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.
Primary Hyperlipidemia
Monotherapy
Zetia®, administered alone, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) 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, Apo B, and non-HDL-C 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-HDL-C in adult patients with mixed hyperlipidemia.
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.
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.
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.
Zetia Dosage and Administration
General Dosing Information
The recommended dose of Zetia is 10 mg once daily.
Zetia can be administered with or without food.
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.
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)].
Patients with Hepatic Impairment
No dosage adjustment is necessary in patients with mild hepatic impairment [see Warnings and Precautions (5.4)].
Patients with Renal Impairment
No dosage adjustment is necessary in patients with renal impairment [see Clinical Pharmacology (12.3)]. When given with simvastatin in patients with moderate to severe renal impairment (estimated glomerular filtration rate <60 mL/min/1.73 m2), doses of simvastatin exceeding 20 mg should be used with caution and close monitoring [see Use in Specific Populations (8.6)].
Geriatric Patients
No dosage adjustment is necessary in geriatric patients [see Clinical Pharmacology (12.3)].
Dosage Forms and Strengths
10-mg tablets are white to off-white, capsule-shaped tablets debossed with "414" on one side.
Contraindications
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)].
Warnings and Precautions
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.
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.
Myopathy/Rhabdomyolysis
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.
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).]
Adverse Reactions
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%).
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.
| Body System/Organ Class Adverse Reaction | Zetia 10 mg (%) n = 2396 | Placebo (%) n = 1159 |
| Gastrointestinal disorders | ||
| Diarrhea | 4.1 | 3.7 |
| General disorders and administration site conditions | ||
| Fatigue | 2.4 | 1.5 |
| Infections and infestations | ||
| Influenza | 2.0 | 1.5 |
| Sinusitis | 2.8 | 2.2 |
| Upper respiratory tract infection | 4.3 | 2.5 |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | 3.0 | 2.2 |
| 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.
| ||
| Body System/Organ Class Adverse Reaction | All Statins* (%) n = 9361 | Zetia + All Statins* (%) n = 11,308 |
| Gastrointestinal disorders | ||
| Diarrhea | 2.2 | 2.5 |
| General disorders and administration site conditions | ||
| Fatigue | 1.6 | 2.0 |
| Infections and infestations | ||
| Influenza | 2.1 | 2.2 |
| Nasopharyngitis | 3.3 | 3.7 |
| Upper respiratory tract infection | 2.8 | 2.9 |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | 2.4 | 2.6 |
| Back pain | 2.3 | 2.4 |
| Myalgia | 2.7 | 3.2 |
| 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.
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 (5.3)]; elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis.
Drug Interactions
[See Clinical Pharmacology (12.3).]
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 (13.2)]. 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 Adverse Reactions (6.1) 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.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C:
There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.
Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy.
All statins are contraindicated in pregnant and nursing women. When Zetia is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin. [See Contraindications (4).]
Nursing Mothers
It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when Zetia is administered to a nursing woman. Zetia should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.
Pediatric Use
The effects of Zetia co-administered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either Zetia co-administered with simvastatin or simvastatin monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161–351 mg/dL) in the Zetia co-administered with simvastatin group compared to 219 mg/dL (range: 149–336 mg/dL) in the simvastatin monotherapy group. The patients received co-administered Zetia and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, co-administered Zetia and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label co-administered Zetia and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.
The results of the study at Week 6 are summarized in Table 3. Results at Week 33 were consistent with those at Week 6.
| Total-C | LDL-C | Apo B | Non-HDL-C | TG* | HDL-C | |
|---|---|---|---|---|---|---|
| ||||||
| Mean percent difference between treatment groups | -12% | -15% | -12% | -14% | -2% | +0.1% |
| 95% Confidence Interval | (-15%, -9%) | (-18%, -12%) | (-15%, -9%) | (-17%, -11%) | (-9%, +4%) | (-3%, +3%) |
From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the Zetia co-administered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group.
During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST ≥3 × ULN) occurred in four (3%) individuals in the Zetia co-administered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (≥10 × ULN) occurred in two (2%) individuals in the Zetia co-administered with simvastatin group and in zero individuals in the simvastatin monotherapy group.
In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls.
Co-administration of Zetia with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, Zetia has not been studied in patients younger than 10 years of age or in pre-menarchal girls.
Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide), there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available.
Geriatric Use
Monotherapy Studies
Of the 2396 patients who received Zetia in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older.
Statin Co-Administration Studies
Of the 11,308 patients who received Zetia + statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older.
No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].
Renal Impairment
When used as monotherapy, no dosage adjustment of Zetia is necessary.
In the Study of Heart and Renal Protection (SHARP) trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m2, and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to ezetimibe 10 mg plus simvastatin 20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years. However, because renal impairment is a risk factor for statin-associated myopathy, doses of simvastatin exceeding 20 mg should be used with caution and close monitoring when administered concomitantly with Zetia in patients with moderate to severe renal impairment.
