when the dose of either medicinal product is increased.

In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking Simvastatin Taj Pharma 40mg and nicotinic acid/laropiprant 2000mg/40mg. Therefore, caution should be used when treating Chinese patients with Simvastatin Taj Pharma (particularly doses of 40mg or higher) co-administered with lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or products containing niacin. Because the risk of myopathy with statins is dose-related, the use of Simvastatin Taj Pharma 80mg with lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or products containing niacin is not recommended in Chinese patients. It is unknown whether there is an increased risk of myopathy in other Asian patients treated with Simvastatin Taj Pharma co-administered with lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or products containing niacin.

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9mmol/L, BMI>30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

Hepatic effects

In clinical studies, persistent increases (to > 3 x ULN) in serum transaminases have occurred in a few adult patients who received Simvastatin Taj Pharma. When Simvastatin Taj Pharma was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels.

It is recommended that liver function tests be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 x ULN and are persistent, Simvastatin Taj Pharma should be discontinued. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy (see above Myopathy/Rhabdomyolysis).

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

The product should be used with caution in patients who consume substantial quantities of alcohol.

As with other lipid-lowering agents, moderate (< 3 x ULN) elevations of serum transaminases have been reported following therapy with Simvastatin Taj Pharma. These changes appeared soon after initiation of therapy with Simvastatin Taj Pharma, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

Use in children and adolescents (10-17 years of age)

Safety and effectiveness of Simvastatin Taj Pharma in patients 10-17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys Tanner Stage II and above and in girls who were at least one year post-menarche. Patients treated with Simvastatin Taj Pharma had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See sections 4.2, 4.8, and 5.1.) Adolescent females should be counselled on appropriate contraceptive methods while on Simvastatin Taj Pharma therapy (see sections 4.3 and 4.6). In patients aged < 18 years, efficacy and safety have not been studied for treatment periods > 48 weeks’ duration and long-term effects on physical, intellectual, and sexual maturation are unknown. Simvastatin Taj Pharma has not been studied in patients younger than 10 years of age, nor in pre-pubertal children and pre-menarchal girls.

Interstitial lung disease

Cases of interstitial lung disease have been reported with some statins, including Simvastatin Taj Pharma, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, nonproductive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Excipient

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

• Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Pharmacodynamic interactions

Interactions with lipid-lowering medicinal products that can cause myopathy when given alone.

The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates. Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased Simvastatin Taj Pharma plasma levels (see below Pharmacokinetic interactions and sections 4.3 and 4.4). When Simvastatin Taj Pharma and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent. Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates. Rare cases of myopathy/rhabdomyolysis have been associated with Simvastatin Taj Pharma co-administered with lipid-modifying doses (≥ 1 g/day) of niacin (see section 4.4).

Pharmacokinetic interactions

Prescribing recommendations for interacting agents are summarized in the table below (further details are provided in the text; see also sections 4.2, 4.3 and 4.4).

Effects of other medicinal products on Simvastatin Taj Pharma

Interactions involving inhibitors of CYP3A4

Simvastatin Taj Pharma is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during Simvastatin Taj Pharma therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), and nefazodone. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to Simvastatin Taj Pharma acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to Simvastatin Taj Pharma acid.

Combination with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated, as well as gemfibrozil, ciclosporin, and danazol (see section 4.3). If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with Simvastatin Taj Pharma must be suspended during the course of treatment. Caution should be exercised when combining Simvastatin Taj Pharma with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil or diltiazem (see sections 4.2 and 4.4).

Fluconazole

Rare cases of rhabdomyolysis associated with concomitant administration of Simvastatin Taj Pharma and fluconazole have been reported (see section 4.4).

Ciclosporin

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin with Simvastatin Taj Pharma; therefore, use with ciclosporin is contraindicated (see sections 4.3 and 4.4). Although the mechanism is not fully understood, ciclosporin has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for Simvastatin Taj Pharma acid is presumably due, in part, to inhibition of CYP3A4.

Danazol

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with Simvastatin Taj Pharma; therefore, use with danazol is contraindicated. (see sections 4.3 and 4.4).

Gemfibrozil

Gemfibrozil increases the AUC of Simvastatin Taj Pharma acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway (see sections 4.3 and 4.4). Concomitant administration with gemfibrozil is contraindicated.

Amiodarone

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with Simvastatin Taj Pharma (see section 4.4). In a clinical trial, myopathy was reported in 6 % of patients receiving Simvastatin Taj Pharma 80mg and amiodarone. Therefore, the dose of Simvastatin Taj Pharma should not exceed 20mg daily in patients receiving concomitant medication with amiodarone.

