INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
ASPEN SIMVASTATIN 10 MG (TABLET)
ASPEN SIMVASTATIN 20 MG (TABLET)
ASPEN SIMVASTATIN 40 MG (TABLET)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ASPEN SIMVASTATIN 10 MG (TABLET)
ASPEN SIMVASTATIN 20 MG (TABLET)
ASPEN SIMVASTATIN 40 MG (TABLET)

COMPOSITION
Each tablet contains:
ASPEN SIMVASTATIN 10 MG: Simvastatin 10 mg (active ingredient), 2,50% m/m ascorbic acid (antioxidant), 0,02% m/m butylated hydroxyanisole (antioxidant)
ASPEN SIMVASTATIN 20 MG: Simvastatin 20 mg (active ingredient), 5,0% m/m
ascorbic acid (antioxidant), 0,04% m/m butylated hydroxyanisole (antioxidant)
ASPEN SIMVASTATIN 40 MG: Simvastatin 40 mg (active ingredient), 10,00% m/m
ascorbic acid (antioxidant), 0,08% m/m butylated hydroxyanisole (antioxidant)

PHARMACOLOGICAL CLASSIFICATION
A 7.5 Serum-cholesterol reducers

PHARMACOLOGICAL ACTION
Simvastatin is a cholesterol-lowering agent derived synthetically from a fermentation
product of Aspergillus terreus. After oral ingestion simvastatin, an inactive lactone, is hydrolysed to the corresponding beta-hydroxyacid, the active form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase , the enzyme that catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol. As a result, simvastatin, reduces total plasma cholesterol, low-density lipoprotein (LDL)- and very low-density lipoprotein (VLDL)-cholesterol concentrations. Apolipoprotein B is also decreased.
In addition, simvastatin moderately increases high-density lipoprotein (HDL)-cholesterol and variably reduces plasma triglycerides.
Pharmacokinetics:
There is extensive first-pass extraction by the liver, with oral bioavailability of the active medicine or metabolites being less than 5%. More than 95% of simvastatin and its beta-hydroxy metabolite are bound to plasma proteins. Following an oral dose, peak plasma concentrations of simvastatin are seen in 1 to 2 hours. Simvastatin is excreted primarily via the liver, and less than 13% of its metabolites are excreted in the urine.

INDICATIONS
HYPERCHOLESTEROLAEMIA
ASPEN SIMVASTATIN is indicated, in combination with diet, to decrease elevated serum total cholesterol and LDL-cholesterol in patients with:

•	Primary hypercholesterolaemia,
•	Heterozygous familial hypercholesterolaemia, or
•	Mixed hyperlipidaemia, when response to diet or other non-pharmacological measures alone is not adequate.

CORONARY HEART DISEASE
ASPEN SIMVASTATIN is indicated in patients with coronary heart disease and hypercholesterolaemia unresponsive to diet, to:

•	Reduce the risk of total mortality, by reducing coronary death,
•	Reduce the risk of non-fatal myocardial infarction,
•	Reduce the risk of undergoing myocardial revascularisation procedures (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty), and
•	Slow the progression of coronary atherosclerosis.

CONTRA-INDICATIONS
Hypersensitivity to simvastatin, other HMG-CoA reductase inhibitors, or any of the ingredients.
Acute or chronic liver disease.
Unexplained persistent elevations of serum transaminases.
Pregnancy and lactation (see WARNINGS).
Porphyria: Safety has not been established.

WARNINGS
The active metabolite of ASPEN SIMVASTATIN is fetotoxic and teratogenic in rats, and it should therefore not be used in female patients of child-bearing potential.
Use in paediatric patients is not recommended, as safety and efficacy have not been established.

