Ezetimibe: Package Insert and Label Information (Page 2 of 4)

6.2 Post-Marketing Experience

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:

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria; erythema multiforme; arthralgia; myalgia; elevated creatine phosphokinase; myopathy/rhabdomyolysis [see Warnings and Precautions (5.3)] ; elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis.

7 DRUG INTERACTIONS

[See Clinical Pharmacology (12.3).]

7.1 Cyclosporine

Caution should be exercised when using ezetimibe and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients receiving ezetimibe and cyclosporine.

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 benefits of alterations in lipid levels provided by ezetimibe.

7.2 Fibrates

The efficacy and safety of co-administration of ezetimibe with fibrates other than fenofibrate have not been studied.

Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile [see Nonclinical Toxicology (13.2)]. Co-administration of ezetimibe with fibrates other than fenofibrate is not recommended until use in patients is adequately studied.

7.3 Fenofibrate

If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see Adverse Reactions (6.1) and the product labeling for fenofibrate].

7.4 Cholestyramine

Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction.

7.5 Coumarin Anticoagulants

If ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 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 1000 mg/kg/day (~10 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.

Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy.

All statins are contraindicated in pregnant and nursing women. When ezetimibe is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin [see Contraindications (4)].

8.3 Nursing Mothers

It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when ezetimibe is administered to a nursing woman. Ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.

8.4 Pediatric Use

The effects of ezetimibe co-administered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either ezetimibe co-administered with simvastatin or simvastatin monotherapy. Inclusion in the study 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: 161–351 mg/dL) in the ezetimibe co-administered with simvastatin group compared to 219 mg/dL (range: 149–336 mg/dL) in the simvastatin monotherapy group. The patients received co-administered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, co-administered ezetimibe and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label co-administered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.

The results of the study at Week 6 are summarized in Table 3. Results at Week 33 were consistent with those at Week 6.

TABLE 3: Mean Percent Difference at Week 6 between the Pooled Ezetimibe Co-administered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia
Total-C LDL-C Apo B Non-HDL-C TG HDL-C

Mean percent difference between treatment groups

-12%

-15%

-12%

-14%

-2%

+0.1%

95% Confidence Interval

(-15%, -9%)

(-18%, -12%)

(-15%, -9%)

(-17%, -11%)

(-9%, +4%)

(-3%, +3%)

From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the ezetimibe co-administered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group.

During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST ≥3 × ULN) occurred in four (3%) individuals in the ezetimibe co-administered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (≥10 × ULN) occurred in two (2%) individuals in the ezetimibe co-administered with simvastatin group and in zero individuals in the simvastatin monotherapy group.

In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls.

Co-administration of ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, ezetimibe has not been studied in patients younger than 10 years of age or in pre-menarchal girls.

Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide), there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available.

8.5 Geriatric Use

Monotherapy Studies

Of the 2396 patients who received ezetimibe in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older.

Statin Co-administration Studies

Of the 11,308 patients who received ezetimibe + statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older.

No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

When used as monotherapy, no dosage adjustment of ezetimibe is necessary. In the Study of Heart and Renal Protection (SHARP) trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m2 , and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to ezetimibe 10 mg plus simvastatin 20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years. However, because renal impairment is a risk factor for statin-associated myopathy, doses of simvastatin exceeding 20 mg should be used with caution and close monitoring when administered concomitantly with ezetimibe in patients with moderate to severe renal impairment.

8.7 Hepatic Impairment

Ezetimibe is not recommended in patients with moderate to severe hepatic impairment [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

Ezetimibe given concomitantly with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels [see Contraindications (4) ; Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks was generally well tolerated. One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events.

In the event of an overdose, symptomatic and supportive measures should be employed.

11 DESCRIPTION

Ezetimibe 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 C24 H21 F2 NO3 . Its molecular weight is 409.4 and its structural formula is:

structure
(click image for full-size original)

Ezetimibe, USP is a white crystalline powder that is freely soluble in ethanol, methanol, and acetone and practically insoluble in water. Ezetimibe, USP has a melting point of about 163°C and is stable at ambient temperature. Ezetimibe Tablets, USP is available as a tablet for oral administration containing 10 mg of ezetimibe, USP and the following inactive ingredients: lactose monohydrate, magnesium stearate, povidone, sodium lauryl sulfate, and sodium starch glycolate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E (in a study of 113 patients), and did not impair adrenocortical steroid hormone production (in a study of 118 patients).

The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol.

Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds (statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). 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 does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, 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 clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins and of fenofibrate [see Clinical Studies (14.1)].

12.2 Pharmacodynamics

Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia.

Administration of ezetimibe with a statin is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of ezetimibe with fenofibrate is effective in improving serum total-C, LDL-C, Apo-B, and non-HDL-C in patients with mixed hyperlipidemia as compared to either treatment alone.

The effects of ezetimibe given either alone or in addition to a statin or fenofibrate on cardiovascular morbidity and mortality have not been established.

12.3 Pharmacokinetics

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 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 Cmax values 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.

Effect of Food on Oral Absorption

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 Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals. Ezetimibe can be administered with or without food.

Distribution

Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.

Metabolism and Excretion

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 of 14 C-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 study 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.

Pediatric Patients: [See Use in Specific Populations (8.4).]

Gender: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men.

Race: Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.

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 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. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, ezetimibe is not recommended in these patients [see Warnings and Precautions (5.4)].

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 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9).

Drug Interactions [See also Drug Interactions (7).]

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” study 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.

TABLE 4: Effect of Co-administered Drugs on Total Ezetimibe

Co-administered Drug and Dosing Regimen

Total Ezetimibe*

Change in AUC

Change in Cmax

Cyclosporine-stable dose required (75–150 mg BID) †,‡

↑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%

*Based on 10 mg dose of ezetimibe.
† Post-renal transplant patients with mild impaired or normal renal function. 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.
‡ See Drug Interactions (7).§ Supralox, 20 mL.

TABLE 5: Effect of Ezetimibe Co-administration on Systemic Exposure to Other Drugs
Co-administered Drug and its Dosage Regimen Ezetimibe Dosage Regimen Change in AUC of Co-administered Drug Change in Cmax of Co-administered 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 to 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 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%

* See Drug Interactions (7).

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