EZETIMIBE AND SIMVASTATIN tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
EZETIMIBE (UNII: EOR26LQQ24) (EZETIMIBE - UNII:EOR26LQQ24), SIMVASTATIN (UNII: AGG2FN16EV) (SIMVASTATIN - UNII:AGG2FN16EV)
Available from:
Actavis Pharma, Inc.
INN (International Name):
EZETIMIBE
Composition:
EZETIMIBE 10 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. Ezetimibe and simvastatin tablets are indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. Ezetimibe and simvastatin tablets are indicated for the reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments
Product summary:
Ezetimibe and Simvastatin Tablets are supplied as follows: 10 mg/10 mg – Each light tan, slightly speckled, round, unscored, biconvex tablet debossed with 511 on one side and  on opposite side contains 10 mg of ezetimibe, USP and 10 mg of simvastatin, USP. Tablets are supplied in bottles of 30 (NDC 45963-565-30), and 90 (NDC 45963-565-08).   10 mg/20 mg – Each light tan, slightly speckled, round, unscored, biconvex tablet debossed with 512 on one side and  on opposite side contains 10 mg of ezetimibe, USP and 20 mg of simvastatin, USP. Tablets are supplied in bottles of 30 (NDC 45963-566-30), and 90 (NDC 45963-566-08). 10 mg/40 mg – Each light tan, slightly speckled, round, unscored, biconvex tablet debossed with 513 on one side and  on opposite side contains 10 mg of ezetimibe, USP and 40 mg of simvastatin, USP. Tablets are supplied in bottles of 30 (NDC 45963-567-30), and 90 (NDC 45963-567-08). 10 mg/80 mg – Each light tan, slightly speckled, capsule shaped, unscored, biconvex tablet debossed with 515 on one side and  on opposite side contains 10 mg of ezetimibe, USP and 80 mg of simvastatin, USP. Tablets are supplied in bottles of 30 (NDC 45963-568-30), and 90 (NDC 45963-568-08). Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Keep container tightly closed. Dispense in a tight, light-resistant container as defined in the USP.
Authorization status:
Abbreviated New Drug Application
Authorization number:
45963-565-08, 45963-565-30, 45963-566-08, 45963-566-30, 45963-567-08, 45963-567-30, 45963-568-08, 45963-568-30

EZETIMIBE AND SIMVASTATIN- ezetimibe and simvastatin tablet

Actavis Pharma, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use EZETIMIBE AND SIMVASTATIN TABLETS

safely and effectively. See full prescribing information for EZETIMIBE AND SIMVASTATIN TABLETS.

EZETIMIBE and SIMVASTATIN tablets, for oral use

Initial U.S. Approval: 2004

RECENT MAJOR CHANGES

Dosage and Administration

Chinese Patients Taking Lipid-Modifying Doses

(greater than or equal to 1 g/day Niacin) of Niacin-Containing Products

– removal (2.7) 04/2019

Warnings and Precautions

Myopathy/Rhabdomyolysis (5.1) 10/2019

INDICATIONS AND USAGE

Ezetimibe and simvastatin tablets, which contain a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor

(statin), is indicated as adjunctive therapy to diet to:

reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary

(heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. (1.1)

reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), as an adjunct to

other lipid-lowering treatments. (1.2)

Limitations of Use (1.3)

No incremental benefit of ezetimibe and simvastatin tablets on cardiovascular morbidity and mortality over and above

that demonstrated for simvastatin has been established.

Ezetimibe and simvastatin tablets have not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

DOSAGE AND ADMINISTRATION

Dose range is 10 mg/10 mg/day to 10 mg/40 mg/day. (2.1)

Recommended usual starting dose is 10 mg/10 mg or 10 mg/20 mg/day. (2.1)

Due to the increased risk of myopathy, including rhabdomyolysis, use of the 10 mg/80-mg dose of ezetimibe and

simvastatin should be restricted to patients who have been taking ezetimibe and simvastatin 10 mg/80 mg chronically

(e.g., for 12 months or more) without evidence of muscle toxicity. (2.2)

Patients who are currently tolerating the 10 mg/80-mg dose of ezetimibe and simvastatin who need to be initiated on an

interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an

alternative statin or statin-based regimen with less potential for the drug-drug interaction. (2.2)

Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10 mg/80-mg dose of ezetimibe

and simvastatin, patients unable to achieve their LDL-C goal utilizing the 10 mg/40-mg dose of ezetimibe and

simvastatin should not be titrated to the 10 mg/80-mg dose, but should be placed on alternative LDL-C-

lowering treatment(s) that provides greater LDL-C lowering. (2.2)

Dosing of ezetimibe and simvastatin should occur either greater than or equal to 2 hours before or greater than or equal

to 4 hours after administration of a bile acid sequestrant. (2.3, 7.5)

DOSAGE FORMS AND STRENGTHS

Tablets (ezetimibe/simvastatin): 10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, 10 mg/80 mg (3)

CONTRAINDICATIONS

Concomitant administration of strong CYP3A4 inhibitors. (4, 5.1)

Concomitant administration of gemfibrozil, cyclosporine, or danazol. (4, 5.1)

Hypersensitivity to any component of this medication (4, 6.2)

Active liver disease or unexplained persistent elevations of hepatic transaminase levels (4, 5.2)

Women who are pregnant or may become pregnant (4, 8.1)

Nursing mothers (4, 8.3)

WARNINGS AND PRECAUTIONS

Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, with the 10 mg/80-

mg dose. (5.1)

Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness.

Ezetimibe and simvastatin should be discontinued immediately if myopathy is diagnosed or suspected. (5.1)

Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks

increase with higher doses and concomitant use of certain

medicines. Predisposing factors include advanced age (greater than or equal to 65), female gender, uncontrolled

hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to

myoglobinuria have been reported. (4, 5.1, 8.5, 8.6)

Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before

initiating therapy and as clinically indicated thereafter. (5.2)

ADVERSE REACTIONS

Common (incidence greater than or equal to 2% and greater than placebo) adverse reactions in clinical trials: headache,

increased ALT, myalgia, upper respiratory tract infection, and diarrhea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088

or www.fda.gov/medwatch.

DRUG INTERACTIONS

Drug Interactions Associated with Increased

Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2,

7.3, 7.8, 12.3)

Interacting Agents

Prescribing

Recommendations

Recommendations

Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole,

erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir,

nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol

Contraindicated with

ezetimibe and simvastatin

Niacin (≥1 g/day)

For Chinese patients, not

recommended with ezetimibe

and simvastatin

Verapamil, diltiazem, dronedarone

Do not exceed 10 mg/10 mg

ezetimibe and simvastatin

daily

Amiodarone, amlodipine, ranolazine

Do not exceed 10 mg/20 mg

ezetimibe and simvastatin

daily

Lomitapide

For patients with HoFH, do

not exceed 10 mg/20 mg

ezetimibe and simvastatin

daily*

Daptomycin

Temporarily suspend

ezetimibe and simvastatin

Grapefruit juice

Avoid grapefruit juice

* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without

evidence of muscle toxicity, do not exceed 10 mg/40 mg ezetimibe and simvastatin when taking lomitapide.

Coumarin anticoagulants: simvastatin prolongs INR. Achieve stable INR prior to starting ezetimibe and simvastatin.

Monitor INR frequently until stable upon initiation or alteration of ezetimibe and simvastatin therapy. (7.8)

Cholestyramine: Combination decreases exposure of ezetimibe. (2.3, 7.5)

Other Lipid-lowering Medications: Use with fenofibrates increases the risk of adverse skeletal muscle effects. Caution

should be used when prescribing with ezetimibe and simvastatin. (5.1, 7.2)

Fenofibrates: Combination increases exposure of ezetimibe. If cholelithiasis is suspected in a patient receiving

ezetimibe and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be

considered. (7.2, 7.7, 12.3)

USE IN SPECIFIC POPULATIONS

Moderate to severe renal impairment: Doses exceeding 10 mg/20 mg/day should be used with caution and close

monitoring (2.5, 8.6).

Chinese patients: May be at higher risk of myopathy; monitor appropriately (5.1, 8.8).

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 10/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Primary Hyperlipidemia

1.2 Homozygous Familial Hypercholesterolemia (HoFH)

1.3 Limitations of Use

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

2.2 Restricted Dosing for 10 mg/80 mg

2.3 Coadministration with Other Drugs

2.4 Patients with Homozygous Familial Hypercholesterolemia

2.5 Patients with Renal Impairment/Chronic Kidney Disease

2.6 Geriatric Patients

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis

5.2 Liver Enzymes

5.3 Endocrine Function

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol

7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone

7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers

7.4 Niacin

7.5 Cholestyramine

7.6 Digoxin

7.7 Fenofibrates (e.g., fenofibrate and fenofibric acid)

7.8 Coumarin Anticoagulants

7.9 Colchicine

7.10 Daptomycin

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8 Chinese Patients

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Primary Hyperlipidemia

14.2 Homozygous Familial Hypercholesterolemia (HoFH)

14.3 Chronic Kidney Disease (CKD)

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Muscle Pain

17.2 Liver Enzymes

17.3 Pregnancy

17.4 Breastfeeding

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in

individuals at significantly increased risk for atherosclerotic vascular disease due to

hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet

restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been

inadequate.

1.1 Primary Hyperlipidemia

Ezetimibe and simvastatin tablets are indicated for the reduction of elevated total cholesterol (total-C),

low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-

high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol

(HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed

hyperlipidemia.

1.2 Homozygous Familial Hypercholesterolemia (HoFH)

Ezetimibe and simvastatin tablets are indicated for the reduction of elevated total-C and LDL-C in

patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering

treatments (e.g., LDL apheresis) or if such treatments are unavailable.

1.3 Limitations of Use

No incremental benefit of ezetimibe and simvastatin tablets on cardiovascular morbidity and mortality

over and above that demonstrated for simvastatin has been established.

Ezetimibe and simvastatin tablets have not been studied in Fredrickson type I, III, IV, and V

dyslipidemias.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The usual dosage range is 10 mg/10 mg/day to 10 mg/40 mg/day. The recommended usual starting dose

is 10 mg/10 mg/day or 10 mg/20 mg/day. Ezetimibe and simvastatin should be taken as a single daily

dose in the evening, with or without food. Patients who require a larger reduction in LDL-C (greater

than 55%) may be started at 10 mg/40 mg/day in the absence of moderate to severe renal impairment

(estimated glomerular filtration rate less than 60 mL/min/1.73 m ). After initiation or titration of

ezetimibe and simvastatin, lipid levels may be analyzed after 2 or more weeks and dosage adjusted, if

needed.

2.2 Restricted Dosing for 10 mg/80 mg

Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of

treatment, use of the 10 mg/80-mg dose of ezetimibe and simvastatin should be restricted to patients

who have been taking ezetimibe and simvastatin 10 mg/80 mg chronically (e.g., for 12 months or more)

without evidence of muscle toxicity [see Warnings and Precautions (5.1)].

Sections or subsections omitted from the full prescribing information are not listed.

Patients who are currently tolerating the 10 mg/80-mg dose of ezetimibe and simvastatin who need to be

initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin

should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug

interaction.

Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10 mg/80-mg

dose of ezetimibe and simvastatin, patients unable to achieve their LDL-C goal utilizing the 10 mg/40-

mg dose of ezetimibe and simvastatin should not be titrated to the 10 mg/80-mg dose, but should be

placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.

