Schedule H

Oral

• Simvastatin tablets: 5 mg, 10 mg, 20 mg, 40 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Primary Hypercholesterolemia (including Heterozygous Familial Hypercholesterolemia)

Parameter Recommendation

Starting dose 10–20 mg once daily in the evening

Titration Assess lipid profile after 4 weeks; increase by 10–20 mg increments

Usual maintenance dose 20–40 mg once daily

Maximum dose 40 mg/day (routine practice); 80 mg/day restricted — see note below

Key Clinical Notes:

• Administer in evening (preferably bedtime) — cholesterol synthesis peaks overnight

• 80 mg/day dose is associated with significantly higher myopathy risk; prescribe ONLY if patient has been stable on this dose for >12 months without muscle toxicity

• Do NOT initiate therapy at 80 mg dose

1. Cardiovascular Risk Reduction (Secondary Prevention in Established Coronary Heart Disease or High-Risk Patients)

Parameter Recommendation

Starting dose 20–40 mg once daily in the evening

Titration Adjust every 4–6 weeks based on LDL-C targets (<70 mg/dL for very high-risk)

Usual maintenance dose 20–40 mg once daily

Maximum dose 40 mg/day for routine use

Key Clinical Notes:

• Continue indefinitely unless intolerance develops

• Monitor for muscle symptoms especially during initial months

• Consider switching to higher-potency statin (rosuvastatin/atorvastatin) if LDL goal not achieved at 40 mg

Secondary Indications — Adults Only (Off-label)

Indication Dose Duration Notes

Diabetic dyslipidemia (Type 2 DM with mixed lipid abnormalities) Start 10–20 mg once daily evening Long-term OFF-LABEL — Based on Indian specialist practice. Use when LDL-C elevated despite lifestyle modification, or as alternative when atorvastatin not tolerated

PAEDIATRIC DOSING (Specialist Only)

Primary Indication: Heterozygous Familial Hypercholesterolemia (HeFH)

Parameter Recommendation

Eligible age ≥10 years

Starting dose 10 mg once daily in the evening

Titration Increase by 10 mg increments every 4 weeks based on LDL-C response

Usual maintenance dose 10–20 mg once daily

Maximum dose 40 mg/day (ages 10–17 years)

Safety Monitoring:

• Baseline and periodic CK, LFTs

• Monitor growth parameters (height, weight)

• Assess for muscle symptoms at each visit

• Specialist supervision mandatory (paediatric cardiologist/endocrinologist)

Secondary Indications — Paediatric (Off-label)

Not recommended.

Statement: Simvastatin use in children below 10 years is NOT recommended except under specialist lipid clinic supervision with documented familial hypercholesterolemia.

Additional Notes:

• Increased myopathy risk in renal impairment

• Avoid combining with fibrates in CKD patients

• Monitor CK if muscle symptoms develop

• Active liver disease or unexplained persistent elevation of serum transaminases (>3× ULN)

• Pregnancy

• Breastfeeding

• Known hypersensitivity to simvastatin or any excipient

• Concomitant use of strong CYP3A4 inhibitors: itraconazole, ketoconazole, posaconazole, clarithromycin, erythromycin, telithromycin, HIV protease inhibitors (ritonavir, nelfinavir, etc.)

• Concomitant use with gemfibrozil

• Concomitant use with ciclosporin or danazol (at any simvastatin dose)

• History of liver disease or significant alcohol consumption

• Pre-existing unexplained muscle pain or elevated CK — evaluate before initiation

• Untreated hypothyroidism — correct thyroid function before starting statin

• Age ≥65 years, female sex, renal impairment, small body frame — higher myopathy susceptibility

• Concurrent use of fibrates (especially fenofibrate) or niacin (≥1 g/day)

• Avoid excessive grapefruit juice intake (>200 mL/day) — increases simvastatin exposure

• Asian patients may have increased systemic exposure — consider lower starting dose

• Major surgery or acute medical illness — consider temporary discontinuation

Aspect Recommendation

Risk category Contraindicated (Category X equivalent)

Rationale Cholesterol synthesis essential for fetal development; statins may impair fetal sterol synthesis; animal teratogenicity data

Preferred alternatives Bile acid sequestrants (cholestyramine, colesevelam) if lipid-lowering essential

Pre-conception advice Discontinue simvastatin at least 1 month prior to planned conception

Monitoring Not applicable — drug should not be used

Aspect Recommendation

Compatibility Not compatible with breastfeeding

Excretion in breast milk Unknown; theoretical risk to nursing infant

Preferred alternatives Cholestyramine (not systemically absorbed)

Infant monitoring If accidental exposure suspected: monitor for GI disturbances, feeding difficulties

Aspect Recommendation

Starting dose 5–10 mg once daily

Titration Slow; increase at ≥6-week intervals

Maximum dose Generally avoid exceeding 20 mg/day unless closely monitored

Special considerations Increased myopathy risk; assess renal function before initiation; review polypharmacy for drug interactions; consider frailty status

Interacting Drug/Class Effect Recommendation

Strong CYP3A4 inhibitors (itraconazole, ketoconazole, clarithromycin, HIV protease inhibitors, nefazodone) Markedly increased simvastatin exposure → rhabdomyolysis risk Contraindicated — do not co-prescribe

