COMPOSITION
ZOCOR ^® 10 mg film-coated tablets: Each tablet contains: Active substance: simvastatin 10 mg; Excipients: monohydrated lactose, butylated hydroxyanisole, ascorbic acid, monohydrated citric acid, microcrystalline cellulose, pregelatinised starch, magnesium stearate, hypromellose, hydroxypropylcellulose, titanium dioxide, talc, yellow iron oxide, red iron oxide.
ZOCOR ^® 20 mg film-coated tablets:Each tablet contains: Active substance: simvastatin 20 mg. Excipients: monohydrated lactose, butylated hydroxyanisole, ascorbic acid, monohydrated citric acid, microcrystalline cellulose, pregelatinised starch, magnesium stearate, hypromellose, hydroxypropylcellulose, titanium dioxide, talc, yellow iron oxide, red iron oxide.
ZOCOR ^® 40 mg film-coated tablets:Each tablet contains: Active substance: simvastatin 40 mg. Excipients: monohydrated lactose, butylated hydroxyanisole, ascorbic acid, monohydrated citric acid, microcrystalline cellulose, pregelatinised starch, magnesium stearate, hypromellose, hydroxypropylcellulose, titanium dioxide, talc, yellow iron oxide, red iron oxide.

PHARMACEUTICAL FORM AND CONTENT
ZOCOR 10 mg film-coated tablets: pack of 20 tablets of 10 mg
ZOCOR 20 mg film-coated tablets: pack of 10 tablets of 20 mg
ZOCOR 40 mg film-coated tablets: pack of 10 tablets of 40 mg

PHARMACOTHERAPEUTIC CATEGORY
ZOCOR is an inhibitor of the enzyme hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), belonging to the group of drugs that reduce cholesterol.

INDICATIONS
ZOCOR is indicated: As an adjunct to diet in patients with primary familial hypercholesterolaemia (heterozygous variant) including mixed hyperlipidaemia (corresponding to type IIa and IIb of the Fredrickson classification) when response to diet and other non-pharmacological measures is inadequate.
In patients with coronary heart disease to reduce the risk of mortality due to coronary artery disease, coronary events, myocardial infarction, cerebrovascular events, and the risk of undergoing revascularisation surgery (aorto-coronary bypass and translumen percutaneous coronary angioplasty.

CONTRAINDICATIONS
ZOCOR should not be used: In patients who are hypersensitive/allergic to the active substance, one of the excipients or substances which are closely related chemically; In patients with active liver disease or persistent transaminase elevations; In case of concomitant therapy with mibefradil, a calcium antagonist belonging to the tetralol class (see also PRECAUTIONS FOR USE and INTERACTIONS. In women who are known or believed to be pregnant or lactating (see also SPECIAL WARNINGS) - Pregnancy and Lactation): In children (see section PRECAUTIONS FOR USE).

PRECAUTIONS FOR USE
Inform your doctor of any current or past disease or medical problem or if you have any allergy. It is particularly important to tell your doctor if you have had any liver disease in the past and if you consume large quantities of alcohol (see Hepatic effects).
Muscle effects(myopathy/rhabdomyolysis): Simvastatin and other inhibitors of HMG-CoA reductase can occasionally cause myopathy which is manifested as muscle pain or weakness associated with elevated levels of creatine kinase (CK) greater than 5 times the upper limit of normal. Myopathy is sometimes manifested in the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria and there have been rare cases of death. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in the plasma (see section UNDESIRABLE EFFECTS and INTERACTIONS).
The risk of myopathy/rhabdomyolysis is dose-dependent. The incidence in clinical studies, where patients were closely monitored and in which excluded drugs known to cause interactions, was 0.03% at about 20 mg and 0.08% at 40 mg and 0.4 at 80 mg.
The concomitant use of simvastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors or nefazodone should be avoided. If therapy with itraconazole, ketoconazole, erythromycin or clarithromycin cannot be avoided, treatment with simvastatin should be suspended during therapy. The concomitant use of simvastatin with mibefradil is contraindicated. Combined use with other drugs, the technical specifications of which indicate a potent inhibitory effect on the activity of CYP3A4 at therapeutic doses, should be avoided unless the beneficial effects of the combination therapy outweigh the increased risk.
In patients taking concomitant cyclosporin, gemfibrozil, other fibrates or lipid lowering doses of niacin (≥ 1 g/day), the dosage of simvastatin should not exceed 10 mg/day. The concomitant use of simvastatin with fibrates or niacin should be avoided unless the benefits of the increased effect on lipid levels is likely to be greater than the increased risk of the combination. Addition of these drugs to simvastatin typically provides a mild reduction of C-LDL but it is possible to achieve a further reduction of TG and further increases of C-HDL. The combination of simvastatin with fibrates and niacin has been used without cases of myopathy in short-term clinical studies with limited number of patients and close monitoring.
The dosage of simvastatin should not exceed 20 mg/day in patients receiving concomitant therapy with amiodarone or verapamil. The concomitant use of simvastatin at doses higher than 20 mg/day and amiodarone should be avoided unless the clinical benefits outweigh the increased risk of myopathy.

