Ezetimibe with simvastatin (Vytorin) for dyslipidaemia

Page created by Nicole Potter
 
CONTINUE READING
OKA4501NPS RADAR March06.qxd      22/3/06    4:10 PM    Page 1

                                                                                                 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.                                                                   01

               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                                                 2. Continuing treatment in patients with coronary
                                                                       heart disease or diabetes mellitus whose cholesterol
        Ezetimibe with simvastatin combination tablets                 levels were inadequately controlled with a statin
        containing ezetimibe 10 mg and either simvastatin              and who have previously received an authority
        40 mg or simvastatin 80 mg are listed on the
                                                                       prescription for either ezetimibe with simvastatin
        Pharmaceutical Benefits Scheme (PBS). Ezetimibe
                                                                       tablets or the combination of ezetimibe and 40 mg
        with simvastatin tablets containing simvastatin
                                                                       or more of a statin.
        20 mg are available but are not PBS listed.
                                                                    3. Patients with homozygous familial hyper-
        Authority required                                             cholesterolaemia who are eligible for
        1. Initial treatment, in conjunction with dietary therapy      PBS-subsidised lipid-lowering medication.
           and exercise, in patients who have coronary heart        Refer to the Schedule of Pharmaceutical Benefits
           disease or diabetes mellitus and whose cholesterol       for full details of the authority requirements.
           levels are inadequately controlled with an HMG-CoA
           reductase inhibitor (statin).
                                                                    Reason for PBS listing
          Inadequate control with a statin is defined as a
          cholesterol level greater than the initial threshold      The Pharmaceutical Benefits Advisory Committee
          for PBS subsidy according to the General Statement        (PBAC) recommended ezetimibe with simvastatin
          for Lipid-Lowering Drugs in the Schedule of               tablets for listing on the basis of similar efficacy,
          Pharmaceutical Benefits after at least 3 months of        safety and cost to those of ezetimibe and simvastatin
          treatment at a daily statin dose of 40 mg or more.        administered separately (that is, cost minimisation).1,2

                                                                                         April 2006
OKA4501NPS RADAR March06.qxd     22/3/06     4:10 PM   Page 2

             Ezetimibe with simvastatin (Vytorin)

           Place in therapy                                              Any combination therapy should only be initiated
                                                                         after a trial of statin monotherapy at an adequate
           Ezetimibe with simvastatin tablets are an alternative         dose for a sufficient duration.
           to a statin plus ezetimibe administered separately.
           They could be considered for:                                 Before starting combination therapy, assess compliance
                                                                         with statin therapy because people often discontinue
           • people already taking ezetimibe and a statin, or
                                                                         lipid-modifying drugs.10 Careful questioning about
           • people receiving statin monotherapy who need                compliance in a non-threatening non-judgmental
             their LDL-C concentration lowered further and for           manner — for example, ‘People often have difficulty
 02          whom adding ezetimibe is an appropriate choice.             taking their pills for one reason or another. Have you
           Ezetimibe with simvastatin tablets are bioequivalent to       ever missed any of your pills?’ — will identify more
           the two drugs co-administered separately.3,4 The main         than half of those with low compliance.11
           effect of ezetimibe is to reduce LDL-C levels by inhibiting   To reduce modifiable risk factors, patients should make
           the absorption of biliary and dietary cholesterol across      diet and lifestyle changes before starting drug therapy
           the intestinal wall. It has little effect on high-density     and continue these throughout treatment.
           lipoprotein–cholesterol or triglyceride levels.
                                                                         An alternative to adding a second drug is to increase the
           In studies in which patients were randomised to receive       dose of statin monotherapy. The cost and convenience
           either ezetimibe, a statin, or a combination of the two,      advantages of this option must be weighed against the
           the combination reduced LDL-C concentration by about          fact that increasing the statin dose increases the risk
           15% more than statin monotherapy.5–7 In studies               of adverse effects and has relatively modest effects
           in which ezetimibe 10 mg was added to ongoing                 on cholesterol levels (each doubling of the statin dose
           statin therapy in patients who had not achieved lipid         achieves in the order of an additional 6% lowering
           targets, ezetimibe reduced LDL-C concentration by             of LDL-C concentration).12 Generally, more than 80%
           up to 25% compared with placebo.8,9                           of the lipid-modifying effects of a statin can be achieved
           Compared with ezetimibe and simvastatin taken separately,     with 50% of the maximum dose.13
           the combination tablets are cheaper for patients              It should be noted that although lowering cholesterol
           (because only one co-payment is required) and may             has been shown to reduce the risk of coronary heart
           be more convenient (because only one tablet is needed),       disease events, optimal lipid targets have not been
           which may help patients to take their medicines correctly.    established. Therefore, the benefits of titrating therapy
           When is adding ezetimibe an                                   to a particular goal are unknown.
           appropriate choice?                                           See the August 2004 issue of NPS RADAR for more
           Ezetimibe is an alternative to other non-statin drugs         detail about the place of ezetimibe in managing
           for people who have had an adequate trial of statin           dyslipidaemia.
           monotherapy and need additional drug therapy to
                                                                         Changing from another statin to ezetimibe
           reach LDL-C goals. There is no need to consider adding
                                                                         with simvastatin combination tablets
           ezetimibe for patients who have reached lipid goals and
           are tolerating statin monotherapy.                            For people taking ezetimibe with statins other than
                                                                         simvastatin, consider whether the cost and potential
           Non-statin lipid-modifying drugs include bile-acid resins
                                                                         convenience of switching to the combination tablets
           (cholestyramine and colestipol), fibrates (gemfibrozil and
                                                                         warrant a change in statin therapy. Adding ezetimibe
           fenofibrate) and nicotinic acid. Ezetimibe is a new lipid-
                                                                         as a separate prescription may be preferable.
           modifying drug that was first PBS listed in August 2004.
           Clinical experience with it is therefore limited compared     Adding ezetimibe to monotherapy with any statin usually
           with that for other lipid-modifying drugs. The effect of      lowers LDL-C concentration by about 15%.5 However,
           ezetimibe on the incidence of coronary heart disease          different statins produce different reductions in LDL-C
           events in people at risk is unknown.                          concentration per milligram. Therefore, switching from