Calcium Channel Blockers

Verapamil

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with Simvastatin Taj Pharma 40mg or 80mg (see section 4.4). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3-fold increase in exposure of Simvastatin Taj Pharma acid, presumably due, in part, to inhibition of CYP3A4. Therefore, the dose of Simvastatin Taj Pharma should not exceed 20mg daily in patients receiving concomitant medication with verapamil.

• Diltiazem

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with Simvastatin Taj Pharma 80mg (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7-fold increase in exposure of Simvastatin Taj Pharma acid, presumably due to inhibition of CYP3A4. Therefore, the dose of Simvastatin Taj Pharma should not exceed 20mg daily in patients receiving concomitant medication with diltiazem.

• Amlodipine

Patients on amlodipine treated concomitantly with Simvastatin Taj Pharma have an increased risk of myopathy. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of Simvastatin Taj Pharma acid. Therefore, the dose of Simvastatin Taj Pharma should not exceed 20mg daily in patients receiving concomitant medication with amlodipine.

Moderate Inhibitors of CYP3A4

Patients taking other medicines labeled as having a moderate inhibitory effect on CYP3A4 concomitantly with Simvastatin Taj Pharma, particularly higher Simvastatin Taj Pharma doses, may have an increased risk of myopathy.

Niacin (nicotinic acid)

Rare cases of myopathy/rhabdomyolysis have been associated with Simvastatin Taj Pharma co-administered with lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid). In a pharmacokinetic study, the co-administration of a single dose of nicotinic acid prolonged-release 2 g with Simvastatin Taj Pharma 20mg resulted in a modest increase in the AUC of Simvastatin Taj Pharma and Simvastatin Taj Pharma acid and in the Cmax of Simvastatin Taj Pharma acid plasma concentrations.

Fusidic acid

The risk of myopathy may be increased by concomitant administration of fusidic acid with statins, including Simvastatin Taj Pharma. Isolated cases of rhabdomyolysis have been reported with Simvastatin Taj Pharma. Temporary suspension of Simvastatin Taj Pharma treatment may be considered. If it proves necessary, patients on fusidic acid and Simvastatin Taj Pharma should be closely monitored (see section 4.4).

Grapefruit juice

Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and Simvastatin Taj Pharma resulted in a 7-fold increase in exposure to Simvastatin Taj Pharma acid. Intake of 240 ml of grapefruit juice in the morning and Simvastatin Taj Pharma in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with Simvastatin Taj Pharma should therefore be avoided.

Colchicine

There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and Simvastatin Taj Pharma in patients with renal insufficiency. Close clinical monitoring of such patients taking this combination is advised.

Rifampicin

Because rifampicin is a potent P450 3A4 inducer, patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of Simvastatin Taj Pharma. In a pharmacokinetic study of normal volunteers, the area under the plasma concentration curve (AUC) for Simvastatin Taj Pharma acid was decreased by 93% with concomitant administration of rifampicin.

Effects of Simvastatin Taj Pharma on the pharmacokinetics of other medicinal products

Simvastatin Taj Pharma does not have an inhibitory effect on cytochrome P450 3A4. Therefore, Simvastatin Taj Pharma is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.

Oral anticoagulants

In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, Simvastatin Taj Pharma 20-40mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. Very rare cases of elevated INR have been reported. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting Simvastatin Taj Pharma and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of Simvastatin Taj Pharma is changed or discontinued, the same procedure should be repeated. Simvastatin Taj Pharma therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

• Pregnancy and lactation

Pregnancy

Simvastatin Taj Pharma is contraindicated during pregnancy (see section 4.3).

Safety in pregnant women has not been established. No controlled clinical trials with Simvastatin Taj Pharma have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to Simvastatin Taj Pharma or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.

Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking Simvastatin Taj Pharma or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with Simvastatin Taj Pharma may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, Simvastatin Taj Pharma should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Simvastatin Taj Pharma should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (See sections 4.3 and 5.3)

Breastfeeding

It is not known whether Simvastatin Taj Pharma or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking Simvastatin Taj Pharma should not breast-feed their infants (see section 4.3).

• Effects on ability to drive and use machines

Simvastatin Taj Pharma has no or negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.

• Undesirable effects

The frequencies of the following adverse events, which have been reported during clinical studies and/or post-marketing use, are categorized based on an assessment of their incidence rates in large, long-term, placebo-controlled, clinical trials including HPS and 4S with 20,536 and 4,444 patients, respectively (see section 5.1). For HPS, only serious adverse events were recorded as well as myalgia, increases in serum transaminases and CK. For 4S, all the adverse events listed below were recorded. If the incidence rates on Simvastatin Taj Pharma were less than or similar to that of placebo in these trials, and there were similar reasonably causally related spontaneous report events, these adverse events are categorized as “rare”.

