Atorvasterol®: composition and dosage form
One film-coated tablet contains 10 mg, 20 mg, 40 mg or 80 mg of atorvastatin as the calcium salt. Four strengths are needed because the dose here is chosen according to the baseline LDL cholesterol, the therapeutic target set and how the patient responds to treatment.
The daily dose is taken whole, all at once, at any time of day and independently of meals. One further condition concerns not the tablet but the plate: before treatment starts the patient should move to a standard low-cholesterol diet and stay on it throughout treatment.
How Atorvasterol® works
Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase. That enzyme limits the rate of cholesterol synthesis: it catalyses the conversion of 3-hydroxy-3-methylglutaryl coenzyme A into mevalonate, and mevalonate is the precursor of the sterols, cholesterol among them. By blocking the enzyme, the medicine shuts off cholesterol production at the narrowest point of the chain.
After that the liver works. In it, triglycerides and cholesterol are built into very low density lipoproteins, and those are carried in the plasma to the peripheral tissues. The low density lipoproteins that arise from them are catabolised mainly through receptors with a high affinity for LDL. From this it is clear why not only total cholesterol falls, but LDL as well, along with apolipoprotein B and triglycerides.
Indications
The indications fall into two large parts — lowering cholesterol and preventing cardiovascular events. The first part in turn covers three different situations.
- primary hypercholesterolaemia, including heterozygous familial hypercholesterolaemia, and combined (mixed) hyperlipidaemia — corresponding to types IIa and IIb of the Fredrickson classification — in adults, adolescents and children from the age of 10, when the response to diet and other non-pharmacological measures is inadequate;
- in adults with the homozygous form of familial hypercholesterolaemia the medicine lowers total cholesterol and LDL, but not on its own: it comes as an addition to other lipid-lowering methods, LDL apheresis for example, or is used when such methods are unavailable;
- prevention of cardiovascular events in adults whose risk is assessed as high, together with correcting the other risk factors.
In prevention there is a subtlety tied to the strengths: for the 10, 20 and 40 mg doses the indication is worded more broadly — prevention of a first and of subsequent cardiovascular events — whereas for the 80 mg dose it speaks of a high assessed risk of a first event.
Method of administration and dosage
The usual starting dose is 10 mg once a day and the maximum is 80 mg once a day. The dose is changed no more often than every 4 weeks: over a shorter period it is too early to judge the effect.
| Situation | Regimen |
| Primary hypercholesterolaemia and mixed hyperlipidaemia | 10 mg a day is enough for most patients; the effect is seen within 2 weeks, the maximum response is usually reached within 4 and is maintained during long-term treatment |
| Heterozygous familial hypercholesterolaemia | start at 10 mg a day, increasing every 4 weeks up to 40 mg; then either up to the maximum of 80 mg, or 40 mg together with bile acid sequestrants |
| Primary prevention | 10 mg a day was used in the trials; higher doses may be needed to reach the target LDL level |
| Secondary prevention | the recommended starting dose is 80 mg a day; it may be reduced during treatment if the target LDL level is maintained |
| Children and adolescents from the age of 10 | start at 10 mg a day, up to 20 mg if needed; there are few data on higher doses and treatment is led by a lipid specialist |
Particular groups need different kinds of attention. In renal impairment no dose adjustment is needed; in hepatic impairment the medicine is used with caution, and in active liver disease it is contraindicated. In people over 70 the safety and efficacy of the recommended doses are the same as in the general population, and in children under 10 atorvastatin is not recommended. And one restriction on combination: in patients receiving hepatitis C antivirals containing elbasvir and grazoprevir the atorvastatin dose must not exceed 20 mg a day.
Contraindications
There are four prohibitions, and three of them are about the liver and pregnancy. The medicine is contraindicated in hypersensitivity to the active substance or to any excipient. It is contraindicated in active liver disease and in unexplained persistently raised serum aminotransferase activity exceeding three times the upper limit of normal.
The third prohibition concerns women and is worded broadly: pregnancy, the breastfeeding period and any woman of childbearing age not using effective methods of pregnancy prevention. The fourth is the only drug contraindication: taking hepatitis C antivirals containing glecaprevir with pibrentasvir at the same time.
Special warnings and precautions
The liver is checked before treatment starts and periodically during it, and outside that schedule if signs of liver damage appear. If aminotransferases have risen, the patient is monitored until they normalise, and with a persistent rise above three times the upper limit of normal the dose is reduced or the medicine withdrawn. Caution is also needed in those who drink heavily or have liver disease in their history. A separate warning concerns stroke: in a post-hoc analysis, in patients without ischaemic heart disease who had recently had a stroke or a TIA, haemorrhagic strokes on the 80 mg dose occurred more often than on placebo.
- before treatment starts, creatine kinase is measured in renal impairment, hypothyroidism, muscle disease in the patient or the family, previous muscle damage on statins or fibrates, liver disease and heavy alcohol use, and after the age of 70 taking the other risk factors into account;
- during treatment the patient must report muscle pain, cramps or weakness at once, especially if general malaise or fever comes with them;
- if creatine kinase rises above 5 times the upper limit of normal the medicine is withdrawn, and with marked muscle complaints withdrawal is considered even below that threshold; with a rise of more than 10 times, or if rhabdomyolysis is suspected, treatment is stopped without exception.
