Ezetimibe
Ezetimibe Prescribing Information
Indications and Usage (Ezetimibe tablet is indicated:
When ezetimibe tablet is used in combination with a statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for information on the safe and effective use. Ezetimibe tablet is indicated :
When Ezetimibe tablet is used in combination with a statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for information on the safe and effective use . | 7/2023 |
Dosage and Administration (
| 7/2023 |
Contraindications (Ezetimibe tablet is contraindicated in patients with a known hypersensitivity to ezetimibe or any of the excipients in ezetimibe tablets. Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported [see Adverse Reactions ( 6.2)] .When used in combination with a statin, fenofibrate, or other LDL-C lowering therapy, ezetimibe tablet is contraindicated in patients for whom a statin, fenofibrate, or other LDL-C lowering therapy are contraindicated. Refer to the Prescribing Information of these products for a list of their contraindications [see Warnings and Precautions ( 5.1)] .
| 7/2023 |
Warnings and Precautions (If ezetimibe tablet is administered with a statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for a description of their risks including, but not limited to, the warnings and precautions [see Contraindications ( 4)] .Increases in serum transaminases have been reported with use of ezetimibe tablets [see Adverse Reactions ( 6.1)] . In controlled clinical combination studies of ezetimibe tablets initiated concurrently with a statin, the incidence of consecutive elevations (≥3 × ULN) in hepatic transaminase levels was 1.3% for patients treated with ezetimibe administered with statins and 0.4% for patients treated with statins alone. Perform liver enzyme testing as clinically indicated and consider withdrawal of ezetimibe tablets if increases in ALT or AST ≥3 × ULN persist.Ezetimibe tablets may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis [see Adverse Reactions ( 6.1)] . In post-marketing reports, most patients who developed rhabdomyolysis were taking a statin or other agents known to be associated with an increased risk of rhabdomyolysis, such as fibrates. If myopathy is suspected, discontinue ezetimibe tablets and other concomitant medications, as appropriate. | 7/2023 |
Ezetimibe tablet is indicated:
- In combination with a statin, or alone when additional low-density lipoprotein cholesterol (LDL-C) lowering therapy is not possible, as an adjunct to diet to reduce elevated LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH).
- In combination with a statin as an adjunct to diet to reduce elevated LDL-C in pediatric patients 10 years of age and older with HeFH.
- In combination with fenofibrate as an adjunct to diet to reduce elevated LDL-C in adults with mixed hyperlipidemia.
- In combination with a statin, and other LDL-C lowering therapies, to reduce elevated LDL-C levels in adults and in pediatric patients 10 years of age and older with homozygous familial hypercholesterolemia (HoFH).
- As an adjunct to diet for the reduction of elevated sitosterol and campesterol levels in adults and in pediatric patients 9 years of age and older with homozygous familial sitosterolemia.
When ezetimibe tablet is used in combination with a statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for information on the safe and effective use.
- The recommended dose of ezetimibe tablet is 10 mg orally once daily, administered with or without food.
- If as dose is missed, take the missed dose as soon as possible. Do not double the next dose.
- Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe tablet.
- Administer ezetimibe tablet at least 2 hours before or 4 hours after administration of a bile acid sequestrant [see Drug Interactions (].)
7 DRUG INTERACTIONSTable 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with Ezetimibe tablets and instructions for preventing or managing them.
Table 3: Clinically Important Drug Interactions with Ezetimibe tablets Cyclosporine Clinical Impact: Concomitant use of ezetimibe and cyclosporine increases ezetimibe and cyclosporine concentrations. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency [ see Clinical Pharmacology].Intervention: Monitor cyclosporine concentrations in patients receiving ezetimibe and cyclosporine. In patients treated with cyclosporine, weigh the potential effects of the increased exposure to ezetimibe from concomitant use against the benefits of alterations in lipid levels provided by ezetimibe. Fibrates Clinical Impact: Both fenofibrate and ezetimibe may increase cholesterol excretion into the bile, leading to cholelithiasis. Co-administration of ezetimibe with fibrates other than fenofibrate is not recommended [ see Adverse Reactions (6.1)].Intervention: If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered. Bile Acid Sequestrants Clinical Impact: Concomitant cholestyramine administration decreased the mean exposure of total ezetimibe. This may result in a reduction of efficacy [see Clinical Pharmacology ].Intervention: In patients taking a bile acid sequestrant, administer ezetimibe at least 2 hours before or 4 hours after the bile acid sequestrant [see Dosage and Administration ].- Cyclosporine: Combination increases exposure of ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients taking ezetimibe concomitantly.
- Fibrates: Coadministration of ezetimibe with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered.