2.3 Coadministration with Other Drugs

Patients taking Verapamil, Diltiazem, or Dronedarone

The dose of ezetimibe and simvastatin should not exceed 10 mg/10 mg/day [see Warnings and

Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

Patients taking Amiodarone, Amlodipine or Ranolazine

The dose of ezetimibe and simvastatin should not exceed 10 mg/20 mg/day [see Warnings and

Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

Patients taking Bile Acid Sequestrants

Dosing of ezetimibe and simvastatin should occur either greater than or equal to 2 hours before or

greater than or equal to 4 hours after administration of a bile acid sequestrant [see Drug Interactions

(7.5)].

2.4 Patients with Homozygous Familial Hypercholesterolemia

The recommended dosage for patients with homozygous familial hypercholesterolemia is ezetimibe and

simvastatin 10 mg/40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 10

mg/80 mg (2.2)]. Ezetimibe and simvastatin should be used as an adjunct to other lipid-lowering

treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose

of ezetimibe and simvastatin tablets should be reduced by 50% if initiating lomitapide. Ezetimibe and

simvastatin tablets dosage should not exceed 10 mg/20 mg/day (or 10 mg/40 mg/day for patients who

have previously taken simvastatin 80 mg/day chronically, e.g., for 12 months or more, without evidence

of muscle toxicity) while taking lomitapide.

2.5 Patients with Renal Impairment/Chronic Kidney Disease

In patients with mild renal impairment (estimated GFR greater than or equal to 60 mL/min/1.73 m ), no

dosage adjustment is necessary. In patients with chronic kidney disease and estimated glomerular

filtration rate less than 60 mL/min/1.73 m , the dose of ezetimibe and simvastatin is 10 mg/20 mg/day in

the evening. In such patients, higher doses should be used with caution and close monitoring [see

Warnings and Precautions (5.1); Clinical Pharmacology (12.3)].

2.6 Geriatric Patients

No dosage adjustment is necessary in geriatric patients [see Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Ezetimibe and simvastatin tablets 10 mg/10 mg are light tan, slightly speckled, round, unscored,

biconvex tablets debossed with 511 on one side and

on opposite side.

Ezetimibe and simvastatin tablets 10 mg/20 mg are light tan, slightly speckled, round, unscored,

biconvex tablets debossed with 512 on one side and

on opposite side.

Ezetimibe and simvastatin tablets 10 mg/40 mg are light tan, slightly speckled, round, unscored,

biconvex tablets debossed with 513 on one side and

on opposite side.

Ezetimibe and simvastatin tablets 10 mg/80 mg are light tan, slightly speckled, capsule shaped,

unscored, biconvex tablets debossed with 515 on one side and

on opposite side.

4 CONTRAINDICATIONS

Ezetimibe and simvastatin tablets are contraindicated in the following conditions:

Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,

posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin,

clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [see Warnings and

Precautions (5.1)].

Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions

(5.1)].

Hypersensitivity to any component of this medication [see Adverse Reactions (6.2)].

Active liver disease or unexplained persistent elevations in hepatic transaminase levels [see

Warnings and Precautions (5.2)].

Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase

during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal

development. Because HMG-CoA reductase inhibitors (statins), such as simvastatin, decrease

cholesterol synthesis and possibly the synthesis of other biologically active substances derived

from cholesterol, ezetimibe and simvastatin may cause fetal harm when administered to a pregnant

woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during

pregnancy should have little impact on the outcome of long-term therapy of primary

hypercholesterolemia. There are no adequate and well-controlled studies of ezetimibe and

simvastatin use during pregnancy; however, in rare reports congenital anomalies were observed

following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin

revealed no evidence of teratogenicity. Ezetimibe and simvastatin should be administered to

women of childbearing age only when such patients are highly unlikely to conceive. If the

patient becomes pregnant while taking this drug, ezetimibe and simvastatin should be discontinued

immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific

Populations (8.1)].

Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small

amount of another drug in this class does pass into breast milk. Because statins have the potential for

serious adverse reactions in nursing infants, women who require ezetimibe and simvastatin treatment

should not breastfeed their infants [see Use in Specific Populations (8.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis

Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with

creatine kinase above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of

rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have

occurred. The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin

acid. Predisposing factors for myopathy include advanced age (greater than or equal to 65 years),

female gender, uncontrolled hypothyroidism, and renal impairment. Chinese patients may be at increased

risk for myopathy [see Use in Specific Populations (8.8)].

The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in

which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were

enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was

approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80

mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients

were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with

simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle

weakness or pain with a serum creatine kinase [CK] greater than 10 times upper limit of normal [ULN])

in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The

incidence of rhabdomyolysis (defined as myopathy with a CK greater than 40 times ULN) in patients on

80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of

myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased

during the subsequent years of treatment. In this trial, patients were carefully monitored and some

interacting medicinal products were excluded.

The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg

compared with other statin therapies with similar or greater LDL-C-lowering efficacy and

compared with lower doses of simvastatin. Therefore, the 10 mg/80-mg dose of ezetimibe and

simvastatin should be used only in patients who have been taking ezetimibe and simvastatin 10

mg/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see

Dosage and Administration, Restricted Dosing for 10 mg/80 mg (2.2)]. If, however, a patient who is

currently tolerating the 10 mg/80-mg dose of ezetimibe and simvastatin needs to be initiated on

an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that

patient should be switched to an alternative statin or statin-based regimen with less potential for

the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including

rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness.

If symptoms occur, treatment should be discontinued immediately [see Warnings and Precautions

(5.2)].

In the Study of Heart and Renal Protection (SHARP), 9270 patients with chronic kidney disease

were allocated to receive ezetimibe and simvastatin 10 mg/20 mg daily (n=4650) or placebo (n=4620).

During a median follow-up period of 4.9 years, the incidence of myopathy (defined as unexplained

muscle weakness or pain with a serum creatine kinase [CK] greater than 10 times upper limit of normal

[ULN]) was 0.2% for ezetimibe and simvastatin and 0.1% for placebo: the incidence of rhabdomyolysis

(defined as myopathy with a CK greater than 40 times ULN) was 0.09% for ezetimibe and simvastatin

and 0.02% for placebo.

In postmarketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported.

Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe.

However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of

ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibric acid

derivatives. Ezetimibe and simvastatin and a fenofibrate, if taking concomitantly, should both be

immediately discontinued if myopathy is diagnosed or suspected.

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune

myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and

elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy

showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive

agents.

All patients starting therapy with ezetimibe and simvastatin or whose dose of ezetimibe and

simvastatin is being increased should be advised of the risk of myopathy, including

rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or

weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms

persist after discontinuing ezetimibe and simvastatin. Ezetimibe and simvastatin therapy should

be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle

symptoms and CK increases resolved when simvastatin treatment was promptly discontinued. Periodic

CK determinations may be considered in patients starting therapy with ezetimibe and simvastatin or

whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.

Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had

complicated medical histories, including renal insufficiency usually as a consequence of long-standing

diabetes mellitus. Such patients taking ezetimibe and simvastatin merit closer monitoring.

Ezetimibe and simvastatin therapy should be discontinued if markedly elevated CPK levels occur or

myopathy is diagnosed or suspected. Ezetimibe and simvastatin therapy should also be temporarily

withheld in any patient experiencing an acute or serious condition predisposing to the development of

renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe

metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

Drug Interactions

The risk of myopathy and rhabdomyolysis is increased by elevated plasma levels of simvastatin and

simvastatin acid. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs that

inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of

myopathy. These include itraconazole, ketoconazole, posaconazole, and voriconazole, the macrolide

antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease

inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, or

grapefruit juice [See Clinical Pharmacology (12.3)]. Combination of these drugs with ezetimibe and

simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable,

therapy with ezetimibe and simvastatin must be suspended during the course of treatment [see

Contraindications (4) and Drug Interactions (7)].

The combined use of ezetimibe and simvastatin with gemfibrozil, cyclosporine, or danazol is

contraindicated [see Contraindications (4) and Drug Interactions (7.1 and 7.2)].

Caution should be used when prescribing fenofibrates with ezetimibe and simvastatin, as these agents

can cause myopathy when given alone and the risk is increased when they are coadministered [see Drug

Interactions (7.2, 7.7)].

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with

colchicine, and caution should be exercised when prescribing ezetimibe and simvastatin with colchicine

[see Drug Interactions (7.9)].

The benefits of the combined use of ezetimibe and simvastatin with the following drugs should be

carefully weighed against the potential risks of combinations: other lipid-lowering drugs (fenofibrates,

or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or

ranolazine [see Dosage and Administration (2.4) and Drug Interactions (7.3)].

Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered

with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products [see

Drug Interactions (7.4)].

Cases of rhabdomyolysis have been reported with ezetimibe and simvastatin administered with

daptomycin. Temporarily suspend ezetimibe and simvastatin in patients taking daptomycin [see Drug

Interactions (7.10)].

Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage

and Administration (2.3, 2.4), Drug Interactions (7), and Clinical Pharmacology (12.3)].

Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

Interacting Agents

Prescribing Recommendations

Strong CYP3A4 Inhibitors,

e.g.:

Contraindicated with ezetimibe and simvastatin

Itraconazole

Ketoconazole

Posaconazole

Voriconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Boceprevir

Telaprevir

Nefazodone

Cobicistat-containing

products

Gemfibrozil

Cyclosporine

Danazol

Niacin (≥1 g/day)

For Chinese patients, not recommended with ezetimibe and simvastatin

Verapamil

Diltiazem

Dronedarone

Do not exceed 10 mg/10 mg ezetimibe and simvastatin daily

Amiodarone

Amlodipine

Ranolazine

Do not exceed 10 mg/20 mg ezetimibe and simvastatin daily

Lomitapide

For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and

simvastatin daily

Daptomycin

Temporarily suspend ezetimibe and simvastatin

Grapefruit juice

Avoid grapefruit juice

For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or

more) without evidence of muscle toxicity, do not exceed 10 mg/40 mg ezetimibe and simvastatin when

taking lomitapide.

5.2 Liver Enzymes

In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (greater than or

equal to 3 X ULN) in serum transaminases was 1.7% overall for patients treated with ezetimibe and

simvastatin and appeared to be dose-related with an incidence of 2.6% for patients treated with

ezetimibe and simvastatin 10 mg/80 mg. In controlled long-term (48-week) extensions, which included

both newly-treated and previously-treated patients, the incidence of consecutive elevations (greater than

or equal to 3 X ULN) in serum transaminases was 1.8% overall and 3.6% for patients treated

with ezetimibe and simvastatin 10 mg/80 mg. These elevations in transaminases were

generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation

of therapy or with continued treatment.

In SHARP, 9270 patients with chronic kidney disease were allocated to receive ezetimibe and

simvastatin 10 mg/20 mg daily (n=4650), or placebo (n=4620). During a median follow-up period of 4.9

years, the incidence of consecutive elevations of transaminases (greater than 3 X ULN) was 0.7% for

ezetimibe and simvastatin and 0.6% for placebo.

It is recommended that liver function tests be performed before the initiation of treatment with ezetimibe

and simvastatin tablets, and thereafter when clinically indicated. There have been rare postmarketing

reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious

liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with

ezetimibe and simvastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart

ezetimibe and simvastatin. Note that ALT may emanate from muscle, therefore ALT rising with CK may

indicate myopathy [see Warnings and Precautions (5.1)].

Ezetimibe and simvastatin should be used with caution in patients who consume substantial quantities of

alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent

transaminase elevations are contraindications to the use of ezetimibe and simvastatin.

5.3 Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase

inhibitors, including simvastatin.