In HPS (see section 5.1) involving 20,536 patients treated with 40mg/day of Simvastatin Taj Pharma (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between patients treated with Simvastatin Taj Pharma 40mg and patients treated with placebo over the mean 5 years of the study. Discontinuation rates due to side effects were comparable (4.8 % in patients treated with Simvastatin Taj Pharma 40mg compared with 5.1 % in patients treated with placebo). The incidence of myopathy was < 0.1 % in patients treated with Simvastatin Taj Pharma 40mg. Elevated transaminases (> 3 x ULN confirmed by repeat test) occurred in 0.21 % (n = 21) of patients treated with Simvastatin Taj Pharma 40mg compared with 0.09 % (n = 9) of patients treated with placebo.

The frequencies of adverse events are ranked according to the following: Very common (> 1/10), Common (≥ 1/100, < 1/10), Uncommon (≥ 1/1000, < 1/100), Rare (≥ 1/10,000, < 1/1000), Very Rare (< 1/10,000), Not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:

Rare: anaemia

Psychiatric disorders:

Very rare: insomnia

Not known: depression

Nervous system disorders:

Rare: headache, paresthesia, dizziness, peripheral neuropathy

Very rare: memory impairment

Respiratory, Thoracic and Mediastinal disorder:

Not known: interstitial lung disease (see section 4.4).

Gastrointestinal disorders:

Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis

Hepato-biliary disorders:

Rare: hepatitis/jaundice

Very rare: fatal and non-fatal hepatic failure

Skin and subcutaneous tissue disorders:

Rare: rash, pruritus, alopecia

Musculoskeletal, connective tissue and bone disorders:

Rare: myopathy* (including myositis), rhabdomyolysis with or without acute renal failure (see section 4.4), myalgia, muscle cramps

* In a clinical trial, myopathy occurred commonly in patients treated with Simvastatin Taj Pharma 80mg/day compared to patients treated with 20mg/day (1.0 % vs 0.02 %, respectively) (see sections 4.4 and 4.5).

Not known: tendinopathy sometimes complicated by tendon rupture, Immune-mediated necrotizing myopathy (see section 4.4)

Reproductive System disorders:

Not known: erectile dysfunction

General disorders and administration site conditions:

Rare: asthenia

An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.

Investigations:

Rare: increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase) (see section 4.4 Hepatic effects), elevated alkaline phosphatase; increase in serum CK levels (see section 4.4).

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including Simvastatin Taj Pharma.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use, including Simvastatin Taj Pharma. 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).

The following additional adverse events have been reported with some statins:

• Sleep disturbances, including nightmares.
• Sexual dysfunction.
• Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI>30kg/m2, raised triglycerides, history of hypertension).

Children and adolescents (10-17 years of age)

In a 48-week study involving children and adolescents (boys Tanner Stage II and above and girls who were at least one year post-menarche) 10-17 years of age with heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability profile of the group treated with Simvastatin Taj Pharma was generally similar to that of the group treated with placebo. The long-term effects on physical, intellectual, and sexual maturation are unknown. No sufficient data are currently available after one year of treatment. (See sections 4.2, 4.4, and 5.1.)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

• Overdose

To date, a few cases of over dosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic and supportive measures should be adopted.

5.  Pharmacological properties

• Pharmacodynamic properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitors

After oral ingestion, Simvastatin Taj Pharma, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy – 3 methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.

Simvastatin Taj Pharma has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of Simvastatin Taj Pharma may involve both reduction of VLDL-cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with Simvastatin Taj Pharma. In addition, Simvastatin Taj Pharma moderately increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and LDL- to HDL-C are reduced.

High Risk of Coronary Heart Disease (CHD) or Existing Coronary Heart Disease

In the Heart Protection Study (HPS), the effects of therapy with Simvastatin Taj Pharma were assessed in 20,536 patients (age 40-80 years), with or without hyperlipidaemia, and with coronary heart disease, other occlusive arterial disease or diabetes mellitus. In this study, 10,269 patients were treated with Simvastatin Taj Pharma 40mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33 %) had LDL-C levels below 116mg/dL; 5,063 patients (25 %) had levels between 116mg/dL and 135mg/dL; and 8,680 patients (42 %) had levels greater than 135mg/dL.