                                        April 2006
OKA4501NPS RADAR March06.qxd      22/3/06    4:10 PM    Page 3

                                                                              Ezetimibe with simvastatin (Vytorin)

        another statin to ezetimibe with simvastatin combination
        tablets may lower LDL-C concentration by more                 Box 1: Reducing the risk of statin myopathy17–19
        or less than adding ezetimibe to the original statin.
                                                                      • Monitor for signs and symptoms of myopathy
        Simvastatin has greater LDL-C-lowering effects per              (unexplained muscle pain, tenderness or weakness).
        milligram than pravastatin or fluvastatin but is less
        potent than atorvastatin.13 Patients whose LDL-C              • Use the lowest statin dose required to achieve
                                                                        therapeutic goals.
        concentrations are inadequately controlled on
        atorvastatin monotherapy could have a greater overall         • Ask patients to report muscle symptoms promptly,
        reduction in LDL-C concentration if ezetimibe is added          particularly if accompanied by malaise, fever                   03
        to atorvastatin than if they switch to ezetimibe with           and/or dark urine.
        simvastatin combination tablets.                              • Avoid, or use cautiously, in combination with drugs known
        See the NPS RADAR review ‘Atorvastatin (Lipitor) for            to increase the risk of statin myopathy (e.g. fibrates,
                                                                        cyclosporin, azole antifungals, macrolide antibiotics).
        the management of lipid disorders’ for a discussion
        of the lipid-modifying effects of atorvastatin compared       • Use statins with caution in patients at particular risk of
        with those of other statins.                                    myopathy (older people, particularly older women; patients
                                                                        with multisystem disease; patients with diabetes and
                                                                        chronic renal failure; patients taking multiple medications).
        Safety issues
                                                                      • Suspend statin therapy temporarily when conditions
        The adverse-effect profile of ezetimibe plus simvastatin        predispose to rhabdomyolysis (e.g. major surgery, trauma,
        in clinical trials was similar to that of simvastatin           acute renal failure).
        monotherapy.5,7,14 However, ezetimibe is a relatively
        new drug so its full adverse-effect profile may not
        yet be known.                                                2 weeks of starting ezetimibe. Five cases included elevated
                                                                     serum creatine kinase (CK) concentration. Twenty-one
        Elevated liver enzyme concentrations appear to be
                                                                     cases were in patients with a history of muscle disorders
        more frequent with the combination of ezetimibe
                                                                     or elevated CK concentration with a statin. In 5 cases
        and simvastatin than with simvastatin alone.4
                                                                     ezetimibe was given with a statin; ADRAC suggests that
        Muscle disorders are known adverse effects of
                                                                     these cases were consistent with an interaction between
        simvastatin and have been reported with ezetimibe.15,16
                                                                     ezetimibe and the statin, with the symptoms of myalgia
        Report suspected adverse reactions to the Adverse            or CK-concentration increase developing within 3 months
        Drug Reactions Advisory Committee (ADRAC) online             of the addition of ezetimibe to long-term statin treatment.
        (see www.tgasime.health.gov.au) or by using the ‘Blue        Two published cases also describe myopathy associated
        Card’ distributed with the Schedule of Pharmaceutical        with the combination of ezetimibe and a statin, with
        Benefits and Australian Prescriber. For information about    muscle and tendon pain and/or CK-concentration
        reporting adverse drug reactions, see the Therapeutic        elevation detected within 2 months of adding ezetimibe
        Goods Administration website (www.tga.gov.au).               to longstanding statin treatment.16

