Zetlow-10 Special Precautions

Use with Statins or Fenofibrate: Concurrent administration of ezetimibe 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 ezetimibe (0.5%) and placebo (0.3%). In controlled clinical combination studies of ezetimibe initiated concurrently with a statin, the incidence of consecutive elevations (≥3 X ULN) in hepatic transaminase levels was 1.3% for patients treated with ezetimibe administered with statins and 0.4% for patients treated with statins alone. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. When ezetimibe 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 ezetimibe and/or the statin.
Myopathy/Rhabdomyolysis: In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe 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 ezetimibe vs 0.1% for placebo, and 0.1% for ezetimibe 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 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 fibrates. Ezetimibe 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, ezetimibe is not recommended in these patients. [See Pharmacology under Actions.]
Ezetimibe is not recommended in patients with moderate to severe hepatic impairment [see previously mentioned and Pharmacology under Actions]. Ezetimibe given concomitantly with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels [see Contraindications; previously mentioned and Pharmacology under Actions].
Renal Impairment: When used as monotherapy, no dosage adjustment of ezetimibe is necessary.
In the Study of Heart and Renal Protection (SHARP) trial of 9,270 patients with moderate to severe renal impairment (6,247 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 3,023 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=4,650) or placebo (n=4,620) 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 ezetimibe in patients with moderate to severe renal impairment.
Use in Children: The effects of ezetimibe 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 ezetimibe 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 to 351 mg/dL) in the ezetimibe co-administered with simvastatin group compared to 219 mg/dL (range: 149 to 336 mg/dL) in the simvastatin monotherapy group. The patients received co-administered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, co-administered ezetimibe and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label co-administered 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 10. Results at Week 33 were consistent with those at Week 6. (See Table 10.)

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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 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 ezetimibe 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 ezetimibe 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 ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, ezetimibe has not been studied in patients younger than 10 years of age or in pre-menarchal 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.
Use in the Elderly: Monotherapy Studies: Of the 2,396 patients who received ezetimibe 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 ezetimibe + statin in clinical studies, 3,587 (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 Pharmacology under Actions].