Drug information: Ezetimibe

1. Drug information: Ezetimibe 卒後研修センター　TTSP薬剤研修生 杉田　栄樹

2. Dosage forms • Tablet: • ZetiaTM:10 mg (capsule shaped)

3. Dosing • Adults (Elderly): • Hyperlipidemias, Sitosterolemia: Oral 10 mg/day • Renal impairment: • Bioavailability increased with severe impairment; no dosing adjustment recommended. • Hepatic impairment: • Bioavailability increased with severe impairment; • Mild impairment (Child-Pugh score 5-6) : No dosing adjustment necessary. • Moderate to severe impairment (Child-Pugh score 7-15) : Use of ezetimibe not recommended.

4. Use • Use in combination with dietary therapy for the treatment of primary hypercholesterolemia (as monotherapy or in combination with HMG-CoA reductase inhibitors); homozygous sitosterolemia; homozygous familial hypercholesterolemia (in combination with atorvastatin or simvastatin); mixed hyperlipidemia (in combination with fenofibrate)

5. CONTRAINDICATIONS • Hypersensitivity to any component of this medication.

6. Administration • May be administered without regard to meals. May be taken at the same time as HMG-CoA reductase inhibitors. Administer 2 hours before or 4 hours after bile acid sequestrants.

7. Mechanism of action • Localizes and appears to act at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. • Reduces total-C, LDL-C, Apo B, and TG, and increases HDL-C in patients with hypercholesterolemia.

8. Pharmacodynamics/kinetics • Protein binding: >90% to plasma proteins • Metabolism: Undergoes conjugation in the small intestine and liver; forms metabolite (active); may undergo enterohepatic recycling • Bioavailability: Variable • Half-life: 22 hours (ezetimibe and metabolite) • Time to peak, plasma: 4-12 hours • Excretion: Feces (78%, 69% as ezetimibe); urine (11%, 9% as metabolite)

9. Drug interaction • Cholestyramine: Bile Acid Seqestrants may decrease the absorption of Ezetimibe. • Cyclosporine: Cyclosporine may increase the serum concentration of Ezetimibe. Ezetimibe may increase the serum concentration of Cyclosporine.

10. Adverse reactions • 1% to 10% • Cardiovascular: Chest pain (3%), dizziness (3%), fatigue (2%) • Central nervous system: Headache (8%) • Gastrointestinal: Diarrhea (3% to 4%), abdominal pain (3%) • Neuromuscular & skeletal: Arthralgia (4%) • Respiratory: Sinusitis (4% to 5%), pharyngitis (2% to 3%) • Postmarking and/or case reports • Anaphylaxis, cholecystitis, CPK increased, hepatitis, hypersensitivity reactions (including angioedema and rash), myaglia, myopathy, nausea, pancreatitis, rhabdomyolysis, thrombocytopenia, transaminases increased, urticaria

11. Monitoring parameter • Total cholesterol profile prior to therapy, and when clinically indicated and/or periodically thereafter. When used in combination with fenofibrate, monitor LFTs and signs and symptoms of cholelithiasis.

12. Ezetimibe/Simvastatin vs Atorvastatin in Patients With Type 2 Diabetes Mellitus and Hypercholesterolemia: The VYTAL Study 卒後研修センター　TTSP薬剤研修生 杉田　栄樹

13. Journal: Mayo clinic proceedings. • Published: December 2006. • Provided by Merck/Schering-Plough

14. Background • High rates of CVD-related morbidity and mortality in this population are attributed in part to lipid abnormalities, typified by increased TG levels, HDL-C levels, and LDL-C. • Solano MP, et al. Management of dyslipidemia in diabetes. Cardiol Rev. 2006;14:125-135. • The challenge of attaining more stringent LDL-C targets has stimulated research into possible new combinations of lipid-lowering drugs. • Kennedy AG, et al. The challenge of achieving national cholesterol goals in patients with diabetes. Diabetes Care. 2005;28:1029-1034. • Ezetimibe has emerged as an effective agent for combined use with statins to achieve the recommended levels of LDL-C. • American Diabetes Association. Standard of medical care in diabetes-2006[published correction appears in Diabetes Care. 2006;29:1192]. Diabetes Care. 2006;14:125-135.

15. Objective • To compare the efficacy and safety of the recommended usual starting and next highest doses with type 2 diabetes mellitus and hypercholesterolemia.

16. Method • Design: Double-blind, multicenter study, RCT • Facility: 147 participating centers in US. • Patient: Type-2 diabetes patients (aged 18-80 years) with hemoglobin A1c levels of 8.5% or less. Patients who had an LDL-C level greater than 100mg/dL and a triglyceride level less than 400mg/dL in the third week of the run-in.

17. Method • Treatment: • Administered daily for 6 weeks. • Starting doses: ezetimibe/simvastatin 10/20 mg/day, vs atorvastatin 10 or 20 mg/day • Next highest doses: ezetimibe/simvastatin 10/40 mg/day, vs atorvastatin 40 mg/day

18. Assessment of Drug effect • Safety was assessed by monitoring clinical adverse events and laboratory adverse events. • Efficacy end points included percent changes from baseline in LDL-C levels (primary) and proportion of patients attaining LDL-C levels less than 70 mg/dL (secondary).

24. Conclusion • Ezetimibe/simcastatin provided additional lipid-modifying benefits over atorvastatin monotherapy at the recommended usual starting and next highest doses in patients with type 2 diabetes. Both treatments were generally well tolerated.

25. In my opinion • 治療効果を見るに当たっては、他のHMG-CoA阻害薬単独での最大治療効果は６週間後といわれているため、併用療法と単剤療法との比較には６週間の治療期間効果は妥当である。しかし、有害事象においては、投与開始の６週間以内であれば有害事象は少ないことがわかるが、治療期間が６週間と短いため、６週間以降に有害事象がないとはいいきれない。つまり、安全性を試験するのであれば、６週間以降の患者の状態もモニタリングする必要があると思われる。