Measurement of creatine-kinase levels: Patients starting therapy with simvastatin or who increase the dosage should have their CK levels monitored periodically but there is no guarantee that this monitoring will prevent myopathy. The CK levels should not be measured in the presence of other factors that can cause transient muscle damage such as strenuous exercise or muscle trauma as this would render interpretation difficult. If the CK levels are significantly elevated (greater than 5 times the upper limits of normal) these should be re-measured after 5-7 days for confirmation before starting therapy.
Before treatment: all patients starting therapy with simvastatin or who increase the dosage, should be informed of the increased risk of myopathy and told to report immediately any type of muscle pain, tenderness or weakness of unknown cause. Statins should be prescribed with caution in patients with predisposing factors for rhabdomyolysis such as: renal damage, hypothyroidism, history of muscle toxicity with a statin or fibrate, personal or family history of hereditary muscle disorders, alcohol abuse. In these cases the CK levels should be measured before commencing treatment. Measurement of CK levels should also be considered in patients aged over 70 years, particularly in the presence of predisposing factors. If the CK levels are significantly elevated (greater than 5 times the upper limits of normal), treatment should not be started and the levels should be re-assessed after 5-7 days. In the above-mentioned cases, the risk of treatment should we weighed against the potential benefit and, in case of treatment, close monitoring of the patient is recommended.

During treatment: if during treatment with statins the patient reports onset of muscle tenderness, weakness or cramps with no apparent cause, the CK levels should be measured. In case of markedly high CK levels (greater than 5 times the upper limits of normal), statin therapy should be stopped. In addition, in case of severe muscle symptoms causing daily discomfort, even if the CK values remain below 5 times the upper limits of normal, discontinuation of the therapy should be considered. If the symptoms regress and the CK levels return to normal, consideration can be given to therapy with a lower dosage and with strict monitoring.
Treatment with simvastatin should be suspended a few days before major elective surgery and if important medical-surgical conditions arise.

Hepatic effect In clinical studies, some patients receiving simvastatin experienced marked and persistent increases in serum transaminases (up to 3 times the maximum limit of normal). When the drug was discontinued or suspended in these patients, the levels of transaminases usually slowly returned to pre-treatment levels. The increases were not associated with jaundice or any other clinical signs or symptoms. There was no evidence of hypersensitivity. Some of these patients exhibited altered hepatic function parameters prior to treatment with simvastatin and/or consumed considerable quantities of alcohol. It is recommended that live-function tests be performed in all patients before treatment begins and periodically thereafter (e.g. twice a year) during the first year of treatment or until one year after the last dose elevation. 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 three times the upper limit o normal and are persistent, the drug should be discontinued.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.

Ophthalmic examination In the absence of any drug therapy, an increase in the prevalence of lens opacities is expected as a result of ageing. Current long-term data from clinical trials does not indicate an adverse effect of simvastatin on the human lens.

Familial homozygous hypercholesterolaemia In patients with the familial homozygous hypercholesterolaemia form, in whom there is a complete absence of LDL, it is unlikely that a clinical benefit can be obtained from ZOCOR therapy.