6 ADVERSE REACTIONS

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

Rhabdomyolysis and myopathy [see Warnings and Precautions (5.1)]

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

6.1 Clinical Trials Experience

Ezetimibe and Simvastatin

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 practice.

In the ezetimibe and simvastatin placebo-controlled clinical trials database of 1420 patients (age range

20 to 83 years, 52% women, 87% Caucasians, 3% Blacks, 5% Hispanics, 3% Asians) with a median

treatment duration of 27 weeks, 5% of patients on ezetimibe and simvastatin and 2.2% of patients on

placebo discontinued due to adverse reactions.

The most common adverse reactions in the group treated with ezetimibe and simvastatin tablets that led

to treatment discontinuation and occurred at a rate greater than placebo were:

Increased ALT (0.9%)

Myalgia (0.6%)

Increased AST (0.4%)

Back pain (0.4%)

The most commonly reported adverse reactions (incidence greater than or equal

to 2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT

(3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%).

Ezetimibe and simvastatin tablets have been evaluated for safety in more than 10,189 patients in clinical

trials.

Table 2 summarizes the frequency of clinical adverse reactions reported in greater than or equal to 2%

of patients treated with ezetimibe and simvastatin (n=1420) and at an incidence greater than placebo,

regardless of causality assessment, from four placebo-controlled trials.

Table 2 : Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe and

Simvastatin and at an Incidence Greater than Placebo, Regardless of Causality

Ezetimibe

Body System/Organ Class

Placebo

10 mg

Simvastatin

Ezetimibe and

Simvastatin

Adverse Reaction

n=371

n=302

n=1234

n=1420

Body as a whole – general disorders

Headache

Gastrointestinal system disorders

Diarrhea

Infections and infestations

Influenza

Upper respiratory tract infection

Musculoskeletal and connective

tissue disorders

Myalgia

Pain in extremity

Includes two placebo-controlled combination studies in which the active ingredients equivalent to

ezetimibe and simvastatin were coadministered and two placebo-controlled studies in which ezetimibe

and simvastatin was administered.

All doses.

Study of Heart and Renal Protection

In SHARP, 9270 patients were allocated to ezetimibe and simvastatin 10 mg/20 mg daily (n=4650) or

placebo (n=4620) for a median follow-up period of 4.9 years. The proportion of patients who

permanently discontinued study treatment as a result of either an adverse event or abnormal safety blood

result was 10.4% vs. 9.8% among patients allocated to ezetimibe and simvastatin and placebo,

respectively. Comparing those allocated to ezetimibe and simvastatin vs. placebo, the incidence of

myopathy (defined as unexplained muscle weakness or pain with a serum CK greater than 10 times ULN)

was 0.2% vs. 0.1% and the incidence of rhabdomyolysis (defined as myopathy with a CK greater than

40 times ULN) was 0.09% vs. 0.02%, respectively. Consecutive elevations of transaminases (greater

than 3 X ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of

unexplained muscle pain or weakness at each study visit: 21.5% vs. 20.9% patients ever reported muscle

symptoms in the ezetimibe and simvastatin and placebo groups, respectively. Cancer was diagnosed

during the trial in 9.4% vs. 9.5% of patients assigned to ezetimibe and simvastatin and placebo,

respectively.

Ezetimibe

Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality

assessment: Musculoskeletal system disorders: arthralgia; Infections and infestations: sinusitis; Body as a

whole – general disorders: fatigue.

Simvastatin

In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with

simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle

weakness or pain with a serum creatine kinase [CK] greater than 10 times upper limit of normal [ULN])

in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The

incidence of rhabdomyolysis (defined as myopathy with a CK greater than 40 times ULN) in patients on

80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of

myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased

during the subsequent years of treatment. In this trial, patients were carefully monitored and some

interacting medicinal products were excluded.

Other adverse reactions reported with simvastatin in placebo-controlled clinical studies, regardless of

causality assessment: Cardiac disorders: atrial fibrillation; Ear and labyrinth disorders: vertigo;

Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, flatulence, gastritis; Skin and

subcutaneous tissue disorders: eczema, rash; Endocrine disorders: diabetes mellitus; Infections and

infestations: bronchitis, sinusitis, urinary tract infections; Body as a whole – general disorders: asthenia,

edema/swelling; Psychiatric disorders: insomnia.

Laboratory Tests

*

Marked persistent increases of hepatic serum transaminases have been noted [see Warnings and

Precautions (5.2)]. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported.

About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value

on one or more occasions. This was attributable to the noncardiac fraction of CK [see Warnings and

Precautions (5.1)].

6.2 Postmarketing Experience

Because the below reactions 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 adverse reactions have been reported in postmarketing experience for ezetimibe and

simvastatin or ezetimibe or simvastatin: pruritus; alopecia; erythema multiforme; a variety of skin

changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails);

dizziness; muscle cramps; myalgia; arthralgia; pancreatitis; paresthesia; peripheral neuropathy; vomiting;

nausea; anemia; erectile dysfunction; interstitial lung disease; myopathy/rhabdomyolysis [see Warnings

and Precautions (5.1)]; hepatitis/jaundice; fatal and non-

fatal hepatic failure; depression; cholelithiasis; cholecystitis; thrombocytopenia; elevations in liver

transaminases; elevated creatine phosphokinase.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see

Warnings and Precautions (5.1)].

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria have been reported.

In addition, an apparent hypersensitivity syndrome has been reported rarely that has included one

or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome,

polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic

anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia,

photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema

multiforme, including Stevens-Johnson syndrome.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness,

amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been

reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation,

with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

7 DRUG INTERACTIONS

[See Clinical Pharmacology (12.3)].

Ezetimibe and Simvastatin

7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol

Strong CYP3A4 inhibitors: The risk of myopathy is increased by reducing the elimination of the

simvastatin component of ezetimibe and simvastatin. Hence when ezetimibe and simvastatin is used with

an inhibitor of CYP3A4 (e.g., as listed below), elevated plasma levels of HMG-CoA reductase

inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of

ezetimibe and simvastatin [See Warnings and Precautions (5.1) and Clinical Pharmacology

(12.3)]. Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is

contraindicated [see Contraindications (4)]. If treatment with itraconazole, ketoconazole, posaconazole,

voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with ezetimibe and

simvastatin must be suspended during the course of treatment.

Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant

administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated

[see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone

Gemfibrozil: Contraindicated with ezetimibe and simvastatin [see Contraindications (4) and Warnings and

Precautions (5.1)].

Fenofibrates (e.g., fenofibrate and fenofibric acid): Caution should be used when prescribing

with ezetimibe and simvastatin [see Warnings and Precautions (5.1) and Drug Interactions (7.7)].

7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers

The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of

amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem or

amlodipine [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) and Table 6 in

Clinical Pharmacology (12.3)].

7.4 Niacin

Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-

modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products. The risk of

myopathy is greater in Chinese patients. In a clinical trial (median follow-up 3.9 years) involving

patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40

mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular

outcomes with the addition of lipid-modifying doses (greater than or equal to 1 g/day) of niacin.

Coadministration of ezetimibe and simvastatin with lipid-modifying doses (greater than or equal to 1

g/day) of niacin is not recommended in Chinese patients. It is unknown if this risk applies to other Asian

patients [see Warnings and Precautions (5.1) and Use in Specific Populations (8.8)].

7.5 Cholestyramine

Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe

approximately 55%. The incremental LDL-C reduction due to adding ezetimibe and simvastatin to

cholestyramine may be reduced by this interaction.

7.6 Digoxin

In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in

plasma digoxin concentrations. Patients taking digoxin should be monitored appropriately when

ezetimibe and simvastatin is initiated.

7.7 Fenofibrates (e.g., fenofibrate and fenofibric acid)

The safety and effectiveness of ezetimibe and simvastatin administered with fibrates have not been

established. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase

inhibitors is increased with concurrent administration of fenofibrates, ezetimibe and simvastatin should

be administered with caution when used concomitantly with a fenofibrate [see Warnings and Precautions

(5.1)].

Fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical

study in dogs, ezetimibe increased cholesterol in the gallbladder bile [see Animal Toxicology and/or

Pharmacology (13.2)]. If cholelithiasis is suspected in a patient receiving ezetimibe and simvastatin and a

fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be

considered [see the product labeling for fenofibrate and fenofibric acid].

7.8 Coumarin Anticoagulants

Simvastatin 20 to 40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin

time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from

2.6 to 3.4 in a normal volunteer study and in a hypercholesterolemic patient study, respectively. With

other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few

patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be

determined before starting ezetimibe and simvastatin and frequently enough during early therapy to

ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has

been documented, prothrombin times can be monitored at the intervals usually recommended for patients

on coumarin anticoagulants. If the dose of ezetimibe and simvastatin is changed or discontinued, the

same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with

changes in prothrombin time in patients not taking anticoagulants.

Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability

of warfarin and prothrombin time in a study of twelve healthy adult males. There have been

postmarketing reports of increased INR in patients who had ezetimibe added to warfarin. Most of these

patients were also on other medications.

The effect of ezetimibe and simvastatin on the prothrombin time has not been studied.

7.9 Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with

colchicine, and caution should be exercised when prescribing ezetimibe and simvastatin with

colchicine.

7.10 Daptomycin

Cases of rhabdomyolysis have been reported with ezetimibe and simvastatin administered with

daptomycin. Both ezetimibe and simvastatin and daptomycin can cause myopathy and rhabdomyolysis

when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration.

Temporarily suspend ezetimibe and simvastatin in patients taking daptomycin [see Warnings and

Precautions (5.1)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X.

[See Contraindications (4).]

Ezetimibe and Simvastatin

Ezetimibe and simvastatin is contraindicated in women who are or may become pregnant. Lipid-lowering

drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed

for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-

lowering drugs during pregnancy should have little impact on long-term outcomes of primary

hypercholesterolemia therapy. There are no adequate and well-controlled studies of ezetimibe and

simvastatin use during pregnancy; however, there are rare reports of congenital anomalies in infants

exposed to statins in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no

evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and

cholesterol or cholesterol derivatives are essential for fetal development. Because statins, such as

simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active

substances derived from cholesterol, ezetimibe and simvastatin may cause fetal harm when administered

to a pregnant woman. If ezetimibe and simvastatin is used during pregnancy or if the patient becomes

pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing potential, who require ezetimibe and simvastatin treatment for a lipid disorder,

should be advised to use effective contraception. For women trying to conceive, discontinuation of

ezetimibe and simvastatin should be considered. If pregnancy occurs, ezetimibe and simvastatin should

be immediately discontinued.

Ezetimibe

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 times the

human exposure at 10 mg daily based on AUC

for total ezetimibe). In rabbits treated with

ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the

human exposure at 10 mg daily based on

for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were

given multiple oral doses.

Multiple-dose studies of ezetimibe coadministered with statins in rats and rabbits during organogenesis

result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in

coadministration therapy compared to monotherapy.

Simvastatin

Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted

in 3 times the human exposure based on mg/m surface area. However, in studies with another

structurally-related statin, skeletal malformations were observed in rats and mice.

There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review

of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another

structurally-related statin, the incidences of congenital anomalies, spontaneous abortions and fetal

deaths/stillbirths did not exceed what would be expected in the general population. The number of cases

is adequate only to exclude a 3- to 4-fold increase in congenital anomalies over the background

incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to

pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

8.3 Nursing Mothers

It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in

this class is excreted in human milk and because of the potential for serious adverse reactions in nursing

infants, women taking simvastatin should not nurse their infants. A decision should be made whether to

discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother

[see Contraindications (4)].

