Ezetimibe Tablets, Usp

Ezetimibe (ez-ET-i-mibe) Tablets

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 are right for you.

What are ezetimibe tablets?

Ezetimibe tablets are a medicine used with a cholesterol lowering diet:

• and with other cholesterol medicines called a statin, or alone (when additional cholesterol lowering treatments are not possible), to lower elevated low-density lipoprotein cholesterol (LDL-C) or bad cholesterol in adults with primary hyperlipidemia (too many fats in your blood), including heterozygous familial hypercholesterolemia (HeFH). HeFH is an inherited condition that causes high levels of bad cholesterol.

• and with a statin to lower LDL-C in adults and children 10 years of age and older with HeFH.

• and with a medicine called fenofibrate to lower elevated LDL-C in adults with mixed hyperlipidemia.

• to lower elevated sitosterol and campesterol levels in adults and in children 9 years of age and older with homozygous familial sitosterolemia (a rare inherited condition that prevents the body from getting rid of cholesterol from plants).

Ezetimibe tablets are also used:

• with a statin and other cholesterol lowering treatments to lower elevated LDL-C levels in adults and patients 10 years of age and older with homozygous familial hypercholesterolemia (HoFH). HoFH is an inherited condition that causes high levels of bad cholesterol.

The safety and effectiveness of ezetimibe tablets have not been established in children:

• younger than 10 years of age with HeFH or HoFH.

• younger than 9 years of age with homozygous familial sitosterolemia.

• with other types of hyperlipemia.

Do not take ezetimibe tablets:

• if you are allergic to ezetimibe, the active ingredient in ezetimibe tablets, or to the inactive ingredients. For a list of inactive ingredients, see the “Inactive ingredients” section that follows.
• If you have active liver disease, do not take ezetimibe tablets while taking cholesterol-lowering medicines called statins.
• If you are pregnant or breast-feeding, do not take ezetimibe tablets while taking a statin.
• If you are a woman of childbearing age, you should use an effective method of birth control to prevent pregnancy while using ezetimibe tablets added to statin therapy.

Ezetimibe tablets have not been studied in children under age 10.

Before you take ezetimibe tablets, tell your healthcare provider about all your medical conditions, including if you:

• have liver problems. Ezetimibe tablets may not be right for you.
• are pregnant or plan to become pregnant. It is not known if ezetimibe tablets will harm your unborn baby. You and your healthcare provider should decide if you will take ezetimibe tablets while you are pregnant.
• are breastfeeding. It is not known if ezetimibe passes into your breast milk. You and your healthcare provider should decide the best way to feed your baby if you take ezetimibe tablets.

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:

•cyclosporine (a medicine for your immune system)

•fibrates (medicine for lowering cholesterol)

•bile acid sequestrants (medicine for lowering LDL-C)

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?

• Take ezetimibe tablets once a day, with or without food. It may be easier to remember to take your dose if you do it at the same time every day, such as with breakfast, dinner, or at bedtime. If you also take another medicine to reduce your cholesterol, ask your doctor if you can take them at the same time.
• If you forget to take ezetimibe tablets, take it as soon as you remember. However, do not take more than one dose of ezetimibe tablets a day.
• Continue to follow a cholesterol-lowering diet while taking ezetimibe tablets. Ask your doctor if you need diet information.
• Keep taking ezetimibe tablets unless your doctor tells you to stop. It is important that you keep taking ezetimibe tablets even if you do not feel sick.

See your doctor regularly to check your cholesterol level and to check for side effects. Your doctor may do blood tests to check your liver before you start taking ezetimibe tablets with a statin and during treatment.

What are the possible side effects of ezetimibe tablets?

Ezetimibe tablets may cause serious side effects including:

• increased liver enzymes. An increase in liver enzymes can happen in people taking ezetimibe tablets alone or with statins. Your healthcare provider may do blood tests to check your liver before and during treatment. Your healthcare provider may need to change or stop your treatment with ezetimibe tablets because of an increase in liver enzymes.

• muscle pain, tenderness, and weakness (myopathy). Muscle problems, including muscle breakdown (rhabdomyolysis) can happen. Tell your healthcare provider right away if:

◦ you have unexplained muscle pain, tenderness, weakness, feel more tired than usual, or fever.

