Simvastatin

Approved Indications:

• Primary Hyperlipidemia and Mixed Dyslipidemia:
• For the treatment of primary hypercholesterolemia (Type IIa) and mixed dyslipidemia (Type IIb) to reduce elevated total cholesterol (Total-C), LDL cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase HDL cholesterol (HDL-C).
• Homozygous Familial Hypercholesterolemia:
• As adjunctive therapy to diet and other lipid-lowering treatments (e.g., LDL apheresis) or when such treatments are unavailable.
• Cardiovascular Risk Reduction in High-Risk Individuals:
• To reduce the risk of:
• Myocardial infarction
• Stroke
• Coronary and non-coronary revascularization procedures
• Cardiovascular mortality in patients with existing coronary heart disease (CHD), diabetes, or peripheral vascular disease.
• Pediatric Hypercholesterolemia:
• Treatment of heterozygous familial hypercholesterolemia in children and adolescents (10–17 years) who have not responded adequately to diet therapy.

Clinically Accepted (Off-label) Uses:

• Type 2 Diabetes with Dyslipidemia:
• Used to manage atherogenic dyslipidemia as part of cardiovascular risk reduction strategies.
• Nonalcoholic Fatty Liver Disease (NAFLD):
• To improve lipid profiles and reduce cardiovascular events in selected NAFLD patients.

Route of Administration: Oral
Available Dosage Forms in Bangladesh (Medex-verified):

• Simvastatin Tablets: 5 mg, 10 mg, 20 mg, 40 mg, 80 mg

Adults:

• Initial Dose: 10–20 mg once daily in the evening.
• Patients at High Cardiovascular Risk or LDL-C >190 mg/dL: 40 mg once daily in the evening.
• Maximum Dose: 80 mg/day (reserved only for patients already tolerating it for ≥12 months without myopathy).

Pediatric Patients (10–17 years) – Heterozygous Familial Hypercholesterolemia:

• Initial Dose: 10 mg once daily in the evening.
• Titration Range: 10–40 mg/day based on response and tolerability.
• Not recommended for use in children <10 years.

Elderly:

• Use lowest effective dose; increased susceptibility to muscle-related side effects.

Renal Impairment:

• Mild to Moderate: No initial dose adjustment.
• Severe Renal Impairment (CrCl <30 mL/min): Initiate at 5 mg/day; use with caution if dose exceeds 10 mg/day.

Hepatic Impairment:

• Contraindicated in active liver disease or persistent unexplained transaminase elevation.

Administration Notes:

• Administer once daily in the evening, with or without food.
• Evening dosing aligns with peak endogenous cholesterol synthesis.

Simvastatin is a lipophilic statin that exerts its lipid-lowering effect by inhibiting HMG-CoA reductase, the rate-limiting enzyme responsible for converting HMG-CoA to mevalonate in the cholesterol biosynthesis pathway. This inhibition reduces intracellular cholesterol levels in hepatocytes, leading to upregulation of LDL receptors on the liver surface, thereby increasing clearance of LDL cholesterol from the bloodstream. The net result is a significant reduction in LDL-C, total cholesterol, Apo B, and triglycerides, and a modest increase in HDL-C.

• Absorption: Rapidly absorbed orally; extensive first-pass extraction in the liver.
• Bioavailability: <5% (due to high first-pass hepatic metabolism).
• Distribution: 95% bound to plasma proteins.
• Metabolism: Hepatically metabolized; a prodrug converted to its active β-hydroxyacid form.
• Primary enzyme: CYP3A4.
• Elimination Half-life: ~2 hours (parent compound); longer for active metabolites.
• Excretion:
• Feces: ~60% (via bile)
• Urine: ~13%
• Time to Peak Concentration: 1.3–2.4 hours (active form)

• Pregnancy:
• FDA Category X – Contraindicated in pregnancy.
• Cholesterol is vital for fetal development, and inhibiting its synthesis may cause fetal harm.
• Simvastatin must be discontinued immediately if pregnancy is detected.
• Lactation:
• Contraindicated.
• Unknown whether Simvastatin is excreted in breast milk, but potential for serious adverse effects exists.
• Contraceptive Advice:
• Effective contraception should be used during therapy.

• Class: Lipid-Lowering Agent
• Subclass: HMG-CoA Reductase Inhibitor (Statin)
• Type: Synthetic, lipophilic statin

• Hypersensitivity to Simvastatin or any component of the formulation.
• Active liver disease or unexplained persistent elevation of serum transaminases.
• Pregnancy or breastfeeding.
• Concurrent use of:
• Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, clarithromycin, HIV protease inhibitors)
• Gemfibrozil, cyclosporine, or danazol (due to risk of severe myopathy/rhabdomyolysis)

• Myopathy and Rhabdomyolysis:
• Risk increases with higher doses and with CYP3A4 inhibitors or fibrates.
• Monitor for unexplained muscle pain or weakness; check serum creatine kinase (CK).
• Hepatic Effects:
• Liver function tests should be performed before initiation and periodically during therapy.
• Discontinue if ALT >3× ULN.
• Drug Interactions:
• Avoid with CYP3A4 inhibitors and certain fibrates.
• Caution with medications that increase Simvastatin plasma levels.
• Alcohol Use:
• Excessive alcohol may increase risk of hepatotoxicity.
• Diabetes Risk:
• Small increase in HbA1c and fasting glucose; benefits generally outweigh risk.

Common (≥1%):

• Musculoskeletal:
• Myalgia, muscle cramps, weakness
• Gastrointestinal:
• Nausea, constipation, abdominal pain, flatulence
• Neurologic:
• Headache, dizziness, insomnia

Less Common (<1%):

• Elevated liver transaminases
• Rash
• Fatigue

Serious and Rare:

• Rhabdomyolysis with acute renal failure due to myoglobinuria
• Hepatitis and rare cases of hepatic failure
• Hypersensitivity reactions (e.g., angioedema, lupus-like syndrome)

Timing:

• Myopathy may occur within the first few months
• Hepatic effects may arise after weeks to months

Major Interactions (CYP3A4-Mediated):

• Avoid with:
• Itraconazole, ketoconazole, posaconazole
• Erythromycin, clarithromycin
• HIV protease inhibitors
• Grapefruit juice
• Other Important Interactions:
• Gemfibrozil: Contraindicated
• Other fibrates (e.g., fenofibrate): Caution advised
• Amiodarone, verapamil, diltiazem: Limit Simvastatin to 10–20 mg/day

Food Interactions:

• Grapefruit juice significantly increases Simvastatin plasma concentration; avoid

Alcohol:

• Increases hepatotoxic risk; use with caution

Metabolism:

• CYP3A4 substrate – potent inhibitors/inducers greatly affect plasma levels

• FDA (2011):
• Restricted 80 mg dose to patients already tolerating it ≥12 months without myopathy.
• Strengthened contraindications and dosing limitations when used with interacting drugs.
• AHA/ACC and NICE Guidelines:
• Simvastatin (20–40 mg) remains a moderate-intensity statin.
• Preferred for cost-effectiveness in moderate-risk patients.
• Atorvastatin and rosuvastatin are favored for high-intensity therapy.
• WHO Essential Medicines List:
• Simvastatin included as a core lipid-lowering therapy.

• Storage Temperature: 20°C to 25°C (68°F to 77°F)
• Excursions: Permissible between 15°C and 30°C
• Humidity & Light: Store in a dry place, protected from light and moisture
• Handling Instructions:
• Keep tablets in the original container
• Protect from excessive heat
• Do not freeze
• Shelf Life: Refer to product labeling; typically 24–36 months unopened