Zetia

Sterol Transporter Inhibitors

Ezetimibe may be administered with or without food.
If taken with a HMG-CoA reductase inhibitor ('statin') or fenofibrate, the daily dose of ezetimibe may be taken at the same time as the statin or fenofibrate.
If prescribed concurrently with a bile acid sequestrant, administer ezetimibe at least 2 hours before or 4 hours after a dose of the bile acid sequestrant.

rhabdomyolysis / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
pancreatitis / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
cholecystitis / Delayed / Incidence not known

elevated hepatic enzymes / Delayed / 1.3-2.7
myasthenia / Delayed / Incidence not known
myopathy / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
depression / Delayed / Incidence not known
cholelithiasis / Delayed / Incidence not known

infection / Delayed / 2.9-4.3
back pain / Delayed / 2.4-4.1
diarrhea / Early / 2.5-4.1
pharyngitis / Delayed / 2.7-3.7
myalgia / Early / 3.2-3.2
abdominal pain / Early / 3.0-3.0
arthralgia / Delayed / 2.6-3.0
sinusitis / Delayed / 2.8-2.8
fatigue / Early / 2.0-2.4
cough / Delayed / 2.3-2.3
influenza / Delayed / 2.0-2.2
weakness / Early / Incidence not known
musculoskeletal pain / Early / Incidence not known
rash / Early / Incidence not known
nausea / Early / Incidence not known
paresthesias / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
headache / Early / Incidence not known
dizziness / Early / Incidence not known

Zetia

Rx

Oral antilipemic; cholesterol absorption inhibitor
Indicated to treat hypercholesterolemia as monotherapy or in combination with other antilipemic agents
Synergistic antilipemic effects with statins

10 mg PO once daily.

10 mg PO once daily.

10 mg PO once daily.

10 mg PO once daily.

10 mg PO once daily.

10 mg PO once daily.

10 mg PO once daily.

10 mg PO once daily.

10 mg PO once daily.

No dosage adjustment is needed in patients with mild hepatic impairment. Due to insufficient data, the manufacturer does not recommend ezetimibe for patients with moderate to severe hepatic impairment.

No dosage adjustment is needed.
 
Intermittent hemodialysis
No dosage adjustment is needed.

Antacids: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Calcium Carbonate: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Calcium Carbonate; Magnesium Hydroxide: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Calcium Carbonate; Simethicone: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Calcium; Vitamin D: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Cholestyramine: (Moderate) The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants, such as cholestyramine. The incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively.
Colesevelam: (Moderate) The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants; the incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively. A similar effect might be expected to occur with the concomitant administration of colesevelam with ezetimibe; however, this potential interaction has not been studied.
Colestipol: (Moderate) The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants; the incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively. A similar effect might be expected to occur with the concomitant administration of colestipol with ezetimibe; however, this potential interaction has not been studied.
Cyclosporine: (Major) Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine.
Eltrombopag: (Moderate) Use caution and monitor for adverse reactions if eltrombopag and ezetimibe are coadministered. Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as ezetimibe, may exhibit an increase in systemic exposure if coadministered with eltrombopag.
Fenofibrate: (Moderate) Monitor for cholelithiasis symptoms during concomitant ezetimibe and fenofibrate use. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. If cholelithiasis is suspected, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.
Fenofibric Acid: (Moderate) Ezetimibe was approved by the FDA for use in combination with fenofibrate as adjunctive therapy to diet for the treatment of hypercholesterolemia in patients with mixed hyperlipidemia in May 2006. However, the safety and effective use of ezetimibe when coadministered with other fibric acid derivatives such as gemfibrozil or clofibrate has not been established. Until further data are available to support efficacy and safety, ezetimibe is not recommended for use with gemfibrozil. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
Gemfibrozil: (Major) The safety and effectiveness of ezetimibe when coadministered with gemfibrozil have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of ezetimibe with gemfibrozil is not recommended. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
Omeprazole; Sodium Bicarbonate: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Sodium Bicarbonate: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Warfarin: (Moderate) Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored.

Ezetimibe/Zetia Oral Tab: 10mg

10 mg/day PO.

10 mg/day PO.

10 mg/day PO.

10 years and older: 10 mg/day PO.
Younger than 10 years: Safety and efficacy have not been established.

