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Zetia

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Zetia

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

Liver Enzymes

In controlled clinical monotherapy studies, the incidence of consecutive elevations ( ≥ 3 X 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 X 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 co-administered 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 X ULN persist, consider withdrawal of ZETIA and/or the statin.

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 X ULN was 0.2% for ZETIA vs. 0.1% for placebo, and 0.1% for ZETIA co-administered 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 X the ULN indicates myopathy.

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.]

Patient Counseling Information

See 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.

Muscle Pain

All patients starting therapy with ezetimibe should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. The risk of this occurring is increased when taking certain types of medication. Patients should discuss all medication, both prescription and over-the-counter, with their physician.

Liver Enzymes

Liver tests should be performed when ZETIA is added to statin therapy and according to statin recommendations.

Pregnancy

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using ZETIA added to statin therapy. Discuss future pregnancy plans with your patients, and discuss when to stop combination ZETIA and statin therapy if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking combination ZETIA and statin therapy and call their healthcare professional.

Breastfeeding

Women who are breastfeeding should be advised to not use ZETIA added to statin therapy. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professionals.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 X the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day ( > 150 X the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drugtreated rats or mice.

No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.

In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 X the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).

Use In Specific Populations

Pregnancy

Pregnancy Category C

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

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

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

All statins are contraindicated in pregnant and nursing women. When ZETIA is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin. [See CONTRAINDICATIONS.]

Nursing Mothers

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

Pediatric Use

The effects of ZETIA co-administered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either ZETIA co-administered with simvastatin or simvastatin monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161- 351 mg/dL) in the ZETIA co-administered with simvastatin group compared to 219 mg/dL (range: 149- 336 mg/dL) in the simvastatin monotherapy group. The patients received co-administered ZETIA and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, co-administered ZETIA and 40-mg simvastatin or 40-mg simvastatin monotherapy for the next 27 weeks, and open-label co-administered ZETIA and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.

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

TABLE 3: Mean Percent Difference at Week 6 Between the Pooled ZETIA Co-Administered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia

  Total-C LDL-C Apo B Non-HDL-C TG* HDL-C
Mean percent difference between treatment groups -12% -1 5% -12% -1 4% -2% +0.1%
95% Confidence Interval (-15%, -9%) (-18%, -12%) (-15%, -9%) (-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 ZETIA co-administered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group.

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

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

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

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

Geriatric Use

Monotherapy Studies

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

Statin Co-Administration Studies

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

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

Renal Impairment

When used as monotherapy, no dosage adjustment of ZETIA is necessary.

In the Study of Heart and Renal Protection (SHARP) trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m², and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to ezetimibe 10 mg plus simvastatin 20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years. However, because renal impairment is a risk factor for statin-associated myopathy, doses of simvastatin exceeding 20 mg should be used with caution and close monitoring when administered concomitantly with ZETIA in patients with moderate to severe renal impairment.

Hepatic Impairment

ZETIA is not recommended in patients with moderate to severe hepatic impairment [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

ZETIA given concomitantly with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels [see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 1/30/2013
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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