Treatment with Simvastatin Taj Pharma 40mg/day compared with placebo significantly reduced the risk of all-cause mortality (1328 [12.9 %] for Simvastatin Taj Pharma-treated patients versus 1507 [14.7 %] for patients given placebo; p = 0.0003), due to an 18 % reduction in coronary death rate (587 [5.7 %] versus 707 [6.9 %]; p = 0.0005; absolute risk reduction of 1.2 %). The reduction in non-vascular deaths did not reach statistical significance. Simvastatin Taj Pharma also decreased the risk of major coronary events (a composite endpoint comprised of non-fatal MI or CHD death) by 27 % (p < 0.0001). Simvastatin Taj Pharma reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other non-coronary revascularization procedures by 30 % (p < 0.0001) and 16 % (p = 0.006), respectively. Simvastatin Taj Pharma reduced the risk of stroke by 25 % (p < 0.0001), attributable to a 30 % reduction in ischemic stroke (p < 0.0001). In addition, within the subgroup of patients with diabetes, Simvastatin Taj Pharma reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21 % (p = 0.0293). The proportional reduction in event rate was similar in each subgroup of patients studied, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women, those aged either under or over 70 years at entry into the study, presence or absence of hypertension, and notably those with LDL cholesterol below 3.0mmol/l at inclusion.

In the Scandinavian Simvastatin Taj Pharma Survival Study (4S), the effect of therapy with Simvastatin Taj Pharma on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309mg/dL (5.5-8.0 mmol/L). In this multicenter, randomised, double-blind, placebo-controlled study, patients with angina or a previous myocardial infarction (MI) were treated with diet, standard care, and either Simvastatin Taj Pharma 20-40mg/day (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years. Simvastatin Taj Pharma reduced the risk of death by 30 % (absolute risk reduction of 3.3 %). The risk of CHD death was reduced by 42 % (absolute risk reduction of 3.5 %). Simvastatin Taj Pharma also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34 %. Furthermore, Simvastatin Taj Pharma significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischemic attacks) by 28 %. There was no statistically significant difference between groups in non-cardiovascular mortality.

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) evaluated the effect of treatment with Simvastatin Taj Pharma 80mg versus 20mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI, coronary revascularization procedure, non-fatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups; Simvastatin Taj Pharma 20mg (n = 1553; 25.7 %) vs. Simvastatin Taj Pharma 80mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C between the two groups over the course of the study was 0.35 ± 0.01mmol/L. The safety profiles were similar between the two treatment groups except that the incidence of myopathy was approximately 1.0 % for patients on Simvastatin Taj Pharma 80mg compared with 0.02 % for patients on 20mg. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %.

Primary Hypercholesterolaemia and Combined Hyperlipidaemia

In studies comparing the efficacy and safety of Simvastatin Taj Pharma 10, 20, 40 and 80mg daily in patients with hypercholesterolemia, the mean reductions of LDL-C were 30, 38, 41 and 47 %, respectively. In studies of patients with combined (mixed) hyperlipidaemia on Simvastatin Taj Pharma 40mg and 80mg, the median reductions in triglycerides were 28 and 33 % (placebo: 2 %), respectively, and mean increases in HDL-C were 13 and 16 % (placebo: 3 %), respectively.

Clinical Studies in Children and Adolescents (10-17 years of age)

In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and above and 76 girls who were at least one year post-menarche) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (heFH) were randomized to Simvastatin Taj Pharma or placebo for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400mg/dL and at least one parent with an LDL-C level > 189mg/dL. The dosage of Simvastatin Taj Pharma (once daily in the evening) was 10mg for the first 8 weeks, 20mg for the second 8 weeks, and 40mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received Simvastatin Taj Pharma 40mg or placebo.

Simvastatin Taj Pharma significantly decreased plasma levels of LDL-C, TG, and Apo B. Results from the extension at 48 weeks were comparable to those observed in the base study. After 24 weeks of treatment, the mean achieved LDL-C value was 124.9mg/dL (range: 64.0-289.0mg/dL) in the Simvastatin Taj Pharma 40mg group compared to 207.8mg/dL (range: 128.0-334.0mg/dL) in the placebo group.

After 24 weeks of Simvastatin Taj Pharma treatment (with dosages increasing from 10, 20 and up to 40mg daily at 8- week intervals),Simvastatin Taj Pharma decreased the mean LDL-C by 36.8 % (placebo: 1.1 % increase from baseline), Apo B by 32.4 % (placebo: 0.5 %), and median TG levels by 7.9 % (placebo: 3.2 %) and increased mean HDL-C levels by 8.3 % (placebo: 3.6 %). The long-term benefits of Simvastatin Taj Pharma on cardiovascular events in children with heFH are unknown. The safety and efficacy of doses above 40mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of Simvastatin Taj Pharma therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

• Pharmacokinetic properties

Simvastatin Taj Pharma is an inactive lactone which is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.

