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The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Liver enzyme abnormalities [see WARNINGS AND PRECAUTIONS]
• Rhabdomyolysis and myopathy [see WARNINGS AND PRECAUTIONS]

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 Co-Administration 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%).

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.

TABLE 1: Clinical Adverse Reactions Occurring in ≥ 2% of Patients Treated with ZETIA and at an Incidence Greater than Placebo, Regardless of Causality

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 X 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]

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.

TABLE 2: Clinical Adverse Reactions Occurring in ≥ 2% of Patients Treated with ZETIA Co-Administered with a Statin and at an Incidence Greater than Statin, Regardless of Causality

Combination with Fenofibrate

This clinical study involving 625 patients with mixed dyslipidemia (age range 20-76 years, 44% women, 79% Caucasians, 0.1% Blacks, 11% Hispanics, 5% Asians) treated for up to 12 weeks and 576 patients treated for up to an additional 48 weeks evaluated co-administration of ZETIA and fenofibrate. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% Cl) for clinically important elevations ( ≥ 3 X ULN, consecutive) in hepatic transaminase levels were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy (n=188) and ZETIA co-administered with fenofibrate (n=183), respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (95% Cl: 0.0%, 3.1%) and 1.7% (95% Cl: 0.6%, 4.0%) for fenofibrate monotherapy and ZETIA co-administered with fenofibrate, respectively [see DRUG INTERACTIONS]. The numbers of patients exposed to co-administration therapy as well as fenofibrate and ezetimibe monotherapy were inadequate to assess gallbladder disease risk. There were no CPK elevations > 10 X ULN in any of the treatment groups.

Post-Marketing Experience

Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval use of ZETIA:

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria; erythema multiforme; arthralgia; myalgia; elevated creatine phosphokinase; myopathy/rhabdomyolysis [see WARNINGS AND PRECAUTIONS]; elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis.

[See CLINICAL PHARMACOLOGY.]

Cyclosporine

Caution should be exercised when using ZETIA and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients receiving ZETIA and cyclosporine.

The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe.

Fibrates

The efficacy and safety of co-administration of ezetimibe with fibrates other than fenofibrate have not been studied.

Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile [see Nonclinical Toxicology]. Co-administration of ZETIA with fibrates other than fenofibrate is not recommended until use in patients is adequately studied.

Fenofibrate

If cholelithiasis is suspected in a patient receiving ZETIA and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see SIDE EFFECTS and the product labeling for fenofibrate].

Cholestyramine

Concomitant Cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to Cholestyramine may be reduced by this interaction.

Coumarin Anticoagulants

If ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.

Last reviewed on RxList: 9/7/2011
This monograph has been modified to include the generic and brand name in many instances.