Ezetrol Special Precautions

When EZETROL is to be administered with a statin or with fenofibrate, please refer to the Package Insert for that particular medication.
Liver Enzymes: In controlled co-administration trials in patients receiving EZETROL with a statin, consecutive transaminase elevations (≥ 3 X the upper limit of normal [ULN]) have been observed. When EZETROL is co-administered with a statin, liver function tests should be performed at initiation of therapy and according to the recommendations of the statin. (See SIDE EFFECTS.)
In the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), 18,144 patients with CHD were randomized to receive ezetimibe/simvastatin 10/40 mg daily (n=9067) or simvastatin 40 mg daily (n=9077). During a median follow-up of 6.0 years, the incidence of consecutive elevations of transaminases (≥3 X ULN) was 2.5% for ezetimibe/simvastatin and 2.3% for simvastatin. (See SIDE EFFECTS.)
In a controlled clinical study in which over 9000 patients with chronic kidney disease were randomized to receive EZETROL 10 mg combined with simvastatin 20 mg daily (n=4650) or placebo (n=4620) (median follow up period of 4.9 years), the incidence of consecutive elevations of transaminases (> 3 X ULN) was 0.7% for EZETROL combined with simvastatin and 0.6% for placebo. (See SIDE EFFECTS.)
Skeletal Muscle: In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with EZETROL 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 CPK > 10 X ULN was 0.2% for EZETROL vs 0.1% for placebo, and 0.1% for EZETROL co-administered with a statin vs 0.4% for statins alone.
In post-marketing experience with EZETROL, cases of myopathy and rhabdomyolysis have been reported regardless of causality. Most patients who developed rhabdomyolysis were taking a statin prior to initiating EZETROL. However, rhabdomyolysis has been reported very rarely with EZETROL monotherapy and very rarely with the addition of EZETROL to agents known to be associated with increased risk of rhabdomyolysis. All patients starting therapy with EZETROL should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. EZETROL and any statin that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of these symptoms and a creatine phosphokinase (CPK) level > 10 times the ULN indicates myopathy.
In IMPROVE-IT, 18,144 patients with CHD were randomized to receive ezetimibe/simvastatin 10/40 mg daily (n=9067) or simvastatin 40 mg daily (n=9077). During a median follow-up of 6.0 years, the incidence of myopathy was 0.2% for ezetimibe/simvastatin and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN or two consecutive observations of CK ≥5 and <10 times ULN. The incidence of rhabdomyolysis was 0.1% for ezetimibe/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN with evidence of renal injury, ≥5 X ULN and <10 X ULN on two consecutive occasions with evidence of renal injury or CK ≥10,000 IU/L without evidence of renal injury. (See SIDE EFFECTS.)
In a clinical trial in which over 9000 patients with chronic kidney disease were randomized to receive EZETROL 10 mg combined with simvastatin 20 mg daily (n=4650) or placebo (n=4620) (median follow up 4.9 years), the incidence of myopathy/rhabdomyolysis was 0.2% for EZETROL combined with simvastatin and 0.1% for placebo. (See SIDE EFFECTS.)
Hepatic Insufficiency: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, EZETROL is not recommended in these patients. [See Pharmacology: Pharmacokinetics: Characteristics in Patients (Special Populations) under Actions.]
Fibrates: The co-administration of ezetimibe with fibrates other than fenofibrate has not been studied. Therefore, co-administration of EZETROL and fibrates (other than fenofibrate) is not recommended (see INTERACTIONS).
Fenofibrate: If cholelithiasis is suspected in a patient receiving EZETROL and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered (see SIDE EFFECTS and the package insert for fenofibrate).
Cyclosporine: Caution should be exercised when initiating ezetimibe in the setting of cyclosporine. Cyclosporine concentrations should be monitored in patients receiving EZETROL and cyclosporine (see INTERACTIONS).
Anticoagulants: If EZETROL is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalized Ratio (INR) should be appropriately monitored (see INTERACTIONS).
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: No studies of the effects on the ability to drive and use of machines have been performed. However, certain side effects that have been reported with EZETROL may affect some patients' ability to drive or operate machinery. Individual responses to EZETROL may vary. (See SIDE EFFECTS.)
USE IN CHILDREN: Safety and effectiveness of EZETROL in patients 6 to 10 years of age with heterozygous familial or non-familial hypercholesterolemia have been evaluated in a 12-week controlled clinical trial. Children treated with EZETROL had an adverse experience profile similar to that of adult patients treated with EZETROL. In this study, there was generally no detectable effect on growth or sexual maturation in either boys or girls. However the effects of ezetimibe for a treatment period greater than 12 weeks on growth and sexual maturation have not been studied (see DOSAGE & ADMINISTRATION and SIDE EFFECTS).
Safety and effectiveness of EZETROL co-administered with simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least one year post-menarche. Adolescent patients treated with EZETROL and up to 40 mg/day simvastatin had an adverse experience profile similar to that of adult patients treated with EZETROL and simvastatin. In this controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See DOSAGE & ADMINISTRATION and SIDE EFFECTS.)