EZETIMIBE- ezetimibe tablet
American Health Packaging
----------
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use EZETIMIBE TABLETS safely and effectively. See full prescribing information for EZETIMIBE TABLETS.
EZETIMIBE tablets, for oral use Initial U.S. Approval: 2002 RECENT MAJOR CHANGESINDICATIONS AND USAGEEZETIMIBE Tablets
When ezetimibe tablets 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 (1). DOSAGE AND ADMINISTRATIONDOSAGE FORMS AND STRENGTHSTablets: 10 mg (3) CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
ADVERSE REACTIONS
To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS
See 17 for PATIENT COUNSELING INFORMATION. Revised: 3/2024 |
Ezetimibe Tablets is indicated:
When ezetimibe tablets 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.
10-mg tablets are white to off white capsule shaped, flat faced, beveled edge tablets, debossed with “A25ˮ on one side and plain on other side.
Ezetimibe tablets 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 tablets 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)].
If ezetimibe tablets 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 X ULN) in hepatic transaminase levels was 1.3% for patients treated with ezetimibe tablets 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 X 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.
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Monotherapy
In 10 double-blind, placebo-controlled clinical trials, 2,396 patients with primary hyperlipidemia (age range 9 to 86 years; 50% female, 90% White, 5% Black or African American, 2% Asian, 3% other races; 3% identified as Hispanic or Latino ethnicity) and elevated LDL-C were treated with ezetimibe tablets 10 mg daily for a median treatment duration of 12 weeks (range 0 to 39 weeks).
Adverse reactions reported in ≥2% of patients treated with ezetimibe tablets and at an incidence greater than placebo in placebo-controlled studies of ezetimibe tablets are shown in Table 1.
Adverse Reaction |
Placebo (%) n = 1,159 |
Ezetimibe Tablets 10 mg (%) n = 2,396 |
Upper respiratory tract infection |
2.5 |
4.3 |
Diarrhea |
3.7 |
4.1 |
Arthralgia |
2.2 |
3.0 |
Sinusitis |
2.2 |
2.8 |
Pain in extremity |
2.5 |
2.7 |
Fatigue |
1.5 |
2.4 |
Influenza |
1.5 |
2.0 |
Combination with a Statin
In 28 double-blind, controlled (placebo or active-controlled) clinical trials, 11,308 patients with primary hyperlipidemia (age range 10 to 93 years, 48% female, 85% White, 7% Black or African American, 3% Asian, 5% other races; 4% identified as Hispanic or Latino ethnicity) and elevated LDL-C were treated with ezetimibe tablets 10 mg/day concurrently with or added to on-going statin therapy for a median treatment duration of 8 weeks (range 0 to 112 weeks).
The incidence of consecutive increased transaminases (≥3 X ULN) was higher in patients receiving ezetimibe tablets administered with statins (1.3%) than in patients treated with statins alone (0.4%).
Adverse reactions reported in ≥2% of patients treated with ezetimibe tablets + statin and at an incidence greater than statin are shown in Table 2.
|
||
Adverse Reaction |
All Statins* (%) n = 9,361 |
Ezetimibe Tablets + All Statins* (%) n = 11,308 |
Nasopharyngitis |
3.3 |
3.7 |
Myalgia |
2.7 |
3.2 |
Upper respiratory tract infection |
2.8 |
2.9 |
Arthralgia |
2.4 |
2.6 |
Diarrhea |
2.2 |
2.5 |
Back pain |
2.3 |
2.4 |
Influenza |
2.1 |
2.2 |
Pain in extremity |
1.9 |
2.1 |
Fatigue |
1.6 |
2.0 |
Combination with Fenofibrate
This clinical trial involving 625 patients with mixed dyslipidemia (age range 20 to 76 years; 44% female, 79% White, 1% Black or African American, 20% other races; 11% identified as Hispanic or Latino ethnicity) treated for up to 12 weeks and 576 patients treated for up to an additional 48 weeks evaluated coadministration of ezetimibe tablets and fenofibrate. Incidence rates for clinically important elevations (≥3 X ULN, consecutive) in hepatic transaminase levels were 4.5% and 2.7% for fenofibrate monotherapy (n=188) and ezetimibe tablets coadministered with fenofibrate (n=183), respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% and 1.7% for fenofibrate monotherapy and ezetimibe tablets coadministered with fenofibrate, respectively
[see
Drug Interactions (7)].
