Simvasterol®: composition and dosage form
One film-coated tablet contains 10 mg, 20 mg or 40 mg of simvastatin. The three strengths are not three different medicines but three points on a scale, where the decision is taken not only from the cholesterol level but also from what the patient takes alongside the statin.
The medicine is taken once a day in the evening — the timing here is not a formality but part of the regimen, and it is given in the product information for every indication without exception. The tablets contain lactose, so they are unsuitable for patients with the rare hereditary galactose intolerance, with lactase deficiency, or with glucose-galactose malabsorption syndrome.
How Simvasterol® works
Simvastatin enters the body in an inactive form: it is a lactone that does nothing by itself. It becomes active in the liver, where it is hydrolysed to the corresponding β-hydroxy acid — a potent inhibitor of HMG-CoA reductase. That enzyme converts HMG-CoA into mevalonate, which is to say it handles the early and at the same time rate-limiting step of cholesterol synthesis.
The result is made up of two mechanisms at once: the production of very-low-density lipoprotein cholesterol falls, and at the same time LDL receptors are induced, so that the breakdown of low-density cholesterol increases. The concentration of apolipoprotein B falls substantially, high-density cholesterol rises slightly and triglycerides fall. The ratio of total cholesterol to HDL and the ratio of LDL to HDL both end up lower, and LDL comes down whether it was raised to begin with or normal.
Indications
The first group of indications is disorders of lipid metabolism: primary hypercholesterolaemia and mixed dyslipidaemia where diet alone and other non-pharmacological measures such as exercise and weight loss prove insufficient. Homozygous familial hypercholesterolaemia belongs here too, but there simvastatin works as an addition to diet and to other lipid-lowering methods such as LDL apheresis, or is used where such treatment is unavailable or unsuitable.
The second group is framed differently — not through a test result but through risk. The medicine is prescribed to reduce morbidity and mortality from circulatory disease in patients with manifest coronary atherosclerosis or with diabetes, and this regardless of whether their cholesterol is raised or normal. Here the statin acts as an adjunct alongside the correction of the other risk factors.
Method of administration and dosage
The dose range is 5 to 80 mg once a day in the evening, and the dose may be changed no more often than every 4 weeks. In hypercholesterolaemia one usually begins with 10-20 mg a day; patients who need their LDL reduced by more than 45% may start on 20-40 mg. In the homozygous familial form, 40 mg in the evening is recommended, or 80 mg split into three administrations: 20 mg in the morning and at midday and 40 mg in the evening. For preventing cardiovascular events in patients at high coronary risk the dose is 20-40 mg a day, and treatment can begin at the same time as diet and exercise.
| What else the patient takes | Dose ceiling | What lies behind the limit |
| Ciclosporin, danazol, gemfibrozil and other fibrates apart from fenofibrate | 10 mg a day | gemfibrozil, ciclosporin and danazol are contraindicated outright; for the other fibrates a hard ceiling applies, and fenofibrate calls for caution because it can itself cause myopathy |
| Amiodarone, amlodipine, verapamil, diltiazem | 20 mg a day | these are moderate inhibitors of the enzyme that processes simvastatin; with diltiazem it is precisely 20 mg that is recommended as the limit |
| Lomitapide in the homozygous familial form | 40 mg a day | the combination raises the risk of muscle damage, and a dose above 40 mg is contraindicated in that situation |
| Creatinine clearance below 30 ml/min | 10 mg a day under ordinary conditions | a dose above 10 mg is prescribed only after very careful weighing, and treatment is begun with the greatest caution |
| Strong CYP3A4 inhibitors and fusidic acid | the medicine is stopped altogether | this is not a ceiling but a prohibition: for the duration of such treatment the statin is withdrawn, and after fusidic acid it is resumed no sooner than 7 days later |
The relationship with bile acid sequestrants is set out separately: simvastatin is taken either at least 2 hours before them or at least 4 hours after. In mild and moderate renal impairment and in old age the dose is not changed.
Contraindications
The medicine is not prescribed where there is hypersensitivity to simvastatin or to any excipient, in active liver disease, and where there is a persistent, unexplained rise in serum transaminases, nor during pregnancy and breastfeeding.
The second half of the list is medicines. The concurrent use of strong CYP3A4 inhibitors is contraindicated: itraconazole, ketoconazole, posaconazole, HIV protease inhibitors such as nelfinavir, erythromycin, clarithromycin, telithromycin and nefazodone. Gemfibrozil, ciclosporin and danazol are separately prohibited. And the last point is narrow but important: in patients with homozygous familial hypercholesterolaemia taking lomitapide, simvastatin at doses above 40 mg a day is contraindicated.
Special warnings and precautions
Simvastatin's main risk is myopathy: muscle pain, tenderness on pressure or weakness with a rise in creatine kinase activity to more than ten times the upper limit of normal. It sometimes turns into rhabdomyolysis, with or without acute renal failure from myoglobinuria; very rarely, fatal outcomes have been described. And that risk depends directly on the dose, which the product information shows in figures.
