Simvastatin

Registered South African indications:

• Hypercholesterolaemia
• Coronary heart disease

Contraindications

South African recommendations

• Hypersensitivity to the active ingredient or any of its excipients 
• Hypersensitivity to other HMG-CoA reductase inhibitors
• Acute or chronic liver diseases 
• Unexplained persistent elevations of serum transaminases
• Pregnancy
• Lactation
• Concomitant admininistration of potent CYP3A4 inhibitors (medicines that increase AUC approximately 5-fold or greater) (e.g. itraconaxole, ketoconazole, Posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicines containing cobicistat)
• In patients with homozygous familial hypercholesterolaemia (HoFH), concomitant administration of lomitapide with doses >40mg simvastatin
• Concomitant administration of gemfibrozil, cyclosporin, or danazol 
• Porphyria: safety has not been established

Recommendations in other jurisdictions

• Hypersensitivity to the active substance or to any of the excipients
• Active liver disease
• Unexplained persistent elevations of serum transaminases
• Pregnancy
• Lactation
• Concomitant administration of potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone and medicinal products containing cobicistat)
• Concomitant administration of gemfibrozil, ciclosporin, or danazol
• In patients with homozygous familial hypercholesterolaemia (HoFH), concomitant administration of lomitapide with doses >40mg simvastatin

Cautions

• Severe renal impairment
• Alcohol abuse
• Diabetes mellitus
• Major surgery
• Hypothyroidism
• Familial history of hereditary muscular disorders
• History of muscular toxicity with a statin or fibrate
• Interstitial lung disease
• Children
• Females
• Lactose intolerance
• Lapp lactose deficiency
• Glucose galactose malabsorption

Forms avail. in SA and covered in this monograph: tab, fct

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

The patient should be placed on a standard cholesterol-lowering diet before receiving simvastatin and should continue on this diet during treatment with simvastatin

Hypercholesterolaemia
In combination with diet, to decrease elevated serum total cholesterol and LDL-cholesterol in patients with
- Primary hypercholesterolemia
- Heterozygous familial hypercholesterolemia (HoFA)
- Combined (mixed) hyperlipidemia when response to diet and other nonpharmacological measures is inadequate

• Oral (tab, fct): Initial: 10mg, at night; Titrate if required at intervals of at least 4 weeks; Maintenance: 10-80mg, at night; Max: 80mg/24hrs

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If LDL-cholesterol levels fall below 1.94mmol/l (75mg/dl) or total plasma cholesterol levels fall below 3.6mmol/l (140mg/dl) the dose of simvastatin should be reduced

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Coronary heart disease
Coronary heart disease and hypercholesterolaemia unresponsive to diet, for
- Risk reduction of total mortality by reducing coronary death
- Risk reduction of non-fatal myocardial infarction
- Risk reduction for undergoing myocardial revascularization procedures (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty)
- Slowing the progression of coronary atherosclerosis

• Oral (tab, fct): Initial: 20mg, at night; Titrate if required at intervals of at least 4 weeks; Maintenance: 20-80mg, at night; Max: 80mg/24hrs

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Simvastatin is effective alone or in combination with bile acid sequestrants. When both medicines are prescribed, simvastatin should be given 1hr before or 4hrs after cholestyramine administration

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Indications and dosages registered in other jurisdictions

Hypercholesterolaemia
- Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (eg. exercise, weight reduction) is inadequate

• Oral (fct): Initial: 10-20mg, at night; Titrate if required at intervals of at least 4 weeks; Maintenance: 10-80mg, at night; Max: 80mg/24hrs

- Patients who requiring a large reduction in LDL-C (more than 45%)

• Oral (fct): Initial: 20-40mg, at night; Titrate if required, at intervals of at least 4 weeks; Maintenance: 20-80mg, at night; Max: 80mg/24hrs

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The patient should be placed on a standard cholesterol-lowering diet, and should continue with this diet during treatment with simvastatin

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The 80mg dose is only recommended in patients with severe hypercholesterolaemia and 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

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Homozygous familial hypercholesterolaemia (Additional agent(s) may be required)
- As an adjunct to diet and other lipid-lowering treatments (e.g. LDL-apheresis) or if such treatments are not appropriate

• Oral (fct): 40mg, at night

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Simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL-apheresis) in these patients or if such treatments are unavailable

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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 cardioprotective therapy
-  In patients at high risk of coronary heart disease (CHD, with or without hyperlipidaemia)

• Oral (fct): Initial: 20-40mg, at night; Titrate at intervals of at least 4 weeks; Maintenance: 20-80mg, at night; Max: 80mg/24hrs

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Drug therapy can be initiated simultaneously with diet and exercise

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For all indications: Simvastatin 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

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For relevant max doses when administering with other drugs see additional prescribing points

Paed. forms avail. in SA and covered in this monograph: fct

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

• Not recommended for use in children

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Indications and dosages registered in other jurisdictions

Heterozygous familial hypercholesterolaemia

Younger than 10 years

• Not established for use

Between 10-17 years

• Oral (fct): Initial: 10mg, at night; Titrate at intervals of at least 4 weeks; Maintenance: 10-40mg, at night; Max: 40mg/24hrs

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Indicated 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)