        Be vigilant for signs of muscle                              Monitor transaminase concentrations
        adverse effects
                                                                     Elevated serum transaminase concentrations occurred
        Simvastatin can cause muscle pain and weakness               in patients taking the combination of ezetimibe and
        and rarely rhabdomyolysis. See Box 1 for information         simvastatin more frequently than in those on simvastatin
        about preventing statin myopathy. More recently,             monotherapy in clinical trials.4 These adverse effects
        muscle disorders have been reported with ezetimibe           appeared to be related to the dose of simvastatin, were
        used alone.15,16 It is not known if ezetimibe can            often asymptomatic and generally resolved after either
        cause rhabdomyolysis.                                        discontinuing treatment or during continuing therapy.
        ADRAC has received 44 reports of muscle disorders,           Similar precautions apply as with statin treatment.
        including myalgia, muscle cramp, weakness and pain,          Measure transaminase concentrations before starting
        with ezetimibe.15 Almost half of the cases occurred within   ezetimibe with simvastatin therapy and periodically

                                                                                             April 2006
OKA4501NPS RADAR March06.qxd      22/3/06    4:10 PM     Page 4

             Ezetimibe with simvastatin (Vytorin)

           during treatment, particularly in patients taking               The manufacturers suggest starting at a dose of
           ezetimibe with simvastatin 10 mg / 80 mg. Stop treatment        ezetimibe with simvastatin of up to 10 mg / 40 mg*
           if transaminase concentrations are persistently above           and individualising dose based on response.3
           three times the upper limit of normal.12
                                                                           People already taking simvastatin can switch directly
           It is usually recommended that restarting statin                to the corresponding dose of ezetimibe with simvastatin.
           treatment be considered after transaminase                      The manufacturer does not provide any specific
           concentrations have returned to normal, because                 dosing recommendations for people switching from
           transaminase elevations often do not recur at                   other statins to ezetimibe with simvastatin tablets. It
 04        rechallenge.12 The likelihood of transaminase                   would seem reasonable to switch to the same milligram
           concentration elevation recurring on rechallenge                statin dose in the fixed-dose combination tablets
           with ezetimibe with simvastatin tablets is unknown              (for example, from atorvastatin 40 mg to ezetimibe
           because clinical experience with the combination                with simvastatin 10 mg / 40 mg). Assess response and
           is more limited. If ezetimibe is restarted, monitor             adjust dose as required.
           transaminase concentrations closely.
                                                                           If lipid goals are not reached using ezetimibe with
           Avoid ezetimibe with simvastatin in people with active liver    simvastatin 10 mg / 40 mg, LDL-C concentration can
           disease or unexplained persistent transaminase elevations       be further reduced by up to 6% by titrating up to
           and use caution in those with a past history of liver disease   the higher strength containing simvastatin 80 mg.5,21
           or who consume excessive amounts of alcohol.3