Hypertriglyceridaemia ZOCOR only has a moderate effect on the reduction of triglycerides and is not indicated where hypertriglyceridaemia is the abnormality of most concern. (e.g. hyperlipidaemia type I, IV and V).

Use in the elderly In patients over 65 years of age who received simvastatin in controlled clinical studies, the efficacy of the drug, assessed in terms of a reduction of the levels of total cholesterol and LDL cholesterol, was similar to that observed in the entire group of subjects; an increase in the frequency of clinical or laboratory undesirable effects was seen.

INTERACTIONS
Interactions and risk of myopathy/rhabdomyolysis The risk of myopathy/rhabdomyolysis is increased with the concomitant use of the following drugs: Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of simvastatin. Cyclosporin, mibefradil, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors or nefadozone, especially with elevated doses of simvastatin (see section PRECAUTIONS FOR USE).
Interactions with lipid lowering drugs that can cause myopathy, even if administered alone.The risk of myopathy is increased also by the following lipid lowering drugs that are not potent inhibitors of CYP3A4 but which can cause myopathy even if used alone: gemfibrozil, other fibrates or niacin administered at lipid lowering dosages (≥ 1 g/day), especially with elevated doses of simvastatin (see section PRECAUTIONS FOR USE). Other drugs: amiodarone or verapamil, with elevated dosages of simvastatin (See section PRECAUTIONS FOR USE). In a clinical study under way, myopathy was observed in 6% of patients treated with 80 mg of simvastatin and amiodarone.
Diltiazem: patients treated concomitantly with simvastatin 80 mg have a slightly increased risk of myopathy. In these patients the risk of myopathy is equivalent to approximately 1%.
In clinical studies, the risk of myopathy in patients receiving 40 mg simvastatin therapy and diltiazem, was similar to the risk of patients treated with 40 mg simvastatin without diltiazem (see section PRECAUTIONS FOR USE).
Other interactions
Digoxin: Concomitant administration of simvastatin and digoxin to healthy volunteers has caused a slight increase (less than 0.3 ng/ml) in the plasma concentrations of the drug (measured using the radio-immuno-assay method) compared to concomitant administration with the placebo and digoxin.
Coumarin derivatives: In two clinical studies one in healthy volunteers and the other in hypercholesterolaemia patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as INR (International Normalised Ratio), increased from a baseline of 1.7 to 1.8 in healthy volunteers and 2.6 -3.4 in the hypercholesterolaemia patients. In patients taking coumarin anticoagulants, prothrombin time should be should be determined before starting simvastatin 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 regularly recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

SPECIAL WARNINGS
Pregnancy ZOCOR is contraindicated during pregnancy. Treatment with Zocor should be suspended for the entire period of pregnancy or until it has been ascertained that the woman is not pregnant (see section CONTRAINDICATIONS). If the patient becomes pregnant whilst receiving ZOCOR therapy, the drug must be discontinued immediately and the doctor consulted who will provide information on the risk to the foetus.
Lactation: It is not known whether simvastatin or its metabolites are excreted in human milk. Since many drugs are excreted in human milk and in view of the potential for serious undesirable reactions caused by ZOCOR in breast-feeding infants, women taking ZOCOR should not breast-feed (see section CONTRAINDICATIONS).
Paediatric use: No studies have been conducted to show safety and efficacy in children.
At present, ZOCOR should not be used in children (see section CONTRAINDICATIONS).
Effects on the ability to drive and operate machinery: No interference.

