Advice on reducing the risk of statin interactions Karen Baxter MSc, MRPharmS and C Rhoda Lee PhD, MRPharmS

Transcription

1 Advice on reducing the risk of statin interactions Karen Baxter MSc, MRPharmS and C Rhoda Lee PhD, MRPharmS VM The editors of Stockley s Drug Interactions highlight the potentially serious interactions with statins and the steps that should be taken to avoid them. Figure 1. Myoglobinuria (dark urine) is a symptom of rhabdomyolysis, a major adverse effect of statins associated with higher doses and drug interactions The statins (HMG-CoA reductase inhibitors) are an increasingly widely prescribed group of drugs. Recent recommendations emphasise that more patients are likely to need statin therapy since acceptable limits for cholesterol have been lowered, 1 and that patients are likely to need higher doses of statins to meet the increasingly aggressive management of elevated lipid levels. Therefore, it is likely that higher doses of statins will be prescribed to a wider range of patients. The use of higher doses of statins increases the risks of adverse effects, particularly those occurring as a result of drug interactions. Although the statins are generally well tolerated, they have two major adverse effects: they raise liver enzymes and can cause skeletal muscle disorders, eg myalgia, myopathy and rhabdomyolysis. Rhabdomyolysis can range from asymptomatic elevations in creatine kinase to acute renal failure, and in its severest form may be lifethreatening. As well as elevated creatine kinase levels, signs and symptoms of rhabdomyolysis include muscle pain, weakness and reddish-brown urine (myoglobinuria, see Figure 1). 2 Although one review reported the incidence of mild myopathies with statins alone as about 1-7 per cent, 3 the overall risk of serious myopathy with the statins is quite low and commonly quoted at per cent. However, the incidence seems to rise markedly if other drugs are being taken concurrently. Thus, a literature review of published reports of rhabdomyolysis between 1985 and 2000 found 15 cases with statins alone, but 54 cases when combined with other drugs. 4 Elevated statin levels The exact mechanism by which statins cause muscle disorders is unclear, although it is thought that elevated statin levels play a key role. 4 Any factor that increases these levels, such as the use of higher doses, can therefore raise the risk of precipitating muscle damage. Statin levels can also rise if any drug given at the same time inhibits their metabolism, and this can be a problem both when a new drug is started and Prescriber 5 June

2 when there is a dosage adjustment in a patient previously stable on an interacting combination. Such changes need to be managed carefully. Statin levels can become elevated if the interacting drug inhibits the metabolism of the statin, with the result that it is cleared from the body more slowly and begins to accumulate. Since statins differ in the way that and extent to which they are metabolised, they do not always interact in the same way. Simvastatin is extensively metabolised by the cytochrome P450 isoenzyme CYP3A4, and any drugs that inhibit this enzyme can cause marked rises in blood statin levels. 5 Atorvastatin (Lipitor) is also metabolised by CYP3A4 but has a relatively low affinity for this isoenzyme, 6 which means that CYP3A4 inhibitors cause smaller but still potentially serious elevations in its levels. Fluvastatin (Lescol) is metabolised primarily by CYP2C9 and rosuvastatin (Crestor) by CYP2C9 and CYP2C19 (although the majority is excreted unchanged 7 ), while the cytochrome P450 system does not appear to be involved in the metabolism of pravastatin. 5 P-glycoprotein inhibition The statins are also P-glycoprotein substrates, and may therefore interact due to inhibition of this carrier, which generally results in increased oral bioavailability. 5 Many drugs that are inhibitors of CYP3A4 are also inhibitors of P- glycoprotein and therefore an You can t Any adverse event must be reported to Sankyo Pharma UK Ltd (please see contact details within PI) or via Abbreviated Prescribing Information OLMETEC Film-Coated Tablets (olmesartan medoxomil): Refer to Summary of Product Characteristics before prescribing. Presentation: OLMETEC is supplied as film-coated tablets containing 10mg, 20mg, or 40mg of olmesartan medoxomil. Indications: Treatment of essential hypertension. Dosage: The recommended starting dose is one OLMETEC 10mg tablet daily. OLMETEC tablets should be taken at about the same time each day, with or without food, for example at breakfast time. In patients whose blood pressure is not adequately controlled at this dose, the dose may be increased to 20mg once daily as the optimal dose. If additional blood pressure reduction is required, the OLMETEC dose may be increased to a maximum of 40mg daily or hydrochlorothiazide therapy may be added. Elderly: The maximum dose in elderly patients is 20mg once daily, owing to limited experience of higher dosages in this patient group. Children and adolescents: Safety and efficacy have not been established in children. Renal impairment: The maximum dose in patients with mild to moderate renal impairment is 20mg OLMETEC once daily, owing to limited experience of higher dosages. The use of OLMETEC in patients with severe renal impairment is not recommended. Hepatic impairment: The use of OLMETEC is not recommended since there is only limited experience in this patient group. Contra-indications: Hypersensitivity to any of the ingredients; Second and third trimesters of pregnancy, lactation; biliary obstruction. Warnings and precautions: Pregnancy and lactation: OLMETEC is contraindicated in second and third trimesters of pregnancy and in lactation. Renal impairment: Periodic monitoring of serum potassium and creatinine levels is recommended. Use of OLMETEC is not recommended in patients with severe renal impairment. Renovascular hypertension: There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system (RAAS). A similar effect may be anticipated with angiotensin II receptor antagonists. Intravascular volume depletion: Sodium and/or volume depletion should be corrected before starting treatment with OLMETEC. Aortic or mitral valve stenosis (obstructive hypertrophic cardiomyopathy): As with other vasodilators special caution is recommended. Primary aldosteronism: Not recommended. Hyperkalaemia: Based on experience with other drugs affecting RAAS, hyperkalaemia may occur during treatment in at risk patients. Close monitoring of serum potassium levels in at risk patients is recommended. Hepatic impairment: Use of OLMETEC in patients with hepatic impairment is not recommended. Ethnic differences: As with all other angiotensin II antagonists, the blood pressure lowering effect of OLMETEC may be reduced in black patients. General: The combination of lithium and