INTERACTIONS
Myopathy caused by medicine interactions:
Concomitant administration of medicines that inhibit cytochrome P450 isoenzyme CYP3A4 may result in high plasma levels of ASPEN SIMVASTATIN, thus increasing the risk of myopathy, and is not recommended. Medicines that inhibit cytochrome P450 isoenzyme CYP3A4 include: cyclosporin, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV-protease inhibitors and nefazodone.
The risk of myopathy is increased when other medicines that cause myopathy, such as fibrates and niacin, are given with ASPEN SIMVASTATIN. A maximum dose of 10 mg ASPEN SIMVASTATIN daily is recommended in patients taking cyclosporin, fibrates or lipid lowering doses of niacin (nicotinic acid).
Digoxin
ASPEN SIMVASTATIN may cause increases in digoxin levels.
Coumarin-derivatives (eg. Warfarin)
A possible increase in the anticoagulant effect of the coumarin anticoagulants may occur. Patients taking a coumarin anticoagulant should have their INR determined before starting ASPEN SIMVASTATIN therapy. The INR should be monitored frequently enough in the early stages of therapy until stabilised. Once a stable INR has been documented, INR can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. When there is a dose adjustment of ASPEN SIMVASTATIN, this procedure should be repeated.
Bile acid sequestrants
ASPEN SIMVASTATIN should be taken 1 hour before or 4 hours after cholestyramine. Concurrent use may decrease the bioavailability of ASPEN SIMVASTATIN.

PREGNANCY AND LACTATION
Safety in pregnancy and lactation has not been established.
The active metabolite of ASPEN SIMVASTATIN is fetotoxic and teratogenic in rats, and it should therefore not be used in female patients of child-bearing potential.

DOSAGE AND DIRECTIONS FOR USE
The patient must follow a cholesterol-lowering diet before initiation of, and while on ASPEN SIMVASTATIN therapy.
HYPERCHOLESTEROLAEMIA
Adults: Initial dose: 10 mg daily as a single dose in the evening.
The dose of ASPEN SIMVASTATIN should be reduced if LDL-cholesterol levels fall below 1,94 mmol/, or total plasma cholesterol levels fall below 3,6 mmol/L.

CORONARY HEART DISEASE
Adults: Initial dose: 20 mg/day as a single dose in the evening.
Dosage Adjustments:
If required, the dose should be adjusted at intervals of not less than 4 weeks, up to a maximum of 80 mg daily as a single dose in the evening.
ASPEN SIMVASTATIN can be taken with meals or on an empty stomach.

DOSAGE IN RENAL INSUFFICIENCY
ASPEN SIMVASTATIN does not undergo significant renal excretion, therefore modification of dose should not be necessary in patients with mild to moderate renal insufficiency. In patients with severe renal insufficiency ASPEN SIMVASTATIN therapy should be closely monitored and doses above 10 mg/day should be implemented with caution.

CONCOMITANT THERAPY
ASPEN SIMVASTATIN is effective alone or in combination with bile acid sequestrants.
When both medicines are prescribed, ASPEN SIMVASTATIN should be given 1 hour before or 4 hours after cholestyramine administration (See INTERACTIONS).
A maximum daily dose of 10 mg ASPEN SIMVASTATIN is recommended in patients taking cyclosporin, fibrates or niacin concomitantly (See INTERACTIONS).

SIDE-EFFECT AND SPECIAL PRECAUTIONS
Side-effects:
Gastro-intestinal:
Constipation, diarrhoea, nausea, vomiting, flatulence, dyspepsia, abdominal pain, cramps, and pancreatitis.
Haematological:
Anaemia, neutropenia.
Skin and appendages:
Skin rash, alopecia.
Musculoskeletal:
Frequent: Myalgia, muscle cramps.
Less frequent: Myopathy, myositis, rhabdomyolysis presenting as muscle pain with
elevated creatine phosphokinase and myoglobinuria leading to renal failure.
Neurological:
Headache, dizziness, fatigue, aesthaenia, paraesthesia, peripheral neuropathy.
Hypersensitivity reactions:
Less frequent: reactions may include angioedema, lupus-like syndrome, polymyalgia rheumatica, vasculitis, thrombocytopenia, increased erythrocyte sedimentation rate, eosinophilia, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, malaise, and dyspnoea.
Other:
Mass gain has been reported.