In rat studies, exposure to ezetimibe in nursing pups was up to half of that observed in maternal plasma.

It is not known whether ezetimibe or simvastatin are excreted into human breast milk. Because a small

amount of another drug in the same class as simvastatin is excreted in human milk and because of the

potential for serious adverse reactions in nursing infants, women who are nursing should not take

ezetimibe and simvastatin [see Contraindications (4)].

8.4 Pediatric Use

The effects of ezetimibe coadministered 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% multiracial) with HeFH were randomized to

receive either ezetimibe coadministered 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

to 351 mg/dL) in the ezetimibe coadministered with simvastatin group compared to 219 mg/dL (range:

149 to 336 mg/dL) in the simvastatin monotherapy group. The patients received coadministered

ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40

mg) for 6 weeks, coadministered ezetimibe and 40 mg simvastatin or 40 mg simvastatin monotherapy for

the next 27 weeks, and open-label coadministered 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.

____________________________

Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of

Lovastatin and Simvastatin

Exposure During Pregnancy, Reproductive Toxicology, 10(6):439-446, 1996.

0-24hr

0-24hr

Table 3: Mean Percent Difference at Week 6 Between the Pooled Ezetimibe Coadministered 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%

+0.1%

95% Confidence Interval

(-15%, -9%)

(-18%, -

12%)

(-15%, -

(-17%, -11%) (-9, +4)

(-3, +3)

* For triglycerides, median % change from baseline.

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 coadministered 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

greater than or equal to 3 X ULN) occurred in four (3%) individuals in the ezetimibe coadministered

with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of

CPK (greater than or equal to 10 X ULN) occurred in two (2%) individuals in the ezetimibe

coadministered 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.

Coadministration of ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied in

adolescents. Also, ezetimibe and simvastatin has not been studied in patients younger than 10 years of

age or in pre-menarchal girls.

Ezetimibe

Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide) there are no pharmacokinetic differences

between adolescents and adults. Pharmacokinetic data in the pediatric population less than 10 years of

age are not available.

Simvastatin

The pharmacokinetics of simvastatin has not been studied in the pediatric population.

8.5 Geriatric Use

Of the 10,189 patients who received ezetimibe and simvastatin in clinical studies, 3242 (32%) were 65

and older (this included 844 (8%) who were 75 and older). No overall differences in safety or

effectiveness were observed between these subjects and younger subjects, 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. Since advanced age (greater than or

equal to 65 years) is a predisposing factor for myopathy, ezetimibe and simvastatin should be

prescribed with caution in the elderly [See Clinical Pharmacology (12.3)].

Because advanced age (greater than or equal to 65 years) is a predisposing factor for myopathy,

including rhabdomyolysis, ezetimibe and simvastatin should be prescribed with caution in the elderly. In

a clinical trial of patients treated with simvastatin 80 mg/day, patients greater than or equal to 65 years

of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients less than 65

years of age [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

In the 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 m , 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 and simvastatin 10 mg/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

ezetimibe and simvastatin exceeding 10 mg/20 mg should be used with caution and close monitoring in

patients with moderate to severe renal impairment. [See Dosage and Administration (2.5), Adverse

Reactions (6.1), and Clinical Studies (14.3).]

8.7 Hepatic Impairment

Ezetimibe and simvastatin is contraindicated in patients with active liver disease or unexplained

persistent elevations in hepatic transaminases [See Contraindications (4) and Warnings and Precautions

(5.2)].

8.8 Chinese Patients

In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin

40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non-

Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). The incidence of

myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe and simvastatin 10/40 mg/day

coadministered with extended-release niacin 2 g/day was 1.24%.

Chinese patients may be at higher risk for myopathy, monitor patients appropriately. Coadministration of

ezetimibe and simvastatin with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-

containing products is not recommended in Chinese patients [see Warnings and Precautions (5.1) and

Drug Interactions (7.4)].

10 OVERDOSAGE

Ezetimibe and Simvastatin

No specific treatment of overdosage with ezetimibe and simvastatin can be recommended.

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

Ezetimibe

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40

mg/day to 18 patients with primary hyperlipidemia for up to 56 days, was generally well tolerated.

A few cases of overdosage have been reported; most have not been associated with adverse

experiences. Reported adverse experiences have not been serious.

Simvastatin

Significant lethality was observed in mice after a single oral dose of 9 g/m . No evidence of lethality

was observed in rats or dogs treated with doses of 30 and 100 g/m , respectively. No specific

diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and

mucoid stools.

A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All

patients recovered without sequelae.

The dialyzability of simvastatin and its metabolites in man is not known at present.

11 DESCRIPTION

Ezetimibe and Simvastatin Tablets contain ezetimibe, USP, a selective inhibitor of intestinal cholesterol

and related phytosterol absorption, and simvastatin, USP, an HMG-CoA reductase inhibitor.

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 molecular formula is C

H F NO and its

molecular weight is 409.4.

Ezetimibe, USP is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and

acetone and practically insoluble in water. Its structural formula is:

Simvastatin, USP an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form, which is

an inhibitor of HMG-CoA reductase. Simvastatin, USP is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-

hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester,

[1S-[1α,3α,7β,8β(2S*,4S*),-8aβ]]. The molecular formula of simvastatin, USP is C

H O and its

molecular weight is 418.57.

Simvastatin, USP is a white to off-white, nonhygroscopic, crystalline powder that is practically

insoluble in water and freely soluble in chloroform, methanol and ethanol. Its structural formula is:

Ezetimibe and simvastatin is available for oral use as tablets containing 10 mg of ezetimibe USP, and 10

mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/10 mg), 20 mg of simvastatin, USP

(ezetimibe and simvastatin tablets 10 mg/20 mg), 40 mg of simvastatin, USP (ezetimibe and simvastatin

tablets 10 mg/40 mg), or 80 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/80 mg).

Each tablet contains the following inactive ingredients: ascorbic acid, butylated hydroxyanisole, citric

acid anhydrous, croscarmellose sodium, hypromellose, iron oxide black, iron oxide red, iron oxide

yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and propyl gallate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ezetimibe and Simvastatin

Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and

simvastatin contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary

mechanisms of action. Ezetimibe and simvastatin reduces elevated total-C, LDL-C, Apo B, TG, and non-

HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis.

Ezetimibe

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. 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 and did not impair adrenocortical steroid hormone

production.

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 [see Clinical Studies (14)].

Simvastatin

Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after

administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-

CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate

limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces very-low-

density lipoproteins (VLDL) and TG and increases HDL-C.

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

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.

12.3 Pharmacokinetics

The results of a bioequivalence study in healthy subjects demonstrated that the ezetimibe and simvastatin

10 mg/10 mg to 10 mg/80 mg combination tablets are bioequivalent to coadministration of

corresponding doses of ezetimibe (ZETIA ) and simvastatin (ZOCOR ) as individual tablets.

Absorption

Ezetimibe

After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically

active phenolic glucuronide (ezetimibe-glucuronide).

Simvastatin

The availability of the β-hydroxyacid to the systemic circulation following an oral dose of simvastatin

was found to be less than 5% of the dose, consistent with extensive hepatic first-pass extraction.

Effect of Food on Oral Absorption

Ezetimibe

Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of

ezetimibe when administered as 10-mg tablets. The C

value of ezetimibe was increased by 38% with

consumption of high-fat meals.

Simvastatin

Relative to the fasting state, the plasma profiles of both active and total inhibitors of HMG-CoA

reductase were not affected when simvastatin was administered immediately before an American Heart

Association recommended low-fat meal.

Distribution

Ezetimibe

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

Simvastatin

Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human

plasma proteins. When radiolabeled simvastatin was administered to rats, simvastatin-derived

radioactivity crossed the blood-brain barrier.

Metabolism and Excretion

Ezetimibe

Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with

subsequent biliary and renal excretion. Minimal oxidative metabolism 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

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.

Simvastatin

Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent

inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is a basis for an assay in

pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base

hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of

simvastatin. The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid

of simvastatin and its 6’-hydroxy, 6’-hydroxymethyl, and 6’-exomethylene derivatives.

Following an oral dose of

C-labeled simvastatin in man, 13% of the dose was excreted in urine and

60% in feces. Plasma concentrations of total radioactivity (simvastatin plus

C-metabolites) peaked at 4

hours and declined rapidly to about 10% of peak by 12 hours postdose.

Specific Populations

Geriatric Patients

Ezetimibe

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 (greater than or equal to 65 years) healthy subjects

compared to younger subjects.

Simvastatin

In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin 40

mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately

45% compared with 18 patients between 18 to 30 years of age.

Pediatric Patients: [See Pediatric Use (8.4)].

Gender

Ezetimibe

In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for

total ezetimibe were slightly higher (less than 20%) in women than in men.

Race

Ezetimibe

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 was similar to those seen in Caucasian subjects.

Hepatic Impairment

Ezetimibe

After a single 10-mg dose of ezetimibe, the mean exposure (based on area under the curve [AUC]) to

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 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 for total

ezetimibe and ezetimibe increased approximately 4-fold compared to healthy subjects.

Renal Impairment

Ezetimibe

After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl less than

or equal to 30 mL/min/1.73 m ), the mean AUC for total ezetimibe and ezetimibe

increased approximately 1.5-fold, compared to healthy subjects (n=9).

Simvastatin

Pharmacokinetic studies with another statin having a similar principal route of elimination to that of

simvastatin have suggested that for a given dose level higher systemic exposure may be achieved in

patients with severe renal impairment (as measured by creatinine clearance).

Drug Interactions [See also Drug Interactions (7)]

No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with

simvastatin. No specific pharmacokinetic drug interaction studies with ezetimibe and simvastatin have

been conducted other than the following study with NIASPAN (Niacin extended-release tablets).

Niacin: The effect of ezetimibe and simvastatin (10 mg/20 mg daily for 7 days) on the pharmacokinetics

of NIASPAN extended-release tablets (1000 mg for 2 days and 2000 mg for 5 days following a low-fat

breakfast) was studied in healthy subjects. The mean C

and AUC of niacin increased 9% and 22%,

respectively. The mean C

and AUC of nicotinuric acid increased 10% and 19%, respectively

(N=13). In the same study, the effect of NIASPAN on the pharmacokinetics of ezetimibe and simvastatin

was evaluated (N=15). While concomitant NIASPAN decreased the mean C

of total ezetimibe (1%),

and simvastatin (2%), it increased the mean C

of simvastatin acid (18%). In addition, concomitant

NIASPAN increased the mean AUC of total ezetimibe (26%), simvastatin (20%), and simvastatin acid

(35%).

Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-

modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products [See Warnings

and Precautions (5.1) and Drug Interactions (7.4)].

Cytochrome P450: 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.

In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the

probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates

that simvastatin is not an inhibitor of CYP3A4 and, therefore, is not expected to affect the plasma levels

of other drugs metabolized by CYP3A4.

Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of

medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma

concentrations of simvastatin acid and an increased risk of myopathy. For example, cyclosporine has

been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase

in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1.

Simvastatin is a substrate for CYP3A4. Inhibitors of CYP3A4 can raise the plasma levels of HMG-

CoA reductase inhibitory activity and increase the risk of myopathy [See Warnings and Precautions (5.1);

Drug Interactions (7.1)].

Ezetimibe

Table 4: Effect of Coadministered Drugs on Total Ezetimibe

Coadministered Drug and Dosing Regimen

Total Ezetimibe

Change in AUC

Change in C

Cyclosporine-stable dose required (75 to 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 m ) who was

receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to

*

max

†,

total

ezetimibe compared to healthy subjects.

