Ezetimibe with simvastatin (Vytorin) for dyslipidaemia

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Galantamine (Reminyl)

Ezetimibe with simvastatin (Vytorin) for dyslipidaemia (eh-ZET-eh-mibe with SIM-va-stat-in)

Summary Ezetimibe with simvastatin combination tablets could be considered for: people already taking ezetimibe and a statin, or people receiving statin monotherapy who need their low-density lipoprotein–cholesterol (LDL-C) concentration lowered further and for whom adding ezetimibe is an appropriate choice. Compared with ezetimibe and simvastatin taken separately, the combination tablets are cheaper for the patient (because only one co-payment is required) and may be more convenient (because only one tablet is needed). For people taking statins other than simvastatin who need additional lowering of LDL-C concentration, consider whether the cost and potential convenience advantages of switching to ezetimibe with simvastatin warrant a change in statin therapy rather than adding ezetimibe as a separate prescription. The adverse-effect profile of ezetimibe plus simvastatin in clinical trials was similar to that of simvastatin monotherapy. However, ezetimibe is a relatively new drug so its full adverse-effect profile may not yet be known. Ensure that patients understand that they must stop taking their previous individual statin and ezetimibe tablets before beginning ezetimibe with simvastatin combination tablets.

PBS listing Ezetimibe with simvastatin combination tablets containing ezetimibe 10 mg and either simvastatin 40 mg or simvastatin 80 mg are listed on the Pharmaceutical Benefits Scheme (PBS). Ezetimibe with simvastatin tablets containing simvastatin 20 mg are available but are not PBS listed.

Authority required 1. Initial treatment, in conjunction with dietary therapy and exercise, in patients who have coronary heart disease or diabetes mellitus and whose cholesterol levels are inadequately controlled with an HMG-CoA reductase inhibitor (statin). Inadequate control with a statin is defined as a cholesterol level greater than the initial threshold for PBS subsidy according to the General Statement for Lipid-Lowering Drugs in the Schedule of Pharmaceutical Benefits after at least 3 months of treatment at a daily statin dose of 40 mg or more.

2. Continuing treatment in patients with coronary heart disease or diabetes mellitus whose cholesterol levels were inadequately controlled with a statin and who have previously received an authority prescription for either ezetimibe with simvastatin tablets or the combination of ezetimibe and 40 mg or more of a statin. 3. Patients with homozygous familial hypercholesterolaemia who are eligible for PBS-subsidised lipid-lowering medication. Refer to the Schedule of Pharmaceutical Benefits for full details of the authority requirements.

Reason for PBS listing The Pharmaceutical Benefits Advisory Committee (PBAC) recommended ezetimibe with simvastatin tablets for listing on the basis of similar efficacy, safety and cost to those of ezetimibe and simvastatin administered separately (that is, cost minimisation).1,2

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Place in therapy Ezetimibe with simvastatin tablets are an alternative to a statin plus ezetimibe administered separately. They could be considered for: • people already taking ezetimibe and a statin, or

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• people receiving statin monotherapy who need their LDL-C concentration lowered further and for whom adding ezetimibe is an appropriate choice. Ezetimibe with simvastatin tablets are bioequivalent to the two drugs co-administered separately.3,4 The main effect of ezetimibe is to reduce LDL-C levels by inhibiting the absorption of biliary and dietary cholesterol across the intestinal wall. It has little effect on high-density lipoprotein–cholesterol or triglyceride levels. In studies in which patients were randomised to receive either ezetimibe, a statin, or a combination of the two, the combination reduced LDL-C concentration by about 15% more than statin monotherapy.5–7 In studies in which ezetimibe 10 mg was added to ongoing statin therapy in patients who had not achieved lipid targets, ezetimibe reduced LDL-C concentration by up to 25% compared with placebo.8,9 Compared with ezetimibe and simvastatin taken separately, the combination tablets are cheaper for patients (because only one co-payment is required) and may be more convenient (because only one tablet is needed), which may help patients to take their medicines correctly.