The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data in children and adolescents are not available.

Absorption

In man Simvastatin Taj Pharma is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the beta-hydroxyacid to the systemic circulation following an oral dose of Simvastatin Taj Pharma was found to be less than 5 % of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hours after administration of Simvastatin Taj Pharma. Concomitant food intake does not affect the absorption.

The pharmacokinetics of single and multiple doses of Simvastatin Taj Pharma showed that no accumulation of medicinal product occurred after multiple dosing.

Distribution

The protein binding of Simvastatin Taj Pharma and its active metabolite is > 95 %.

Elimination

Simvastatin Taj Pharma is taken up actively into the hepatocytes by the transporter OATP1B1. Simvastatin Taj Pharma is a substrate of CYP3A4 (see sections 4.3 and 4.5). The major metabolites of Simvastatin Taj Pharma present in human plasma are the beta-hydroxyacid and four additional active metabolites. Following an oral dose of radioactive Simvastatin Taj Pharma to man, 13 % of the radioactivity was excreted in the urine and 60 % in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile as well as unabsorbed medicinal product. Following an intravenous injection of the beta-hydroxyacid metabolite, its half-life averaged 1.9 hours. An average of only 0.3 % of the IV dose was excreted in urine as inhibitors.

Special populations

Carriers of the SLCO1B1 gene c.521T>C allele have lower OATP1B1 activity. The mean exposure (AUC) of the main active metabolite, Simvastatin Taj Pharma acid is 120 % in heterozygote carriers (CT) of the C allele and 221 % in homozygote (CC) carriers relative to that of patients who have the most common genotype (TT). The C allele has a frequency of 18 % in the European population. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of Simvastatin Taj Pharma, which may lead to an increased risk of rhabdomyolysis (see section 4.4).

• Preclinical safety data

Based on conventional animal studies regarding pharmacodynamics, repeated dose toxicity, genotoxicity and carcinogenicity, there are no other risks for the patient than may be expected on account of the pharmacological mechanism. At maximally tolerated doses in both the rat and the rabbit, Simvastatin Taj Pharma produced no foetal malformations, and had no effects on fertility, reproductive function or neonatal development.

6. Pharmaceutical particulars

• List of excipients

Tablet core:

Lactose monohydrate, Cellulose, microcrystalline, Starch (maize) pregelatinised 1500, Butylhydroxyanisole, Ascorbic acid, Citric acid, anhydrous, Silica, colloidal anhydrous, Talc, Magnesium stearate

Tablet coating:

Hypromellose, Iron oxide, red, Iron oxide, yellow, Triethyl citrate, Titanium dioxide, Talc, Povidone K-30

• Incompatibilities

Not applicable.

• Shelf life

3 years.

Shelf life after first opening of the HDPE container: 6 months

• Special precautions for storage

Do not store above 30°C. Store in the original package, in order to protect from light and moisture.

After first opening of the HDPE container: Store below 25°C.

• Nature and contents of container

PVC/PVDC/Aluminium blister(s).

HDPE (High-Density PolyEthylene) container with PP (PolyPropylene) cap.

Pack sizes:
Blisters:

10, 20, 28, 30, 50, 60, 98 and 100 tablets.

Tablet container: (100, 250 and 500 tablets.)

Not all pack sizes may be marketed.

• Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements

Manufactured in India by:
Taj PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Simvastatin Tablets USP 10mg Taj Pharma

Package leaflet: Information for the patient.

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Simvastatin Taj Pharma is and what it is used for
2. What you need to know before you take Simvastatin Taj Pharma
3. How to take Simvastatin Taj Pharma
4. Possible side effects
5. How to store Simvastatin Taj Pharma
6. Contents of the pack and other information

1.What Simvastatin Taj Pharma is and what it is used for

Simvastatin Taj Pharma contains the active substance simvastatin. Simvastatin Taj Pharma is a medicine used to lower levels of total cholesterol, “bad” cholesterol (LDL cholesterol), and fatty substances called triglycerides in the blood. In addition Simvastatin Taj Pharma raises levels of “good” cholesterol (HDL cholesterol). Simvastatin Taj Pharma is a member of the class of medicines called statins.

Cholesterol is one of several fatty substances found in the bloodstream. Your total cholesterol is made up mainly of LDL and HDL cholesterol.

LDL cholesterol is often called “bad” cholesterol because it can build up in the walls of your arteries forming plaque. Eventually this plaque build-up can lead to a narrowing of the arteries.

This narrowing can slow or block blood flow to vital organs such as the heart and brain. This blocking of blood flow can result in a heart attack or stroke.

