INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
SIMASPEN 10 (Tablets)
SIMASPEN 20 (Tablets)
SIMASPEN 40 (Tablets)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

SIMASPEN 10 (Tablets)
SIMASPEN 20 (Tablets)
SIMASPEN 40 (Tablets)

COMPOSITION
Sugar free.
SIMASPEN 10
Each tablet contains simvastatin (micronised) 10 mg.
Also contains
Butylated hydroxyanisole NMT 0,0389% m/m (antioxidant)
Ascorbic acid NMT 2,676% m/m (antioxidant synergist)
Citric acid monohydrate NMT 1,338% m/m (sequesterant)

SIMASPEN 20
Each tablet contains simvastatin (micronised) 20 mg.
Also contains
Butylated hydroxyanisole NMT 0,0389% m/m (antioxidant)
Ascorbic acid NMT 2,676% m/m (antioxidant synergist)
Citric acid monohydrate NMT 1,338% m/m (sequesterant)

SIMASPEN 40
Each tablet contains simvastatin (micronised) 40 mg.
Also contains
Butylated hydroxyanisole NMT 0,0389% m/m (antioxidant)
Ascorbic acid NMT 2,676% m/m (antioxidant synergist)
Citric acid monohydrate NMT 1,338% m/m (sequesterant)

PHARMACOLOGICAL CLASSIFICATION
A 7.5 Serum-cholesterol reducers.

PHARMACOLOGICAL ACTION
Mechanism of action
Simvastatin is a cholesterol-lowering agent derived synthetically from a fermentation product of Aspergillus terreus. Simvastatin, the inactive lactone, is hydrolysed to the beta-hydroxyacid after oral ingestion. The acid is the principal metabolite and inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate. 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 reduces plasma triglycerides.
Pharmacokinetics
There is extensive first pass extraction by the liver, with oral bioavailability of 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:
Simaspen is indicated, in combination with a diet, to decrease elevatedserum 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 are not adequate.
Coronary heart disease: In patients with coronary heart disease and hypercholesterolaemia unresponsive to diet, Simaspen is indicated to

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

CONTRA-INDICATIONS
Simvastatinis contra-indicated in the following conditions:

-	Hypersensitivity to simvastatin, other HMG-CoA reductase inhibitors or any component of this preparation
-	Acute or chronic hepatic diseases or unexplained persistent elevations of serum transaminases
-	Pregnancy and lactation
-	Porphyria: Safety has not been established

WARNINGS
The active metabolite of Simaspen 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.
Simaspen is not effective in severe hypertriglyceridaemia.

INTERACTIONS
Myopathy caused by medicine interactions:
Concomitant administration of medicines that inhibit cytochrome P450 isoenzyme CYP3A4 may result in high plasma levels of Simaspen, 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 Simaspen. A maximum dose of 10 mg Simaspen daily is recommended in patients taking cyclosporin, fibrates or lipid-lowering doses of niacin (nicotinic acid).
Digoxin:
Simaspen may cause increases in digoxin levels.
Coumarin-derivatives (e.g. Warfarin):
A possible increase in the anticoagulant effect of the coumarin anticoagulants may occur. Patients taking a coumarin anticoagulant should have their prothrombin time determined before starting Simaspen therapy. The prothrombin time should be monitored frequently enough in the early stages of therapy until stabilised. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. When there is a dose adjustment of Simaspen, this procedure should be repeated.
Bile acid sequestrants:
Simaspen should be taken 1 hour before or 4 hours after cholestyramine. Concurrent use may decrease the bioavailability of Simaspen.

PREGNANCY AND LACTATION
Safety in pregnancy and lactation has not been established. The active metabolite of Simaspen 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 Simaspen therapy.
Hypercholesterolaemia:
Adults
Initial dose: 10 mg daily as a single dose in the evening.
The dose of Simaspen should be reduced if LDL-cholesterol levels fall below 1,94 mmol/L, 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.
Simaspen can be taken with meals or on an empty stomach.
Dosage In Renal Insufficiency:
Simaspen does not undergo significant renal excretion, thereforemodification of dose should not be necessary in patients with mild to moderate renal insufficiency. In patients with severe renal insufficiency Simaspen therapy should be closely monitored and doses above 10 mg/day should be implemented with caution.
Concomitant therapy:
Simaspenis effective alone or in combination with bile acid sequesterants. When both medicines are prescribed, Simaspen should be given 1 hour before or 4 hours after cholestyramine administration. (See Interactions).
A maximum daily dose of 10 mg Simaspen is recommended in patients taking cyclosporin, fibrates or niacin concomitantly (See Interactions).

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-Effects
Gastro-intestinal disorders:
Constipation, diarrhoea, nausea, vomiting, flatulence, dyspepsia, abdominal pain, cramps and pancreatitis.
Blood and lymphatic system disorders:
Anaemia, neutropenia.
Skin and appendages disorders:
Skin rash, alopecia.
Musculoskeletal system disorders:
Frequent: Myalgia, muscle cramps.
Less frequent: Myopathy, myositis, rhabdomyolysis presenting as muscle pain with elevated creatine phosphokinase and myoglobinuria leading to renal failure.
Central and peripheral nervous system disorders:
Headache, dizziness, fatigue, asthenia, paraesthesia, peripheral neuropathy.
Hypersensitivity reactions:
Less frequent: Reactions may include angioedema, lupus-like syndrome, polymyalgia, rheumatica, vasculitis, thrombocytopaenia, 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
Simaspen 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 Simaspen therapy and periodically until one year after the last elevation in dose. Simaspen 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 Simaspen 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. Simaspen 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 Simaspen concomitantly with immunosuppressants, fibrates or lipid-lowering doses of niacin should be carefully considered, and the dose of Simaspen 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, Simaspen should be temporarily discontinued if systemic azole derivative-antifungal therapy is required.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Overdosage with simvastatin may manifest in any of the symptoms described under ‘Side-Effects and Special Precautions’. There is no specific antidote for simvastatin. Treatment is symptomatic and supportive. General measures should be taken and hepatic function should be monitored.

IDENTIFICATION
SIMASPEN 10: Peach coloured, film-coated, oval shaped tablets debossed with `SST' on one side and `10' on other side with intact coating.
SIMASPEN 20: Tan coloured, film-coated, oval shaped tablets debossed with `SST' on one side and `20' on other side with intact coating.
SIMASPEN 40: Brick red coloured, film-coated, oval shaped tablets debossed with `SST' on one side and `40' on other side with intact coating.

PRESENTATION
SIMASPEN 10: Carton containing 28 or 100 tablets packed in PVdC coated PVC blister strips.
SIMASPEN 20: Carton containing 28 or 100 tablets packed in PVdC coated PVC blister strips.
SIMASPEN 40: Carton containing 28 or 100 tablets packed in PVdC coated PVC blister strips.

STORAGE INSTRUCTIONS
Store below 25°C, protected from light and moisture. Do not remove the blister from the carton until required for use.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
SIMASPEN 10: 36/7.5/0370
SIMASPEN 20: 36/7.5/0371
SIMASPEN 40: 36/7.5/0372

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
RANBAXY (SA) (PTY) LTD
Third Floor, Outspan House,
1006 Lenchen Avenue North,
Centurion,
Pretoria.

DATE OF PUBLICATION OF THE PACKAGE INSERT
May 2004

Marketed by Aspen Pharmacare (Pty) Ltd. for Ranbaxy (SA) (Pty) Ltd.



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Source: Pharmaceutical Industry
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