See 7. Drug Interactions.

Supralox, 20 mL.

Table 5: Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs

Coadministered Drug and its

Ezetimibe Dosage

Change in AUC

Change in C

Dosage Regimen

Regimen

of Coadministered Drug

of Coadministered Drug

Warfarin, 25 mg single dose on

10 mg QD, 11 days

↓2% (R-warfarin)

↑3% (R-warfarin)

Day 7

↓4% (S-warfarin)

↑1% (S-warfarin)

Digoxin, 0.5 mg single dose

10 mg QD, 8 days

↑2%

↓7%

Gemfibrozil, 600 mg BID,

10 mg QD, 7 days

↓1%

↓11%

7 days*

Ethinyl estradiol &

10 mg QD, Days 8-14 of

Ethinyl estradiol

Ethinyl estradiol

Levonorgestrel, QD, 21 days

21 day oral contraceptive

↓9%

cycle

Levonorgestrel

Levonorgestrel

↓ 5%

Glipizide, 10 mg on Days 1

10 mg QD, Days 2-9

↓3%

↓5%

and 9

Fenofibrate, 200 mg QD,

10 mg QD, 14 days

↑11%

↑7%

14 days

Cyclosporine, 100 mg single

20 mg QD, 8 days

↑15%

↑10%

dose Day 7*

Statins

Lovastatin 20 mg QD,

10 mg QD, 7 days

↑19%

↑3%

7 days

Pravastatin 20 mg QD,

10 mg QD, 14 days

↓20%

↓24%

14 days

Atorvastatin 10 mg QD,

10 mg QD, 14 days

↓4%

↑ 7%

14 days

Rosuvastatin 10 mg QD,

10 mg QD, 14 days

↑19%

↑17%

14 days

Fluvastatin 20 mg QD,

10 mg QD, 14 days

↓39%

↓27%

14 days

See 7. Drug Interactions.

Simvastatin

Table 6: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure

Coadministered

Drug or Grapefruit

Juice

Dosing of

Coadministered Drug

or Grapefruit Juice

Dosing of

Simvas tatin

Geometric Mean Ratio (Ratio with /

without coadministered drug) No

Effect = 1.00

AUC

C

Contraindicated with ezetimibe and simvastatin [see Contraindications (4) and Warnings and

Precautions (5.1)]

Telithromycin

200 mg QD for 4 days

80 mg

simvastatin

acid

simvastatin

Nelfinavir

1250 mg BID for

14 days

20 mg QD

28 days

simvastatin

acid

simvastatin

Itraconazole

200 mg QD for 4 days

80 mg

simvastatin

acid

simvastatin

13.1

13.1

Posaconazole

100 mg (oral suspension)

QD for 13 days

200 mg (oral suspension)

QD for 13 days

40 mg

40 mg

simvastatin

acid

simvastatin

simvastatin

acid

simvastatin

10.3

10.6

11.4

Gemfibrozil

600 mg BID for 3 days

40 mg

simvastatin

acid

simvastatin

2.85

1.35

2.18

0.91

Avoid grapefruit juice with ezetimibe and simvastatin [see Warnings and Precautions (5.1)]

simvastatin

max

max

Grapefruit Juice

(high dose)

200 mL of double-

strength TID

60 mg single

dose

acid

simvastatin

Grapefruit Juice

(low dose)

8 oz (about 237 mL) of

single-strength

20 mg single

dose

simvastatin

acid

simvastatin

Avoid taking with >10 mg/10 mg ezetimibe and simvastatin, based on clinical and/or postmarketing

simvastatin experience [see Warnings and Precautions (5.1)]

Verapamil SR

240 mg QD Days 1-7

then 240 mg BID on Days

8-10

80 mg on

Day 10

simvastatin

acid

simvastatin

Diltiazem

120 mg BID for 10 days

80 mg on

Day 10

simvastatin

acid

simvastatin

2.69

3.10

2.69

2.88

Diltiazem

120 mg BID for 14 days

20 mg on

Day 14

simvastatin

Dronedarone

400 mg BID for 14 days

40 mg QD

for 14 days

simvastatin

acid

simvastatin

1.96

3.90

2.14

3.75

Avoid taking with >10 mg/20 mg ezetimibe and simvastatin, based on clinical and/or postmarketing

simvastatin experience [see Warnings and Precautions (5.1)]

Amiodarone

400 mg QD for 3 days

40 mg on

Day 3

simvastatin

acid

simvastatin

1.75

1.76

1.72

1.79

Amlodipine

10 mg QD for 10 days

80 mg on

Day 10

simvastatin

acid

simvastatin

1.58

1.77

1.56

1.47

Ranolazine SR

1000 mg BID for 7 days

80 mg on

Day 1 and

Days 6-9

simvastatin

acid

simvastatin

2.26

1.86

2.28

1.75

Avoid taking with >10 mg/20 mg ezetimibe and simvastatin (or 10 mg/40 mg for patients who

have previously taken 80 mg simvastatin chronically, e.g., for 12 months or more, without

evidence of muscle toxicity), based on clinical experience

Lomitapide

60 mg QD for 7 days

40 mg single

dose

simvastatin

acid

simvastatin

Lomitapide

10 mg QD for 7 days

20 mg single

dose

simvastatin

acid

simvastatin

No dosing adjustments required for the following:

Fenofibrate

160 mg QD for 14 days

80 mg QD

Days 8-14

simvastatin

acid

simvastatin

0.64

0.89

0.89

0.83

Propranolol

80 mg single dose

80 mg single

dose

total

inhibitor

active

inhibitor

0.79

0.79

↓ from 33.6 to 21.1

ng·eq/mL

↓from 7.0 to 4.7

ng·eq/mL

Results based on a chemical assay except results with propranolol as indicated.

Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin,

clarithromycin, HIV protease inhibitors, and nefazodone.

Simvastatin acid refers to the β-hydroxyacid of simvastatin.

The effect of amounts of grapefruit juice between those used in these two studies on simvastatin

pharmacokinetics has not been studied.

Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was

administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes

following single dose simvastatin on Day 3.

Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was

administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Ezetimibe and Simvastatin

No animal carcinogenicity or fertility studies have been conducted with the combination of ezetimibe

and simvastatin. The combination of ezetimibe with simvastatin did not show evidence of mutagenicity 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 ezetimibe and simvastatin with or without

metabolic activation. There was no evidence of genotoxicity at doses up to 600 mg/kg with the

combination of ezetimibe and simvastatin (1:1) in the in vivo mouse micronucleus test.

Ezetimibe

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 times the human exposure at 10 mg daily based on

for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also

conducted in mice at doses up to 500 mg/kg/day (greater than 150 times the human exposure at 10 mg

daily based on AUC

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 times the human exposure at 10 mg

daily based on AUC

for total ezetimibe).

Simvastatin

In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100,

and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times

higher than the mean human plasma drug level, respectively, (as total inhibitory activity based on AUC)

after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid-

and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the

liver was significantly increased in mid- and high-dose females. Drug treatment also significantly

increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the

Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in

controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.

In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a

tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80

mg simvastatin as measured by AUC).

In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence

of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of

simvastatin than in humans given 80 mg simvastatin (as measured by AUC).

A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced

hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day).

Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular

cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid

neoplasms appears to be consistent with findings from other statins. These treatment levels represented

plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the

mean human plasma drug exposure after an 80-mg daily dose.

No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat

or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in

an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an

in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in

mouse bone marrow.

There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body

weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day);

however, this effect was not observed during a subsequent fertility study in which simvastatin was

administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis

including epididymal maturation). No microscopic changes were observed in the testes of rats from

either study. At 180 mg/kg/day (which produces exposure levels 22 times higher than those in humans

taking 80 mg/day based on surface area, mg/m ), seminiferous tubule degeneration (necrosis and loss of

spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased

spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day (approximately 2

times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is

unclear.

13.2 Animal Toxicology and/or Pharmacology

CNS Toxicity

Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at

0-24hr

0-24hr

0-24hr

180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean

plasma drug level in humans taking 80 mg/day.

A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration

of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60

mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma

drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory

activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal

ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a

mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell

infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were

seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug

levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day.

Similar CNS vascular lesions have been observed with several other drugs of this class.

There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25

times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19

times) and at two years at 50 mg/kg/day (5 times).

Ezetimibe

The hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed Rhesus monkeys, dogs,

rats, and mouse models of human cholesterol metabolism. Ezetimibe was found to have an ED value

of 0.5 μg/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED values in

dogs, rats, and mice were 7, 30, and 700 μg/kg/day, respectively. These results are consistent with

ezetimibe being a potent cholesterol absorption inhibitor.

In a rat model, where the glucuronide metabolite of ezetimibe (ezetimibe-glucuronide) was administered

intraduodenally, the metabolite was as potent as ezetimibe in inhibiting the absorption of cholesterol,

suggesting that the glucuronide metabolite had activity similar to the parent drug.

In 1-month studies in dogs given ezetimibe (0.03 to 300 mg/kg/day), the concentration of cholesterol in

gallbladder bile increased ~2- to 4-fold. However, a dose of 300 mg/kg/day administered to dogs for

one year did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day

study in mice given ezetimibe (0.3 to 5 mg/kg/day) and fed a low-fat or cholesterol-rich diet, the

concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels,

respectively.

A series of acute preclinical studies was performed to determine the selectivity of ezetimibe for

inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of

C-cholesterol with no effect

on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-

soluble vitamins A and D.

In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug-metabolizing

enzymes. In toxicity studies, a pharmacokinetic interaction of ezetimibe with statins (parents or their

active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.

14 CLINICAL STUDIES

14.1 Primary Hyperlipidemia

Ezetimibe and Simvastatin

Ezetimibe and simvastatin reduces total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C

in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks

and maintained during chronic therapy.

Ezetimibe and simvastatin is effective in men and women with hyperlipidemia. Experience in non-

Caucasians is limited and does not permit a precise estimate of the magnitude of the effects of ezetimibe

and simvastatin.

Five multicenter, double-blind studies conducted with either ezetimibe and simvastatin or

coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin in patients with primary

hyperlipidemia are reported: two were comparisons with simvastatin, two were comparisons with

atorvastatin, and one was a comparison with rosuvastatin.

In a multicenter, double-blind, placebo-controlled, 12-week trial, 1528 hyperlipidemic patients were

randomized to one of ten treatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg, 20 mg, 40

mg, or 80 mg), or ezetimibe and simvastatin (10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, or 10 mg/80

mg).

When patients receiving ezetimibe and simvastatin were compared to those receiving all doses of

simvastatin, ezetimibe and simvastatin significantly lowered total-C, LDL-C, Apo B, TG, and non-HDL-

C. The effects of ezetimibe and simvastatin on HDL-C were similar to the effects seen with simvastatin.

Further analysis showed ezetimibe and simvastatin significantly increased HDL-C compared with

placebo. (See Table 7.) The lipid response to ezetimibe and simvastatin was similar in patients with TG

levels greater than or less than 200 mg/dL.

Table 7: Response to Ezetimibe and Simvastatin in Patients with Primary Hyperlipidemia (Mean

% Change from Untreated Baseline )

*

Treatment

(Daily Dose)

Total-C

LDL-C

Apo B

HDL-C

Non-HDL-

Pooled data (All

ezetimibe and

simvastatin doses)

Pooled data (All

simvastatin doses)

Ezetimibe 10 mg

Placebo

Ezetimibe and

simvastatin by

dose

10 mg/10 mg

10 mg/20 mg

10 mg/40 mg

10 mg/80 mg

Simvastatin by

dose

10 mg

20 mg

40 mg

80 mg

For triglycerides, median % change from baseline.

