Simvastatin (Zocor)

1. Health Canada Product Monograph — Simvastatin

• Used as an adjunct to diet to reduce the risk of death, heart attack, and stroke in adults at high risk of cardiovascular events because of existing coronary heart disease, other blood vessel disease, or diabetes after age 40, regardless of baseline cholesterol level.
• Used to slow progression of coronary artery narrowing, including reducing new blockages, in people with high cholesterol and coronary heart disease.
• Used to lower elevated total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides in patients with primary high cholesterol or mixed hyperlipidemia.
• Used in adolescents with heterozygous familial hypercholesterolemia to lower cholesterol levels.

Contraindicated in pregnancy. Confirm pregnancy status and discuss alternative therapy with the prescriber before dispensing.

• Contraindicated in pregnancy, because cholesterol and its byproducts are essential building blocks for fetal development and lowering them could harm the developing baby.
• Should not be used in women who are pregnant, trying to become pregnant, or think they might be pregnant; treatment should be paused for the duration of pregnancy or until pregnancy has been ruled out.
• Women of childbearing potential should use effective contraception while on therapy and should tell their prescriber right away if pregnancy occurs.

• Contraindicated while breastfeeding, since it is not known whether simvastatin passes into breast milk and because of the potential for serious effects in a nursing infant.

• Approved for use in older adults, with cholesterol-lowering effectiveness similar to that seen in younger patients and no overall increase in adverse effects in clinical experience.
• Older adults (65 years and above) may be more susceptible to muscle-related side effects such as myopathy, so this group should be monitored closely, particularly at higher doses.

• Approved for adolescent boys and girls aged 10 to under 18 years (girls must be at least one year past their first period) who have heterozygous familial hypercholesterolemia; the usual starting dose is 10 mg once daily in the evening, individualized up to a maximum of 40 mg per day.
• Not studied in children under 10 years of age or in girls who have not yet begun menstruating, and doses above 40 mg/day have not been studied in this age group.
• No effect on growth, sexual maturation, or menstrual cycle length was seen in the adolescent study; adolescent females should be counselled on effective contraception while on therapy.

• Usual adult dosage ranges from 5 to 40 mg once daily in the evening, with the starting dose depending on the indication, commonly 40 mg/day for cardiovascular risk reduction or 10 mg/day for cholesterol lowering alone.
• The 80 mg/day dose is discouraged because of a higher risk of muscle toxicity and is reserved for patients already tolerating it long-term with no evidence of muscle problems, or those at high cardiovascular risk who cannot tolerate alternative treatments.
• A lower starting dose and cautious titration are used in patients with severe kidney impairment or those taking certain interacting medications.
• If a dose is missed, it should be taken as soon as remembered unless it is nearly time for the next dose, in which case the missed dose should be skipped; doses should never be doubled.
• Therapy is usually paused a few days before major elective surgery or when a serious acute medical condition develops.

• Abdominal pain may occur.
• Constipation may occur.
• Flatulence (gas) may occur.
• Nausea may occur.
• Diarrhea may occur.
• Indigestion may occur.
• Acid regurgitation (heartburn) may occur.
• Headache may occur.
• Weakness (asthenia) may occur.
• Skin rash may occur.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Simvastatin may cause muscle pain, tenderness, or weakness (myopathy) that can rarely progress to severe muscle breakdown (rhabdomyolysis) with kidney injury.
• Liver enzyme elevations may occur and can signal liver injury; rare cases of liver failure have been reported.
• Rare cases of an autoimmune muscle condition (immune-mediated necrotizing myopathy) have been reported, causing persistent muscle weakness that continues even after the drug is stopped.
• Severe allergic (hypersensitivity) reactions may occur, including facial or throat swelling, difficulty breathing, or a lupus-like syndrome with joint pain, fever, and blood vessel inflammation.
• Peripheral neuropathy (nerve pain, numbness, or weakness in the limbs) may occur.
• Cognitive changes such as memory loss, confusion, or forgetfulness have been reported rarely and are generally reversible after stopping the drug.
• Blood sugar and hemoglobin A1c increases may occur and can occasionally tip a person with pre-diabetes risk factors into diabetes.
• Rare cases of severe skin reactions, including Stevens-Johnson syndrome, have been reported.
• Interstitial lung disease has been reported rarely.
• Existing myasthenia gravis or ocular myasthenia may be triggered or made worse.
• Pancreatitis and hepatitis have been reported rarely.
• Seek immediate medical attention for unexplained muscle pain, tenderness, or weakness (especially with fever or fatigue), signs of liver problems such as yellowing skin or eyes or dark urine, or signs of a severe allergic reaction.

