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Ezetrol (ezetimibe)



Conclusion

Ezetrol (ezetimibe) is a new type of lipid reducing drug, which significantly reduces LDL (app. 17%) and the total cholesterol levels. When co-administered with statins, cholesterol reductions are increased. It is well documented that patients receiving cholesterol-reducing medication, are not sufficiently managed (1).

 

Ezetrol’s use is indicated for the treatment of patients with primary hypercholesterolemia, whom are not sufficiently treated with statin as monotherapy. Patients treated with statin’s and ezetimibe, must be followed with routine blood analysis. Generally ezetimibe is well tolerated.

 

Ezetimibe’s position in lipid reduction therapy, is as a supplement to statins, for patients who have not achieved sufficient LDL-reductions with statin in monotherapy. Trials elucidating ezetimibe’s effect on the complications of arteriosclerosis, have yet to be completed.

 

Options for lipid reduction therapy, after e.g. simvastatin 40mg x 1-2/dy. or atorvastatin up to 80mg/dy., is add-on treatment with ezetimibe or other absorption inhibiting drugs. Simvastatin 40 mg x 2/dy is the cheapest in today’s market.

Ezetimibe was released for use the 30th August 2004.


Background

Ezetimibe is a new class of lipid reducing drugs, which selectively hinders the absorption of cholesterol and plant sterols in the jejunum. Ezetimibe does not influence the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol or the fat-soluble vitamins A or D. The statins hinder the livers endogenous cholesterol synthesis. The statins and ezetimibe have two different working mechanisms, complementing the reduction of cholesterol levels.

 

Ezetimibe is indicated as add-on therapy to statin treatment, for patients with primary hypercholesterolemia, homozygous familial hypercholesterolemia and the rare sitosterolemia. Ezetimibe in monotherapy is indicated when statin treatment is not appropriate.

 

Ezetimibe is taken as 10mg tablets, which is the start- and maintenance dosage, regardless of meals. Ezetimibe is conjugated to the pharmacological active phenol gluconid. In plasma ezetimibe-glucuronid 80-90% and ezetimibe 10-20%, both bind > 90% to plasma protein. T½ is app. 22 h. for both elements.

 

For patients with moderate liver impairment, the average AUC for total-ezetimibe was increased about 4 times, therefore ezetimibe is not recommended to patients with moderate to severe liver impairment. There is no need dosage adjustment, for the geriatric, or patients with mild liver or kidney impairment.


Effect

Mono therapy

Two placebo, double blind RCT’s lasting twelve weeks, randomised 827 and 892 patients, respectively, to placebo or ezetimibe 10 mg. Efficacy assessments where reduction in LDL-cholesterol levels. There was a significant reduction in LDL of app. 17% (0,75 mM) after 12 weeks, compared to an increase of 0,4-0,8% in placebo. The rate of adverse effects was that of placebo.


Co-administration therapy

Short term studies

Four placebo controlled double-blind trials lasting twelve weeks, totalling 2.382 patients examined the effect of ezetimibe 10mg, pravastatin (4) (10, 20 and 40mg), simvastatin (5) (10, 20, 40 and 80mg), lovastatin (6) (10, 20 and 40mg) and atorvastatin (7) (10, 20, 40 and 80mg) and the co-administration therapy of statin with ezetimibe. All results where statistically significant (p<0,01) for ezetimibe and pooled statin dosages, compared to both pooled statins and ezetimibe in monotherapy.

 

Cholst-

erol

 

 

Placebo

 

 

n=256

Ezetimbe

10 mg

 

n=262

Monotherapy: Statin in pooled dosis

Co-administration therapy:

Ezetimibe 10mg + statin in pooled dosis

pravastatin

n=205

simvastatin

n=263

lovastatin

n= 220

atorvastatin

n=248

pravastatin

n=204

simvastatin

n=274

lovastatin

n=192

atorvastatin

n=255

LDL B

E

mmol/L

4,6

4,6

4,6

4,7

4,6

4,7

4,6

4,6

4,5

4,7

4,6

3,8

3,5

3,0

3,5

2,7

2,8

2,3

2,8

2,2

D 0

D -0,8

D -1,1

D -1,7

D -1,1

D -2,0

D -1,8

D -2,3

D -1,7

D -2,5

0%

-17%

-24%

-36%

-24%

-42%

-39%

-50%

-38%

-55%

Total B

Choles- E

terol

mmol/L

6,8

6,9

6,8

7,1

6,9

7,0

6,8

6,9

6,9

6,9

6,9

6,0

5,6

6,1

5,7

4,8

5,0

4,3

5,7

4,0

D 0,1

D -0,9

D -1,2

D -1,0

D -1,2

D -2,2

D -1,8

D -2,6

D -1,2

D -2,8

1,5%

-13%

-17%

-14%

-17%

-32%

-27%

-38%

-18%

-41%

B=baseline. E=endpoint.

 

Triglyceride levels where positively, significantly altered. The HDL changes where not all statistically significant, for the co-administration therapy compared to statin as monotherapy.

 

In all four trials, treatment related adverse effects where observed among patients whom received statin as monotherapy (15-19%) or co-administration treatment (17-23%); all compared to placebo. Elevated transaminases where found among 1,84% (17 of 925) patients whom received combination therapy in the four trials. No one receiving ezetimibe as monotherapy (n=262), had elevated transaminases. No patient experienced hepatitis, icterus or other signs of liver dysfunction. Six patients in three of the trials (4,5,7) registered raised CK-levels, five receiving co-administration therapy and one receiving ezetimibe as monotherapy.