           Consider drug interactions with simvastatin                     Information for patients
           Drug interactions for simvastatin apply to ezetimibe with       Explain the symptoms of possible adverse effects on
           simvastatin. Inhibitors of CYP3A4 (such as ketoconazole,        muscle of ezetimibe with simvastatin. Ask patients to
           verapamil and grapefruit juice) can increase simvastatin        report unexplained muscle pain or weakness promptly.
           levels and elevate the risk of adverse effects.                 Ensure that patients understand that they must stop
           The manufacturer recommends that ezetimibe with                 taking their previous statin and ezetimibe tablets before
           simvastatin tablets not be used with fibrates (gemfibrozil,     beginning ezetimibe with simvastatin combination
           fenofibrate) because the combination of simvastatin             tablets and that they should not take more than one
           and a fibrate increases the risk of myopathy and the            ezetimibe with simvastatin tablet at a time.
           safety of ezetimibe in combination with fibrates has            Discuss the importance of lifestyle changes in reducing
           not been established.3                                          overall cardiovascular risk. Information about lifestyle
                                                                           changes for patients is available from the Heart
           Dosing issues                                                   Foundation’s national telephone information service,
                                                                           Heartline (Ph 1300 36 27 87) or online
           Each ezetimibe with simvastatin combination tablet              (www.heartfoundation.com.au).
           contains ezetimibe 10 mg. Combination tablets
           containing simvastatin doses of 20 mg, 40 mg and                For more detailed information about ezetimibe with
           80 mg are available in Australia. Only the ezetimibe with       simvastatin, suggest or provide the Vytorin consumer
           simvastatin 10 mg / 40 mg and 10 mg / 80 mg strengths           medicine information (CMI).
           are listed on the PBS.                                          * 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.
           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

                                        April 2006
OKA4501NPS RADAR March06.qxd                 22/3/06         4:10 PM      Page 5

                                                                                                                              Ezetimibe with simvastatin (Vytorin)

        References
        1. Pharmaceutical Benefits Advisory Committee. July 2005   5.  Bays HE, et al. Clin Ther 2004;26:1758–73.                 15. Adverse Drug Reactions Advisory Committee.
           PBAC outcomes — positive recommendations.               6.  Feldman T, et al. Am J Cardiol 2004;93:1481–6.                 Australian Adverse Drug Reactions Bulletin 2005;24:15.
           Canberra: Australian Government Department of Health    7.  Goldberg AC, et al. Mayo Clin Proc 2004;79:620–9.          16. Fux R, et al. Ann Intern Med 2004;140:671–2.
           and Ageing, 2005. http://www.health.gov.au/internet                                                                    17. Pasternak R, et al. J Am Coll Cardiol 2002;40:567–72.
                                                                   8.  Pearson TA, et al. Mayo Clin Proc 2005;80:587–95.
           /wcms/publishing.nsf/Content/pbacrec-jul05-positive
                                                                   9.  Farnier M, et al. Int J Cardiol 2005;102:327–32.           18. Hamilton-Craig I. Med J Aust 2001;175:486–9.
           (accessed 30 August 2005).
                                                                   10. Simons L, et al. Med J Aust 1996;164:208–11.               19. Thompson P, et al. JAMA 2003;289:1681–90.
        2. Pharmaceutical Benefits Advisory Committee. March
           2005 PBAC outcomes — positive recommendations.          11. Stephenson BJ, et al. JAMA 1993;269:2779–81.               20. Center for Drug Evaluation and Research. Zetia
           Canberra: Australian Government Department of Health    12. National Cholesterol Education Program Expert Panel            (ezetimibe) tablets approval package. Rockville,
           and Ageing, 2005. http://www.health.gov.au/internet         on Detection, Evaluation, and Treatment of High Blood          Maryland: United States Food and Drug Administration,    05
           /wcms/publishing.nsf/Content/pbacrec-mar05-positive         Cholesterol in Adults. Final report. Bethesda, Maryland:       2002. http://www.fda.gov/cder/foi/nda/2002/
           (accessed 30 August 2005).                                  National Institutes of Health — National Heart Lung            21445_Zetia.htm (accessed 30 August 2005).
        3. Merck Sharp and Dohme (Australia) Pty Ltd. Vytorin          and Blood Institute, 2002. http://www.nhlbi.nih.gov        21. Ballantyne CM, et al. Am Heart J 2005;149:464–73.
           product information. 12 August 2005.                        /guidelines/cholesterol/atp3_rpt.htm
        4. Therapeutic Goods Administration. Vytorin                   (accessed 30 August 2005).
           (ezetimibe/simvastatin) request for ADEC advice.        13. Australian Medicines Handbook 2005.
           Canberra: Australian Government Department              14. Masana L, et al. Clin Ther 2005;27:174–84.
           of Health and Ageing, 30 August 2004.

                                                                               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.

                                                                                                                                   April 2006
You can also read