Zetia (ezetimibe) Side Effects, Warnings, and Drug Interactions

Zetia (ezetimibe) is a lipid-lowering compound used to treat high cholesterol. Common side effects of ezetimibe include diarrhea, abdominal pain, back pain, joint pain, muscle aches, and sinus infection (sinusitis).

Serious side effects of ezetimibe include hypersensitivity reactions (including angioedema - swelling of the skin and underlying tissues of the head and neck - that can be life-threatening), skin rash, nausea, pancreatitis, muscle damage (myopathy or rhabdomyolysis), and hepatitis.

Drug interactions of ezetimibe include cholestyramine, colestipol, colesevelam, and cyclosporine.

There are no adequate studies of ezetimibe in pregnant women. The benefits of using ezetimibe during pregnancy must be weighed against potential but unknown risks. There are no adequate studies of ezetimibe in breastfeeding women. The benefits of using ezetimibe in nursing women must be weighed against potential but unknown risks.

The most common side effects of Zetia are:

• diarrhea,
• abdominal pain,
• back pain,
• joint pain,
• muscle aches, and
• sinusitis.

Hypersensitivity reactions, including angioedema (swelling of the skin and underlying tissues of the head and neck that can be life-threatening) and skin rash rarely occur.

Other important side effects include:

• Nausea,
• pancreatitis,
• muscle damage (myopathy or rhabdomyolysis) and
• hepatitis

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

• Liver enzyme abnormalities
• Rhabdomyolysis and myopathy

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 Coadministration 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 × ULN) was higher in patients receiving Zetia administered with statins (1.3%) than in patients treated with statins alone (0.4%).

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 Coadministered 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 coadministration 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 — 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 coadministered 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 coadministered with fenofibrate, respectively [see DRUG INTERACTIONS]. The numbers of patients exposed to coadministration therapy as well as fenofibrate and ezetimibe monotherapy were inadequate to assess gallbladder disease risk. There were no CPK elevations > 10 — 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; elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis.

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 coadministration 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. Coadministration 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.

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.