When is adding ezetimibe an appropriate choice? Ezetimibe is an alternative to other non-statin drugs for people who have had an adequate trial of statin monotherapy and need additional drug therapy to reach LDL-C goals. There is no need to consider adding ezetimibe for patients who have reached lipid goals and are tolerating statin monotherapy. Non-statin lipid-modifying drugs include bile-acid resins (cholestyramine and colestipol), fibrates (gemfibrozil and fenofibrate) and nicotinic acid. Ezetimibe is a new lipidmodifying drug that was first PBS listed in August 2004. Clinical experience with it is therefore limited compared with that for other lipid-modifying drugs. The effect of ezetimibe on the incidence of coronary heart disease events in people at risk is unknown.

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Any combination therapy should only be initiated after a trial of statin monotherapy at an adequate dose for a sufficient duration. Before starting combination therapy, assess compliance with statin therapy because people often discontinue lipid-modifying drugs.10 Careful questioning about compliance in a non-threatening non-judgmental manner — for example, ‘People often have difficulty taking their pills for one reason or another. Have you ever missed any of your pills?’ — will identify more than half of those with low compliance.11 To reduce modifiable risk factors, patients should make diet and lifestyle changes before starting drug therapy and continue these throughout treatment. An alternative to adding a second drug is to increase the dose of statin monotherapy. The cost and convenience advantages of this option must be weighed against the fact that increasing the statin dose increases the risk of adverse effects and has relatively modest effects on cholesterol levels (each doubling of the statin dose achieves in the order of an additional 6% lowering of LDL-C concentration).12 Generally, more than 80% of the lipid-modifying effects of a statin can be achieved with 50% of the maximum dose.13 It should be noted that although lowering cholesterol has been shown to reduce the risk of coronary heart disease events, optimal lipid targets have not been established. Therefore, the benefits of titrating therapy to a particular goal are unknown. See the August 2004 issue of NPS RADAR for more detail about the place of ezetimibe in managing dyslipidaemia.

Changing from another statin to ezetimibe with simvastatin combination tablets For people taking ezetimibe with statins other than simvastatin, consider whether the cost and potential convenience of switching to the combination tablets warrant a change in statin therapy. Adding ezetimibe as a separate prescription may be preferable. Adding ezetimibe to monotherapy with any statin usually lowers LDL-C concentration by about 15%.5 However, different statins produce different reductions in LDL-C concentration per milligram. Therefore, switching from

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another statin to ezetimibe with simvastatin combination tablets may lower LDL-C concentration by more or less than adding ezetimibe to the original statin. Simvastatin has greater LDL-C-lowering effects per milligram than pravastatin or fluvastatin but is less potent than atorvastatin.13 Patients whose LDL-C concentrations are inadequately controlled on atorvastatin monotherapy could have a greater overall reduction in LDL-C concentration if ezetimibe is added to atorvastatin than if they switch to ezetimibe with simvastatin combination tablets. See the NPS RADAR review ‘Atorvastatin (Lipitor) for the management of lipid disorders’ for a discussion of the lipid-modifying effects of atorvastatin compared with those of other statins.

Safety issues The adverse-effect profile of ezetimibe plus simvastatin in clinical trials was similar to that of simvastatin monotherapy.5,7,14 However, ezetimibe is a relatively new drug so its full adverse-effect profile may not yet be known. Elevated liver enzyme concentrations appear to be more frequent with the combination of ezetimibe and simvastatin than with simvastatin alone.4 Muscle disorders are known adverse effects of simvastatin and have been reported with ezetimibe.15,16 Report suspected adverse reactions to the Adverse Drug Reactions Advisory Committee (ADRAC) online (see www.tgasime.health.gov.au) or by using the ‘Blue Card’ distributed with the Schedule of Pharmaceutical Benefits and Australian Prescriber. For information about reporting adverse drug reactions, see the Therapeutic Goods Administration website (www.tga.gov.au).