HDL cholesterol is often called “good” cholesterol because it helps keep the bad cholesterol from building up in the arteries and protects against heart disease.

Triglycerides are another form of fat in your blood that may increase your risk for heart disease.

You should stay on a cholesterol-lowering diet while taking this medicine.

Simvastatin Taj Pharma is used in addition to your cholesterol lowering diet if you have:

• a raised cholesterol level in your blood (primary hypercholesterolaemia) or elevated fat levels in your blood (mixed hyperlipidaemia).
• a hereditary illness (homozygous familial hypercholesterolaemia) that increases the cholesterol level in your blood. You may also receive other treatments.
• coronary heart disease (CHD) or are at high risk of CHD (because you have diabetes, history of stroke, or other blood vessel disease). Simvastatin Taj Pharma may prolong your life by reducing the risk of heart disease problems, regardless of the amount of cholesterol in your blood.

In most people, there are no immediate symptoms of high cholesterol. Your doctor can measure your cholesterol with a simple blood test. Visit your doctor regularly, keep track of your cholesterol, and discuss your goals with your doctor.

2. What you need to know before you take Simvastatin Taj Pharma

Do not take Simvastatin Taj Pharma

• if you are allergic (hypersensitive) to simvastatin or any of the other ingredients of this medicine (listed in section 6: Contents of the pack and other information).
• if you currently have liver problems
• if you are pregnant or breast-feeding
• if you are taking medicine(s) with one or more than one of the following active ingredients::
  • itraconazole, ketoconazole, posaconazole or voriconazole (used to treat fungal infections)
  • erythromycin, clarithromycin or telithromycin (used to treat infections)
  • HIV protease inhibitors such as indinavir, nelfinavir, ritonavir, and saquinavir (HIV protease inhibitors are used for HIV infections)
  • boceprevir or telaprevir (used to treat hepatitis C virus infection)
  • nefazodone (used to treat depression)
  • cobicistat
  • gemfibrozil (used to lower cholesterol)
  • ciclosporin (used in organ transplant patients)
  • danazol (a man-made hormone used to treat endometriosis, a condition in which the lining of the uterus grows outside the uterus).
• if you are taking or have taken in the last 7 days, a medicine called fusidic acid (a medicine for bacterial infection) orally or by injection. The combination of fusidic acid and Simvastatin Taj Pharma can lead to serious muscle problems (rhabdomyolysis)
• Do not take more than 40mg Simvastatin Taj Pharma if you are taking lomitapide (used to treat a serious and rare genetic cholesterol condition)

Ask your doctor if you are not sure if your medicine is listed above.

Warnings and precautions

Tell your doctor:

• about all your medical conditions including allergies.
• if you drink large amounts of alcohol.
• if you have ever had liver disease. Simvastatin Taj Pharma may not be right for you.
• if you are due to have an operation. You may need to stop taking Simvastatin Taj Pharma tablets for a short time.
• if you are Asian, because a different dose may be applicable to you.
• Your doctor should do a blood test before you start taking simvastatin and if you have any symptoms of liver problems while you take simvastatin. This is to check how well your liver is working.
• Your doctor may also want you to have blood tests to check how well your liver is working after you start taking simvastatin
• While you are on this medicine your doctor will monitor you closely if you have diabetes or are at risk of developing diabetes. You are likely to be at risk of developing diabetes if you have high levels of sugars and fats in your blood, are overweight and have high blood pressure.
• Tell your doctor if you have severe lung disease.

Contact your doctor immediately if you experience unexplained muscle pain, tenderness, or weakness. This is because on rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage; and very rare deaths have occurred.

The risk of muscle breakdown is greater at higher doses of simvastatin, particularly the 80-mg dose. The risk of muscle breakdown is also greater in certain patients. Talk with your doctor if any of the following applies:

• you consume large amounts of alcohol
• you have kidney problems
• you have thyroid problems
• you are 65 years or older
• you are female
• you have ever had muscle problems during treatment with cholesterol-lowering medicines called “statins” or fibrates
• you or a close family member have a hereditary muscle disorder.

Also tell your doctor or pharmacist if you have a muscle weakness that is constant. Additional tests and medicines may be needed to diagnose and treat this.

Children and adolescents

Safety and effectiveness of simvastatin have been studied in 10-17 year old boys and in girls who had started their menstrual period (menstruation) at least one year before (see section 3: How to take Simvastatin Taj Pharma). Simvastatin Taj Pharma has not been studied in children under the age of 10 years. For more information, talk to your doctor.