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:
Blood Disorders: thrombocytopenia
Gastrointestinal Disorders: abdominal pain; pancreatitis; nausea
Hepatobiliary Disorders: elevations in liver transaminases, including elevations more than 5 X ULN; hepatitis; cholelithiasis; cholecystitis
Immune System Disorders: Hypersensitivity reactions including: anaphylaxis, angioedema, rash, and urticaria
Musculoskeletal Disorders: elevated creatine phosphokinase; myopathy/rhabdomyolysis
Nervous System Disorders: dizziness; paresthesia; depression; headache
Skin and Subcutaneous Tissue Disorders: erythema multiforme
Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with ezetimibe tablets and instructions for preventing or managing them.
Cyclosporine |
|
Clinical Impact: |
Concomitant use of ezetimibe tablets 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 (12.3)]. |
Intervention: |
Monitor cyclosporine concentrations in patients receiving ezetimibe tablets 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 tablets. |
Fibrates |
|
Clinical Impact: |
Both fenofibrate and ezetimibe may increase cholesterol excretion into the bile, leading to cholelithiasis. Co-administration of ezetimibe tablets with fibrates other than fenofibrate is not recommended [see Adverse Reactions (6.1)]. |
Intervention: |
If cholelithiasis is suspected in a patient receiving ezetimibe tablets 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 (12.3)]. |
Intervention: |
In patients taking a bile acid sequestrant, administer ezetimibe tablets at least 2 hours before or 4 hours after the bile acid sequestrant [see Dosage and Administration (2)]. |
Risk Summary
There are insufficient data on ezetimibe use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits orally administered ezetimibe during the period of organogenesis at doses that resulted in up to 10 and 150 times, respectively, the human exposure at the MRHD, based on AUC
(see Data). Ezetimibe tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When ezetimibe tablets is administered with a statin, refer to the Prescribing Information for the statin.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats (gestation days 6-15) and rabbits (gestation days 7-19), there was no evidence of maternal toxicity or embryolethal effects at the doses tested (250, 500, 1,000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1,000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC
0-24hrfor total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1,000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC
0-24hr for total ezetimibe). The animal-to-human exposure multiple for total ezetimibe at the no-observed effect level was 6 times for rat and 134 times for rabbit. Fetal exposure to ezetimibe (conjugated and unconjugated) was confirmed in subsequent placental transfer studies conducted using a maternal dose of 1,000 mg/kg/day. The fetal maternal plasma exposure ratio (total ezetimibe) was 1.5 for rats on gestation day 20 and 0.03 for rabbits on gestation day 22.
The effect of ezetimibe on prenatal and postnatal development and maternal function was evaluated in pregnant rats at doses of 100, 300 or 1,000 mg/kg/day from gestation day 6 through lactation day 21. No maternal toxicity or adverse developmental outcomes were observed up to and including the highest dose tested (17 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe).
Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis resulted in higher ezetimibe and statin exposures. Reproductive findings occurred at lower doses in combination therapy compared to monotherapy.
Risk Summary
There is no information about the presence of ezetimibe in human milk. Ezetimibe is present in rat milk
(see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. There is no information about the effects of ezetimibe on the breastfed infant or the effects of ezetimibe on milk production. Ezetimibe tablets should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.
Data
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.
The safety and effectiveness of ezetimibe tablets in combination with a statin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of ezetimibe tablets for this indication is based on a double-blind, placebo-controlled clinical trial in 248 pediatric patients (142 males and 106 postmenarchal females) 10 years of age and older with HeFH [see Clinical Studies (14)] . In this limited controlled trial, there was no significant effect on growth or sexual maturation in the adolescent males or females, or on menstrual cycle length in females.
The safety and effectiveness of ezetimibe tablets in combination with a statin, and other LDL-C lowering therapies, to reduce LDL-C have been established in pediatric patients 10 years of age and older with HoFH. Use of ezetimibe tablets for this indication is based on a 12-week double-blind, placebo-controlled clinical trial followed by an uncontrolled extension period in 7 pediatric patients 11 years of age and older with HoFH [see Clinical Studies (14)] .
