HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ZETIA safely and effectively. See full prescribing information for ZETIA.
ZETIA ® (ezetimibe) Tablets
Initial U.S. Approval: 2002
INDICATIONS AND USAGE
ZETIA is an inhibitor of intestinal cholesterol (and related phytosterol) absorption indicated as an adjunct to diet to:
-
Reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary hyperlipidemia, alone or in combination with an HMG-CoA reductase inhibitor (statin) (1.1)
-
Reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate (1.1)
-
Reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin (1.2)
-
Reduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia) (1.3)
Limitations of Use (1.4)
-
The effect of ZETIA on cardiovascular morbidity and mortality has not been determined.
-
ZETIA has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.
DOSAGE AND ADMINISTRATION
-
One 10-mg tablet once daily, with or without food (2.1)
-
Dosing of ZETIA should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. (2.3, 7.4)
DOSAGE FORMS AND STRENGTHS
-
Statin contraindications apply when ZETIA is used with a statin:
-
Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels (4, 5.2)
-
Women who are pregnant or may become pregnant (4, 8.1)
-
Nursing mothers (4, 8.3)
-
Known hypersensitivity to product components (4, 6.2)
WARNINGS AND PRECAUTIONS
-
ZETIA is not recommended in patients with moderate or severe hepatic impairment. (5.4, 8.7, 12.3)
-
Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur when ZETIA is added to a statin. Therefore, when ZETIA is added to statin therapy, monitor hepatic transaminase levels before and during treatment according to the recommendations for the individual statin used. (5.2)
-
Skeletal muscle effects (e.g., myopathy and rhabdomyolysis):
-
Cases of myopathy and rhabdomyolysis have been reported in patients treated with ZETIA coadministered with a statin and with ZETIA administered alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. (5.3, 6.2)
ADVERSE REACTIONS
-
Common adverse reactions in clinical trials:
-
ZETIA coadministered with a statin (incidence ≥2% and greater than statin alone):
-
nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, and diarrhea (6)
-
ZETIA administered alone (incidence ≥2% and greater than placebo):
-
upper respiratory tract infection, diarrhea, arthralgia, sinusitis, and pain in extremity (6)
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
-
Cyclosporine: Combination increases exposure of ZETIA and cyclosporine. Cyclosporine concentrations should be monitored in patients taking ZETIA concomitantly. (7.1, 12.3)
-
Fenofibrate: Combination increases exposure of ZETIA. If cholelithiasis is suspected in a patient receiving ZETIA and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. (6.1, 7.3)
-
Fibrates: Coadministration of ZETIA with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. (7.2)
-
Cholestyramine: Combination decreases exposure of ZETIA. (2.3, 7.4, 12.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 8/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
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
Monotherapy
ZETIA®, administered alone, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia.
Combination Therapy with HMG-CoA Reductase Inhibitors (Statins)
ZETIA, administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia.
Combination Therapy with Fenofibrate
ZETIA, administered in combination with fenofibrate, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in adult patients with mixed hyperlipidemia.
1.2 Homozygous Familial Hypercholesterolemia (HoFH)
The combination of ZETIA and atorvastatin or simvastatin is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
1.3 Homozygous Sitosterolemia
ZETIA is indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.
1.4 Limitations of Use
The effect of ZETIA on cardiovascular morbidity and mortality has not been determined.
ZETIA has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
The recommended dose of ZETIA is 10 mg once daily.
ZETIA can be administered with or without food.
2.2 Concomitant Lipid-Lowering Therapy
ZETIA may be administered with a statin (in patients with primary hyperlipidemia) or with fenofibrate (in patients with mixed hyperlipidemia) for incremental effect. For convenience, the daily dose of ZETIA may be taken at the same time as the statin or fenofibrate, according to the dosing recommendations for the respective medications.
2.3 Coadministration with Bile Acid Sequestrants
Dosing of ZETIA should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant [see Drug Interactions (7.4)].
2.5 Patients with Renal Impairment
No dosage adjustment is necessary in patients with renal impairment [see Clinical Pharmacology (12.3)]. When given with simvastatin in patients with moderate to severe renal impairment (estimated glomerular filtration rate <60 mL/min/1.73 m2), doses of simvastatin exceeding 20 mg should be used with caution and close monitoring [see Use in Specific Populations (8.6)].
3 DOSAGE FORMS AND STRENGTHS
10-mg tablets are white to off-white, capsule-shaped tablets debossed with "414" on one side.
