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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。