Ezetimibe lowers serum cholesterol concentrations by selectively inhibiting the absorption of cholesterol and related phytosterols by the small intestine.[27153] Ezetimibe has a mechanism of action that is unique compared to other available antilipemic agents and is complementary to that of the HMG-CoA reductase inhibitors, resulting in synergistic cholesterol-lowering effects when these drugs are used in combination.[27153] [27155] Ezetimibe does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. Ezetimibe localizes at the brush border of the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in the blood clearance of cholesterol. When ezetimibe is given as monotherapy, a compensatory increase in cholesterol synthesis occurs. With ongoing therapy, the overall effects of ezetimibe monotherapy are to reduce total cholesterol (13%), LDL-cholesterol (18%), and Apo-B (16%) in patients with hypercholesterolemia. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols (sitosterol and campesterol).[27154] In a 2 week study of 18 hypercholesterolemic patients, ezetimibe has been reported to inhibit intestinal cholesterol absorption by 54% relative to placebo.[27154]
 
In humans, the effects of ezetimibe to reduce triglycerides (8%) or to lower HDL-cholesterol (1%) are less prominent than its LDL-lowering effects; ezetimibe therapy usually results in increased HDL-C levels. In animal models (rodents), ezetimibe reduces the cholesterol content in chylomicrons without affecting the triglyceride content.[27157] In rodents, ezetimibe has no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins (A, D, and E), and does not impair adrenocortical steroid hormone production.[27157]

Ezetimibe is administered orally. Following systemic absorption, ezetimibe is extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Ezetimibe and ezetimibe-glucuronide are highly bound (greater than 90%) to human plasma proteins. Ezetimibe is rapidly metabolized by glucuronidation to ezetimibe-glucuronide in the small intestine and liver. Metabolism by oxidative metabolism is minimal. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P-450 isoenzymes. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10% to 20% and 80% to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from the plasma with a half-life of about 22 hours. Ezetimibe is enterohepatically recirculated, as evidenced by multiple peaks in its plasma concentrations.[27158] After oral administration of radiolabeled ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) accounts for approximately 93% of the total plasma radioactivity. After 48 hours, the plasma radioactivity is undetectable. Over a 10 day period, approximately 78% and 11% of the administered dose is recovered in the feces and urine, respectively. Ezetimibe is the major component recovered in the feces and accounts for 69% of the administered dose, while ezetimibe-glucuronide is the major component recovered in the urine and accounts for 9% of the administered dose.
 
 Affected cytochrome P450 (CYP) isoenzymes and drug transporters: None

After oral administration of a single 10 mg dose to fasting adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL are attained within 4 to 12 hours. Mean peak concentrations (Cmax 45 to 71 ng/mL) of ezetimibe-glucuronide are attained within 1 to 2 hours. The absolute bioavailability of ezetimibe is not known. The apparent oral bioavailability of ezetimibe is variable; the coefficient of variation, based on intersubject variability, is 35 to 60% for AUC values. The concomitant administration of food (high-fat vs. non-fat meals) has no effect on the extent of absorption of ezetimibe. However, coadministration with a high-fat meal increases the peak concentration (Cmax) of ezetimibe by 38%.

There are insufficient data on use of ezetimibe in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Ezetimibe was not teratogenic when orally administered to pregnant rats and rabbits at doses that were 10 to 150 times, respectively, the maximum recommended human dose (MRHD). An increase in the incidence of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) was observed in pregnant rats that received 10 times the MRHD of ezetimibe. In pregnant rabbits at doses 150 times MRHD, an increased incidence of extrathoracic ribs was reported. Placental transfer studies found the fetal-maternal plasma exposure for total ezetimibe (conjugated and unconjugated ezetimibe) to be 1.5 for rats and 0.03 for rabbits on gestation day 20 and 22, respectively. When ezetimibe and a statin were coadministered to rats and rabbits during organogenesis, reproductive findings were found to occur at lower doses with combination therapy compared to either agent administered alone.[27987] [65049]

There is no information available regarding the presence of ezetimibe in human milk or the effects of ezetimibe on the breastfed infant or on milk production. Ezetimibe was present in the milk of lactating rats. The pup to maternal plasma ratio for total ezetimibe was 0.5 on lactation day 12. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for infant growth and development, including synthesis of steroids and cell membranes. Since the effect of ezetimibe on infant lipid metabolism is unknown, breast-feeding is not recommended during treatment with ezetimibe. If pharmacotherapy is necessary for the nursing mother, an alternative agent such as a nonabsorbable resin (cholestyramine, colesevelam, or colestipol) may be considered. These agents do not enter the bloodstream and thus will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant.