VYTORIN- 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:
Merck Sharp & Dohme Corp.
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. VYTORIN® is 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. VYTORIN is 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 unav
Product summary:
No. 3873 — Tablets VYTORIN 10/10 are white to off-white capsule-shaped tablets with code "311" on one side. They are supplied as follows: NDC 66582-311-31 bottles of 30 NDC 66582-311-54 bottles of 90 NDC 66582-311-87 bottles of 10,000 (If repackaged in blisters, then opaque or light-resistant blisters should be used.) No. 3874 — Tablets VYTORIN 10/20 are white to off-white capsule-shaped tablets with code "312" on one side. They are supplied as follows: NDC 66582-312-31 bottles of 30 NDC 66582-312-54 bottles of 90 No. 3875 — Tablets VYTORIN 10/40 are white to off-white capsule-shaped tablets with code "313" on one side. They are supplied as follows: NDC 66582-313-31 bottles of 30 NDC 66582-313-54 bottles of 90 No. 3876 — Tablets VYTORIN 10/80 are white to off-white capsule-shaped tablets with code "315" on one side. They are supplied as follows: NDC 66582-315-31 bottles of 30 NDC 66582-315-54 bottles of 90 Storage Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature.] Keep container tightly closed. Storage of 10,000, 5000, and 2500 count bottles Store bottle of 10,000 VYTORIN 10/10 and 10/20, 5000 VYTORIN 10/40, and 2500 VYTORIN 10/80 capsule-shaped tablets at 20-25°C (68-77°F). [See USP Controlled Room Temperature.] Store in original container until time of use. When product container is subdivided, repackage into a tightly-closed, light-resistant container. Entire contents must be repackaged immediately upon opening.
Authorization status:
New Drug Application
Authorization number:
66582-311-01, 66582-311-28, 66582-311-31, 66582-311-54, 66582-311-82, 66582-311-87, 66582-312-01, 66582-312-27, 66582-312-28, 66582-312-31, 66582-312-54, 66582-312-82, 66582-312-87, 66582-313-01, 66582-313-27, 66582-313-31, 66582-313-52, 66582-313-54, 66582-313-74, 66582-313-86, 66582-315-01, 66582-315-31, 66582-315-52, 66582-315-54, 66582-315-66, 66582-315-74

VYTORIN- ezetimibe and simvastatin tablet

Merck Sharp & Dohme Corp.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use VYTORIN safely and effectively. See full

prescribing information for VYTORIN.

VYTORIN (ezetimibe and simvastatin) tablets, for oral use

Initial U.S. Approval: 2004

RECENT MAJOR CHANGES

Warnings and Precautions

Myopathy/Rhabdomyolysis (5.1)

10/2019

INDICATIONS AND USAGE

VYTORIN, which contains 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 VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for

simvastatin has been established.

VYTORIN has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

DOSAGE AND ADMINISTRATION

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

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

Due to the increased risk of myopathy, including rhabdomyolysis, use of the 10/80-mg dose of VYTORIN should be

restricted to patients who have been taking VYTORIN 10/80 mg chronically (e.g., for 12 months or more) without

evidence of muscle toxicity. (2.2)

Patients who are currently tolerating the 10/80-mg dose of VYTORIN 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 10/80-mg dose of VYTORIN,

patients unable to achieve their LDL-C goal utilizing the 10/40-mg dose of VYTORIN should not be titrated to the

10/80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.

(2.2)

Dosing of VYTORIN should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.

(2.3, 7.5)

DOSAGE FORMS AND STRENGTHS

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

dose. (5.1)

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

®

VYTORIN 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 (≥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 ≥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 Merck Sharp & Dohme Corp., a subsidiary of Merck &

Co., Inc., at 1-877-888-4231 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

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 VYTORIN

Niacin (≥1 g/day)

For Chinese patients, not recommended with VYTORIN

Verapamil, diltiazem, dronedarone

Do not exceed 10/10 mg VYTORIN daily

Amiodarone, amlodipine, ranolazine

Do not exceed 10/20 mg VYTORIN daily

Lomitapide

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

daily

Daptomycin

Temporarily suspend VYTORIN

Grapefruit juice

Avoid grapefruit juice

Coumarin anticoagulants: simvastatin prolongs INR. Achieve stable INR prior to starting VYTORIN. Monitor INR

frequently until stable upon initiation or alteration of VYTORIN 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 VYTORIN. (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 10/20 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: 5/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Primary Hyperlipidemia

1.2 Homozygous Familial Hypercholesterolemia (HoFH)

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 10/40 mg VYT ORIN when taking lomitapide.

1.3 Limitations of Use

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

2.2 Restricted Dosing for 10/80 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

VYTORIN is 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)

VYTORIN is 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 VYTORIN on cardiovascular morbidity and mortality over and above that

demonstrated for simvastatin has been established.

VYTORIN has 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 10/10 mg/day to 10/40 mg/day. The recommended usual starting dose is

10/10 mg/day or 10/20 mg/day. VYTORIN 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

10/40 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 VYTORIN, lipid levels may be analyzed

after 2 or more weeks and dosage adjusted, if needed.

2.2 Restricted Dosing for 10/80 mg

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

treatment, use of the 10/80-mg dose of VYTORIN should be restricted to patients who have been taking

VYTORIN 10/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see

Warnings and Precautions (5.1)].

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

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

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

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 10/80-mg dose of

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

should not be titrated to the 10/80-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 VYTORIN should not exceed 10/10 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 VYTORIN should not exceed 10/20 mg/day [see Warnings and Precautions (5.1), Drug

Interactions (7.3), and Clinical Pharmacology (12.3)].