◦ you have muscle problems that do not go away even after your healthcare provider has advised you to stop taking ezetimibe tablets. Your healthcare provider may do further tests to diagnose the cause of your muscle problems.

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:

• upper respiratory tract infection

• diarrhea • joint pain • pain in arms or legs

• flu-like symptoms • inflammation of the sinuses • feeling tired

The most common side effects of ezetimibe tablets taken with a statin include:

• runny nose, sore throat

• joint pain

• flu-like symptoms

• muscle aches and pains

• diarrhea

• pain in arms or legs

• upper respiratory tract infection

• back pain

• feeling tired

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?

• Store ezetimibe tablets at room temperature between 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).

• Protect from moisture.

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, USP.

Inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured for:

AvKARE

Pulaski, TN 38478

Mfg. Rev. 04-2024-06

AV Rev. 11/24 (A)

In the event of overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When ezetimibe 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 to 15) and rabbits (gestation days 7 to 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 AUC0-24hr for 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 AUC0-24hr 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 AUC0-24hr 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 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.

Ezetimibe is a dietary cholesterol absorption inhibitor. The chemical name of ezetimibe is 1-(4- fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4- hydroxyphenyl)-2-azetidinone. The molecular formula is C24H21F2NO3. Its molecular

weight is 409.4 and its structural formula is::

Ezetimibe, USP is a white, crystalline powder that is freely to very 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 are available as a tablet for oral administration containing 10 mg of ezetimibe, USP and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, and sodium lauryl sulfate.

Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if ezetimibe should be discontinued

[see Use in Specific Populations (8.1)].

Advise patients that ezetimibe 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)].

Instruct patients to take ezetimibe tablets only as prescribed. If a dose is missed, it should be taken as soon as possible. Advise

patients not to double their next dose.

Manufactured for:

AvKARE

Pulaski, TN 38478

Mfg. Rev. 04-2024-06

AV Rev. 11/24 (A)

Increases in serum transaminases have been reported with use of ezetimibe [see Adverse Reactions (6.1)]. In controlled clinical

combination studies of ezetimibe 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 administered with statins and 0.4% for patients treated with statins

alone. Perform liver enzyme testing as clinically indicated and consider withdrawal of ezetimibe if increases in ALT or AST ≥ 3 X ULN

persist.

The safety and effectiveness of ezetimibe 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 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 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 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 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

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 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 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 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 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)].

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)].

Ezetimibe tablets are 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 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)].

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Liver enzyme abnormalities [see Warnings and Precautions (5.2)]

• Rhabdomyolysis and myopathy [see Warnings and Precautions (5.3)]

Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with ezetimibe and

instructions for preventing or managing them.

No dosage adjustment of ezetimibe is necessary in patients with renal impairment.

Ezetimibe 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 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

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 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 ng/mL to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 mg 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 10 mg tablets. The Cmax 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 m2), 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 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.

Ezetimibe 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)].

Ezetimibe tablets are 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 tablets are 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 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 reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases 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 studies in 1719 patients with primary hyperlipidemia, ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo (see Table 6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.

^* For triglycerides, median % change from baseline

^† Baseline - on no lipid-lowering drug

^‡ Ezetimibe significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo.

Combination with Statins

Ezetimibe Added to On-going Statin Therapy

In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients 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 or placebo in addition to their on-going statin.

Ezetimibe, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (see Table 7). LDL-C reductions induced by Ezetimibe were generally consistent across all statins.

^* Patients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin)

^† For triglycerides, median % change from baseline

^‡ Baseline - on a statin alone.

^§ Ezetimibe + statin significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to statin alone.

Ezetimibe Initiated Concurrently with a Statin

In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, ezetimibe or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.

When all patients receiving ezetimibe with a statin were compared to all those receiving the corresponding statin alone, ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the statin administered alone. LDL-C reductions induced by ezetimibe were generally consistent across all statins. (See footnote ‡, Tables 8 to 11.)

^* For triglycerides, median % change from baseline

^† Baseline - on no lipid-lowering drug

^‡ Ezetimibe + all doses of atorvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of atorvastatin pooled (10 to 80 mg).

^* For triglycerides, median % change from baseline

^† Baseline - on no lipid-lowering drug

^‡ Ezetimibe + all doses of simvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of simvastatin pooled (10 to 80 mg).