Other medicines and Simvastatin Taj Pharma

Tell your doctor if you are taking, have recently taken or might take any other medicine(s) with any of the following active ingredients. Taking simvastatin with any of the following medicines can increase the risk of muscle problems (some of these have already been listed in the above section “Do not take Simvastatin Taj Pharma.”)

• If you need to take oral fusidic acid to treat a bacterial infection you will need to temporarily stop using this medicine. Your doctor will tell you when it is safe to restart Simvastatin Taj Pharma.

Taking Simvastatin Taj Pharma with fusidic acid may rarely lead to muscle weakness, tenderness or pain

(rhabdomyolysis). See more information regarding rhabdomyolysis in section 4.

• ciclosporin (often used in organ transplant patients),
• danazol (a man-made hormone used to treat endometriosis, a condition in which the lining of
• the uterus grows outside the uterus),
• medicines with an active ingredient like itraconazole, ketoconazole, fluconazole posaconazole, or voriconazole (used to treat fungal infections),
• fibrates with an active ingredient like gemfibrozil and bezafibrate (used to lower cholesterol),
• erythromycin, clarithromycin or telithromycin, (used to treat bacterial infections),
• HIV protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir (used to treat AIDS),
• Hepatitis C antiviral agents such as boceprevir, telaprevir, elbasvir or grazoprevir (used to treat hepatitis C virus infection),
• nefazodone (used to treat depression),
• medicines with the active ingredient cobicistat
• amiodarone (used to treat an irregular heartbeat),
• verapamil, diltiazem or amlodipine (used to treat high blood pressure, chest pain associated with heart disease, or other heart conditions),
• lomitapide (used to treat a serious and rare genetic cholesterol condition),
• colchicine (used to treat gout),

As well as the medicines listed above, tell your doctor or pharmacist if you are taking, have

recently taken any other medicines, including those obtained without a prescription.

In particular, tell your doctor if you are taking medicine(s) with any of the following active ingredients:

• medicines with an active ingredient to prevent blood clots, such as warfarin phenprocoumon or acenocoumarol (anticoagulants).
• fenofibrate (also used to lower cholesterol).
• niacin (also used to lower cholesterol)
• rifampicin ( used to treat tuberculosis)

You should also tell any doctor who is prescribing a new medicine for you that you are taking simvastatin.

Simvastatin Taj Pharma with food and drink

Grapefruit juice contains one or more components that alter how the body uses some medicinal products, including simvastatin. Consuming grapefruit juice should be avoided.

Pregnancy and breast-feeding

Do not take Simvastatin Taj Pharma if you are pregnant, trying to get pregnant or think you may be pregnant.

If you get pregnant while taking Simvastatin Taj Pharma, stop taking it immediately and contact your doctor.

Do not take Simvastatin Taj Pharma if you are breast-feeding, because it is not known if the medicine is passed into breast milk.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Simvastatin Taj Pharma is not expected to interfere with your ability to drive or to use machinery. However, it should be taken into account that some people get dizzy after taking simvastatin.

Simvastatin Taj Pharma contains lactose

Simvastatin Taj Pharma tablets contain a sugar called lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. How to take Simvastatin Taj Pharma

Your doctor will determine the appropriate tablet strength for you, depending on your condition, your current treatment and your personal risk status.

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

You should stay on a cholesterol-lowering diet while taking simvastatin.

Dosage:

The recommended dose is simvastatin 5mg, 10mg, 20mg, 40mg, or 80mg tablet by mouth once a day.

Adults:

The usual starting dose is 10, 20 or, in some cases, 40mg a day. Your doctor may adjust your dose after at least 4 weeks to a maximum of 80mg a day. Do not take more than 80mg a day.

Your doctor may prescribe lower doses, particularly if you are taking certain medicinal products listed above or have certain kidney conditions.

The 80mg dose is only recommended for adult patients with very high cholesterol levels and at

high risk of heart disease problems who have not reached their cholesterol goal on lower doses.

Use in children and adolescents:

For children (10 -17 years old), the recommended usual starting dose is 10mg a day in the evening. The maximum recommended dose is 40mg a day.

Method of administration:

Take simvastatin in the evening. You can take it with or without food. Keep taking Simvastatin Taj Pharma unless your doctor tells you to stop.

If your doctor has prescribed Simvastatin Taj Pharma along with another medicine for lowering cholesterol containing any bile acid sequestrant, you should take Simvastatin Taj Pharma at least 2 hours before or 4 hours after taking the bile acid sequestrant.

If you take more simvastatin than you should

• Please contact your doctor or pharmacist.

If you forget to take simvastatin

• Do not take extra double dose to make up for a forgotten tablet just take your normal amount of Simvastatin Taj Pharma at the usual time the next day.