Patients taking Bile Acid Sequestrants

Dosing of VYTORIN 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 VYTORIN

10/40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 10/80 mg (2.2)].

VYTORIN 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 VYTORIN should be reduced by 50% if initiating lomitapide. VYTORIN dosage should not exceed

10/20 mg/day (or 10/40 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 VYTORIN is 10/20 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

VYTORIN 10/10, (ezetimibe 10 mg and simvastatin 10 mg tablets) are white to off-white capsule-

shaped tablets with code "311" on one side.

VYTORIN 10/20, (ezetimibe 10 mg and simvastatin 20 mg tablets) are white to off-white capsule-

shaped tablets with code "312" on one side.

VYTORIN 10/40, (ezetimibe 10 mg and simvastatin 40 mg tablets) are white to off-white capsule-

shaped tablets with code "313" on one side.

VYTORIN 10/80, (ezetimibe 10 mg and simvastatin 80 mg tablets) are white to off-white capsule-

shaped tablets with code "315" on one side.

4 CONTRAINDICATIONS

VYTORIN is 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, VYTORIN 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 VYTORIN 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. VYTORIN 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, VYTORIN 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 VYTORIN 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 (≥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] >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 >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 10/80-mg dose of VYTORIN should

be used only in patients who have been taking VYTORIN 10/80 mg chronically (e.g., for 12

months or more) without evidence of muscle toxicity [see Dosage and Administration, Restricted

Dosing for 10/80 mg (2.2)]. If, however, a patient who is currently tolerating the 10/80-mg dose of

VYTORIN 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 VYTORIN 10/20 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] >10 times upper limit of normal [ULN]) was 0.2% for VYTORIN

and 0.1% for placebo: the incidence of rhabdomyolysis (defined as myopathy with a CK > 40 times

ULN) was 0.09% for VYTORIN 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. VYTORIN 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 VYTORIN or whose dose of VYTORIN 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 VYTORIN. VYTORIN 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 VYTORIN 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 VYTORIN merit closer monitoring.

VYTORIN therapy should be discontinued if markedly elevated CPK levels occur or myopathy is

diagnosed or suspected. VYTORIN 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 VYTORIN is

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

VYTORIN must be suspended during the course of treatment [see Contraindications (4) and Drug

Interactions (7)].

The combined use of VYTORIN 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 VYTORIN, 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 VYTORIN with colchicine [see Drug

Interactions (7.9)].

The benefits of the combined use of VYTORIN 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), Drug Interactions (7.3)].

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

with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products [see Drug Interactions (7.4)].

Cases of rhabdomyolysis have been reported with VYTORIN administered with daptomycin.

Temporarily suspend VYTORIN 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

Pres cribing

Recommendations

Strong CYP3A4 Inhibitors,

e.g.:

Itraconazole

Ketoconazole

Posaconazole

Voriconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Boceprevir

Telaprevir

Nefazodone

Cobicistat-containing

Contraindicated with

VYTORIN

products

Gemfibrozil

Cyclosporine

Danazol

Niacin (≥1 g/day)

For Chinese patients, not

recommended with VYTORIN

Verapamil

Diltiazem

Dronedarone

Do not exceed 10/10 mg

VYTORIN daily

Amiodarone

Amlodipine

Ranolazine

Do not exceed 10/20 mg

VYTORIN daily

Lomitapide

For patients with HoFH, do

not exceed 10/20 mg

VYTORIN daily

Daptomycin

Temporarily suspend

VYTORIN

Grapefruit juice

Avoid grapefruit juice

5.2 Liver Enzymes

In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (≥3 × ULN) in

serum transaminases was 1.7% overall for patients treated with VYTORIN and appeared to be dose-

related with an incidence of 2.6% for patients treated with VYTORIN 10/80. In controlled long-term

(48-week) extensions, which included both newly-treated and previously-treated patients, the incidence

of consecutive elevations (≥3 × ULN) in serum transaminases was 1.8% overall and 3.6% for patients

treated with VYTORIN 10/80. 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 VYTORIN 10/20 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 (>3 × ULN) was 0.7% for VYTORIN and 0.6% for placebo.

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

VYTORIN, 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 VYTORIN,

promptly interrupt therapy. If an alternate etiology is not found do not restart VYTORIN. Note that ALT

may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and

Precautions (5.1)].

VYTORIN 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 VYTORIN.

5.3 Endocrine Function

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

inhibitors, including simvastatin.

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 10/4 0 mg VYTORIN when taking

lomitapide.

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

VYTORIN

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 VYTORIN (ezetimibe and simvastatin) placebo-controlled clinical trials database of 1420 patients

(age range 20-83 years, 52% women, 87% Caucasians, 3% Blacks, 5% Hispanics, 3% Asians) with a

median treatment duration of 27 weeks, 5% of patients on VYTORIN and 2.2% of patients on placebo

discontinued due to adverse reactions.

The most common adverse reactions in the group treated with VYTORIN 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 ≥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%).

VYTORIN has been evaluated for safety in more than 10,189 patients in clinical trials.

Table 2 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with

VYTORIN (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 VYTORIN and at an Incidence Greater than Placebo,

Regardless of Causality

Body System/Organ

Clas s

Adverse Reaction

Placebo

(%)

n=371

Ezetimibe

10 mg

(%)

n=302

Simvas tatin

(%)

n=1234

VYTORIN

(%)

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

*

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