3 interaction may occur via both mechanisms. Fibrates The statins may also interact with other drugs that damage muscles, the best-known example being with fibrates. Of the fibrates, gemfibrozil appears to be most commonly implicated, and it has now been shown that it raises the levels of a number of statins. The mechanism for this effect is uncertain, but may involve inhibition of statin glucuronidation. More recently gemfibrozil has also been shown to be an inhibitor of CYP2C8. The most common statin/ fibrate interaction was that between cerivastatin (now withdrawn) and gemfibrozil. This combination was thought to be up to 80 times more likely to cause fatal rhabdomyolysis, and it seems likely that CYP2C8 inhibition was largely responsible for the severity of this interaction. Because rhabdomyolysis with this statin alone appeared to be more common than with other statins, cerivastatin was withdrawn in 2001/2002. Healthcare costs There appears to be very little information about the impact of statin interactions on healthcare costs, but one Canadian study found that patients taking drugs known to interact with statins consumed more than double the healthcare resources of patients taking statins and no interacting drugs. 8 Drug interactions, therefore, greatly control everything......but you have the power to help control BP Olmetec potency puts you in control. Olmetec 20mg delivers more potent BP reduction than losartan 50mg, valsartan 80mg, irbesartan 150mg and candesartan 8mg. 1-3 That s the power you could prescribe. AIIA comparison is at usual maintenance doses 4 Olmesartan medoxomil Power in your hands OLMETEC is not recommended. In patients with severe congestive heart failure or underlying renal disease including renal artery stenosis, treatment with drugs that affect RAAS has been associated with acute hypotension or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with angiotensin II receptor antagonists. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke. Drug interactions: OLMETEC may be administered with or without food. No clinically relevant interactions were observed with pravastatin, hydrochlorothiazide, antacids, warfarin or digoxin. Concomitant use of lithium, NSAIDs, potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and drugs that may increase serum potassium levels is not recommended. The blood pressure lowering effect of OLMETEC may be increased by concomitant use of other antihypertensive agents. No clinically relevant interactions between OLMETEC and drugs metabolised by cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 are expected. Effects on ability to drive and use machines: The effect of OLMETEC tablets on the ability to drive has not been specifically studied. Occasionally dizziness or fatigue may occur in patients taking antihypertensive therapy. Side effects: In clinical studies, the overall incidence of treatment-emergent adverse events was comparable to placebo. The only adverse drug reaction that was unequivocally related to treatment was dizziness. Common: Dizziness, bronchitis, cough, pharyngitis, abdominal pain, diarrhoea, dyspepsia, gastroenteritis, nausea, back, joint, skeletal and chest pain, fatigue, influenza-like symptoms, peripheral oedema, haematuria, urinary tract infection, increased creatine phosphokinase, hypertriglyceridaemia, hyperuricaemia, liver enzyme elevations. Uncommon: Vertigo, angina pectoris, rash. Rare: Hyperkalaemia, hypotension. Very Rarely: Hypersensitivity reactions. Postmarketing experience: The following have been reported very rarely (<1/10,000): Thrombocytopenia, abdominal pain, allergic conditions such as angioneurotic oedema, dermatitis allergic, facial oedema, urticaria, acute renal failure, renal insufficiency, asthenia, abnormal renal function tests, abnormal hepatic function tests. Please consult the Summary of Product Characteristics for a full list of side effects. Legal Category: POM. Package quantities, marketing authorisation numbers and basic NHS cost: OLMETEC 10mg (28 tablets), PL 08265/0015, 10.95, OLMETEC 20mg (28 tablets), PL 08265/ , OLMETEC 40mg (28 tablets) PL 08265/ Marketing Authorisation Holder: Sankyo Pharma UK Ltd, Sankyo House, Repton Place, White Lion Road, Amersham, Buckinghamshire, HP7 9LP. OLMETEC is a registered trademark, the property of Sankyo Co., Ltd, Tokyo, Japan. Further information from: Medical Information, Sankyo Pharma UK Ltd, Sankyo House, Repton Place, White Lion Road, Amersham HP7 9LP. Tel: (01494) medinfo@sankyo.co.uk. Date of preparation: January References: 1. Basile JN et al. Journal of Human Hypertension 2006; 20: Oparil S. J Human Hypertens 2001; 3(5): , Brunner HR, Stumpe KO. Clin Drug Invest 2003; 23(7): UK SmPCs accessed Apr 2006 at Date of preparation: April 2006 OLM356