^* For triglycerides, median % change from baseline

^† Baseline - on no lipid-lowering drug

^‡ Ezetimibe + all doses of pravastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG compared to all doses of pravastatin pooled (10 to 40 mg).

^* For triglycerides, median % change from baseline

^† Baseline - on no lipid-lowering drug

^‡ Ezetimibe + all doses of lovastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of lovastatin pooled (10 to 40 mg).

Combination with Fenofibrate

In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, ezetimibe alone, 160 mg fenofibrate alone, or ezetimibe and 160 mg fenofibrate in the 12-week study. After completing the 12-week study, eligible patients were assigned to ezetimibe co-administered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks.

Ezetimibe co-administered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone. The percent decrease in TG and percent increase in HDL-C for Ezetimibe co-administered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 12).

^* For triglycerides, median % change from baseline

^† Baseline - on no lipid-lowering drug

The changes in lipid endpoints after an additional 48 weeks of treatment with ezetimibe co-administered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above.

• 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)].

Ezetimibe 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 and other concomitant medications, as appropriate.

Ezetimibe tablets USP, 10 mg are white to off-white, capsule-shaped tablets debossed with "AA69" on one side and plain on other side.

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:

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

To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993; email [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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 and at an incidence greater than placebo in placebo-controlled

studies of ezetimibe is shown in Table 1.

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 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 administered with

statins (1.3%) than in patients treated with statins alone (0.4%).

Adverse reactions reported in ≥ 2% of patients treated with ezetimibe + statin and at an incidence greater than statin are shown in

Table 2.

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 co-administration of ezetimibe 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 co-administered 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 co-administered with fenofibrate, respectively [see Drug Interactions (7)].

Advise the patient to read the FDA-Approved Patient Labeling (Patient Information).

Inform patients that ezetimibe may cause liver enzyme elevations [see Warnings and Precautions (5.2)].

Ezetimibe tablets USP, 10 mg are supplied as white to off-white, capsule-shaped tablets debossed with “AA69” on one side and plain on other side.



They are supplied as follows:

NDC 50268-298-12 (10 tablets per card, 2 cards per carton)

Dispensed in Unit Dose Package. For Institutional Use Only.

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 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 1000 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).

If ezetimibe 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)].

In the event of overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When ezetimibe 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 to 15) and rabbits (gestation days 7 to 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 AUC0-24hr for 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 AUC0-24hr 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 AUC0-24hr 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 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.

Ezetimibe is a dietary cholesterol absorption inhibitor. The chemical name of ezetimibe is 1-(4- fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4- hydroxyphenyl)-2-azetidinone. The molecular formula is C24H21F2NO3. Its molecular

weight is 409.4 and its structural formula is::

Ezetimibe, USP is a white, crystalline powder that is freely to very 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 are available as a tablet for oral administration containing 10 mg of ezetimibe, USP and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, and sodium lauryl sulfate.

Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if ezetimibe should be discontinued

[see Use in Specific Populations (8.1)].

Advise patients that ezetimibe 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)].

Instruct patients to take ezetimibe tablets only as prescribed. If a dose is missed, it should be taken as soon as possible. Advise

patients not to double their next dose.

Manufactured for:

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Increases in serum transaminases have been reported with use of ezetimibe [see Adverse Reactions (6.1)]. In controlled clinical

combination studies of ezetimibe 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 administered with statins and 0.4% for patients treated with statins

alone. Perform liver enzyme testing as clinically indicated and consider withdrawal of ezetimibe if increases in ALT or AST ≥ 3 X ULN

persist.

The safety and effectiveness of ezetimibe 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 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 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 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 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

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 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 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 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 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)].

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)].

Ezetimibe tablets are 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 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)].

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Liver enzyme abnormalities [see Warnings and Precautions (5.2)]

• Rhabdomyolysis and myopathy [see Warnings and Precautions (5.3)]

Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with ezetimibe and

instructions for preventing or managing them.

Ezetimibe (ez-ET-i-mibe) Tablets

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 are right for you.

What are ezetimibe tablets?

Ezetimibe tablets are a medicine used with a cholesterol lowering diet:

• and with other cholesterol medicines called a statin, or alone (when additional cholesterol lowering treatments are not possible), to lower elevated low-density lipoprotein cholesterol (LDL-C) or bad cholesterol in adults with primary hyperlipidemia (too many fats in your blood), including heterozygous familial hypercholesterolemia (HeFH). HeFH is an inherited condition that causes high levels of bad cholesterol.