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Children and adolescents should be placed on a standard cholesterol-lowering diet before simvastatin treatment initiation; this diet should be continued during simvastatin treatment

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The experience of simvastatin in pre-pubertal children is limited

Pregnancy 

• Contraindicated
• Safety in pregnant women has not been established. No controlled clinical trials with simvastatin 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 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 or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with simvastatin 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 must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with simvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant

Breastfeeding

• Contraindicated
• It is not known whether simvastatin 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 must not breastfeed their infants

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; dose adjustment recommended

CrCl (ml/min)	Dose
> 30	No adjustment necessary
< 30	Initial: 5mg once daily; Doses above 10mg, daily should be carefully considered, and cautiously implemented

Hepatic Impairment

• Contraindicated

Elderly

• No dose adjustment recommended

Porphyria Information

South African recommendations

• Contraindicated

Recommendations in other jurisdictions

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Depression
• Headache
• Paresthesia
• Dizziness
• Peripheral neuropathy
• Memory impairment

Respiratory Disorders

• Interstitial lung disease 

Gastrointestinal Disorders

• Constipation
• Abdominal pain
• Flatulence
• Dyspepsia
• Diarrhea
• Nausea and vomiting
• Pancreatitis

Hepatobiliary disorders

• Hepatitis
• Jaundice
• Hepatic failure

Musculoskeletal Disorders

• Myopathy 
• Rhabdomyolysis 
• Acute renal failure 
• Myalgia
• Muscle cramps

Blood and Lymphatic System Disorders

• Anaemia

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Alopecia

• Amiodarone
• Amlodipine
• Ranolazine
• Diltiazem
• Verapamil
• Lomitapide 
• CYP3A4 inhibitors
• Itraconaxole
• Ketoconazole
• Posaconazole
• Voriconazole
• HIV protease inhibitors
• Nelfinavir
• Boceprevir
• Telaprevir
• Erythromycin
• Clarithromycin
• Telithromycin
• Nefazodone
• Cobicistat
• CYP3A4 inducers
• OATP1B1 inhibitors
• Fibrates
• Niacin (nicotinic acid)
• Colchicine
• Coumarin anticoagulants
• Fusidic acid
• Cyclosporin
• Danazol
• Gemfibrozil
• Fluconazole
• Grapefruit juice

None routine. Specific cases may require

• Hepatic function
• Creatine phosphokinase (CK)
• Blood glucose

Coadministration dosing

• In patients taking simvastatin concomitantly with fibrates, other than gemfibrozil or fenofibrate, the dose of simvastatin should not exceed 10mg/day
• In patients taking amiodarone amlodipine, verapamil or diltiazem, or products containing elbasvir or grazoprevir concomitantly with simvastatin, the dose of simvastatin should not exceed 20mg/day
• In patients taking lomitapide concomitantly with simvastatin, the dose of simvastain must not exceed 40mg/day

Simvastatin is a selective, competitive inhibitor of HMG CoA reductase, the enzyme which converts HMG CoA to mevalonate, a precursor of sterols. Decreased hepatic cholesterol levels stimulates upregulation of hepatic LDL-C receptors which increases hepatic uptake of LDL-C and reduces serum LDL-C concentrations.

Tablet 10mg

• Adco-Simvastatin (Adcock)
• Arrow Simvastatin (Arrow)
• Aspen Simvastatin (Pharmacare)
• Austell Simvastatin (Austell)
• Biovac Simvastatin (Arrow)
• Choleste 10 (Unicorn)
• Cipla Simvastatin (Cipla Medpro)
• Lipidex (Sandoz)
• Novatin (Novagen)
• Simayla Simvastatin (Ranbaxy)
• Simcard 10 (iPharma)
• Simvacor (Pharma Dynamics)
• Simvotin (Ranbaxy)
• Zocor (MSD) originator
• Zysim (Zydus)

Tablet 20mg

• Adco-Simvastatin (Adcock)
• Arrow Simvastatin (Arrow)
• Aspen Simvastatin (Pharmacare)
• Austell Simvastatin (Austell)
• Biovac Simvastatin (Arrow)
• Choleste 20 (Unicorn)
• Cipla Simvastatin (Cipla Medpro)
• Lipidex (Sandoz)
• Mylan simvasatin (Mylan)
• Novatin (Novagen)
• Simayla Simvastatin (Ranbaxy)
• Simcard 20 (iPharma)
• Simvacor (Pharma Dynamics)
• Simvotin (Ranbaxy)
• Zocor (MSD) originator
• Zysim (Zydus)

Tablet 40mg

• Adco-Simvastatin (Adcock)
• Arrow Simvastatin (Arrow)
• Aspen Simvastatin (Pharmacare)
• Austell Simvastatin (Austell)
• Biovac Simvastatin (Arrow)
• Choleste (Unicorn)
• Cipla Simvastatin (Cipla Medpro)
• Novatin (Novagen)
• Simayla Simvastatin (Ranbaxy)
• Simcard (Cipla Medpro)
• Simvacor (Pharma Dynamics)
• Simvotin (Ranbaxy)
• Zocor (MSD) originator
• Zysim (Zydus)

Tablet 80mg

• Cipla Simvastatin (Cipla Medpro)
• Simcard (Cipla Medpro)
• Zysim (Zydus)