The safety and effectiveness of ezetimibe tablets as an adjunct to diet for the reduction of elevated sitosterol and campesterol levels have been established in adults and pediatric patients 9 years of age and older with homozygous familial sitosterolemia. Use of ezetimibe tablets for this indication is based on an 8-week double-blind, placebo-controlled clinical trial in 4 patients 9 years of age and older with homozygous sitosterolemia with elevated plasma sitosterol levels (>5 mg/dL) [see Clinical Studies (14)] .
The safety and effectiveness of ezetimibe tablets have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, in pediatric patients younger than 9 years of age with homozygous familial sitosterolemia, or in pediatric patients with other types of hyperlipidemia.
Of the 2,396 patients who received ezetimibe tablets in clinical trials, 669 (28%) were 65 years of age and older, and 111 (5%) were 75 years of age and older. Of the 11,308 patients who received ezetimibe tablets in combination with a statin in clinical trials, 3587 (32%) were 65 years of age and older, and 924 (8%) were 75 years of age and older [see Clinical Studies (14)] . No overall differences in safety or effectiveness of ezetimibe tablets have been observed between patients 65 years of age and older and younger patients. No clinically meaningful differences in the pharmacokinetics of ezetimibe were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology (12.3)].
No dosage adjustment of ezetimibe tablets is necessary in patients with renal impairment.
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 [see Clinical Pharmacology (12.3)] .
In the event of overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
Ezetimibe, USP is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. The chemical name of ezetimibe, USP is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C
24H
21F
2NO
3. Its molecular weight is 409.4 and its structural formula is:
Ezetimibe, USP is a white to off white, crystalline powder that is soluble in methanol. Ezetimibe, USP has a melting point of about 163°C and is stable at ambient temperature. Ezetimibe Tablet, USP is available as a tablet for oral administration containing 10 mg of ezetimibe, USP and the following inactive ingredients: lactose monohydrate, croscarmellose sodium, Hypromellose, sodium lauryl sulfate, crospovidone, microcrystalline cellulose, and magnesium stearate.
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by 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 localizes 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. This causes a reduction of hepatic cholesterol stores and an increase in LDL receptors, resulting in clearance of cholesterol from the blood.
Ezetimibe Tablet reduces total cholesterol (total-C), LDL-C, apolipoprotein (Apo) B, and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with hyperlipidemia.
In a 2-week clinical trial in 18 hypercholesterolemic patients, ezetimibe tablet inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe Tablet had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E (in a trial of 113 patients) and did not impair adrenocortical steroid hormone production (in a trial of 118 patients).
Absorption
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 tablets to fasted adults, mean ezetimibe peak plasma concentrations (C
max) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (T
max).
Ezetimibe-glucuronide mean C max values of 45 to 71 ng/mL were achieved between 1 and 2 hours (T max). 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.
Effect of Food
Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as ezetimibe tablets 10-mg tablets. The C
max value of ezetimibe was increased by 38% with consumption of high-fat meals.
Distribution
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
Elimination
Metabolism
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.
Excretion
Following oral administration of
14C-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.
Specific Populations
Geriatric Patients
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.
Gender
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.
Race
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.
Renal Impairment
After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m
2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9).
Hepatic Impairment
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 trial (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
[see
Use in Specific Populations (8.7)]
.
Drug Interactions
Ezetimibe tablets 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* |
|
Change in AUC |
Change in C max |
|
↑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 dose § |
↓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 C max of Coadministered Drug |
Warfarin, 25-mg single dose on Day 7 |
10 mg QD, 11 days |
↓2% (R-warfarin) ↓4% (S-warfarin) |
↑3% (R-warfarin) ↑1% (S-warfarin) |
Digoxin, 0.5-mg single dose |
10 mg QD, 8 days |
↑2% |
↓7% |
Gemfibrozil, 600 mg BID, 7 days * |
10 mg QD, 7 days |
↓1% |
↓11% |
Ethinyl estradiol & Levonorgestrel, QD, 21 days |
10 mg QD, days 8-14 of 21d oral contraceptive cycle |
Ethinyl estradiol 0% Levonorgestrel 0% |
Ethinyl estradiol ↓9% Levonorgestrel ↓5% |
Glipizide, 10 mg on Days 1 and 9 |
10 mg QD, days 2-9 |
↓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% |
A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1,500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 X the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 X the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.
