ZETIA ^® is indicated:

• In combination with a statin, or alone when additional low-density lipoprotein cholesterol (LDL-C) lowering therapy is not possible, as an adjunct to diet to reduce elevated LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH).
• In combination with a statin as an adjunct to diet to reduce elevated LDL-C in pediatric patients 10 years of age and older with HeFH.
• In combination with fenofibrate as an adjunct to diet to reduce elevated LDL-C in adults with mixed hyperlipidemia.
• In combination with a statin, and other LDL-C lowering therapies, to reduce elevated LDL-C levels in adults and in pediatric patients 10 years of age and older with homozygous familial hypercholesterolemia (HoFH).
• As an adjunct to diet for the reduction of elevated sitosterol and campesterol levels in adults and in pediatric patients 9 years of age and older with homozygous familial sitosterolemia.

When ZETIA is used in combination with a statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for information on the safe and effective use.

ZETIA is indicated (1):

• In combination with a statin, or alone when additional low density lipoprotein cholesterol (LDL-C) lowering therapy is not possible, as an adjunct to diet to reduce elevated LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH).
• In combination with a statin as an adjunct to diet to reduce elevated LDL-C in pediatric patients 10 years of age and older with HeFH.
• In combination with fenofibrate as an adjunct to diet to reduce elevated LDL-C in adults with mixed hyperlipidemia.
• In combination with a statin, and other LDL-C lowering therapies, to reduce elevated LDL-C levels in adults and in pediatric patients 10 years of age and older with homozygous familial hypercholesterolemia (HoFH).
• As an adjunct to diet for the reduction of elevated sitosterol and campesterol levels in adults and in pediatric patients 9 years of age and older with homozygous familial sitosterolemia.

When ZETIA is used in combination with a statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for information on the safe and effective use (1).

• The recommended dose of ZETIA is 10 mg orally once daily, administered with or without food.
• If as dose is missed, take the missed dose as soon as possible. Do not double the next dose.
• Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ZETIA.
• Administer ZETIA at least 2 hours before or 4 hours after administration of a bile acid sequestrant [see Drug Interactions (7)].

• 10-mg orally once daily, with or without food (2)
• Administer ZETIA either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. (2)
• Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ZETIA. (2)

ZETIA is contraindicated in patients with a known hypersensitivity to ezetimibe or any of the excipients in ZETIA. Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported [see Adverse Reactions (6.2)].

When used in combination with a statin, fenofibrate, or other LDL-C lowering therapy, ZETIA is contraindicated in patients for whom a statin, fenofibrate, or other LDL-C lowering therapy are contraindicated. Refer to the Prescribing Information of these products for a list of their contraindications [see Warnings and Precautions (5.1)].

• Hypersensitivity to ezetimibe or any excipient of ZETIA. (4)
• When used in combination with a statin, fenofibrate, or other LDL-C lowering therapy, ZETIA is contraindicated in patients for whom a statin, fenofibrate, or other LDL-C lowering therapy are contraindicated. Refer to the Prescribing Information of these products for a list of their contraindications. (4)

• Risks Associated with Combination Treatment with a Statin, Fenofibrate, or Other LDL-C Lowering Therapies: Refer to the Prescribing Information of these products for a description of their risks including, but not limited to, the warnings and precautions. (5.1)
• Liver Enzyme Abnormalities and Monitoring: Increases in serum transaminases have been reported with use of ZETIA. Perform liver enzyme testing as clinically indicated and consider withdrawal of ZETIA if increases in ALT or AST ≥3 × ULN persist. (5.2)
• Skeletal Muscle Effects (e.g., Myopathy and Rhabdomyolysis): ZETIA may cause myopathy and rhabdomyolysis. In post-marketing reports, most patients who developed rhabdomyolysis were taking a statin or other agents known to be associated with an increased risk of rhabdomyolysis, such as fibrates. If myopathy is suspected, discontinue ZETIA and other concomitant medications, as appropriate. (5.3)

If ZETIA is administered with a statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for a description of their risks including, but not limited to, the warnings and precautions [see Contraindications (4)].

Increases in serum transaminases have been reported with use of ZETIA [see Adverse Reactions (6.1)]. In controlled clinical combination studies of ZETIA initiated concurrently with a statin, the incidence of consecutive elevations (≥3 × ULN) in hepatic transaminase levels was 1.3% for patients treated with ZETIA administered with statins and 0.4% for patients treated with statins alone. Perform liver enzyme testing as clinically indicated and consider withdrawal of ZETIA if increases in ALT or AST ≥3 × ULN persist.

ZETIA may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis [see Adverse Reactions (6.1)]. In post-marketing reports, most patients who developed rhabdomyolysis were taking a statin or other agents known to be associated with an increased risk of rhabdomyolysis, such as fibrates. If myopathy is suspected, discontinue ZETIA and other concomitant medications, as appropriate.

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

• Liver enzyme abnormalities [see Warnings and Precautions (5.2)]
• Rhabdomyolysis and myopathy [see Warnings and Precautions (5.3)]

• Common adverse reactions in clinical trials:
  • ZETIA administered alone (incidence ≥2% and greater than placebo): upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. (6.1)
  • ZETIA coadministered with a statin (incidence ≥2% and greater than statin alone): nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, diarrhea, back pain, influenza, pain in extremity, and fatigue. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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, 2,396 patients with primary hyperlipidemia (age range 9 to 86 years; 50% female, 90% White, 5% Black or African American, 2% Asian, 3% other races; 3% identified as Hispanic or Latino ethnicity) and elevated LDL-C were treated with ZETIA 10 mg daily 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 are shown in Table 1.

Combination with a Statin

In 28 double-blind, controlled (placebo or active-controlled) clinical trials, 11,308 patients with primary hyperlipidemia (age range 10 to 93 years, 48% female, 85% White, 7% Black or African American, 3% Asian, 5% other races; 4% identified as Hispanic or Latino ethnicity) 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%).

Adverse reactions reported in ≥2% of patients treated with ZETIA + statin and at an incidence greater than statin are shown in Table 2.

Combination with Fenofibrate

This clinical trial involving 625 patients with mixed dyslipidemia (age range 20 to 76 years; 44% female, 79% White, 1% Black or African American, 20% other races; 11% identified as Hispanic or Latino ethnicity) treated for up to 12 weeks and 576 patients treated for up to an additional 48 weeks evaluated coadministration of ZETIA and fenofibrate. Incidence rates for clinically important elevations (≥3 × ULN, consecutive) in hepatic transaminase levels were 4.5% and 2.7% 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% and 1.7% for fenofibrate monotherapy and ZETIA coadministered with fenofibrate, respectively [see Drug Interactions (7)].

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:

Blood Disorders: thrombocytopenia

Gastrointestinal Disorders: abdominal pain; pancreatitis; nausea

Hepatobiliary Disorders: elevations in liver transaminases, including elevations more than 5 X ULN; hepatitis; cholelithiasis; cholecystitis

Immune System Disorders: Hypersensitivity reactions including: anaphylaxis, angioedema, rash, and urticaria

Musculoskeletal Disorders: elevated creatine phosphokinase; myopathy/rhabdomyolysis

Nervous System Disorders: dizziness; paresthesia; depression; headache

Skin and Subcutaneous Tissue Disorders: erythema multiforme