Drug information: Ezetimibe

卒後研修センター　 TTSP薬剤研修生

杉田　栄樹

Dosage forms

• Tablet: – ZetiaTM:10 mg (capsule shaped)

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 dosi

ng adjustment necessary.– Moderate to severe impairment (Child-Pugh scor

e 7-15) : Use of ezetimibe not recommended.

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)

CONTRAINDICATIONS

• Hypersensitivity to any component of this medication.

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.

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.

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)

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.

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, hypers

ensitivity reactions (including angioedema and rash), myaglia, myopathy, nausea, pancreatitis, rhabdomyolysis, thrombocytopenia, transaminases increased, urticaria

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.

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

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

Background• High rates of CVD-related morbidity and mortality in this popula

tion 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-2

006[published correction appears in Diabetes Care. 2006;29:1192]. Diabetes Care. 2006;14:125-135.

Objective

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

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.

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

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).

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.

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。