Be vigilant for signs of muscle adverse effects

Box 1: Reducing the risk of statin myopathy17–19 • Monitor for signs and symptoms of myopathy (unexplained muscle pain, tenderness or weakness). • Use the lowest statin dose required to achieve therapeutic goals. • Ask patients to report muscle symptoms promptly, particularly if accompanied by malaise, fever and/or dark urine. • Avoid, or use cautiously, in combination with drugs known to increase the risk of statin myopathy (e.g. fibrates, cyclosporin, azole antifungals, macrolide antibiotics). • Use statins with caution in patients at particular risk of myopathy (older people, particularly older women; patients with multisystem disease; patients with diabetes and chronic renal failure; patients taking multiple medications). • Suspend statin therapy temporarily when conditions predispose to rhabdomyolysis (e.g. major surgery, trauma, acute renal failure).

2 weeks of starting ezetimibe. Five cases included elevated serum creatine kinase (CK) concentration. Twenty-one cases were in patients with a history of muscle disorders or elevated CK concentration with a statin. In 5 cases ezetimibe was given with a statin; ADRAC suggests that these cases were consistent with an interaction between ezetimibe and the statin, with the symptoms of myalgia or CK-concentration increase developing within 3 months of the addition of ezetimibe to long-term statin treatment. Two published cases also describe myopathy associated with the combination of ezetimibe and a statin, with muscle and tendon pain and/or CK-concentration elevation detected within 2 months of adding ezetimibe to longstanding statin treatment.16

Monitor transaminase concentrations

Simvastatin can cause muscle pain and weakness and rarely rhabdomyolysis. See Box 1 for information about preventing statin myopathy. More recently, muscle disorders have been reported with ezetimibe used alone.15,16 It is not known if ezetimibe can cause rhabdomyolysis.

Elevated serum transaminase concentrations occurred in patients taking the combination of ezetimibe and simvastatin more frequently than in those on simvastatin monotherapy in clinical trials.4 These adverse effects appeared to be related to the dose of simvastatin, were often asymptomatic and generally resolved after either discontinuing treatment or during continuing therapy.

ADRAC has received 44 reports of muscle disorders, including myalgia, muscle cramp, weakness and pain, with ezetimibe.15 Almost half of the cases occurred within

Similar precautions apply as with statin treatment. Measure transaminase concentrations before starting ezetimibe with simvastatin therapy and periodically

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during treatment, particularly in patients taking ezetimibe with simvastatin 10 mg / 80 mg. Stop treatment if transaminase concentrations are persistently above three times the upper limit of normal.12

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It is usually recommended that restarting statin treatment be considered after transaminase concentrations have returned to normal, because transaminase elevations often do not recur at rechallenge.12 The likelihood of transaminase concentration elevation recurring on rechallenge with ezetimibe with simvastatin tablets is unknown because clinical experience with the combination is more limited. If ezetimibe is restarted, monitor transaminase concentrations closely. Avoid ezetimibe with simvastatin in people with active liver disease or unexplained persistent transaminase elevations and use caution in those with a past history of liver disease or who consume excessive amounts of alcohol.3

Consider drug interactions with simvastatin Drug interactions for simvastatin apply to ezetimibe with simvastatin. Inhibitors of CYP3A4 (such as ketoconazole, verapamil and grapefruit juice) can increase simvastatin levels and elevate the risk of adverse effects. The manufacturer recommends that ezetimibe with simvastatin tablets not be used with fibrates (gemfibrozil, fenofibrate) because the combination of simvastatin and a fibrate increases the risk of myopathy and the safety of ezetimibe in combination with fibrates has not been established.3

Dosing issues Each ezetimibe with simvastatin combination tablet contains ezetimibe 10 mg. Combination tablets containing simvastatin doses of 20 mg, 40 mg and 80 mg are available in Australia. Only the ezetimibe with simvastatin 10 mg / 40 mg and 10 mg / 80 mg strengths are listed on the PBS. Patients should not take more than one ezetimibe with simvastatin tablet at a time because there is no advantage to using ezetimibe doses above 10 mg.20

