Simvastatin

Is simvastatin safe?

Yes, at the doses most people now take. Simvastatin, first sold as Zocor, has been used since 1991, and its 4S trial was one of the first to show a cholesterol drug saving lives: deaths fell by 30% among 4,444 people with heart disease. At 20 to 40 mg a day, serious muscle damage is rare. We score it 83, a little below atorvastatin (87).

The gap comes from two things. The 80 mg dose carries a clearly higher risk of muscle injury, and simvastatin interacts with more common medicines, several of which cap the dose or rule it out altogether.

The 80 mg restriction

The SEARCH trial, published in The Lancet in 2010, gave 12,064 heart attack survivors either 20 mg or 80 mg a day for about 6.7 years. Myopathy, meaning muscle pain or weakness with a large rise in the muscle enzyme CK, occurred in 53 people on 80 mg (0.9%) against 2 on 20 mg. Rhabdomyolysis, the dangerous form that can damage the kidneys, occurred in about 0.4% on 80 mg and almost none on 20 mg, according to the US label.

In June 2011 the FDA acted. New patients should not start on 80 mg; only people who had already taken it for 12 months or more without muscle problems should continue. The current US label sets the maximum recommended dose at 40 mg and says people who need stronger cholesterol lowering should switch treatment rather than go up to 80 mg. Zocor itself is no longer sold in the 80 mg strength.

In the label's wider trial data, myopathy rates were about 0.03% at 20 mg, 0.08% at 40 mg and 0.61% at 80 mg. Most people who stop statins because of aches are not having this kind of muscle injury; blinded trials show most such aches are not caused by the drug, as the atorvastatin page explains.

Dose limits with other medicines

Simvastatin is broken down by the liver enzyme CYP3A4CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary, and blocking that enzyme can multiply its levels. The current US label sets these rules:

Taken with	US label rule
Clarithromycin, erythromycin, itraconazole, ketoconazole, posaconazole, voriconazole, some HIV and hepatitis C drugs, nefazodone	ContraindicatedContraindicationA situation in which a medicine should not be used, because the risk clearly outweighs any benefit, such as a known allergy to it.More in the glossary; pause simvastatin during short courses
Cyclosporine, danazol, gemfibrozil	Contraindicated
Verapamil, diltiazem, dronedarone	No more than 10 mg a day
Amlodipine, amiodarone, ranolazine	No more than 20 mg a day
Lomitapide	Halve the dose
Daptomycin	Consider pausing simvastatin
Grapefruit juice	Avoid

The amlodipine limit matters because the two are so often prescribed together for people with high blood pressure and cholesterol. The UK MHRA reported in 2012 that amlodipine 10 mg raised simvastatin exposure by about 1.6 times, and that raised CK was seen in 1% of people taking simvastatin 40 mg with amlodipine against 0.36% on simvastatin alone in the Heart Protection Study. It asked prescribers to review anyone on 40 mg with amlodipine or diltiazem.

Simvastatin can also nudge up the INR in people on warfarin, so the label asks for an INR check when starting or changing the dose, and it can raise digoxin levels.

Who has a higher muscle risk?

The label lists age 65 or over, untreated underactive thyroid, kidney disease, higher doses and interacting drugs. It also notes that Chinese patients may be at higher risk, and advises against high-dose niacin with simvastatin in Chinese patients. People with severe kidney disease should start at 5 mg.

Report unexplained muscle pain, tenderness or weakness to your doctor promptly, especially with fever, tiredness or dark urine. Yellow skin or eyes, or pain in the upper right of the belly, can signal rare liver injuryDrug-induced liver injuryLiver damage caused by a medicine, herbal product or supplement. It is usually rare and unpredictable, but it can be serious.More in the glossary.

Practical points

• Take it in the evening, as the label says. A missed dose should be taken as soon as possible, not doubled.
• Tell every prescriber and pharmacist you take simvastatin, especially before a new antibiotic or antifungal, because a short course of clarithromycin or itraconazole means pausing it.
• Avoid grapefruit juice.
• People also taking aspirin or blood pressure medicines should ask a pharmacist to check their whole list of medicines.
• The label contraindicates it in acute liver failure or decompensated cirrhosis.

If side effects bother you, talk to your doctor before stopping. A lower dose or a different statin often solves the problem.

How we scored it

Track record (97), dependence (98) and overdose marginOverdose marginHow far a normal dose is from a harmful one. A wide margin means an accidental extra dose is unlikely to cause serious harm.More in the glossary (92) are strong, and serious side effects (84) reflect rare muscle injury at usual doses. Interactions (50) is the weakest factor because of the long list of contraindicationsContraindicationA situation in which a medicine should not be used, because the risk clearly outweighs any benefit, such as a known allergy to it.More in the glossary and dose caps, and regulatory warnings (70) reflect the 2011 FDA restriction on 80 mg.