Baseline - on no lipid-lowering drug.

Ezetimibe and simvastatin doses pooled (10 mg/10 mg to 10 mg/80 mg) significantly reduced total-C,

LDL-C, Apo B, TG, and non-HDL-C compared to simvastatin and significantly increased HDL-C

compared to placebo.

In a multicenter, double-blind, controlled, 23-week study, 710 patients with known CHD or CHD risk

equivalents, as defined by the NCEP ATP III guidelines, and an LDL-C greater than or equal to 130

mg/dL were randomized to one of four treatment groups: coadministered ezetimibe and simvastatin

equivalent to ezetimibe and simvastatin (10 mg/10 mg, 10 mg/20 mg, and 10 mg/40 mg) or simvastatin 20

mg. Patients not reaching an LDL-C less than 100 mg/dL had their simvastatin dose titrated at 6-week

intervals to a maximal dose of 80 mg.

At Week 5, the LDL-C reductions with ezetimibe and simvastatin 10 mg/10 mg, 10 mg/20 mg, or 10

mg/40 mg were significantly larger than with simvastatin 20 mg (see Table 8).

Table 8: Response to Ezetimibe and Simvastatin after 5 Weeks in Patients with CHD or CHD

Risk Equivalents and an LDL-C ≥130 mg/dL

Simvastatin

Ezetimibe and

Simvastatin

Ezetimibe and

Simvastatin

Ezetimibe and

Simvastatin

20 mg

10 mg/10 mg

10 mg/20 mg

10 mg/40 mg

Mean baseline

LDL-C

Percent change

LDL-C

In a multicenter, double-blind, 6-week study, 1902 patients with primary hyperlipidemia, who had not

met their NCEP ATP III target LDL-C goal, were randomized to one of eight treatment groups:

ezetimibe and simvastatin (10 mg/10 mg, 10 mg/20 mg, or 10 mg/40 mg, or 10 mg/80 mg) or atorvastatin

(10 mg, 20 mg, 40 mg, or 80 mg).

Across the dosage range, when patients receiving ezetimibe and simvastatin were compared to those

receiving milligram-equivalent statin doses of atorvastatin, ezetimibe and simvastatin lowered total-C,

LDL-C, Apo B, and non-HDL-C significantly more than atorvastatin. Only the 10 mg/40 mg and 10

mg/80 mg ezetimibe and simvastatin doses increased HDL-C significantly more than the corresponding

milligram-equivalent statin dose of atorvastatin. The effects of ezetimibe and simvastatin on TG were

similar to the effects seen with atorvastatin (See Table 9).

Table 9: Response to Ezetimibe and Simvastatin and Atorvastatin in Patients with Primary

Hyperlipidemia (Mean % Change from Untreated Baseline )

Treatment

(Daily Dose)

Total-C

LDL-C

Apo B

HDL-C

Non-HDL-

Ezetimibe and

simvastatin by

dose

*

10 mg/10 mg

10 mg/20 mg

10 mg/40 mg

10 mg/80 mg

Atorvastatin by

dose

10 mg

20 mg

40 mg

80 mg

For triglycerides, median % change from baseline.

Baseline - on no lipid-lowering drug.

Ezetimibe and simvastatin doses pooled (10 mg/10 mg to 10 mg/80 mg) provided significantly greater

reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to atorvastatin doses pooled (10 mg to

80 mg).

p<0.05 for difference with atorvastatin at equal mg doses of the simvastatin component.

In a multicenter, double-blind, 24-week, forced-titration study, 788 patients with primary

hyperlipidemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to receive

coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin (10 mg/10 mg and 10

mg/20 mg) or atorvastatin 10 mg. For all three treatment groups, the dose of the statin was titrated at 6-

week intervals to 80 mg. At each pre-specified dose comparison, ezetimibe and simvastatin lowered

LDL-C to a greater degree than atorvastatin (see Table 10).

Table 10: Response to Ezetimibe and Simvastatin and Atorvastatin in Patients with Primary

Hyperlipidemia (Mean % Change from Untreated Baseline )

Treatment

Total-C

LDL-C

Apo B

HDL-C

Non-HDL-

Week 6

Atorvastatin 10 mg

Ezetimibe and

simvastatin 10 mg/10

Ezetimibe and

simvastatin 10 mg/20

Week 12

Atorvastatin 20 mg

Ezetimibe and

simvastatin 10 mg/20

Ezetimibe and

simvastatin 10 mg/40

Week 18

Atorvastatin 40 mg

Ezetimibe and

simvastatin 10 mg/40

Week 24

Atorvastatin 80 mg

Ezetimibe and

simvastatin 10 mg/80

For triglycerides, median % change from baseline.

Baseline - on no lipid-lowering drug.

Atorvastatin: 10 mg start dose titrated to 20 mg, 40 mg, and 80 mg through Weeks 6, 12, 18, and 24.

Ezetimibe and simvastatin: 10 mg/10 mg start dose titrated to 10 mg/20 mg, 10 mg/40 mg, and 10 mg/80

mg through Weeks 6, 12, 18, and 24.

p≤0.05 for difference with atorvastatin in the specified week.

Ezetimibe and simvastatin: 10 mg/20 mg start dose titrated to 10 mg/40 mg, 10 mg/40 mg, and 10

mg/80 mg through Weeks 6, 12, 18, and 24.

Data pooled for common doses of ezetimibe and simvastatin at Weeks 18 and 24.

In a multicenter, double-blind, 6-week study, 2959 patients with primary hyperlipidemia, who had not

met their NCEP ATP III target LDL-C goal, were randomized to one of six treatment groups: ezetimibe

and simvastatin (10 mg/20 mg, 10 mg/40 mg, or 10 mg/80 mg) or rosuvastatin (10 mg, 20 mg, or 40 mg).

The effects of ezetimibe and simvastatin and rosuvastatin on total-C, LDL-C, Apo B, TG, non-HDL-C

and HDL-C are shown in Table 11.

*

Table 11: Response to Ezetimibe and Simvastatin and Rosuvastatin in Patients with Primary

Hyperlipidemia (Mean % Change from Untreated Baseline )

Treatment

(Daily Dose)

Total-C

LDL-C

Apo B

HDL-C

Non-HDL-

Ezetimibe and

simvastatin by dose

10 mg/20 mg

10 mg/40 mg

10 mg/80 mg

Rosuvastatin by

dose

10 mg

20 mg

40 mg

For triglycerides, median % change from baseline.

Baseline - on no lipid-lowering drug.

Ezetimibe and simvastatin doses pooled (10 mg/20 mg to 10 mg/80 mg) provided significantly greater

reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to rosuvastatin doses pooled (10 mg to

40 mg).

p<0.05 vs. rosuvastatin 10 mg.

p<0.05 vs. rosuvastatin 20 mg.

p<0.05 vs. rosuvastatin 40 mg.

In a multicenter, double-blind, 24-week trial, 214 patients with type 2 diabetes mellitus treated with

thiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3 months and simvastatin 20 mg for

a minimum of 6 weeks were randomized to receive either simvastatin 40 mg or the coadministered

active ingredients equivalent to ezetimibe and simvastatin 10 mg/20 mg. The median LDL-

C and HbA1c levels at baseline were 89 mg/dL and 7.1%, respectively.

Ezetimibe and simvastatin 10 mg/20 mg was significantly more effective than doubling the dose of

simvastatin to 40 mg. The median percent changes from baseline for ezetimibe and simvastatin vs.

simvastatin were: LDL-C -25% and -5%; total-C -16% and -5%; Apo B -19% and -5%; and non-HDL-C

-23% and -5%. Results for HDL-C and TG between the two treatment groups were not significantly

different.

Ezetimibe

In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary

hyperlipidemia, ezetimibe significantly lowered total-C (-13%), LDL-C (-19%), Apo B (-14%), and TG

(-8%), and increased HDL-C (+3%) compared to placebo. Reduction in LDL-C was consistent across

age, sex, and baseline LDL-C.

Simvastatin

In two large, placebo-controlled clinical trials, the Scandinavian Simvastatin Survival Study (N=4,444

patients) and the Heart Protection Study (N=20,536 patients), the effects of treatment with simvastatin

were assessed in patients at high risk of coronary events because of existing coronary heart disease,

diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease. Simvastatin was

proven to reduce: the risk of total mortality by reducing CHD deaths; the risk of non-fatal myocardial

infarction and stroke; and the need for coronary and non-coronary revascularization procedures.

No incremental benefit of ezetimibe and simvastatin on cardiovascular morbidity and mortality over and

above that demonstrated for simvastatin has been established.

14.2 Homozygous Familial Hypercholesterolemia (HoFH)

A double-blind, randomized, 12-week study was performed in patients with a clinical and/or genotypic

diagnosis of HoFH. Data were analyzed from a subgroup of patients (n=14) receiving simvastatin 40 mg

at baseline. Increasing the dose of simvastatin from 40 to 80 mg (n=5) produced a reduction of LDL-C

of 13% from baseline on simvastatin 40 mg. Coadministered ezetimibe and simvastatin equivalent to

ezetimibe and simvastatin (10 mg/40 mg and 10 mg/80 mg pooled, n=9), produced a reduction of LDL-C

of 23% from baseline on simvastatin 40 mg. In those patients coadministered ezetimibe and simvastatin

equivalent to ezetimibe and simvastatin (10 mg/80 mg, n=5), a reduction of LDL-C of 29% from baseline

on simvastatin 40 mg was produced.

14.3 Chronic Kidney Disease (CKD)

The Study of Heart and Renal Protection (SHARP) was a multinational, randomized, placebo-controlled,

double-blind trial that investigated the effect of ezetimibe and simvastatin on the time to a first major

vascular event (MVE) among 9438 patients with moderate to severe chronic kidney disease

(approximately one-third on dialysis at baseline) who did not have a history of myocardial infarction or

coronary revascularization. An MVE was defined as nonfatal MI, cardiac death, stroke, or any

revascularization procedure. Patients were allocated to treatment using a method that took into account

the distribution of 8 important baseline characteristics of patients already enrolled and minimized the

imbalance of those characteristics across the groups.

*

For the first year, 9438 patients were allocated 4:4:1, to ezetimibe and simvastatin 10 mg/20 mg,

placebo, or simvastatin 20 mg daily, respectively. The 1-year simvastatin arm enabled the comparison of

ezetimibe and simvastatin to simvastatin with regard to safety and effect on lipid levels. At 1 year the

simvastatin-only arm was re-allocated 1:1 to ezetimibe and simvastatin 10 mg/20 mg or placebo. A total

of 9270 patients were ever allocated to ezetimibe and simvastatin 10 mg/20 mg (n=4650) or placebo

(n=4620) during the trial. The median follow-up duration was 4.9 years. Patients had a mean age of 61

years; 63% were male, 72% were Caucasian, and 23% were diabetic; and, for those not on dialysis at

baseline, the median serum creatinine was 2.5 mg/dL and the median estimated glomerular filtration

rate (eGFR) was 25.6 mL/min/1.73 m , with 94% of patients having an eGFR less than 45

mL/min/1.73m . Eligibility did not depend on lipid levels. Mean LDL-C at baseline was 108 mg/dL. At 1

year, the mean LDL-C was 26% lower in the simvastatin arm and 38% lower in the ezetimibe and

simvastatin arm relative to placebo. At the midpoint of the study (2.5 years), the mean LDL-C was 32%

lower for ezetimibe and simvastatin relative to placebo. Patients no longer taking study medication were

included in all lipid measurements.