No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.
In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1,000 mg/kg/day in male or female rats (~7 X the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe).
Primary Hyperlipidemia in Adults
Ezetimibe Tablet reduces total-C, LDL-C, Apo B, and non-HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.
Monotherapy
In two multicenter, double-blind, placebo-controlled, 12-week trials in 1719 patients (age range 18 to 86 years, 52% females; 91% White, 5% Black or African American, 1% Asian, 3% other races mostly identified as Hispanic or Latino ethnicity) with primary hyperlipidemia, ezetimibe tablet significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to placebo (see
Table 6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.
Treatment Group |
N |
Total-C |
LDL-C |
ApoB |
Non-HDL-C |
|
Trial 1† |
Placebo |
205 |
+1 |
+1 |
-1 |
+1 |
Ezetimibe |
622 |
-12 |
-18 |
-15 |
-16 |
|
Trial 2† |
Placebo |
226 |
+1 |
+1 |
-1 |
+2 |
Ezetimibe |
666 |
-12 |
-18 |
-16 |
-16 |
|
Pooled Data† (Trials 1 &2) |
Placebo |
431 |
0 |
+1 |
-2 |
+1 |
Ezetimibe |
1288 |
-13 |
-18 |
-16 |
-16 |
Combination with Statins: Ezetimibe Tablet Added to On-going Statin Therapy
In a multicenter, double-blind, placebo-controlled, 8-week trial, 769 patients (age range 22 to 85 years, 42% females; 90% White, 6% Black or African American, 1% Asian, 3% other races; and 2% identified as Hispanic or Latino ethnicity) with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy but who had not met their NCEP ATP II target LDL-C goal, were randomized to receive either ezetimibe tablet or placebo in addition to their on-going statin.
Ezetimibe Tablet, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared with a statin administered alone (see Table 7). LDL-C reductions induced by Ezetimibe Tablet were generally consistent across all statins.
Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
Non-HDL-C |
On-going Statin + Placebo ‡ |
390 |
-2 |
-4 |
-3 |
-3 |
On-going Statin + Ezetimibe Tablet ‡ |
379 |
-17 |
-25 |
-19 |
-23 |
Combination with Statins: Ezetimibe Tablet Initiated Concurrently with a Statin
In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2,382 patients (age range 18 to 87 years, 57% female; 88% White, 5% Black or African American, 2% Asian, 5% other races mostly identified as Hispanic or Latino) with hyperlipidemia, ezetimibe tablet or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.
When all patients receiving ezetimibe tablet with a statin were compared to all those receiving the corresponding statin alone, ezetimibe tablet significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to the statin administered alone. LDL-C reductions induced by ezetimibe tablet were generally consistent across all statins. (See footnote †, Tables 8 to 11.)
|
|||||
Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
Non-HDL-C |
Placebo |
60 |
+4 |
+4 |
+3 |
+4 |
Ezetimibe Tablet |
65 |
-14 |
-20 |
-15 |
-18 |
Atorvastatin 10 mg |
60 |
-26 |
-37 |
-28 |
-34 |
Ezetimibe Tablet + Atorvastatin 10 mg |
65 |
-38 |
-53 |
-43 |
-49 |
Atorvastatin 20 mg |
60 |
-30 |
-42 |
-34 |
-39 |
Ezetimibe Tablet + Atorvastatin 20 mg |
62 |
-39 |
-54 |
-44 |
-50 |