- Bile Acid Sequestrants: Cholestyramine combination decreases exposure of ezetimibe.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.Revised: 03/2024
10-mg tablets are white to off-white, capsule-shaped tablets debossed with "OP" on one side and "70" on other side.
Ezetimibe tablets is not recommended for use in patients with moderate to severe hepatic impairment (Child-Pugh B or C) due to the unknown effects of the increased exposure to ezetimibe
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of ezetimibe tablet to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmaxvalues of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.
Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as ezetimibe 10-mg tablets. The Cmaxvalue of ezetimibe was increased by 38% with consumption of high-fat meals.
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. 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 eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
Following oral administration of14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.
Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.
In a multiple-dose trial with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects. However, the difference in plasma concentrations is not clinically meaningful.
In a multiple-dose trial with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in females than in males.
Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and White subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in White subjects.
After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9).
After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects
Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a "cocktail" trial of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes.
Coadministered Drug and Dosing Regimen | Total Ezetimibe Based on 10 mg dose of ezetimibe | |
|---|---|---|
Change in AUC | Change in Cmax | |
Cyclosporine-stable dose required (75–150 mg BID)See DRUG INTERACTIONS (7).,Post-renal transplant patients with mild impaired or normal renal function. In a different trial, 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. | ↑240% | ↑290% |
Fenofibrate, 200 mg QD, 14 days | ↑48% | ↑64% |
Gemfibrozil, 600 mg BID, 7 days | ↑64% | ↑91% |
Cholestyramine, 4 g BID, 14 days | ↓55% | ↓4% |
Aluminum & magnesium hydroxide combination antacid, single doseSupralox, 20 mL | ↓4% | ↓30% |
Cimetidine, 400 mg BID, 7 days | ↑6% | ↑22% |
Glipizide, 10 mg, single dose | ↑4% | ↓8% |
Statins | ||
Lovastatin 20 mg QD, 7 days | ↑9% | ↑3% |
Pravastatin 20 mg QD, 14 days | ↑7% | ↑23% |
Atorvastatin 10 mg QD, 14 days | ↓2% | ↑12% |
Rosuvastatin 10 mg QD, 14 days | ↑13% | ↑18% |
Fluvastatin 20 mg QD, 14 days | ↓19% | ↑7% |
Coadministered Drug and its Dosage Regimen | Ezetimibe Dosage Regimen | Change in AUC of Coadministered Drug | Change in Cmaxof Coadministered Drug |
|---|---|---|---|
Warfarin, 25 mg single dose on day 7 | 10 mg QD, 11 days | ↓2% (R-warfarin) | ↑3% (R-warfarin) |
Digoxin, 0.5 mg single dose | 10 mg QD, 8 days | ↑2% | ↓7% |
Gemfibrozil, 600 mg BID, 7 daysSee Drug Interactions (7). | 10 mg QD, 7 days | ↓1% | ↓11% |
Ethinyl estradiol & Levonorgestrel, QD, 21 days | 10 mg QD, days 8 to 14 of 21d oral contraceptive cycle | Ethinyl estradiol | Ethinyl estradiol |
Glipizide, 10 mg on days 1 and 9 | 10 mg QD, days 2 to 9 | ↓3% | ↓5% |
Fenofibrate, 200 mg QD, 14 days | 10 mg QD, 14 days | ↑11% | ↑7% |
Cyclosporine, 100 mg single dose day 7 | 20 mg QD, 8 days | ↑15% | ↑10% |
Statins | |||
Lovastatin 20 mg QD, 7 days | 10 mg QD, 7 days | ↑19% | ↑3% |
Pravastatin 20 mg QD, 14 days | 10 mg QD, 14 days | ↓20% | ↓24% |
Atorvastatin 10 mg QD, 14 days | 10 mg QD, 14 days | ↓4% | ↑7% |
Rosuvastatin 10 mg QD, 14 days | 10 mg QD, 14 days | ↑19% | ↑17% |
Fluvastatin 20 mg QD, 14 days | 10 mg QD, 14 days | ↓39% | ↓27% |
Ezetimibe tablet is contraindicated in patients with a known hypersensitivity to ezetimibe or any of the excipients in ezetimibe tablets. Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported
Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following additional adverse reactions have been identified during post-approval use of ezetimibe tablets:
When used in combination with a statin, fenofibrate, or other LDL-C lowering therapy, ezetimibe tablet is contraindicated in patients for whom a statin, fenofibrate, or other LDL-C lowering therapy are contraindicated. Refer to the Prescribing Information of these products for a list of their contraindications
If ezetimibe tablet is administered with a statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for a description of their risks including, but not limited to, the warnings and precautions