4 Interacting Evidence for an interaction Statin affected/implicated drug atorvastatin fluvastatin pravastatin rosuvastatin simvastatin Amiodarone amiodarone inhibits CYP3A4, and? X X X dose should not there is some evidence of an exceed 20mg daily increased incidence of myopathy unless the clinical when amiodarone is given with high benefit outweighs doses of simvastatin; rhabdomyo- the risks; counsel lysis has been reported in patients on the combination Azithromycin azithromycin did not change X X X X X atorvastatin levels, and would not be expected to interact with other statins Ciclosporin ciclosporin causes marked start at start at start at contraindicated makers advise dose elevations in statin levels (7-fold lowest dose; lowest dose; lowest dose; should not exceed with rosuvastatin), and cases of counsel counsel counsel 10mg daily; be myalgia and/or rhabdomyolysis aware that have been reported with atorva- ciclosporin dosage statin, fluvastatin, pravastatin and adjustments may simvastatin; atorvastatin is also sometimes be reported to increase ciclosporin necessary; counsel levels by 26-54%, whereas simvastatin appears to reduce them by about 30%; fluvastatin, pravastatin and rosuvastatin do not appear to cause significant changes in ciclosporin levels Clarithromycin clarithromycin inhibits CYP3A4 and caution X caution X contraindicated; raises atorvastatin levels, and would advised; advised; withdraw simvatherefore be predicted to raise sim- counsel counsel statin during short vastatin levels; unexpectedly, courses of clarithromycin modestly raises clarithromycin pravastatin levels; rhabdomyolysis has been seen with simvastatin Clopidogrel statins metabolised by the cyto-? X X X? chrome P450 isoenzyme CYP3A4 appear to interfere with the antiplatelet action of clopidogrel; there is insufficient evidence to recommend changes to current practice Colchicine case reports describe myopathy or counsel counsel counsel counsel counsel rhabdomyolysis in patients given colchicine with fluvastatin, pravastatin or simvastatin; this effect seems possible with all statins Table 1. Drug interactions with statins and safety advice Prescriber 5 June

