ZETIA — ezetimibe tablet
Physicians Total Care, Inc.
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.
1.1 Primary Hyperlipidemia
ZETIA 1, administered alone, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B) in patients with primary (heterozygous familial and non-familial) hyperlipidemia.
Combination Therapy with HMG-CoA Reductase Inhibitors (Statins)
ZETIA, administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, and Apo B in patients with primary (heterozygous familial and non-familial) hyperlipidemia.
Combination Therapy with Fenofibrate
ZETIA, administered in combination with fenofibrate, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-high-density lipoprotein cholesterol (non-HDL-C) in adult patients with mixed hyperlipidemia.
1.2 Homozygous Familial Hypercholesterolemia (HoFH)
The combination of ZETIA and atorvastatin or simvastatin is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
1.3 Homozygous Sitosterolemia
ZETIA is indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.
1.4 Limitations of Use
The effect of ZETIA on cardiovascular morbidity and mortality has not been determined.
ZETIA has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.
2.1 General Dosing Information
The recommended dose of ZETIA is 10 mg once daily.
ZETIA can be administered with or without food.
2.2 Concomitant Lipid-Lowering Therapy
ZETIA may be administered with a statin (in patients with primary hyperlipidemia) or with fenofibrate (in patients with mixed hyperlipidemia) for incremental effect. For convenience, the daily dose of ZETIA may be taken at the same time as the statin or fenofibrate, according to the dosing recommendations for the respective medications.
2.3 Co-Administration with Bile Acid Sequestrants
Dosing of ZETIA should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant [see Drug Interactions (7.4)].
2.4 Patients with Hepatic Impairment
No dosage adjustment is necessary in patients with mild hepatic impairment [see Warnings and Precautions (5.4)].
2.5 Patients with Renal Impairment
No dosage adjustment is necessary in patients with renal impairment [see Clinical Pharmacology (12.3)].
2.6 Geriatric Patients
No dosage adjustment is necessary in geriatric patients [see Clinical Pharmacology (12.3)].
10-mg tablets are white to off-white, capsule-shaped tablets debossed with “414” on one side.
ZETIA is contraindicated in the following conditions:
- The combination of ZETIA with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels.
- Women who are pregnant or may become pregnant. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ZETIA in combination with a statin may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy. [See Use in Specific Populations (8.1).]
- Nursing mothers. Because statins may pass into breast milk, and because statins have the potential to cause serious adverse reactions in nursing infants, women who require ZETIA treatment in combination with a statin should be advised not to nurse their infants [see Use in Specific Populations (8.3)].
- Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria have been reported with ZETIA [see Adverse Reactions (6.2)].
5.1 Use with Statins or Fenofibrate
Concurrent administration of ZETIA with a specific statin or fenofibrate should be in accordance with the product labeling for that medication.
5.2 Liver Enzymes
In controlled clinical monotherapy studies, the incidence of consecutive elevations (≥3 × the upper limit of normal [ULN]) in hepatic transaminase levels was similar between ZETIA (0.5%) and placebo (0.3%).
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. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. When ZETIA is co-administered with a statin, liver tests should be performed at initiation of therapy and according to the recommendations of the statin. Should an increase in ALT or AST ≥3 × ULN persist, consider withdrawal of ZETIA and/or the statin.
In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ZETIA 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 creatine phosphokinase (CPK) >10 × ULN was 0.2% for ZETIA vs 0.1% for placebo, and 0.1% for ZETIA co-administered with a statin vs 0.4% for statins alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs.
In post-marketing experience with ZETIA, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ZETIA. However, rhabdomyolysis has been reported with ZETIA monotherapy and with the addition of ZETIA to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. ZETIA and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and a CPK level >10 × the ULN indicates myopathy.
5.4 Hepatic Impairment
Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate to severe hepatic impairment, ZETIA is not recommended in these patients. [See Clinical Pharmacology (12.3).]
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)]
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%).
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.
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-contr olled studies of ZETIA, regardless of causality assessment, are shown in Table 1.
|Body System/Organ Class Adverse Reaction||ZETIA 10 mg (%)n = 2396||Placebo(%)n = 1159|
|General disorders and administration site conditions|
|Infections and infestations|
|Upper respiratory tract infection||4.3||2.5|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||2.7||2.5|
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%). [See Warnings and Precautions (5.2).]
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
|Body System/Organ Class Adverse Reaction||All Statins *(%)n = 9361||ZETIA + All Statins *(%)n = 11,308|
|General disorders and administration site conditions|
|Infections and infestations|
|Upper respiratory tract infection||2.8||2.9|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||1.9||2.1|
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 × 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 (7.3)]. 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 × ULN in any of the treatment groups.
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 (5.3)] ; elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis.
[See Clinical Pharmacology (12.3).]
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.
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 (13.2)]. Co-administration of ZETIA with fibrates other than fenofibrate is not recommended until use in patients is adequately studied.
If cholelithiasis is suspected in a patient receiving ZETIA and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see Adverse Reactions (6.1) and the product labeling for fenofibrate].
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.
7.5 Coumarin Anticoagulants
If ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.
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