Long term trials

One placebo controlled double blind trial lasting twenty-four weeks, with three treatment groups randomised 788 patients to atorvastatin or co-administration therapy with ezetimibe 10 mg and simvastatin in two different starting dosages.  The statin doses were force-titrated to the maximum 80 mg/dy. The key efficacy measure was LDL-reduction after 6 weeks. Results are in the following table.

 

Length

Dosage

LDL reduction mmol/L

LDL reduction %

6 weeks treatment

atorvastatin 10 mg

1,76

37,2%

ezetimibe 10 mg + simvastatin 10 mg

2,16

46,1%

ezetimibe 10 mg + simvastatin 20 mg

2,34

50,3%

24 weeks treatment

atorvastatin 80 mg

2,47

52,5%

ezetimibe 10 mg + simvastatin 80 mg

2,77

59,4%

The three treatment-groups where comparable concerning adverse effects, such as elevated transaminases (2,0 – 2,4 %). Of the patients receiving co-administration therapy, 0,4% had elevated CK-levels associated with muscle pain.

 

A 23-week placebo controlled double blind trial (9) with 1069 patients, randomised patients to four treatment groups: simvastatin or ezetimbe 10 mg + simvastatin in doses of 10, 20 and 40mg, respectively. Patients where up-titrated when necessary to achieve sufficient LDL-levels. The primary efficacy objective was LDL-cholesterol goal attainment < 2,6 mmol/L after 5 weeks of treatment (according to American guidelines). 46% of the simvastatin treated and 80% in the pooled co-administration group achieved LDL-goals (p<0,001). All treatment groups where comparable with regard to adverse affects.

 

The short-term trial with ezetimibe and atorvastatin (7) continued 12 months (10), with the same results as the primary trial, regarding efficacy and adverse effects.


Adverse effects

In the trials, the rate of adverse effects, are comparable to placebo.

 

For ezetimibe given as monotherapy, the most frequent adverse effects are gastrointestinal symptoms and headache. Ezetimibe coadministered with statins, increased the frequency of gastrointestinal- and musculoskeletal adverse effects, and transaminase elevations. CK-elevations associated with muscle pain was registered.


Interactions

No clinically significant pharmacokinetic interactions have been observed between ezetimibe and other drugs, metabolised by CYP P450. Simultaneous treatment with cholestyramine reduced ezetimibe’s AUC app. 55%. Cyclosporine increased ezetimibe’s AUC. Simultaneous co-administration with ezetimibe and fibrates, is not recommended.


Prices

Prices for the 30th August 2004 are used. Ezetimibe is not subsidised.

Drug

Package

Recommended daily dose

Price per recommended daily dose.

Ezetrol (ezetimibe)

10 mg, 28 tablets

10 mg, 98 tablets

10 mg

16,70 Kr.

16,10 Kr.

More information can be found at the following web site: http://www.produktresume.dk/docushare/dscgi/ds.py/View/Collection-96


References

  1. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assassment Project (L-TAP). Arch Intern Med. 2000;160:459-67.
  2. Knopp RH, Gitter H, Truitt T, Bays H, Manion CV et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 2003;24:729-41.
  3. Dujovne C, Ettinger M, McNeer JF, Lipka LJ, LeBeaut AP et al. Efficacy and Safety of a Potent New Selective Cholesterol Absorption Inhibitor, Ezetimibe, in Patients With Primary Hypercholesteremia. Am J Cardiol 2002;90:1092-7.
  4. Melani L, Mills R, Hassman D, Lipetz R, Lipka L et al. Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia; a prosepktive, randomized, double-blind trial. Eur Heart J 2003;24:717-28.
  5. Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ et al. Ezetimibe Coadministered With Simvastatin in Patients With Primary Hypercholesetrolemia. J Am Coll Cardiol 2002;40:2125-34.
  6. Kerzner B, Corbelli J, Sharp S, Lipka L, Melani L et al. Efficacy and Safety of Ezetimibe Coadministered With Lovastatin in Primary Hypercholesterolemia. Am J Cardiol 2003;91:418-24.
  7. Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ et al. Effect of Ezetimibe Coadministered With Atorvastatin in 628 Patients With Primary Hypercholesterolemia. Circulation 2003;107:2409-15.
  8. Ballantyne CM, Blazing MA, King TR, Brady WE, Palmisano J. Effiacy and Safety of Ezetimibe Coadministered With Simvastatin Compared With Atorvastatin in Adults With Hypercholesterolemia. Am J Cardiol 2004;93:1487-94.
  9. Feldman T, Koren M, Insull W, McKenney J, Schrott H. Treatment of High-Risk Patients With Ezetrimibe Plus Simvastatin Co-administration Versus Simvastatin Alone to Attain National Cholesterol Education Program Adult Treatment Panel III Low-Density Lipoprotein Cholesterol Goals. Am J Cardiol 2004;93:1481-6.
  10. Ballantyne CM, Lipka LJ; Sager PT, Strony J, Alizadeh J et al. Long-term saefty and tolerability profile of ezetimibe and atorvaststin coadministration therapy in patients with primary hypercholesterolemia. Int J Clin Pract 2004;58:653-8.
  11. Gagné C, Gaudet D, Bruckert E. Efficacy and Safety of Ezetimibe Coadministered With Atorvastatin or Simvastatin in Patients With Homozygous Familial Hypercholesterolemia. Circulation 2002;105:2469-75.
  12. Salen G, von Bergmann K, Lütjohann D, Kwiterovich P, Kane J. Ezetimibe Effectively Reduces Plasma Plant Sterols in Patients With Sitosterolemia. Circulation 2004;109:966-71.

Last modified: October 12th 2004


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