5 Interacting Evidence for an interaction Statin affected/implicated drug atorvastatin fluvastatin pravastatin rosuvastatin simvastatin Danazol severe rhabdomyolysis and myo-? X X X makers advise dose globinuria have been seen when should not exceed simvastatin was given with danazol; 10mg daily; this was possibly due to inhibition counsel of CYP3A4 Diltiazem diltiazem raises simvastatin levels by makers advise X X X makers advise dose inhibition of CYP3A4; rhabdomyo- caution; should not exceed lysis has been seen with diltiazem counsel 40mg daily; and atorvastatin or simvastatin counsel Erythromycin erythromycin inhibits CYP3A4 and caution caution has caution X contraindicated; modestly raises atorvastatin levels, advised; been advised advised; withdraw and would therefore be predicted counsel due to counsel simvastatin during to raise simvastatin levels; problems short courses of unexpectedly, clarithromycin with the other erythromycin modestly raised pravastatin levels macrolides in 1 of 2 studies; erythromycin but no slightly reduces rosuvastatin levels; interaction is unspecified macrolides have been expected implicated in cases of rhabdomyolysis with atorvastatin, pravastatin and simvastatin Fibrates gemfibrozil markedly increases levels undertake with caution caution makers contra- avoid gemfibrozil of pravastatin, rosuvastatin and caution, advised with advised with indicate 40mg where possible; simvastatin, whereas fenofibrate especially all fibrates; all fibrates; dose; rosuva- makers of simvadoes not; because of the increased with counsel counsel statin 5mg statin advise dose risks of muscle toxicity, eg myopathy gemfibrozil; should be used should not exceed or rhabdomyolysis, it is generally counsel to start; 10mg daily, except accepted that use of a statin in counsel with fenofibrate conjunction with a fibrate should where no dose only be undertaken if the benefits restriction is outweigh the risks; the incidence of advised; counsel all statin/fibrate interactions leading to patients myopathy has been put at up to 5%; creatine kinase levels should be measured before initiation Fluconazole fluconazole inhibits the cytochrome caution caution X X contraindicated; P450 isoenzymes CYP2C9 and advised; advised; withdraw CYP3A4 and so causes a modest counsel counsel simvastatin during increase in fluvastatin levels, and short courses of would be predicted to increase fluconazole simvastatin and possibly atorvastatin levels; it has no clinically significant effect on pravastatin or rosuvastatin levels; rhabdomyolysis has been seen when fluconazole is used with atorvastatin and simvastatin Table 1. Drug interactions with statins and safety advice 13 (cont.) 40 Prescriber 5 June

6 Interacting Evidence for an interaction Statin affected/implicated drug atorvastatin fluvastatin pravastatin rosuvastatin simvastatin Fusidic acid 2 cases of rhabdomyolysis have counsel X X X counsel been described in patients given atorvastatin or simvastatin with systemic fusidic acid; fusidic acid was also a possible contributing factor in an interaction attributed to simvastatin and tacrolimus Grapefruit juice grapefruit juice markedly increases small X X X avoid grapefruit the plasma levels of simvastatin, quantities of juice but only modestly affects those of grapefruit atorvastatin; pravastatin seems not juice to interact acceptable Itraconazole itraconazole causes a marked rise in caution X X X contraindicated; the serum levels of atorvastatin and advised; withdraw simvasimvastatin, a nonsignificant change counsel statin during short in pravastatin levels, and no change courses of itraconain fluvastatin or rosuvastatin levels; zole rhabdomyolysis has been seen with simvastatin Ketoconazole there is much less information caution X X X contraindicated; regarding the interactions of advised; withdraw simvaketoconazole and the statins but it counsel statin during short would be expected to interact in the courses of ketosame way as itraconazole; conazole ketoconazole did not change rosuvastatin levels Nicotinic acid cases of rhabdomyolysis have been caution caution caution caution start makers advise dose (Niacin) attributed to the concurrent use of advised; advised; advised; with a 5mg should not exceed nicotinic acid and simvastatin or counsel counsel counsel dose; counsel 10mg daily; counsel pravastatin; nicotinic acid in doses of greater than 1g daily is associated with myopathy Phenytoin in an isolated case, phenytoin it may be it may be X X it may be prudent to reduced the cholesterol-lowering prudent to prudent to check the lipideffect of simvastatin, fluvastatin check the check the lowering effects are and atorvastatin lipid-lowering lipid-lowering adequate effects are effects are adequate; adequate; monitor monitor Protease the levels of atorvastatin and use with X X X contraindicated inhibitors simvastatin appear to be markedly caution and increased by lopinavir/ritonavir, consider a nelfinavir, ritonavir and ritonavir with lower dose saquinavir; 2 cases of rhabdo- (10mg); myolysis have been attributed to counsel Table 1. Drug interactions with statins and safety advice 13 (cont.) Prescriber 5 June