• Use with caution in patients who drink substantial amounts of alcohol or have a history of liver disease.
• Use with caution in patients with severe kidney impairment, where a lower starting dose and close monitoring are needed.
• Use with caution in older adults, women, people with a personal or family history of muscle disorders, or those with poorly controlled hypothyroidism, as these factors increase the risk of muscle toxicity.
• Use with caution in patients undergoing major surgery, trauma, or other conditions that raise the risk of muscle breakdown.
• Use with caution, generally at the lowest necessary dose, in Asian patients, who have shown a higher risk of muscle-related side effects in clinical studies.
• Use with caution in patients with a prior episode of muscle toxicity on another statin.
• Liver function tests are recommended before starting therapy and periodically thereafter, particularly with higher doses.
• Use caution with driving or operating machinery if dizziness occurs, even though simvastatin has no direct effect on these abilities.

• Contraindicated in patients with known hypersensitivity to simvastatin or any ingredient in the formulation.
• Contraindicated in active liver disease or unexplained persistent elevations in liver enzymes.
• Contraindicated during pregnancy.
• Contraindicated during breastfeeding.
• Contraindicated with concurrent use of strong CYP3A4 inhibitors, including certain antifungal medications (itraconazole, ketoconazole, posaconazole, voriconazole), certain antibiotics (erythromycin, clarithromycin, telithromycin), HIV or hepatitis C protease inhibitors (such as boceprevir or telaprevir), nefazodone, and medications containing cobicistat.
• Contraindicated with concurrent use of gemfibrozil, cyclosporine, or danazol.

• Strong CYP3A4 inhibitors significantly raise simvastatin blood levels and markedly increase the risk of muscle toxicity, so combined use is contraindicated.
• Gemfibrozil, cyclosporine, and danazol substantially increase the risk of myopathy and rhabdomyolysis and must not be combined with simvastatin.
• Amiodarone, amlodipine, verapamil, and diltiazem raise simvastatin levels and muscle toxicity risk, so simvastatin doses are capped lower when these are used together.
• Other fibrates besides gemfibrozil, and high-dose niacin, can each independently cause muscle toxicity and add to the risk when combined with simvastatin.
• Lomitapide, fostamatinib, fusidic acid, colchicine, elbasvir/grazoprevir, and daptomycin have each been associated with increased myopathy or rhabdomyolysis risk when combined with simvastatin, requiring dose limits, temporary suspension of simvastatin, or avoidance depending on the specific agent.
• Coumarin-type anticoagulants such as warfarin may have their blood-thinning effect enhanced, so clotting time (INR) should be monitored closely when starting, stopping, or changing the simvastatin dose.
• Cholestyramine and other bile acid resin medications can reduce simvastatin absorption if taken too close together, so doses should be separated by at least two hours.
• Moderate CYP3A4 inhibitors and inhibitors of the OATP1B1 transport protein can raise simvastatin levels and may require dose adjustment.
• Digoxin levels may rise slightly with concurrent simvastatin use, so patients on digoxin should be monitored.

• Grapefruit and grapefruit juice should be avoided, as they can raise simvastatin blood levels through the same enzyme pathway and increase the risk of muscle-related side effects.
• May be taken with or without food, as food does not meaningfully change how the drug is absorbed.

• Taken once daily in the evening, since the body produces most of its cholesterol overnight.

• Store at controlled room temperature (15-30 degrees C) and keep out of reach and sight of children.

• Simvastatin is a cholesterol-lowering statin used to reduce cardiovascular risk and treat high cholesterol, taken alongside a cholesterol-conscious diet.
• Take the prescribed dose once daily in the evening, with or without food, and avoid grapefruit or grapefruit juice.
• Common side effects include stomach upset, gas, constipation, headache, and tiredness.
• Contact your doctor or pharmacist right away if you develop unexplained muscle pain, tenderness or weakness, signs of liver problems (yellowing skin or eyes, dark urine, unusual tiredness), or signs of a severe allergic reaction such as swelling or difficulty breathing.
• This medication must not be used during pregnancy or breastfeeding; tell your prescriber immediately if you become pregnant while taking it.
• Store at room temperature away from children, and take it consistently every evening since it works best with ongoing daily use.