SIDE EFFECTS

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% CI) 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% CI: 0.0%, 3.1%) and 1.7% (95% CI: 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.

Read the entire FDA prescribing information for Zetia (Ezetimibe Tablets) »