4 CONTRAINDICATIONS
ZETIA is contraindicated in the following conditions:
-
The combination of ZETIA with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels.
-
Women who are pregnant or may become pregnant. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ZETIA in combination with a statin may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy. [See Use in Specific Populations (8.1).]
-
Nursing mothers. Because statins may pass into breast milk, and because statins have the potential to cause serious adverse reactions in nursing infants, women who require ZETIA treatment in combination with a statin should be advised not to nurse their infants [see Use in Specific Populations (8.3)].
-
Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria have been reported with ZETIA [see Adverse Reactions (6.2)].
5 WARNINGS AND PRECAUTIONS
5.1 Use with Statins or Fenofibrate
Concurrent administration of ZETIA with a specific statin or fenofibrate should be in accordance with the product labeling for that medication.
5.2 Liver Enzymes
In controlled clinical monotherapy studies, the incidence of consecutive elevations (≥3 × the upper limit of normal [ULN]) in hepatic transaminase levels was similar between ZETIA (0.5%) and placebo (0.3%).
In controlled clinical combination studies of ZETIA initiated concurrently with a statin, the incidence of consecutive elevations (≥3 × ULN) in hepatic transaminase levels was 1.3% for patients treated with ZETIA administered with statins and 0.4% for patients treated with statins alone. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. When ZETIA is coadministered with a statin, liver tests should be performed at initiation of therapy and according to the recommendations of the statin. Should an increase in ALT or AST ≥3 × ULN persist, consider withdrawal of ZETIA and/or the statin.
5.3 Myopathy/Rhabdomyolysis
In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ZETIA compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of creatine phosphokinase (CPK) >10 × ULN was 0.2% for ZETIA vs. 0.1% for placebo, and 0.1% for ZETIA coadministered with a statin vs. 0.4% for statins alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs.
In post-marketing experience with ZETIA, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ZETIA. However, rhabdomyolysis has been reported with ZETIA monotherapy and with the addition of ZETIA to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. ZETIA and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and a CPK level >10 × the ULN indicates myopathy.
5.4 Hepatic Impairment
Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate to severe hepatic impairment, ZETIA is not recommended in these patients. [See Clinical Pharmacology (12.3).]
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Monotherapy Studies: In the ZETIA controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on ZETIA and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with ZETIA that led to treatment discontinuation and occurred at a rate greater than placebo were:
-
Arthralgia (0.3%)
-
Dizziness (0.2%)
-
Gamma-glutamyltransferase increased (0.2%)
The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in the ZETIA monotherapy controlled clinical trial database of 2396 patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%).
Statin Coadministration Studies: In the ZETIA + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on ZETIA + statin and 3.3% of patients on statin alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with ZETIA + statin that led to treatment discontinuation and occurred at a rate greater than statin alone were:
-
Alanine aminotransferase increased (0.6%)
-
Myalgia (0.5%)
-
Fatigue, aspartate aminotransferase increased, headache, and pain in extremity (each at 0.2%)
The most commonly reported adverse reactions (incidence ≥2% and greater than statin alone) in the ZETIA + statin controlled clinical trial database of 11,308 patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%).
6.1 Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Monotherapy
In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary hyperlipidemia (age range 9–86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with ZETIA 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks).
Adverse reactions reported in ≥2% of patients treated with ZETIA and at an incidence greater than placebo in placebo-controlled studies of ZETIA, regardless of causality assessment, are shown in Table 1.
The frequency of less common adverse reactions was comparable between ZETIA and placebo.
Combination with a Statin
In 28 double-blind, controlled (placebo or active-controlled) clinical trials, 11,308 patients with primary hyperlipidemia (age range 10–93 years, 48% women, 85% Caucasians, 7% Blacks, 4% Hispanics, 3% Asians) and elevated LDL-C were treated with ZETIA 10 mg/day concurrently with or added to on-going statin therapy for a median treatment duration of 8 weeks (range 0 to 112 weeks).
The incidence of consecutive increased transaminases (≥3 × ULN) was higher in patients receiving ZETIA administered with statins (1.3%) than in patients treated with statins alone (0.4%). [See Warnings and Precautions (5.2).]
Clinical adverse reactions reported in ≥2% of patients treated with ZETIA + statin and at an incidence greater than statin, regardless of causality assessment, are shown in Table 2.
|