Gemfibrozil Inhibits statin glucuronidation → severe myopathy/rhabdomyolysis Contraindicated

Ciclosporin Increased simvastatin levels Contraindicated at any dose

Danazol Increased simvastatin levels Contraindicated

Amiodarone Moderate CYP3A4 inhibition Limit simvastatin to 10 mg/day maximum

Verapamil Moderate CYP3A4 inhibition Limit simvastatin to 10 mg/day maximum

Diltiazem Moderate CYP3A4 inhibition Limit simvastatin to 10 mg/day maximum

Amlodipine Weak CYP3A4 inhibition Limit simvastatin to 20 mg/day maximum

Dronedarone CYP3A4 inhibition Limit simvastatin to 10 mg/day maximum

Interacting Drug Effect Recommendation

Warfarin Possible modest increase in INR Monitor INR when initiating, changing dose, or stopping simvastatin

Niacin (≥1 g/day) Additive myopathy risk Use combination cautiously; monitor for muscle symptoms

Fenofibrate Lower myopathy risk than gemfibrozil, but still elevated If combination necessary, use lowest effective simvastatin dose; monitor CK

Colchicine Increased myopathy risk Use together only if unavoidable; monitor closely

Rifampicin CYP3A4 induction → reduced simvastatin efficacy Monitor lipid response; may need alternative statin

Fluconazole Moderate CYP3A4 inhibition Caution with concurrent use; temporary statin pause may be considered

Digoxin Possible slight increase in digoxin levels Monitor digoxin levels if symptoms suggest toxicity

Ranolazine Weak CYP3A4 inhibition Limit simvastatin to 20 mg/day maximum

• Myalgia (muscle pain without CK elevation)

• Headache

• Gastrointestinal disturbances: nausea, dyspepsia, abdominal pain, constipation, flatulence

• Elevated hepatic transaminases (usually transient, <3× ULN)

• Sleep disturbances (insomnia, vivid dreams)

• Upper respiratory tract infection

• Dizziness

Adverse Effect Clinical Notes

Rhabdomyolysis Rare but potentially fatal; presents with severe muscle pain, weakness, dark urine; CK >10× ULN; STOP drug immediately; requires hospitalisation, IV fluids, renal monitoring

Myopathy CK elevation 5–10× ULN with muscle symptoms; discontinue and monitor

Hepatotoxicity Rare; persistent transaminase elevation >3× ULN; discontinue if confirmed

Immune-mediated necrotising myopathy Very rare; may persist after drug discontinuation; requires specialist management

Hypersensitivity reactions Rash, urticaria, angioedema (rare)

New-onset diabetes mellitus Class effect; slightly increased risk with high-intensity statin therapy

4–12 weeks after initiation or dose change Lipid profile, LFTs

If muscle symptoms develop CK immediately; if >5× ULN, discontinue; if 3–5× ULN, repeat in 1 week

Long-term (stable therapy) Lipid profile every 6–12 months; LFTs annually; CK only if symptomatic

High-risk patients (renal impairment, drug interactions, elderly) More frequent CK monitoring as clinically indicated

Brand Name Manufacturer

Simvotin Sun Pharma

Zimstat Cipla

Simlor Unichem

Simcard USV

Simvas Ranbaxy/Sun Pharma

Zosta FDC Ltd

Fixed-Dose Combinations available:

• Simvastatin + Ezetimibe

Strength Approximate Price per Tablet

Note: Not included in NLEM 2022 (atorvastatin is the listed statin). Prices vary by brand and region.

1. Evening dosing is essential — simvastatin has a short half-life (~2–3 hours for active metabolites); hepatic cholesterol synthesis peaks at night.

1. Do NOT initiate at 80 mg dose — this dose carries unacceptable myopathy risk and is reserved only for patients already stable on it for >12 months.

1. Drug interaction awareness is critical — simvastatin is extensively metabolised by CYP3A4; always check for interacting drugs before prescribing.

1. Consider switching to atorvastatin or rosuvastatin if patient needs calcium channel blockers (amlodipine, diltiazem, verapamil) or if higher LDL-lowering potency is required.

1. Myalgia workup — if patient reports muscle symptoms, check CK promptly. Many patients with myalgia have normal CK and can continue with dose reduction or statin switch.

1. Lower starting dose in Asians and elderly — pharmacokinetic data suggest higher systemic exposure; start at 5–10 mg.

statin; lipid-lowering; dyslipidemia; hypercholesterolemia; cardiovascular-prevention; myopathy-risk; CYP3A4-substrate; evening-dosing; pregnancy-contraindicated; hepatic-monitoring

RxIndia v1.1 — 10 Jan 2025

• CDSCO approved prescribing information

• Indian Pharmacopoeia

• API Textbook of Medicine

• NLEM 2022 (for context on statin class)

• Lipid Association of India Guidelines

• AIIMS Drug Formulary

• Goodman and Gilman's The Pharmacological Basis of Therapeutics

• Harrison's Principles of Internal Medicine

• Indian hospital prescribing protocols (tertiary care centres)