7 Interacting Evidence for an interaction Statin affected/implicated drug atorvastatin fluvastatin pravastatin rosuvastatin simvastatin Protease inhibitors (cont.) ritonavir used with simvastatin; pravastatin does not seem to be significantly affected Rifampicin rifampicin lowers the serum levels of it may be it may be X X it may be prudent to fluvastatin and simvastatin, but an prudent to prudent to check the lipidinteraction has not been widely check the check the lowering effects are reported; it seems likely that lipid-lowering lipid-lowering adequate hepatically metabolised statins will effects are effects are be affected adequate adequate Sildenafil rhabdomyolysis occurred in a patient X X X X consider taking simvastatin and sildenafil; counselling no pharmacokinetic interaction appears to occur between atorvastatin and sildenafil St John s wort St John s wort modestly decreases X X X X it may be prudent to the plasma level of simvastatin, but check the lipidnot pravastatin lowering effects are adequate Tacrolimus an isolated case of rhabdomyolysis X X X X consider occurred following the concurrent counselling use of tacrolimus and simvastatin; the patient was also taking fusidic acid (see above) Telithromycin telithromycin markedly raised simva- contraindica- X X X contraindicated; statin levels, and is predicted to do ted; withdraw withdraw simvathe same with atorvastatin; it is not atorvastatin statin during short expected to interact with fluvastatin during short courses of or pravastatin courses of telithromycin telithromycin Verapamil verapamil inhibits CYP3A4 and? X X X makers advise dose causes marked rises in simvastatin should not exceed levels but serious interactions seem 20mg daily; rare counsel Warfarin case reports suggest that the effects the makers of all the statins advise monitoring, despite little evidence that an of warfarin can be increased by interaction occurs in many cases; fluvastatin shares a metabolic pathway with fluvastatin, rosuvastatin and simva- warfarin and so there is more reason to consider monitoring with this combination statin; studies have not found an interaction; the exception is possibly fluvastatin, where moderate INR increases have been seen more frequently X = not known to be affected/implicated in an interaction? = some uncertainty about any interaction Table 1. Drug interactions with statins and safety advice 13 (cont.) 42 Prescriber 5 June

8 increase the cost of caring for patients taking statins. Recommendations for risk reduction In order to reduce the risks of muscle disorders the CSM (now the Commission on Human Medicines) advises that statins should be used with care in patients who are at increased risk of this adverse effect. 9 Advanced age (said to be over 80 years in the USA and over 70 years in the UK and Australia), 1,10,11 untreated hypothyroidism, alcohol abuse, the perioperative period and impaired renal function (especially related to diabetes) are all independent risk factors for the development of statin-induced myopathy, 1,10,11 and it would be prudent to take a more cautious approach in patients with these co-existent problems. It is also recommended that patients on a statin should be made aware of the risks of myopathy and rhabdomyolysis, and asked to report promptly any unexplained muscle pain, tenderness or weakness, especially if accompanied by malaise, fever or dark urine. 9 In many cases reinforcement of this advice will be sufficient to manage the use of potentially interacting drugs, but in other cases dose adjustments and even temporary withdrawal of the statin may be necessary. Safety advice relating to various interactions is given in Table 1. If symptoms of myopathy occur, creatine kinase should be measured. If this is markedly elevated (some authorities suggest more than five times the upper limit of normal, ULN, 12 and others more than 10 times the ULN 1 ), the statin should be stopped immediately. At lower raised levels (3-10 times the ULN), 1 the patient should be monitored weekly until there is either no longer cause for concern or the statin has to be stopped. 1 Conclusion The incidence of severe adverse interactions with the statins is low, but has the potential to rise as more recent prescribing guidelines are adopted. All statins do not have the same propensity to interact, but in most cases all interactions can be managed by following the simple precautions described here. References 1. Pasternak RC, Smith SC Jr, Bairey- Merz CN, et al; American College of Cardiology; American Heart Association; National Heart, Lung and Blood Institute. ACC/ AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 2002;106: Allison RC, Bedsole DL. The other medical causes of rhabdomyolysis. Am J Med Sci 2003;326: Ucar M, Mjörndal T, Dahlqvist R. HMG-CoA reductase inhibitors and myotoxicity. Drug Saf 2000;22: Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 2001;35: Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet 2002; 41: Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 2003;42: Roach AE, Tsikouris JP, Haase KK. Rosuvastatin. A new HMG-CoA reductase inhibitor for hypercholesterolemia. Formulary 2002;37: Einarson TR, Metge CJ, Iskedjian M, et al. An examination of the effect of cytochrome P450 drug interactions of hydroxymethylglutaryl-coenzyme A reductase inhibitors on health care utilization: a Canadian population-based study. Clin Ther 2002;24: CSM/Medicines Control Agency. HMG CoA reductase inhibitors (statins) and myopathy. Current Problems 2002;28: CSM/Medicines and Healthcare products Regulatory Agency. Statins and cytochrome P450 interactions. Current Problems 2004;30: Adverse Drug Reactions Advisory Committee. Risk factors for myopathy and rhabdomyolysis with the statins. Aust Adverse Drug React Bull 2004;23: BNF. No 51, March Baxter K, ed. Stockley s Drug Interactions. London: Pharmaceutical Press. Electronic version (May 2006). Karen Baxter is executive editor and Rhoda Lee is staff editor of Stockley s Drug Interactions Forum If you have any issues you would like to air with your colleagues or comments on articles published in Prescriber, the Editor would be pleased to receive them and, if appropriate, publish them on our Forum page. Please send your comments to: The Editor, Prescriber, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, or to prescriber@wiley.co.uk Prescriber 5 June