• and with a statin to lower LDL-C in adults and children 10 years of age and older with HeFH.

• and with a medicine called fenofibrate to lower elevated LDL-C in adults with mixed hyperlipidemia.

• to lower elevated sitosterol and campesterol levels in adults and in children 9 years of age and older with homozygous familial sitosterolemia (a rare inherited condition that prevents the body from getting rid of cholesterol from plants).

Ezetimibe tablets are also used:

• with a statin and other cholesterol lowering treatments to lower elevated LDL-C levels in adults and patients 10 years of age and older with homozygous familial hypercholesterolemia (HoFH). HoFH is an inherited condition that causes high levels of bad cholesterol.

The safety and effectiveness of ezetimibe tablets have not been established in children:

• younger than 10 years of age with HeFH or HoFH.

• younger than 9 years of age with homozygous familial sitosterolemia.

• with other types of hyperlipemia.

Do not take ezetimibe tablets:

• if you are allergic to ezetimibe, the active ingredient in ezetimibe tablets, or to the inactive ingredients. For a list of inactive ingredients, see the “Inactive ingredients” section that follows.
• If you have active liver disease, do not take ezetimibe tablets while taking cholesterol-lowering medicines called statins.
• If you are pregnant or breast-feeding, do not take ezetimibe tablets while taking a statin.
• If you are a woman of childbearing age, you should use an effective method of birth control to prevent pregnancy while using ezetimibe tablets added to statin therapy.

Ezetimibe tablets have not been studied in children under age 10.

Before you take ezetimibe tablets, tell your healthcare provider about all your medical conditions, including if you:

• have liver problems. Ezetimibe tablets may not be right for you.
• are pregnant or plan to become pregnant. It is not known if ezetimibe tablets will harm your unborn baby. You and your healthcare provider should decide if you will take ezetimibe tablets while you are pregnant.
• are breastfeeding. It is not known if ezetimibe passes into your breast milk. You and your healthcare provider should decide the best way to feed your baby if you take ezetimibe tablets.

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:

•cyclosporine (a medicine for your immune system)

•fibrates (medicine for lowering cholesterol)

•bile acid sequestrants (medicine for lowering LDL-C)

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?

• Take ezetimibe tablets once a day, with or without food. It may be easier to remember to take your dose if you do it at the same time every day, such as with breakfast, dinner, or at bedtime. If you also take another medicine to reduce your cholesterol, ask your doctor if you can take them at the same time.
• If you forget to take ezetimibe tablets, take it as soon as you remember. However, do not take more than one dose of ezetimibe tablets a day.
• Continue to follow a cholesterol-lowering diet while taking ezetimibe tablets. Ask your doctor if you need diet information.
• Keep taking ezetimibe tablets unless your doctor tells you to stop. It is important that you keep taking ezetimibe tablets even if you do not feel sick.

See your doctor regularly to check your cholesterol level and to check for side effects. Your doctor may do blood tests to check your liver before you start taking ezetimibe tablets with a statin and during treatment.

What are the possible side effects of ezetimibe tablets?

Ezetimibe tablets may cause serious side effects including:

• increased liver enzymes. An increase in liver enzymes can happen in people taking ezetimibe tablets alone or with statins. Your healthcare provider may do blood tests to check your liver before and during treatment. Your healthcare provider may need to change or stop your treatment with ezetimibe tablets because of an increase in liver enzymes.

• muscle pain, tenderness, and weakness (myopathy). Muscle problems, including muscle breakdown (rhabdomyolysis) can happen. Tell your healthcare provider right away if:

◦ you have unexplained muscle pain, tenderness, weakness, feel more tired than usual, or fever.

◦ you have muscle problems that do not go away even after your healthcare provider has advised you to stop taking ezetimibe tablets. Your healthcare provider may do further tests to diagnose the cause of your muscle problems.

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:

• upper respiratory tract infection

• diarrhea • joint pain • pain in arms or legs

• flu-like symptoms • inflammation of the sinuses • feeling tired

The most common side effects of ezetimibe tablets taken with a statin include:

• runny nose, sore throat

• joint pain

• flu-like symptoms

• muscle aches and pains

• diarrhea

• pain in arms or legs

• upper respiratory tract infection

• back pain

• feeling tired

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?

