Ezetimibe with simvastatin (Vytorin) for dyslipidaemia
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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 2006OKA4501NPS 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 2006OKA4501NPS 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 2006OKA4501NPS 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 2006OKA4501NPS RADAR March06.qxd 22/3/06 4:10 PM Page 5
Ezetimibe with simvastatin (Vytorin)
References
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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.
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