In the primary intent-to-treat analysis, 639 (15.2%) of 4193 patients initially allocated to ezetimibe and

simvastatin and 749 (17.9%) of 4191 patients initially allocated to placebo experienced an MVE. This

corresponded to a relative risk reduction of 16% (p=0.001) (see Figure 1). Similarly, 526 (11.3%) of

4650 patients ever allocated to ezetimibe and simvastatin and 619 (13.4%) of 4620 patients ever

allocated to placebo experienced a major atherosclerotic event (MAE; a subset of the MVE composite

that excluded non-coronary cardiac deaths and hemorrhagic stroke), corresponding to a relative risk

reduction of 17% (p=0.002). The trial demonstrated that treatment with ezetimibe and simvastatin 10

mg/20 mg versus placebo reduced the risk for MVE and MAE in this CKD population. The study design

precluded drawing conclusions regarding the independent contribution of either ezetimibe or

simvastatin to the observed effect.

The treatment effect of ezetimibe and simvastatin on MVE was attenuated among patients on dialysis at

baseline compared with those not on dialysis at baseline. Among 3023 patients on dialysis at baseline,

ezetimibe and simvastatin reduced the risk of MVE by 6% (RR 0.94: 95% CI 0.80 to 1.09) compared

with 22% (RR 0.78: 95% CI 0.69 to 0.89) among 6247 patients not on dialysis at baseline (interaction

P=0.08).

Fig ure 1: Effect of Ezetimibe and Simvastatin on the Primary Endpoint of Risk of Major Vascular Events

The individual components of MVE in all patients ever allocated to ezetimibe and simvastatin or placebo

are presented in Table 12.

Table 12: Number of First Events for Each Component of the Major Vascular Event Composite

Endpoint in SHARP

Outcome

Ezetimibe and

Simvastatin

10 mg/20 mg

Placebo

Risk Ratio

P-value

(N=4650)

(N=4620)

(95% CI)

Major Vascular Events

701 (15.1%)

814 (17.6%)

0.85 (0.77 to 0.94)

0.001

Nonfatal MI

134 (2.9%)

159 (3.4%)

0.84 (0.66 to 1.05)

0.12

Cardiac Death

253 (5.4%)

272 (5.9%)

0.93 (0.78 to 1.10)

0.38

Any Stroke

171 (3.7%)

210 (4.5%)

0.81 (0.66 to 0.99)

0.038

Non-hemorrhagic Stroke

131 (2.8%)

174 (3.8%)

0.75 (0.60 to 0.94)

0.011

Hemorrhagic Stroke

45 (1.0%)

37 (0.8%)

1.21 (0.78 to 1.86)

0.40

Any Revascularization

284 (6.1%)

352 (7.6%)

0.79 (0.68 to 0.93)

0.004

*Intention-to-treat analysis on all SHARP patients ever allocated to ezetimibe and simvastatin or

placebo.

Among patients not on dialysis at baseline, ezetimibe and simvastatin did not reduce the risk of

progressing to end-stage renal disease compared with placebo (RR 0.97: 95% CI 0.89 to 1.05).

*

16 HOW SUPPLIED/STORAGE AND HANDLING

Ezetimibe and Simvastatin Tablets are supplied as follows:

10 mg/10 mg – Each light tan, slightly speckled, round, unscored, biconvex tablet debossed with 511 on

one side and

on opposite side contains 10 mg of ezetimibe, USP and 10 mg of simvastatin, USP.

Tablets are supplied in bottles of 30 (NDC 45963-565-30), and 90 (NDC 45963-565-08).

10 mg/20 mg – Each light tan, slightly speckled, round, unscored, biconvex tablet debossed with 512 on

one side and

on opposite side contains 10 mg of ezetimibe, USP and 20 mg of simvastatin, USP.

Tablets are supplied in bottles of 30 (NDC 45963-566-30), and 90 (NDC 45963-566-08).

10 mg/40 mg – Each light tan, slightly speckled, round, unscored, biconvex tablet debossed with 513 on

one side and

on opposite side contains 10 mg of ezetimibe, USP and 40 mg of simvastatin, USP.

Tablets are supplied in bottles of 30 (NDC 45963-567-30), and 90 (NDC 45963-567-08).

10 mg/80 mg – Each light tan, slightly speckled, capsule shaped, unscored, biconvex tablet debossed

with 515 on one side and

on opposite side contains 10 mg of ezetimibe, USP and 80 mg of

simvastatin, USP. Tablets are supplied in bottles of 30 (NDC 45963-568-30), and 90 (NDC 45963-568-

08).

Storage

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Keep container tightly

closed.

Dispense in a tight, light-resistant container as defined in the USP.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-

recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.

Patients should be advised about substances they should not take concomitantly with ezetimibe

and simvastatin tablets [see Contraindications (4) and Warnings and Precautions (5.1)]. Patients

should also be advised to inform other healthcare professionals prescribing a new medication or

increasing the dose of an existing medication that they are taking ezetimibe and simvastatin

tablets .

17.1 Muscle Pain

All patients starting therapy with ezetimibe and simvastatin tablets should be advised of the risk of

myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain,

tenderness or weakness particularly if accompanied by malaise or fever or if these muscle signs or

symptoms persist after discontinuing ezetimibe and simvastatin tablets. Patients using the 10 mg/80-

mg dose should be informed that the risk of myopathy, including rhabdomyolysis, is increased

with the use of the 10 mg/80-mg dose. The risk of myopathy, including rhabdomyolysis, occurring

with use of ezetimibe and simvastatin tablets is increased when taking certain types of medication or

consuming grapefruit juice. Patients should discuss all medication, both prescription and over the

counter, with their healthcare professional.

17.2 Liver Enzymes

It is recommended that liver function tests be performed before the initiation of ezetimibe and

simvastatin tablets, and thereafter when clinically indicated. All patients treated with ezetimibe and

simvastatin tablets should be advised to report promptly any symptoms that may indicate liver injury,

including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

17.3 Pregnancy

Women of childbearing age should be advised to use an effective method of birth control to prevent

pregnancy while using ezetimibe and simvastatin tablets. Discuss future pregnancy plans with your

patients, and discuss when to stop taking ezetimibe and simvastatin tablets if they are trying to conceive.

Patients should be advised that if they become pregnant they should stop taking ezetimibe and simvastatin

tablets and call their healthcare professional.

17.4 Breastfeeding

Women who are breastfeeding should be advised to not use ezetimibe and simvastatin tablets. Patients

who have a lipid disorder and are breastfeeding should be advised to discuss the options with their

healthcare professional.

Brands listed are the trademarks of their respective owners.

Manufactured by:

Watson Pharma Private Limited

Verna, Salcette Goa 403 722 INDIA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Rev. B 10/2019

Patient Information

Ezetimibe and Simvastatin (e zet’ i mibe and sim” va’ statin)

Tablets

Read this Patient Information carefully before you start taking ezetimibe and simvastatin tablets and each

time you get a refill. 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 and simvastatin tablets, ask your doctor. Only your doctor can determine if ezetimibe and

simvastatin tablets are right for you.

What are ezetimibe and simvastatin tablets?

Ezetimibe and simvastatin tablets are a prescription medicine that contains 2 cholesterol lowering

medicines, ezetimibe and simvastatin. Ezetimibe and simvastatin tablets are used along with diet to:

lower the level of your “bad” cholesterol (LDL)

increase the level of your “good” cholesterol (HDL)

lower the level of fat in your blood (triglycerides)

Ezetimibe and simvastatin tablets are for patients who cannot control their cholesterol levels by diet and

exercise alone.

Ezetimibe and simvastatin tablets have not been shown to reduce heart attacks or strokes more than

simvastatin alone.

It is not known if ezetimibe and simvastatin tablets are safe and effective in children under 10 years of

age or in girls who have not started their period (menses).

The usual dose of ezetimibe and simvastatin tablets is 10 mg/10 mg to 10 mg/40 mg 1 time each day.

Ezetimibe and simvastatin tablets 10 mg/80 mg increase your chance of developing muscle damage. The

10 mg/80 mg dose should only be used by people who:

have been taking ezetimibe and simvastatin tablets 10 mg/80 mg chronically (such as 12 months or

more) without having muscle damage

do not need to take certain other medicines with ezetimibe and simvastatin tablets that would increase

your chance of getting muscle damage.

If you are unable to reach your LDL-cholesterol goal using ezetimibe and simvastatin tablets 10 mg/40

mg, your doctor should switch you to another cholesterol-lowering medicine.

Who should not take ezetimibe and simvastatin tablets?

Do not take ezetimibe and simvastatin tablets if you take:

Certain anti-fungal medicines including:

○ itraconazole

○ ketoconazole

○ posaconazole

○ voriconazole

HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, or atazanavir)

Certain hepatitis C virus protease inhibitors (such as boceprevir or telaprevir)

Certain antibiotics, including:

○ erythromycin

○ clarithromycin

○ telithromycin

nefazodone

medicines containing cobicistat

A fibric acid medicine for lowering cholesterol called gemfibrozil

cyclosporine

danazol

Ask your doctor or pharmacist for a list of these medicines if you are not sure.

Also do not take ezetimibe and simvastatin tablets if you:

are allergic to ezetimibe or simvastatin or any of the ingredients in ezetimibe and simvastatin tablets.

See the end of this leaflet for a complete list of ingredients in ezetimibe and simvastatin tablets.

have liver problems.

are pregnant or plan to become pregnant. Ezetimibe and simvastatin tablets may harm your unborn

baby. If you are a woman of childbearing age, you should use an effective method of birth control to

prevent pregnancy while using ezetimibe and simvastatin tablets. If you become pregnant while

taking ezetimibe and simvastatin tablets, stop taking ezetimibe and simvastatin tablets and call your

doctor.

are breastfeeding or plan to breastfeed. It is not known if ezetimibe and simvastatin passes into your

breast milk. You and your doctor should decide the best way to feed your baby if you take ezetimibe

and simvastatin tablets.

What should I tell my doctor before and while taking ezetimibe and simvastatin tablets?

Tell your doctor if you:

have unexplained muscle aches or weakness

have kidney problems

have or have had liver problems or drink more than 2 glasses of alcohol daily

have thyroid problems

are 65 years of age or older

are Chinese

Also see “What are the possible side effects of ezetimibe and simvastatin tablets?”

Tell your doctor about all the medicines you take, including prescription and over-the-counter

medicines, vitamins, and herbal supplements.

Tell your doctor who prescribes ezetimibe and simvastatin tablets if another doctor increases the dose

of another medicine you are taking.

Talk to your doctor before you start taking any new medicines.

Taking ezetimibe and simvastatin tablets with certain other medicines may affect each other causing side

effects. Ezetimibe and simvastatin tablets may affect the way other medicines work, and other medicines

may affect how ezetimibe and simvastatin tablets works.

Taking ezetimibe and simvastatin tablets with certain substances can increase the risk of muscle

problems. It is especially important to tell your doctor if you take:

fibric acid derivatives (such as fenofibrate)

amiodarone or dronedarone (drugs used to treat an irregular heartbeat)

verapamil, diltiazem, amlodipine, or ranolazine (drugs used to treat high blood pressure, chest pain

associated with heart disease, or other heart conditions)

grapefruit juice (which should be avoided while taking ezetimibe and simvastatin tablets)

colchicine (a medicine used to treat gout)

lomitapide (a medicine used to treat a serious and rare genetic cholesterol condition)

daptomycin (a drug used to treat complicated skin and bloodstream infections)

large doses of niacin or nicotinic acid

Tell your doctor if you are taking niacin or a niacin-containing product, as this may increase your risk

of muscle problems, especially if you are Chinese.