Atorvastatin 40 mg |
66 |
-32 |
-45 |
-37 |
-41 |
Ezetimibe Tablet + Atorvastatin 40 mg |
65 |
-42 |
-56 |
-45 |
-52 |
Atorvastatin 80 mg |
62 |
-40 |
-54 |
-46 |
-51 |
Ezetimibe Tablet + Atorvastatin 80 mg |
63 |
-46 |
-61 |
-50 |
-58 |
Pooled data (All Atorvastatin Doses) * |
248 |
-32 |
-44 |
-36 |
-41 |
Pooled data (All Ezetimibe Tablet + Atorvastatin Doses) * |
255 |
-41 |
-56 |
-45 |
-52 |
|
|||||
Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
Non-HDL-C |
Placebo |
70 |
-1 |
-1 |
0 |
-1 |
Ezetimibe Tablet |
61 |
-13 |
-19 |
-14 |
-17 |
Simvastatin 10 mg |
70 |
-18 |
-27 |
-21 |
-25 |
Ezetimibe Tablet + Simvastatin 10 mg |
67 |
-32 |
-46 |
-35 |
-42 |
Simvastatin 20 mg |
61 |
-26 |
-36 |
-29 |
-33 |
Ezetimibe Tablet + Simvastatin 20 mg |
69 |
-33 |
-46 |
-36 |
-42 |
Simvastatin 40 mg |
65 |
-27 |
-38 |
-32 |
-35 |
Ezetimibe Tablet + Simvastatin 40 mg |
73 |
-40 |
-56 |
-45 |
-51 |
Simvastatin 80 mg |
67 |
-32 |
-45 |
-37 |
-41 |
Ezetimibe Tablet + Simvastatin 80 mg |
65 |
-41 |
-58 |
-47 |
-53 |
Pooled data (All Simvastatin Doses) * |
263 |
-26 |
-36 |
-30 |
-34 |
Pooled data (All Ezetimibe Tablet +Simvastatin Doses) * |
274 |
-37 |
-51 |
-41 |
-47 |
|
|||||
Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
Non-HDL-C |
Placebo |
65 |
0 |
-1 |
-2 |
0 |
Ezetimibe Tablet |
64 |
-13 |
-20 |
-15 |
-17 |
Pravastatin 10 mg |
66 |
-15 |
-21 |
-16 |
-20 |
Ezetimibe Tablet + Pravastatin 10 mg |
71 |
-24 |
-34 |
-27 |
-32 |
Pravastatin 20 mg |
69 |
-15 |
-23 |
-18 |
-20 |
Ezetimibe Tablet + Pravastatin 20 mg |
66 |
-27 |
-40 |
-31 |
-36 |
Pravastatin 40 mg |
70 |
-22 |
-31 |
-26 |
-28 |
Ezetimibe Tablet + Pravastatin 40 mg |
67 |
-30 |
-42 |
-32 |
-39 |
Pooled data (All Pravastatin Doses) * |
205 |
-17 |
-25 |
-20 |
-23 |
Pooled data (All Ezetimibe Tablet + Pravastatin Doses) * |
204 |
-27 |
-39 |
-30 |
-36 |
|
|||||
Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
Non-HDL-C |
Placebo |
64 |
+1 |
0 |
+1 |
+1 |
Ezetimibe Tablet |
72 |
-13 |
-19 |
-14 |
-16 |
Lovastatin 10 mg |
73 |
-15 |
-20 |
-17 |
-19 |
Ezetimibe Tablet + Lovastatin 10 mg |
65 |
-24 |
-34 |
-27 |
-31 |
Lovastatin 20 mg |
74 |
-19 |
-26 |
-21 |
-24 |
Ezetimibe Tablet + Lovastatin 20 mg |
62 |
-29 |
-41 |
-34 |
-39 |
Lovastatin 40 mg |
73 |
-21 |
-30 |
-25 |
-27 |
Ezetimibe Tablet + Lovastatin 40 mg |
65 |
-33 |
-46 |
-38 |
-43 |
Pooled data (All Lovastatin Doses) * |
220 |
-18 |
-25 |
-21 |
-23 |
Pooled data (All Ezetimibe Tablet + Lovastatin Doses) * |
192 |
-29 |
-40 |
-33 |
-38 |
Combination with Fenofibrate
In a multicenter, double-blind, placebo-controlled, clinical trial in patients with mixed hyperlipidemia, 625 patients (age range 20 to 76 years, 44% female; 79% White, 1% Black or African American, 20% other races; and 11% identified as Hispanic or Latino ethnicity) were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, ezetimibe tablet alone, 160 mg fenofibrate alone, or ezetimibe tablet and 160 mg fenofibrate in the 12-week trial. After completing the 12-week trial, eligible patients were assigned to ezetimibe tablet coadministered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks.
Ezetimibe Tablet coadministered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone (see Table 12).
Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
Non-HDL-C |
Placebo |
63 |
0 |
0 |
-1 |
0 |
Ezetimibe Tablet |
185 |
-12 |
-13 |
-11 |
-15 |
Fenofibrate 160 mg |
188 |
-11 |
-6 |
-15 |
-16 |
Ezetimibe Tablet + Fenofibrate 160 mg |
183 |
-22 |
-20 |
-26 |
-30 |
The changes in lipid endpoints after an additional 48 weeks of treatment with ezetimibe tablet coadministered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above.
HeFH in Pediatric Patients
The effects of ezetimibe tablet coadministered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in males and females with HeFH. In a multicenter, double-blind, controlled trial followed by an open-label phase, 142 males and 106 postmenarchal females, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% White, 4% Asian, 2% Black or African American, 13% multi-racial; 14% identified as Hispanic or Latino ethnicity) with HeFH were randomized to receive either ezetimibe tablet coadministered with simvastatin or simvastatin monotherapy. Inclusion in the trial required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161 to 351 mg/dL) in the ezetimibe tablet coadministered with simvastatin group compared to 219 mg/dL (range: 149 to 336 mg/dL) in the simvastatin monotherapy group. The patients received coadministered ezetimibe tablet and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, coadministered ezetimibe tablet and 40- mg simvastatin or 40-mg simvastatin monotherapy for the next 27 weeks, and open-label coadministered ezetimibe tablet and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.
The results of the trial at Week 6 are summarized in Table 13. Results at Week 33 were consistent with those at Week 6.
Total-C |
LDL-C |
Apo B |
Non-HDL-C |
|
Mean percent difference between treatment groups |
-12% |
-15% |
-12% |
-14% |
95% Confidence Interval |
(-15%, -9%) |
(-18%, -12%) |
(-15%, -9%) |
(-17%, -11%) |
HoFH in Adults and Pediatric Patients
A trial was conducted to assess the efficacy of ezetimibe tablet in the treatment of HoFH. This double-blind, randomized, 12-week trial enrolled 50 patients (age range 11 to 74 years, 58% female; 90% White, 2% Black or African American, 8% other races identified as Hispanic or Latino) with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), ezetimibe tablet administered with atorvastatin or simvastatin (40 mg), or ezetimibe tablet administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine
[see
Drug Interactions (7)]
, ezetimibe was dosed at least 4 hours before or after administration of resins. Mean baseline LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the group randomized to ezetimibe tablet plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. Ezetimibe tablet, administered with atorvastatin or simvastatin (40- and 80-mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with ezetimibe tablet plus 80-mg atorvastatin or with ezetimibe tablet plus 80-mg simvastatin, LDL-C was reduced by 27%.
Homozygous Sitosterolemia (Phytosterolemia) in Adults and Pediatric Patients
A trial was conducted to assess the efficacy of ezetimibe tablet in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients (age range 9 to 72 years, 65% females; 89% White, 3% Asian, 8% other races identified as Hispanic or Latino) with homozygous sitosterolemia with elevated plasma sitosterol levels (>5 mg/dL) on their current therapeutic regimen (diet, bile-acid-binding resins, statins, ileal bypass surgery and/or LDL apheresis), were randomized to receive ezetimibe tablet (n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine
[see
Drug Interactions (7)]
, ezetimibe tablet was dosed at least 2 hours before or 4 hours after resins were administered. Excluding the one subject receiving LDL apheresis, ezetimibe tablet significantly lowered plasma sitosterol and campesterol, by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had increases in sitosterol and campesterol of 4% and 3% from baseline, respectively. For patients treated with ezetimibe tablet, mean plasma levels of plant sterols were reduced progressively over the course of the trial. Reductions in sitosterol and campesterol were consistent between patients taking ezetimibe tablet concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).
Ezetimibe Tablets, USP 10 mg, are white to off white capsule shaped, flat faced, beveled edge tablets, debossed with ‘A25’ on one side and plain on other side. They are supplied as follows:
Unit dose packages of 30 (3 x 10) NDC 60687-373-21
Storage
tore at 25°C (77°F); excursions permitted between 15 to 30°C (59 to 86°F). [See USP Controlled Room Temperature.] Protect from moisture.
FOR YOUR PROTECTION: Do not use if blister is torn or broken.