If you stop taking simvastatin

• Talk to your doctor or pharmacist because your cholesterol may rise again.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following terms are used to describe how often side effects have been reported:

Rare (may affect up to 1 of 1000 people),

Very rare (may affect up to 1 of 10,000 people),

Not known (frequency cannot be estimated from the available data),

The following rare serious side effects were reported.

If any of these serious side effects happen, stop taking the medicine and tell your doctor immediately or go to the emergency room at your nearest hospital.

• muscle pain, tenderness, weakness, or cramps. On rare occasions, these muscle problems can be serious, including muscle breakdown resulting in kidney damage; and very rare deaths have occurred.
• hypersensitivity (allergic) reactions including:
• swelling of the face, tongue and throat which may cause difficulty in breathing (angioedema)
• severe muscle pain usually in the shoulders and hips,
• rash with weakness of limbs and neck muscles,
• pain or inflammation of the joints (polymyalgia rheumatica),
• inflammation of the blood vessels (vasculitis),
• unusual bruising, skin eruptions and swelling (dermatomyositis), hives, skin sensitivity to the sun, fever, flushing,
• shortness of breath (dyspnoea) and feeling unwell,
• lupus-like disease picture (including rash, joint disorders, and effects on blood cells),
• inflammation of the liver with the following symptoms: yellowing of the skin and eyes, itching, dark-coloured urine or pale-coloured stool, feeling tired or weak, loss of appetite; liver failure (very rare),
• inflammation of the pancreas often with severe abdominal pain.

The following very rare serious side effect was reported:

• a serious allergic reaction which causes difficulty in breathing or dizziness (anaphylaxis)

The following side effects have also been reported rarely:

• low red blood cell count (anaemia),
• numbness or weakness of the arms and legs,
• headache, tingling sensation, dizziness,
• digestive disturbances (abdominal pain, constipation, flatulence, indigestion, diarrhoea, nausea, vomiting),
• rash, itching, hair loss,
• weakness,
• trouble sleeping (very rare),
• poor memory (very rare), memory loss, confusion.

The following side effects have also been reported but the frequency cannot be estimated from the available information (frequency not known):

• erectile dysfunction,
• depression,
• tendon problems, sometimes complicated by rupture of the tendon,
• inflammation of the lungs causing breathing problems including persistent cough and/or shortness of breath or fever.

Additional possible side effects reported with some statins:

• sleep disturbances, including nightmares,
• sexual difficulties,
• This is more likely if you have high levels of sugars and fats in your blood, are overweight and have high blood pressure. Your doctor will monitor you while you are taking this medicine.
• muscle pain, tenderness, or weakness that is constant that may not go away after stopping Simvastatin Taj Pharma (frequency not known).

Laboratory Values

Elevations in some laboratory blood tests of liver function and a muscle enzyme (creatine kinase) have been observed.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Simvastatin Taj Pharma

Keep this medicine out of the sight and reach of children.

This medicinal product does not require any special storage conditions.

Do not use this medicine after the expiry date which is stated on the blister and carton after

EXP. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Simvastatin Taj Pharma tablets contain

• The active substance is simvastatin (10mg, 20mg, 40mg and 80mg).

Each film-coated tablet contains 10mg simvastatin.

Each film-coated tablet contains 20mg simvastatin.

Each film-coated tablet contains 40mg simvastatin.

• The other ingredients are:

Tablet core:

Butylated hydroxyanisole

Ascorbic acid

Citric acid monohydrate

Microcrystalline cellulose

Pregelatinised maize starch

Lactose monohydrate

Magnesium stearate

Film coating:

Hypromellose

Hydroxypropyl cellulose

Titanium dioxide

Talc

Iron oxide yellow – For 10 and 20mg

Iron oxide red – For 10, 20, 40 and 80mg

What Simvastatin Taj Pharma tablets looks like and contents of the pack

Film-coated tablets

Simvastatin Taj Pharma 10mg film-coated tablets:

Light pink coloured, round shaped, biconvex, film coated tablets.

Simvastatin Taj Pharma 20mg film-coated tablets:

Light pink coloured, round shaped, biconvex, film coated tablets.

Simvastatin Taj Pharma 40mg film-coated tablets:

Pink coloured, round shaped, biconvex, film coated tablets.

Simvastatin Taj Pharma 10mg, 20mg and 40mg film-coated tablets are available in blister packs containing 10, 14, 28, 30, 50, 56, 84, 90, 98 and 100 tablets.

Simvastatin Taj Pharma 10, 20 and 40 film-coated tablets are also available in bottle packs containing 250, 500 and 1000 tablets (for hospital or dose dispensing use only).

Not all pack sizes may be marketed

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com