Hepatic Impairment
Zetia is not recommended in patients with moderate to severe hepatic impairment [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].
Zetia given concomitantly with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels [see Contraindications (4); Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
Overdosage
In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks was generally well tolerated. One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events.
In the event of an overdose, symptomatic and supportive measures should be employed.
Zetia Description
Zetia (ezetimibe) is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. The chemical name of ezetimibe is 1 - (4 - fluorophenyl) - 3(R) - [3 - (4 - fluorophenyl) - 3(S) - hydroxypropyl] - 4(S) - (4 - hydroxyphenyl) - 2 - azetidinone. The empirical formula is C24H21F2NO3. Its molecular weight is 409.4 and its structural formula is:
Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Ezetimibe has a melting point of about 163°C and is stable at ambient temperature. Zetia is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, povidone USP, and sodium lauryl sulfate NF.
Zetia - Clinical Pharmacology
Mechanism of Action
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In a 2-week clinical study in 18 hypercholesterolemic patients, Zetia inhibited intestinal cholesterol absorption by 54%, compared with placebo. Zetia had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E (in a study of 113 patients), and did not impair adrenocortical steroid hormone production (in a study of 118 patients).
The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol.
Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds (statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols.
Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins and of fenofibrate [see Clinical Studies (14.1)].
Pharmacodynamics
Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
Zetia reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of Zetia with a statin is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of Zetia with fenofibrate is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a statin or fenofibrate on cardiovascular morbidity and mortality have not been established.
Pharmacokinetics
Absorption
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of Zetia to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.
Effect of Food on Oral Absorption
Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as Zetia 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals. Zetia can be administered with or without food.
Distribution
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
Metabolism and Excretion
Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated.
In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.
Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.
Specific Populations
Geriatric Patients: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects.
Pediatric Patients: [See Use in Specific Populations (8.4).]
Gender: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men.
Race: Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.
Hepatic Impairment: After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, Zetia is not recommended in these patients [see Warnings and Precautions (5.4)].
Renal Impairment: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9).
Drug Interactions [See also Drug Interactions (7)]
Zetia had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a "cocktail" study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes.
| Co-Administered Drug and Dosing Regimen | Total Ezetimibe * | |
|---|---|---|
| Change in AUC | Change in Cmax | |
| ||
| Cyclosporine-stable dose required (75–150 mg BID)†,‡ | ↑240% | ↑290% |
| Fenofibrate, 200 mg QD, 14 days‡ | ↑48% | ↑64% |
| Gemfibrozil, 600 mg BID, 7 days‡ | ↑64% | ↑91% |
| Cholestyramine, 4 g BID, 14 days‡ | ↓55% | ↓4% |
| Aluminum & magnesium hydroxide combination antacid, single dose§ | ↓4% | ↓30% |
| Cimetidine, 400 mg BID, 7 days | ↑6% | ↑22% |
| Glipizide, 10 mg, single dose | ↑4% | ↓8% |
| Statins | ||
| Lovastatin 20 mg QD, 7 days | ↑9% | ↑3% |
| Pravastatin 20 mg QD, 14 days | ↑7% | ↑23% |
| Atorvastatin 10 mg QD, 14 days | ↓2% | ↑12% |
| Rosuvastatin 10 mg QD, 14 days | ↑13% | ↑18% |
| Fluvastatin 20 mg QD, 14 days | ↓19% | ↑7% |
| Co-Administered Drug and its Dosage Regimen | Ezetimibe Dosage Regimen | Change in AUC of Co-Administered Drug | Change in Cmax of Co-Administered Drug |
|---|---|---|---|
| |||
| Warfarin, 25 mg single dose on day 7 | 10 mg QD, 11 days | ↓2% (R-warfarin) ↓4% (S-warfarin) | ↑3% (R-warfarin) ↑1% (S-warfarin) |
| Digoxin, 0.5 mg single dose | 10 mg QD, 8 days | ↑2% | ↓7% |
| Gemfibrozil, 600 mg BID, 7 days* | 10 mg QD, 7 days | ↓1% | ↓11% |
| Ethinyl estradiol & Levonorgestrel, QD, 21 days | 10 mg QD, days 8–14 of 21d oral contraceptive cycle | Ethinyl estradiol 0% Levonorgestrel 0% | Ethinyl estradiol ↓9% Levonorgestrel ↓5% |
| Glipizide, 10 mg on days 1 and 9 | 10 mg QD, days 2–9 | ↓3% | ↓5% |
| Fenofibrate, 200 mg QD, 14 days* | 10 mg QD, 14 days | ↑11% | ↑7% |
| Cyclosporine, 100 mg single dose day 7* | 20 mg QD, 8 days | ↑15% | ↑10% |
| Statins | |||
| Lovastatin 20 mg QD, 7 days | 10 mg QD, 7 days | ↑19% | ↑3% |
| Pravastatin 20 mg QD, 14 days | |||
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