Advise the patient to read the FDA-Approved Patient Labeling (Patient Information).
Inform patients that ezetimibe tablet may cause liver enzyme elevations [see Warnings and Precautions (5.2)].
Muscle Pain
Advise patients that ezetimibe tablet may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication and they should discuss all medication, both prescription and over-the-counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever
[see
Warnings and Precautions (5.3), and
Drug Interactions (7)]
.
Pregnancy
Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if ezetimibe tablet should be discontinued
[see
Use in Specific Populations (8.1)]
.
Breastfeeding
Advise patients who have a lipid disorder and are breastfeeding to discuss the options with their healthcare provider
[see
Use in Specific Populations (8.2)]
.
Missed Dose
Instruct patients to take ezetimibe tablet only as prescribed. If a dose is missed, it should be taken as soon as possible. Advise patients not to double their next dose.
To order more Patient Information Sheets call American Health Packaging at 1‐800‐707‐4621.
American Health Packaging unit dose blisters (see
How Supplied section) contain drug product from Ascend Laboratories, LLC as follows:
(10 mg / 30 UD) NDC 60687-373-21 packaged from NDC 67877-490
Distributed by:
American Health Packaging
Columbus, OH 43217
8437321/0724
8437321/0724
Ezetimibe (e zet' i mibe) Tablets, USP for oral use
Read this information carefully before you start taking ezetimibe tablets and each time you get more ezetimibe tablets. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about ezetimibe tablets, ask your doctor. Only your doctor can determine if ezetimibe tablets is right for you.
What is ezetimibe tablets?
Ezetimibe tablets is a medicine used with a cholesterol lowering diet:
Ezetimibe tablets is also used:
The safety and effectiveness of ezetimibe tablets has not been established in children:
Do not take ezetimibe tablets :
Before you take ezetimibe tablets, tell your healthcare provider about all your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Talk to your healthcare provider before you start taking any new medicines.
Taking ezetimibe tablets with certain other medicines may affect each other causing side effects. Ezetimibe tablets may affect the way other medicines work, and other medicines may affect how ezetimibe tablets works.
Especially tell your healthcare provider if you take:
Ask your healthcare provider or pharmacist for a list of medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take ezetimibe tablets?
What are the possible side effects of ezetimibe tablets?
Ezetimibe tablets may cause serious side effects including:
Your chances of getting muscle problems are higher if you are also taking statins or fibrates.
The most common side effects of ezetimibe tablets taken alone include:
The most common side effects of ezetimibe tablets taken with a statin include:
Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of ezetimibe tablets.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088.
How should I store ezetimibe tablets?
Keep ezetimibe tablets and all medicines out of the reach of children.
General information about safe and effective use of ezetimibe tablets.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ezetimibe tablets for a condition for which it was not prescribed. Do not give ezetimibe tablets to other people, even if they have the same symptoms you have. It may harm them.
You can ask your pharmacist or healthcare provider for information about ezetimibe tablets that is written for health professionals.
What are the ingredients in ezetimibe tablets?
Active ingredient: ezetimibe.
Inactive ingredients:
Lactose monohydrate, croscarmellose sodium, Hypromellose, sodium lauryl sulfate, crospovidone, microcrystalline cellulose, and magnesium stearate.
To order more Patient Information Sheets call American Health Packaging at 1‐800‐707‐4621.
Distributed by:
American Health Packaging
Columbus, OH 43217
8437321/0724
NDC 60687- 373-21
Ezetimibe
Tablets, USP
10 mg
30 Tablets (3 x 10) Rx Only
Each Tablet Contains:
Ezetimibe, USP..........................................................................10 mg
Usual Dosage: One tablet daily. See full prescribing information.
Store at 20° to 25°C (68° to 77°F); excursions permitted between
15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Protect from moisture.
FOR YOUR PROTECTION: Do not use if blister is torn or broken.
The drug product contained in this package is from
NDC # 67877-490, Ascend Laboratories, LLC.
Distributed by: American Health Packaging, Columbus, Ohio 43217
737321
0437321/0724
EZETIMIBE
ezetimibe tablet |
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
|
Labeler - American Health Packaging (929561009) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
American Health Packaging | 929561009 | repack(60687-373) |