The point of this protocol is that atorvastatin, like other HMG-CoA reductase inhibitors, in rare cases damages skeletal muscle — from myalgia and myositis to myopathy and rhabdomyolysis, a potentially life-threatening state with a many-fold rise in creatine kinase, myoglobinaemia and myoglobinuria that can lead to renal failure. The risk grows when it is combined with drugs that raise the atorvastatin concentration. Simultaneous use with fusidic acid is not recommended, and for the duration of such therapy atorvastatin is better withdrawn. And finally, statins raise glucose levels and in some patients at high risk of diabetes may cause hyperglycaemia requiring diabetes care; the benefit of reducing vascular risk outweighs this, so treatment is not interrupted, but patients in the risk group are monitored.
Interaction with other medicines
The whole picture of interactions follows from two facts: atorvastatin is metabolised by cytochrome P450 3A4 and is a substrate of the hepatic uptake transporter OATP1B1. Everything that inhibits CYP3A4 or the transport proteins therefore raises the plasma concentration of atorvastatin and with it the risk of myopathy.
- strong CYP3A4 inhibitors — ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir and darunavir — are avoided where possible; if they cannot be avoided, a lower starting and maximum dose is used and the patient is monitored;
- moderate CYP3A4 inhibitors — erythromycin, diltiazem, verapamil, fluconazole — also raise the concentration, and for erythromycin with statins an increased risk of myopathy has been shown;
- inducers of cytochrome P450 3A — efavirenz, rifampicin, St John's wort — by contrast lower the atorvastatin concentration to a variable degree;
- with rifampicin the mechanism is twofold — enzyme induction and inhibition of the OATP1B1 transporter in hepatocytes — so atorvastatin is taken at the same time as it: delayed dosing was associated with a marked fall in concentration;
- the risk of myopathy is also raised by drugs capable of causing it on their own: fibric acid derivatives including gemfibrozil, ezetimibe and niacin.
The practical conclusion is simple: if the interacting drug cannot be done without, it is worth looking for an alternative that does not enter into that interaction, and if there is none, weighing the benefit against the risk and lowering the maximum atorvastatin dose.
Pregnancy and breastfeeding
Atorvastatin is contraindicated in pregnancy, and the ban reaches further than pregnancy itself: women of childbearing age must use effective methods of preventing it during treatment. Safety of use in pregnant women has not been established, no controlled clinical trials have been carried out, and rare cases of congenital malformations have been described after intrauterine exposure to HMG-CoA reductase inhibitors; animal studies showed harmful effects on reproduction.
The product information explains separately why interrupting treatment is not alarming. Atherosclerosis is a chronic process, and simply stopping lipid-lowering medicines for the duration of a pregnancy should have little effect on the long-term risk associated with primary hypercholesterolaemia. Treatment is therefore stopped for the duration of the pregnancy or until it is established that the patient is not pregnant. Atorvastatin is contraindicated during breastfeeding too: whether it and its metabolites pass into human milk is not known, but in rats the concentrations in milk and plasma are similar, and adverse reactions in the child could be severe.
Adverse effects
The scale of the data is worth stating: in the placebo-controlled trial database 16,066 patients were treated for an average of 53 weeks, and 5.2% on atorvastatin against 4.0% on placebo stopped treatment because of adverse reactions. Common are nasopharyngitis, allergic reactions, hyperglycaemia, headache, pharyngolaryngeal pain, nosebleeds, constipation, flatulence, dyspepsia, nausea and diarrhoea, pain in the muscles, joints and limbs, muscle cramps, joint swelling and back pain, as well as abnormal liver function tests and a rise in creatine kinase.
Uncommonly recorded are hypoglycaemia, weight gain, anorexia, nightmares and insomnia, dizziness, paraesthesia, taste disturbances and amnesia, blurred vision, tinnitus, vomiting, abdominal pain, pancreatitis, hepatitis, urticaria, rash, itching, alopecia, malaise, weakness and peripheral oedema. Rarely described are thrombocytopenia, peripheral neuropathy, cholestasis, angioedema and bullous rash including Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as myopathy, myositis, rhabdomyolysis and tendon ruptures. Very rarely — anaphylaxis, hearing loss, liver failure and gynaecomastia.
Overdose
The product information describes neither an antidote nor a protocol of its own for atorvastatin overdose: no specific treatment simply exists. What remains is symptomatic therapy and, if necessary, measures to support vital functions.
Two parameters are monitored separately — liver function and creatine kinase activity. And one more thing is worth knowing in advance: haemodialysis will not significantly increase the clearance of atorvastatin, because the medicine binds extensively to plasma proteins.
How to get a prescription for Atorvasterol® online
Statins are the case where a prescription is needed not so much for the first course as for the monitoring: liver tests before the start and periodically, creatine kinase where risk factors exist, a dose review no more often than every 4 weeks. The doctor therefore needs your test results and your list of medicines. 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 lipids and the liver: give your latest lipid profile with total cholesterol, LDL and triglycerides, the date of the test, and also ALT and AST — with a persistent threefold rise the medicine is contraindicated. Say how long you have been on a low-cholesterol diet and whether you have been treated with statins before; if so, whether there were muscle complaints. Be sure to list your medicines: hepatitis C antivirals with glecaprevir and pibrentasvir are incompatible with atorvastatin, with elbasvir and grazoprevir the dose is capped at 20 mg, and ciclosporin, clarithromycin, azole antifungals, HIV protease inhibitors, verapamil, diltiazem, fibrates, ezetimibe and niacin call for a lower dose and monitoring. Report kidney and thyroid disease, muscle disease in yourself and your family, how much alcohol you drink, and any past stroke or TIA. Women of childbearing age must state their contraceptive method: without one the medicine is not prescribed.
