1. Medical uses

2. Contraindications

3. Adverse effects

4. Overdose

5. Pharmacology
    Mechanism of action  Pharmacokinetics 

6. See also

7. References

Ezetimibe is a medication used to treat high blood cholesterol. It is less preferred than statins when used as sole treatment for high blood cholesterol. It may be used in combination with a statin if a statin alone is insufficient.

It acts by decreasing cholesterol absorption in the small intestine.

In the United States as of 2015, the 10-mg pill costs between US$4.84 and 7.88.^[1] In 2016 it was the 144th most prescribed medication in the United States with more than 4 million prescriptions.^[2]

Medical uses

A review found that ezetimibe used as sole treatment slightly lowered plasma levels of lipoprotein(a), but the effect was not large enough to be important.^[3] A review found that adding ezetimibe to statin treatment of high blood cholesterol had no effect on overall mortality or cardiovascular mortality, although it significantly reduced the risk of MI and stroke.^[4] A 2015 trial found that adding ezetimibe to simvastatin had no effect on overall mortality but did lower the risk of heart attack or stroke in people with prior heart attack.^[5][5] Several treatment guidelines recommend adding ezetimibe in select high risk persons in whom LDL goals cannot be achieved by maximally tolerated statin alone.^{[6][7][8][9][10]}

Ezetimibe is indicated in the United States as an add-on to dietary measures to reduce levels of certain lipids in people with:^[12]

• Primary hyperlipidemia, alone or with a statin
• Mixed hyperlipidemia, in combination with fenofibrate
• Homozygous familial hypercholesterolemia, in combination with specific statins
• Homozygous sitosterolemia

Ezetimibe improves the non-alcoholic fatty liver disease activity score but the available evidence indicates it does not improve outcomes of hepatic steatosis.^[11]

Contraindications

The two contraindications to taking ezetimibe are a previous allergic reaction to it, including symptoms of rash, angioedema, and anaphylaxis, and severe liver disease, especially when taken with a statin.^[12]

Ezetimibe may have significant medication interactions with ciclosporin and with fibrates other than fenofibrate.^[13]

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with ezetimibe therapy include headache and/or diarrhea (steatorrhea). Infrequent adverse effects (0.1–1% of patients) include myalgia and/or raised liver function test (ALT/AST) results. Rarely (<0.1% of patients), hypersensitivity reactions (rash, angioedema) or myopathy may occur.^[13] Cases of muscle problems (myalgia and rhabdomyolysis) have been reported and are included as warnings on the label for ezetimibe.^[13]

Overdose

The incidence of overdose with ezetimibe is rare; subsequently, few data exist on the effects of overdose. However, an acute overdose of ezetimibe is expected to produce an exaggeration of its usual effects, leading to loose stools, abdominal pain, and fatigue.^[14]

Pharmacology

Mechanism of action

Ezetimibe inhibits the absorption of cholesterol from the small intestine and decreases the amount of cholesterol normally available to liver cells, leading them to absorb more from circulation, thus lowering levels of circulating cholesterol. It apparently blocks the critical mediator of cholesterol absorption, the Niemann-Pick C1-like 1 protein on the gastrointestinal tract epithelial cells, as well as in hepatocytes; it blocks aminopeptidase N and interrupts a caveolin 1–annexin A2 complex involved in trafficking cholesterol.^[15]

Pharmacokinetics

Within 4–12 hours of the oral administration of a 10-mg dose to fasting adults, the attained mean ezetimibe peak plasma concentration (C_max) was 3.4–5.5 ng/ml. Following oral administration, ezetimibe is absorbed and extensively conjugated to a phenolic glucuronide (active metabolite). Mean C_max (45–71 ng/ml) of ezetimibe-glucuronide is attained within 1–2 hours. The concomitant administration of food (high-fat vs. nonfat meals) has no effect on the extent of absorption of ezetimibe. However, coadministration with a high-fat meal increases its C_max by 38%. The absolute bioavailability cannot be determined, since ezetimibe is insoluble in aqueous media suitable for injection. Ezetimibe and its active metabolites are highly bound to human plasma proteins (90%).^[13]

Ezetimibe is primarily metabolized in the liver and the small intestine via glucuronide conjugation with subsequent renal and biliary excretion.^[16] Both the parent compound and its active metabolite are eliminated from plasma with a half-life around 22 hours, allowing for once-daily dosing. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P450 isoenzymes, which explains its limited number of drug interactions. No dose adjustment is needed in patients with renal insufficiency or mild hepatic dysfunction (Child-Pugh score 5–6). Due to insufficient data, the manufacturer does not recommend ezetimibe for patients with moderate to severe hepatic impairment (Child-Pugh score 7–15). In patients with mild, moderate, or severe hepatic impairment, the mean AUC values for total ezetimibe are increased about 1.7-fold, 3-to-4-fold, and 5-to-6-fold, respectively, compared to healthy subjects.^[13]

See also

• Cholesterol absorption inhibitor
• Ezetimibe/simvastatin
• Ezetimibe/atorvastatin
• Niacin
• SCH-48461

References

• Brown garden eel
• Brown Gelly
• Brown Gelly Cairns
• Brown Gerygone
• Brown Gibson Model
• Brown Girl Dreaming
• Browngoods
• Brown Goshawk
• Brown Greater Galago
• Brown Hairstreak
• Brown Hairy Dwarf Porcupine
• Brown-Haley
• Brown Hall (Georgia Tech)
• Brown Hand Center
• Brown Hare
• Brown hare (disambiguation)
• Brown hawk
• Brown Hawker
• Brown Hawk Owl
• Brown Hawk-Owl
• Brown-headed Apalis
• Brown-headed Barbet
• Brown-headed Cowbird
• Brown-headed Crow
• Brown-headed Greenlet