It is also important to tell your doctor if you are taking coumarin anticoagulants (drugs that prevent

blood clots, such as warfarin).

Tell your doctor about all the medicines you take, including any prescription and nonprescription

medicines, vitamins, and herbal supplements.

How should I take ezetimibe and simvastatin tablets?

Take ezetimibe and simvastatin tablets exactly as your doctor tells you to take it.

Do not change your dose or stop taking ezetimibe and simvastatin tablets without talking to your

doctor.

Take ezetimibe and simvastatin tablets 1 time each day in the evening.

Take ezetimibe and simvastatin tablets with or without food.

While taking ezetimibe and simvastatin tablets, continue to follow your cholesterol-lowering diet

and to exercise as your doctor told you to.

If you miss a dose, do not take an extra dose. Just resume your usual schedule.

Your doctor should do fasting blood tests to check your cholesterol while you take ezetimibe and

simvastatin tablets. Your doctor may change your dose of ezetimibe and simvastatin tablets if needed.

If you take too many ezetimibe and simvastatin tablets, call your doctor or Poison Control Center at

1-800-222-1222 or go to the nearest hospital emergency room right away.

What are the possible side effects of ezetimibe and simvastatin tablets?

Ezetimibe and simvastatin tablets may cause serious side effects, including:

Muscle pain, tenderness and weakness (myopathy). Muscle problems, including muscle

breakdown, can be serious in some people and rarely cause kidney damage that can lead to death.

Tell your doctor right away if:

you have unexplained muscle pain, tenderness, or weakness, especially if you have a fever

or feel more tired than usual, while you take ezetimibe and simvastatin tablets.

○ you have muscle problems that do not go away even after your doctor has advised you to stop

taking ezetimibe and simvastatin tablets. Your doctor may do further tests to diagnose the cause of

your muscle problems.

Your chances of getting muscle problems are higher if you:

are taking certain other medicines while you take ezetimibe and simvastatin tablets

are 65 years of age or older

are female

have thyroid problems (hypothyroidism) that are not controlled

have kidney problems

are taking higher doses of ezetimibe and simvastatin tablets, particularly the 10 mg/80 mg dose

are Chinese

Liver problems. Your doctor should do blood tests to check your liver before you start taking

ezetimibe and simvastatin tablets and if you have any symptoms of liver problems while you take

ezetimibe and simvastatin tablets. Call your doctor right away if you have the following symptoms

of liver problems:

○ loss of appetite

○ upper belly pain

○ dark urine

○ yellowing of your skin or the whites of your eyes

○ feel tired or weak

The most common side effects of ezetimibe and simvastatin tablets include:

headache

increased liver enzyme levels

muscle pain

upper respiratory infection

diarrhea

Additional side effects that have been reported in general use with ezetimibe and simvastatin tablets or

with ezetimibe or simvastatin tablets (tablets that contain the active ingredients of ezetimibe and

simvastatin) include:

allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty

in breathing or swallowing (which may require treatment right away), rash, hives; joint pain;

inflammation of the pancreas; nausea; dizziness; tingling sensation; depression; gallstones; trouble

sleeping; poor memory; memory loss; confusion; erectile dysfunction; breathing problems including

persistent cough and/or shortness of breath or fever.

Tell your doctor if you have any side effect that bothers you or does not go away.

These are not all the possible side effects of ezetimibe and simvastatin tablets. For more information,

ask your doctor or pharmacist.

Call your doctor about medical advice about side effects. You may report side effects to FDA at 1-

800-FDA-1088.

How should I store ezetimibe and simvastatin tablets?

Store ezetimibe and simvastatin tablets at room temperature between 68°F to 77°F (20°C to 25°C).

Keep ezetimibe and simvastatin tablets in its original container until you use it.

Keep ezetimibe and simvastatin tablets in a tightly closed container, and keep ezetimibe and

simvastatin tablets out of light.

Keep ezetimibe and simvastatin tablets and all medicines out of the reach of children.

General Information about the safe and effective use of ezetimibe and simvastatin tablets.

Ezetimibe and simvastatin tablets work to reduce your cholesterol in two ways. It reduces the

cholesterol absorbed in your digestive tract, as well as the cholesterol your body makes by itself.

Ezetimibe and simvastatin tablets do not help you lose weight.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.

Do not use ezetimibe and simvastatin tablets for a condition for which it was not prescribed. Do not give

ezetimibe and simvastatin tablets to other people, even if they have the same condition that you have. It

may harm them.

This Patient Information summarizes the most important information about ezetimibe and simvastatin

tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or

doctor for information about ezetimibe and simvastatin tablets that is written for health professionals.

For more information, call Actavis at 1-800-272-5525.

What are the ingredients in ezetimibe and simvastatin tablets?

Active Ingredients: ezetimibe and simvastatin

Inactive ingredients: ascorbic acid, butylated hydroxyanisole, citric acid anhydrous, croscarmellose

sodium, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, lactose monohydrate,

magnesium stearate, microcrystalline cellulose, and propyl gallate.

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

Brands listed are the trademarks of their respective owners.

Manufactured by:

Watson Pharma Private Limited

Verna, Salcette Goa 403 722 INDIA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Rev. B 10/2019

PRINCIPAL DISPLAY PANEL

NDC 45963-565-30

Ezetimibe and Simvastatin Tablets

10 mg/10 mg

PHARMACIST: Dispense the accompanying Patient Information Leaflet to each patient.

Actavis

30 Tablets

Rx Only

PRINCIPAL DISPLAY PANEL

NDC 45963-566-30

Ezetimibe and Simvastatin Tablets

10 mg/20 mg

PHARMACIST: Dispense the accompanying Patient Information Leaflet to each patient.

Actavis

30 Tablets

Rx Only

PRINCIPAL DISPLAY PANEL

NDC 45963-567-30

Ezetimibe and Simvastatin Tablets

10 mg/40 mg

PHARMACIST: Dispense the accompanying Patient Information Leaflet to each patient.

Actavis

30 Tablets

Rx Only

PRINCIPAL DISPLAY PANEL

NDC 45963-568-30

Ezetimibe and Simvastatin Tablets

10 mg/80 mg

PHARMACIST: Dispense the accompanying Patient Information Leaflet to each patient.

Actavis

30 Tablets

Rx Only

EZETIMIBE AND SIMVASTATIN

ezetimibe and simvastatin tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:459 6 3-56 5

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

EZETIMIBE (UNII: EOR26 LQQ24) (EZETIMIBE - UNII:EOR26 LQQ24)

EZETIMIBE

10 mg

SIMVASTATIN (UNII: AGG2FN16 EV) (SIMVASTATIN - UNII:AGG2FN16 EV)

SIMVASTATIN

10 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

BUTYLATED HYDRO XYANISO LE (UNII: REK49 6 0 K2U)

ANHYDRO US CITRIC ACID (UNII: XF417D3PSL)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

HYPRO MELLO SE 2 9 10 ( 5 MPA.S) (UNII: R75537T0 T4)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

PRO PYL GALLATE (UNII: 8 D4SNN7V9 2)

Product Characteristics

Color

BROWN (light tan, slightly speckled)

S core

no sco re

S hap e

ROUND

S iz e

6 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:459 6 3-56 5-30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

2

NDC:459 6 3-56 5-0 8

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

3

NDC:459 6 3-56 5-32

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

0 4/26 /20 17

4

NDC:459 6 3-56 5-0 5

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

0 4/26 /20 17

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 29 6 8

0 4/26 /20 17

EZETIMIBE AND SIMVASTATIN

ezetimibe and simvastatin tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:459 6 3-56 6

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

EZETIMIBE (UNII: EOR26 LQQ24) (EZETIMIBE - UNII:EOR26 LQQ24)

EZETIMIBE

10 mg

SIMVASTATIN (UNII: AGG2FN16 EV) (SIMVASTATIN - UNII:AGG2FN16 EV)

SIMVASTATIN

20 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

BUTYLATED HYDRO XYANISO LE (UNII: REK49 6 0 K2U)

ANHYDRO US CITRIC ACID (UNII: XF417D3PSL)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

HYPRO MELLO SE 2 9 10 ( 5 MPA.S) (UNII: R75537T0 T4)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

PRO PYL GALLATE (UNII: 8 D4SNN7V9 2)

Product Characteristics

Color

BROWN (light tan, slightly speckled)

S core

no sco re

S hap e

ROUND

S iz e

8 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:459 6 3-56 6 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

2

NDC:459 6 3-56 6 -0 8

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

3

NDC:459 6 3-56 6 -32

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

0 4/26 /20 17

4

NDC:459 6 3-56 6 -0 5

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

0 4/26 /20 17

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 29 6 8

0 4/26 /20 17

EZETIMIBE AND SIMVASTATIN

ezetimibe and simvastatin tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:459 6 3-56 7

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

EZETIMIBE (UNII: EOR26 LQQ24) (EZETIMIBE - UNII:EOR26 LQQ24)

EZETIMIBE

10 mg

SIMVASTATIN (UNII: AGG2FN16 EV) (SIMVASTATIN - UNII:AGG2FN16 EV)

SIMVASTATIN

40 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

BUTYLATED HYDRO XYANISO LE (UNII: REK49 6 0 K2U)

ANHYDRO US CITRIC ACID (UNII: XF417D3PSL)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

HYPRO MELLO SE 2 9 10 ( 5 MPA.S) (UNII: R75537T0 T4)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

PRO PYL GALLATE (UNII: 8 D4SNN7V9 2)

Product Characteristics

Color

BROWN (light tan, slightly speckled)

S core

no sco re

S hap e

ROUND

S iz e

10 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:459 6 3-56 7-30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

2

NDC:459 6 3-56 7-0 8

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

3

NDC:459 6 3-56 7-32

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

0 4/26 /20 17

4

NDC:459 6 3-56 7-0 5

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

0 4/26 /20 17

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 29 6 8

0 4/26 /20 17

EZETIMIBE AND SIMVASTATIN

ezetimibe and simvastatin tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:459 6 3-56 8

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

EZETIMIBE (UNII: EOR26 LQQ24) (EZETIMIBE - UNII:EOR26 LQQ24)

EZETIMIBE

10 mg

SIMVASTATIN (UNII: AGG2FN16 EV) (SIMVASTATIN - UNII:AGG2FN16 EV)

SIMVASTATIN

8 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

BUTYLATED HYDRO XYANISO LE (UNII: REK49 6 0 K2U)

ANHYDRO US CITRIC ACID (UNII: XF417D3PSL)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

HYPRO MELLO SE 2 9 10 ( 5 MPA.S) (UNII: R75537T0 T4)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

PRO PYL GALLATE (UNII: 8 D4SNN7V9 2)

Actavis Pharma, Inc.

Product Characteristics

Color

BROWN (light tan, slightly speckled)

S core

no sco re

S hap e

OVAL (capsule shaped)

S iz e

18 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:459 6 3-56 8 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

2

NDC:459 6 3-56 8 -0 8

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

3

NDC:459 6 3-56 8 -32

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

0 4/26 /20 17

4

NDC:459 6 3-56 8 -0 5

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 4/26 /20 17

0 4/26 /20 17

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 29 6 8

0 4/26 /20 17

Labeler -

Actavis Pharma, Inc. (119723554)

Revised: 10/2019

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