• Store ezetimibe tablets at room temperature between 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).

• Protect from moisture.

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, USP.

Inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured for:

AvKARE

Pulaski, TN 38478

Mfg. Rev. 04-2024-06

AV Rev. 11/24 (A)

No dosage adjustment of ezetimibe is necessary in patients with renal impairment.

Ezetimibe 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 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

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 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 ng/mL to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 mg 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 10 mg tablets. The Cmax 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 m2), 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 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.

Ezetimibe 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)].

Ezetimibe tablets are 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 tablets are 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 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 reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases 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 studies in 1719 patients with primary hyperlipidemia, ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo (see Table 6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.

^* For triglycerides, median % change from baseline

^† Baseline - on no lipid-lowering drug

^‡ Ezetimibe significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo.

Combination with Statins

Ezetimibe Added to On-going Statin Therapy

In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients 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 or placebo in addition to their on-going statin.

Ezetimibe, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (see Table 7). LDL-C reductions induced by Ezetimibe were generally consistent across all statins.

^* Patients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin)

^† For triglycerides, median % change from baseline

^‡ Baseline - on a statin alone.

^§ Ezetimibe + statin significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to statin alone.

Ezetimibe Initiated Concurrently with a Statin

In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, ezetimibe or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.

When all patients receiving ezetimibe with a statin were compared to all those receiving the corresponding statin alone, ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the statin administered alone. LDL-C reductions induced by ezetimibe were generally consistent across all statins. (See footnote ‡, Tables 8 to 11.)

^* For triglycerides, median % change from baseline

^† Baseline - on no lipid-lowering drug

^‡ Ezetimibe + all doses of atorvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of atorvastatin pooled (10 to 80 mg).

^* For triglycerides, median % change from baseline

^† Baseline - on no lipid-lowering drug

^‡ Ezetimibe + all doses of simvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of simvastatin pooled (10 to 80 mg).

^* For triglycerides, median % change from baseline

^† Baseline - on no lipid-lowering drug

^‡ Ezetimibe + all doses of pravastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG compared to all doses of pravastatin pooled (10 to 40 mg).

^* For triglycerides, median % change from baseline

^† Baseline - on no lipid-lowering drug

^‡ Ezetimibe + all doses of lovastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of lovastatin pooled (10 to 40 mg).

Combination with Fenofibrate

In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, ezetimibe alone, 160 mg fenofibrate alone, or ezetimibe and 160 mg fenofibrate in the 12-week study. After completing the 12-week study, eligible patients were assigned to ezetimibe co-administered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks.

Ezetimibe co-administered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone. The percent decrease in TG and percent increase in HDL-C for Ezetimibe co-administered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 12).

^* For triglycerides, median % change from baseline

^† Baseline - on no lipid-lowering drug

The changes in lipid endpoints after an additional 48 weeks of treatment with ezetimibe co-administered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above.

• 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)].

Ezetimibe 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 and other concomitant medications, as appropriate.

Ezetimibe tablets USP, 10 mg are white to off-white, capsule-shaped tablets debossed with "AA69" on one side and plain on other side.

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:

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

To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993; email [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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 and at an incidence greater than placebo in placebo-controlled

studies of ezetimibe is shown in Table 1.

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 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 administered with

statins (1.3%) than in patients treated with statins alone (0.4%).

Adverse reactions reported in ≥ 2% of patients treated with ezetimibe + statin and at an incidence greater than statin are shown in

Table 2.

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 co-administration of ezetimibe 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 co-administered 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 co-administered with fenofibrate, respectively [see Drug Interactions (7)].

Advise the patient to read the FDA-Approved Patient Labeling (Patient Information).

Inform patients that ezetimibe may cause liver enzyme elevations [see Warnings and Precautions (5.2)].

Ezetimibe tablets USP, 10 mg are supplied as white to off-white, capsule-shaped tablets debossed with “AA69” on one side and plain on other side.



They are supplied as follows:

NDC 50268-298-12 (10 tablets per card, 2 cards per carton)

Dispensed in Unit Dose Package. For Institutional Use Only.

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 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 1000 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).

If ezetimibe 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)].