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The manufacturers suggest starting at a dose of ezetimibe with simvastatin of up to 10 mg / 40 mg* and individualising dose based on response.3 People already taking simvastatin can switch directly to the corresponding dose of ezetimibe with simvastatin. The manufacturer does not provide any specific dosing recommendations for people switching from other statins to ezetimibe with simvastatin tablets. It would seem reasonable to switch to the same milligram statin dose in the fixed-dose combination tablets (for example, from atorvastatin 40 mg to ezetimibe with simvastatin 10 mg / 40 mg). Assess response and adjust dose as required. If lipid goals are not reached using ezetimibe with simvastatin 10 mg / 40 mg, LDL-C concentration can be further reduced by up to 6% by titrating up to the higher strength containing simvastatin 80 mg.5,21

Information for patients Explain the symptoms of possible adverse effects on muscle of ezetimibe with simvastatin. Ask patients to report unexplained muscle pain or weakness promptly. Ensure that patients understand that they must stop taking their previous statin and ezetimibe tablets before beginning ezetimibe with simvastatin combination tablets and that they should not take more than one ezetimibe with simvastatin tablet at a time. Discuss the importance of lifestyle changes in reducing overall cardiovascular risk. Information about lifestyle changes for patients is available from the Heart Foundation’s national telephone information service, Heartline (Ph 1300 36 27 87) or online (www.heartfoundation.com.au). For more detailed information about ezetimibe with simvastatin, suggest or provide the Vytorin consumer medicine information (CMI). * Except for people with homozygous familial hypercholesterolaemia, who should start at an ezetimibe with simvastatin dose of either 10 mg / 40 mg or 10 mg / 80 mg.

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References 1. Pharmaceutical Benefits Advisory Committee. July 2005 PBAC outcomes — positive recommendations. Canberra: Australian Government Department of Health and Ageing, 2005. http://www.health.gov.au/internet /wcms/publishing.nsf/Content/pbacrec-jul05-positive (accessed 30 August 2005). 2. Pharmaceutical Benefits Advisory Committee. March 2005 PBAC outcomes — positive recommendations. Canberra: Australian Government Department of Health and Ageing, 2005. http://www.health.gov.au/internet /wcms/publishing.nsf/Content/pbacrec-mar05-positive (accessed 30 August 2005). 3. Merck Sharp and Dohme (Australia) Pty Ltd. Vytorin product information. 12 August 2005. 4. Therapeutic Goods Administration. Vytorin (ezetimibe/simvastatin) request for ADEC advice. Canberra: Australian Government Department of Health and Ageing, 30 August 2004.

5. 6. 7. 8. 9. 10. 11. 12.

Bays HE, et al. Clin Ther 2004;26:1758–73. Feldman T, et al. Am J Cardiol 2004;93:1481–6. Goldberg AC, et al. Mayo Clin Proc 2004;79:620–9. Pearson TA, et al. Mayo Clin Proc 2005;80:587–95. Farnier M, et al. Int J Cardiol 2005;102:327–32. Simons L, et al. Med J Aust 1996;164:208–11. Stephenson BJ, et al. JAMA 1993;269:2779–81. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Final report. Bethesda, Maryland: National Institutes of Health — National Heart Lung and Blood Institute, 2002. http://www.nhlbi.nih.gov /guidelines/cholesterol/atp3_rpt.htm (accessed 30 August 2005). 13. Australian Medicines Handbook 2005. 14. Masana L, et al. Clin Ther 2005;27:174–84.

15. Adverse Drug Reactions Advisory Committee. Australian Adverse Drug Reactions Bulletin 2005;24:15. 16. Fux R, et al. Ann Intern Med 2004;140:671–2. 17. Pasternak R, et al. J Am Coll Cardiol 2002;40:567–72. 18. Hamilton-Craig I. Med J Aust 2001;175:486–9. 19. Thompson P, et al. JAMA 2003;289:1681–90. 20. Center for Drug Evaluation and Research. Zetia (ezetimibe) tablets approval package. Rockville, Maryland: United States Food and Drug Administration, 2002. http://www.fda.gov/cder/foi/nda/2002/ 21445_Zetia.htm (accessed 30 August 2005). 21. Ballantyne CM, et al. Am Heart J 2005;149:464–73.

Date prepared: January 2006 The information contained in this material is derived from a critical analysis of a wide range of authoritative evidence. Any treatment decisions based on this information should be made in the context of the clinical circumstances of each patient.

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