DOSE, METHOD AND TIME OF ADMINISTRATION
The patient should be placed on a standard cholesterol lowering diet before receiving ZOCOR and should continue on this diet during treatment with ZOCOR.
Hypercholesterolaemia: The starting dose is usually 10 mg/day as a single dose taken in the evening. Dosage adjustments, if required, can be made at intervals of not less than 4 weeks up to a maximum of 40 mg/day administered in a single dose in the evening.
If the levels of cholesterol-LDL fall below 75 mg/dl (1.94 mmol/l) or if the levels of plasma total cholesterol fall below 140 mg/dl (3.6 mmol/l) a reduction in the dosage of ZOCOR should be considered.
Coronary heart disease: Patients with coronary heart disease can be treated with a starting dose of 20 mg/day given as a single dose in the evening. Adjustment of dosage, if required, should be made as described in the previous paragraph (see section DOSE, METHOD AND TIME OF ADMINISTRATION - Hypercholesterolaemia).
Concomitant therapy: ZOCOR is effective alone or in combination with bile-acid sequestrants. In patients taking concomitant cyclosporin, fibrates or niacin, amiodarone or verapamil with simvastatin, see section PRECAUTIONS FOR USE - Muscle effects.
Dosage in renal impairment: Since ZOCOR does not undergo significant renal excretion, no dosage adjustments are required in patients with moderate renal impairment. In patients with severe renal impairment (creatinine clearance less than 30 ml/min), dosages higher than 10 mg/day should be carefully assessed and, if considered necessary, increased with caution.

OVERDOSE
If you think you have taken an excessive dose of ZOCOR, contact your doctor immediately. Some cases of overdose have been reported. No specific symptoms have been reported and all patients recovered without sequellae. The maximum dose taken was 450 mg. In case of overdose, general measures should be taken.

UNDESIRABLE EFFECTS
Any drug can have unforeseen or undesirable effects, so-called side effects. The majority of side effects were mild and transient in nature. Fewer than 2% of patients abandoned the controlled clinical studies due to undesirable effects attributable to ZOCOR. In all the pre-marketing controlled clinical studies, undesirable effects considered by the investigator as possibly, probably or definitely drug related, occurring with a frequency of 1% or more were: abdominal pain, constipation and flatulence. Other undesirable effects occurring in 0.5-0.9% of patients were weakness and headache. Cases of myopathy (muscle disease) have been reported.

Since myopathy can be serious in rare cases, you should contact your doctor immediately in case of pain, tenderness or muscle weakness (see section PRECAUTIONS FOR USE). The following undesirable effects have been reported in uncontrolled clinical studies or with marketed use: nausea, diarrhoea, skin rash, digestive disorders, pruritus, alopecia, dizziness, muscle cramps, muscle pain, pancreatitis, paraesthesia, peripheral neuropathy, vomiting, anaemia. In rare cases, there have been reports of skeletal muscle lesions and liver disease, yellowing of the skin and mucosa. There have been rare reports of apparent hypersensitivity syndrome, including some of the following conditions: swelling of the face, tongue and throat, syndrome similar to SLE, polymyalgia rheumatica (inflammatory disease of the muscles), dermatomyositis (inflammatory disease of the skin and muscles), inflammation of the blood vessels, decreased platelet count, elevated white cell count, eosinophilia, elevated erythrocyte sedimentation rate (ESR), arthritis, joint pain, urticaria, hypersensitivity reaction due to exposure to sunlight, fever, flushing, respiratory difficulties, malaise.
Laboratory test findings: As with all cholesterol lowering agents, following treatment with simvastatin, moderate increases of the serum transaminases have been reported (less than 3 times the maximum limit of normal). These changes, which appeared immediately after the start of simvastatin therapy, were frequently transient and were not accompanied by any other symptomatology and, generally speaking, did not require suspension of the treatment. Marked and persistent increases of serum transaminases have been reported infrequently. Elevated alkaline phosphatase and y-glytamyl transpeptidase have been reported. There have been reports of elevated serum creatine-kinase (CK) levels of skeletal muscle origin (see section PRECAUTIONS FOR USE)
Muscle effects (myopathy/rhabdomyolysis): The following undesirable events have been reported during ZOCOR treatment, but a causal relationship to therapy with the drug has not been demonstrated: depression, erythema multiforme, including Stevens-Johnson syndrome, leucopenia and purpura.
The patient is invited to inform his doctor if any undesirable effects other than those described above are experienced.

EXPIRY AND STORAGE
Expiry: check the expiry date on the pack. The shelf life is quoted for the product in an unopened and correctly stored pack.

IMPORTANT: DO NOT USE THIS MEDICINE AFTER THE EXPIRY DATE PRINTED ON THE PACK. Store below 30ºC.

Keep the medicine out of the reach of children.