- in a study of 41,413 patients the rate of myopathy was about 0.03% on the 20 mg dose, 0.08% on 40 mg and 0.61% on 80 mg a day;
- in patients after a myocardial infarction who received 80 mg for an average of 6.7 years the rate reached 1.0% against 0.02% on the 20 mg dose, and about half the cases fell in the first year of treatment;
- carrying the C allele of the SLCO1B1 gene raises systemic exposure: on the 80 mg dose the one-year risk of myopathy is 15% in CC homozygotes, 1.5% in CT heterozygotes and 0.3% with the commonest TT genotype;
- in patients of Chinese origin on the 40 mg dose the rate was about 0.24% against 0.05% in the others, so in patients of Asian origin the smallest necessary dose is chosen;
- creatine kinase is measured before treatment starts in people aged 65 and over, in women, in renal impairment, in untreated or resistant hypothyroidism, where there are hereditary muscle diseases in the family, after a previous muscular complication on statins or fibrates, and in alcohol dependence;
- if the baseline creatine kinase is more than five times above normal, treatment is not begun; if it rises above that threshold during treatment unrelated to exertion, the medicine is withdrawn;
The second organ in importance is the liver. Tests are done before treatment begins and thereafter as clinically indicated, and on the 80 mg dose additionally before the dose is changed, 3 months after moving to it, and then roughly every six months during the first year. A persistent rise in transaminases to more than three times normal calls for withdrawal; a moderate rise soon after the start is most often transient and needs no withdrawal. A useful detail: ALT can also come from muscle tissue, so its rise together with a rise in creatine kinase points not to the liver but to myopathy. Of the rest it is worth knowing that statins raise blood glucose slightly and in people with prediabetes, obesity, high triglycerides or hypertension can bring it to a level needing treatment — but that is no reason to stop the therapy, because the reduction in vascular risk outweighs it.
Interaction with other medicines
Almost all of simvastatin's interactions grow from one root: it is processed by the enzyme CYP3A4, and everything that inhibits that enzyme raises the concentration of the active acid in the blood. Strong inhibitors — those that increase the area under the curve roughly fivefold or more — are contraindicated, and if treatment with them is necessary, simvastatin is withdrawn for that period and, where needed, a different statin with a lower interaction potential is used instead. Moderate inhibitors, which increase exposure two- to fivefold, call for the dose to be reviewed, and grapefruit juice is best not drunk at all while taking simvastatin.
Two combinations stand apart. Fusidic acid given systemically is incompatible with statins: cases of rhabdomyolysis have been described, some of them fatal, so the statin is withdrawn for the whole course and resumed no sooner than seven days after the last dose. Niacin in lipid-modifying doses from 1 g a day has rarely but genuinely produced myopathy together with statins, and in a study of patients of Chinese origin the rate rose from 0.24% to 1.24%, so the combination is not recommended for patients of Asian origin.
Pregnancy and breastfeeding
Simvastatin is not used in pregnancy. Formally this is a prohibition with a fairly mild justification: a prospective analysis of about 200 pregnancies exposed to simvastatin or related medicines in the first trimester showed that the rate of congenital malformations did not differ from the general population, and the sample was large enough to rule out a 2.5-fold or greater rise in that rate.
The logic of the ban is different. Treating the mother may lower the fetal level of mevalonate, the precursor of cholesterol, while atherosclerosis develops over years, so a pause in a lipid-lowering medicine for the duration of a pregnancy has little effect on the long-term outcome. The medicine is therefore not used in pregnant women, in those planning a pregnancy, or where one is suspected, and it is stopped for the whole period or until pregnancy has been ruled out. Whether simvastatin passes into breast milk is unknown, but breastfeeding during treatment is not advised because of the possibility of serious reactions in the child.
Adverse effects
The safety profile is well studied: in the HPS trial 20,536 patients received 40 mg a day or placebo for an average of five years, and the proportion who stopped treatment because of adverse reactions was practically the same — 4.8% against 5.1%. The rate of myopathy on the 40 mg dose was below 0.1%, and a persistent rise in transaminases to more than three times normal occurred in 0.21% against 0.09% on placebo.
The reactions themselves are mostly rare. From the muscles these are myopathy, including myositis, rhabdomyolysis with or without acute renal failure, muscle pain and cramps, and very rarely muscle rupture. From the digestive tract — constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting and pancreatitis; from the liver — hepatitis and jaundice and, very rarely, hepatic failure, including fatal. Headache, paraesthesia, dizziness, peripheral neuropathy, blurred and other visual disturbances, anaemia, rash, itching, hair loss and asthenia have also been described, and very rarely insomnia, memory disturbance, gynaecomastia and anaphylaxis; with unknown frequency, depression, erectile dysfunction and interstitial lung disease.
Overdose
The overdose section is, for simvastatin, short and remarkably calm: only a few cases have been described, the largest dose taken was 3.6 g, and all the patients recovered without complications.
There are no specific methods for treating an overdose. Symptomatic and supportive treatment is given, guided by the patient's condition. If the medicine has been taken at a dose considerably above the one prescribed, it is worth seeking medical help and telling the doctor how many tablets were taken and when.
How to get a prescription for Simvasterol® online
With simvastatin the dose is set not only by the lipid profile but by the list of other medicines: ciclosporin, danazol and gemfibrozil close the medicine off entirely, fibrates lower the ceiling to 10 mg, amiodarone and verapamil to 20 mg, and strong antifungals and macrolides require the statin to be withdrawn for the whole course. The doctor therefore needs the full list of what you take, not just your symptoms. On e-zdrowie.com you fill in a medical questionnaire, the doctor reviews the answers and, if the medicine is suitable, issues an electronic prescription: the code arrives by message, and any Polish pharmacy will dispense the tablets against it.
Begin the questionnaire with your lipid profile and its date — total cholesterol, LDL, HDL, triglycerides — and say how long you have been on a reduced-cholesterol diet, because the medicine supplements it rather than replacing it. Give your liver function tests and your creatinine with clearance: active liver disease and a persistent rise in transaminases are outright contraindications, and a clearance below 30 ml/min changes the dose. Report any muscle problems in the past on statins or fibrates, hereditary muscle disease in the family, hypothyroidism, and how much alcohol you drink — that is the list for which creatine kinase is measured before treatment starts. Name separately antifungals, macrolides, amiodarone, verapamil, diltiazem, fibrates, and medicines for HIV and hepatitis C. Women of childbearing age need to state their method of contraception: in pregnancy and when planning one, simvastatin is not prescribed.