LABORATORY TEST FINDINGS
Marked and persistent increases of serum transaminases and elevated alkaline phosphatase and gamma-glutamyl transpeptidase have been reported. Liver function test abnormalities have generally been mild and transient. Increases in serum creatinine kinase (CK) levels, derived from skeletal muscle, have been reported (See SPECIAL PRECAUTIONS).
Special precautions:
ASPEN SIMVASTATIN should be used with caution in patients who:

•	Consume substantial amounts of alcohol and/or who have a history of liver disease.
•	May be predisposed to developing renal failure secondary to rhabdomyolysis such as in those with severe acute infection, hypotension, severe metabolic, endocrine or electrolyte disorders, uncontrolled seizures, major surgery or trauma. There is an increased risk of developing renal failure if rhabdomyolysis occurs.
•	Have severe renal impairment.

Hepatic Effects:
Liver function tests, including serum transaminase determinations are recommended prior to initiation of ASPEN SIMVASTATIN therapy and periodically until one year after the last elevation in dose. ASPEN SIMVASTATIN should be discontinued if the rise in transaminase levels is persistent and/or increases to three times or more the Upper Limit of Normal (ULN).
Myopathy
Reducing the risk of myopathy:
1. General measures
Patients starting therapy with ASPEN SIMVASTATIN should be advised of the risk of myopathy and should report, promptly, unexplained muscle pain, tenderness or weakness. A creatinine kinase (CK) level above 10 times the Upper Limit of Normal (ULN) in a patient, with unexplained symptoms, indicates myopathy. ASPEN SIMVASTATIN should be discontinued if myopathy is diagnosed or suspected.
2. Measures to reduce the risk of myopathy caused by medicine interactions
The benefits and risks of using ASPEN SIMVASTATIN concomitantly with immunosuppressants, fibrates or lipid-lowering doses of niacin should be carefully considered, and the dose of ASPEN SIMVASTATIN should generally not exceed 10 mg/day. Concomitant administration with cyclosporin, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV-protease inhibitors and nefazodone, is not recommended.
In patients receiving cyclosporin, ASPEN SIMVASTATIN should be temporarily discontinued if systemic azole-derivative antifungal therapy is required.

KNOWN SYMPTOMS OF OVER-DOSAGE AND PARTICULARS OF ITS TREATMENT
(See SIDE-EFFECTS AND SPECIAL PRECAUTIONS)
General measures should be adopted and liver function should be monitored.
Treatment is symptomatic and supportive.

IDENTIFICATION
ASPEN SIMVASTATIN 10 MG TABLETS: Dark peach to pink coloured, oval shaped, bisected film-coated tablet with “SM/10”on one side.
ASPEN SIMVASTATIN 20 MG TABLETS: Dark tan coloured, oval shaped, bisected film-coated tablet with SM/20 on one side.
ASPEN SIMVASTATIN 40 MG TABLETS: Pink coloured, oval shaped, bisected film-coated tablet with SM/40 on one side.

PRESENTATION
Blister strips of 10 tablets with clear, colourless, plastic blister and silver aluminum foil.
Blisters strips are packed in cartons containing 30 tablets.

STORAGE INSTRUCTIONS
Store in a dry place below 25ºC.
Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
ASPEN SIMVASTATIN 10 MG: 37/7.5/0335
ASPEN SIMVASTATIN 20 MG: 37/7.5/0336
ASPEN SIMVASTATIN 40 MG: 37/7.5/0337

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
PHARMACARE LIMITED
Building 12, Healthcare Park
Woodlands Drive, Woodmead
Johannesburg, South Africa

DATE OF PUBLICATION OF THE PACKAGE INSERT
18 August 2004

575002/05/05/11
UNIPRINT - POS

New addition to this site: August 2006
Source: Pharmaceutical Industry
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