ezetimibe 10 MG Oral Tablet

Details

Generic Name: EZETIMIBE

Brand Name: Zetia

Substance Name(s):
EZETIMIBE

DRUG INTERACTIONS

7 [See Clinical Pharmacology (12.3).] 1.Cyclosporine: Combination increases exposure of ZETIA and cyclosporine.

Cyclosporine concentrations should be monitored in patients taking ZETIA concomitantly.

(7.1, 12.3) 2.Fenofibrate: Combination increases exposure of ZETIA.

If cholelithiasis is suspected in a patient receiving ZETIA and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.

(6.1, 7.3) 3.Fibrates: Coadministration of ZETIA with fibrates other than fenofibrate is not recommended until use in patients is adequately studied.

(7.2) 4.Cholestyramine: Combination decreases exposure of ZETIA.

(2.3, 7.4, 12.3) 7.1 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.

7.2 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 [see Nonclinical Toxicology (13.2)].

Coadministration of ZETIA with fibrates other than fenofibrate is not recommended until use in patients is adequately studied.

7.3 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].

7.4 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.

7.5 Coumarin Anticoagulants If ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.

OVERDOSAGE

10 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.

DESCRIPTION

11 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.

image of ezetimibe chemical structure

CLINICAL STUDIES

14 14.1 Primary Hyperlipidemia ZETIA reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia.

Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.

Monotherapy In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hyperlipidemia, ZETIA significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo (see Table 6 ).

Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.

TABLE 6: Response to ZETIA in Patients with Primary Hyperlipidemia (MeanFor triglycerides, median % change from baseline.

% Change from Untreated BaselineBaseline – on no lipid-lowering drug.) Treatment Group N Total-C LDL-C Apo B Non-HDL-C TG HDL-C Study 1 ZETIA significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo.

Placebo 205 +1 +1 -1 +1 -1 -1 Ezetimibe 622 -12 -18 -15 -16 -7 +1 Study 2 Placebo 226 +1 +1 -1 +2 +2 -2 Ezetimibe 666 -12 -18 -16 -16 -9 +1 Pooled Data (Studies 1 & 2) Placebo 431 0 +1 -2 +1 0 -2 Ezetimibe 1288 -13 -18 -16 -16 -8 +1 Combination with Statins ZETIA Added to On-going Statin Therapy In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either ZETIA or placebo in addition to their on-going statin.

ZETIA, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (see Table 7 ).

LDL-C reductions induced by ZETIA were generally consistent across all statins.

TABLE 7: Response to Addition of ZETIA to On-Going Statin TherapyPatients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin).

in Patients with Hyperlipidemia (MeanFor triglycerides, median % change from baseline.

% Change from Treated BaselineBaseline – on a statin alone.) Treatment (Daily Dose) N Total-C LDL-C Apo B Non-HDL-C TG HDL-C On-going Statin + PlaceboZETIA + statin significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to statin alone.

390 -2 -4 -3 -3 -3 +1 On-going Statin + ZETIA 379 -17 -25 -19 -23 -14 +3 ZETIA Initiated Concurrently with a Statin In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, ZETIA or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.

When all patients receiving ZETIA with a statin were compared to all those receiving the corresponding statin alone, ZETIA significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the statin administered alone.

LDL-C reductions induced by ZETIA were generally consistent across all statins.

(See footnote Tables 8 to 11.) TABLE 8: Response to ZETIA and Atorvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (MeanFor triglycerides, median % change from baseline.

% Change from Untreated BaselineBaseline – on no lipid-lowering drug.) Treatment (Daily Dose) N Total-C LDL-C Apo B Non-HDL-C TG HDL-C Placebo 60 +4 +4 +3 +4 -6 +4 ZETIA 65 -14 -20 -15 -18 -5 +4 Atorvastatin 10 mg 60 -26 -37 -28 -34 -21 +6 ZETIA + Atorvastatin 10 mg 65 -38 -53 -43 -49 -31 +9 Atorvastatin 20 mg 60 -30 -42 -34 -39 -23 +4 ZETIA + Atorvastatin 20 mg 62 -39 -54 -44 -50 -30 +9 Atorvastatin 40 mg 66 -32 -45 -37 -41 -24 +4 ZETIA + Atorvastatin 40 mg 65 -42 -56 -45 -52 -34 +5 Atorvastatin 80 mg 62 -40 -54 -46 -51 -31 +3 ZETIA + Atorvastatin 80 mg 63 -46 -61 -50 -58 -40 +7 Pooled data (All Atorvastatin Doses)ZETIA + all doses of atorvastatin pooled (10–80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of atorvastatin pooled (10–80 mg).

248 -32 -44 -36 -41 -24 +4 Pooled data (All ZETIA + Atorvastatin Doses) 255 -41 -56 -45 -52 -33 +7 TABLE 9: Response to ZETIA and Simvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (MeanFor triglycerides, median % change from baseline.

% Change from Untreated BaselineBaseline – on no lipid-lowering drug.) Treatment (Daily Dose) N Total-C LDL-C Apo B Non-HDL-C TG HDL-C Placebo 70 -1 -1 0 -1 +2 +1 ZETIA 61 -13 -19 -14 -17 -11 +5 Simvastatin 10 mg 70 -18 -27 -21 -25 -14 +8 ZETIA + Simvastatin 10 mg 67 -32 -46 -35 -42 -26 +9 Simvastatin 20 mg 61 -26 -36 -29 -33 -18 +6 ZETIA + Simvastatin 20 mg 69 -33 -46 -36 -42 -25 +9 Simvastatin 40 mg 65 -27 -38 -32 -35 -24 +6 ZETIA + Simvastatin 40 mg 73 -40 -56 -45 -51 -32 +11 Simvastatin 80 mg 67 -32 -45 -37 -41 -23 +8 ZETIA + Simvastatin 80 mg 65 -41 -58 -47 -53 -31 +8 Pooled data (All Simvastatin Doses)ZETIA + all doses of simvastatin pooled (10–80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of simvastatin pooled (10–80 mg).

263 -26 -36 -30 -34 -20 +7 Pooled data (All ZETIA + Simvastatin Doses) 274 -37 -51 -41 -47 -29 +9 TABLE 10: Response to ZETIA and Pravastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (MeanFor triglycerides, median % change from baseline.

% Change from Untreated BaselineBaseline – on no lipid-lowering drug.) Treatment (Daily Dose) N Total-C LDL-C Apo B Non-HDL-C TG HDL-C Placebo 65 0 -1 -2 0 -1 +2 ZETIA 64 -13 -20 -15 -17 -5 +4 Pravastatin 10 mg 66 -15 -21 -16 -20 -14 +6 ZETIA + Pravastatin 10 mg 71 -24 -34 -27 -32 -23 +8 Pravastatin 20 mg 69 -15 -23 -18 -20 -8 +8 ZETIA + Pravastatin 20 mg 66 -27 -40 -31 -36 -21 +8 Pravastatin 40 mg 70 -22 -31 -26 -28 -19 +6 ZETIA + Pravastatin 40 mg 67 -30 -42 -32 -39 -21 +8 Pooled data (All Pravastatin Doses)ZETIA + all doses of pravastatin pooled (10–40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG compared to all doses of pravastatin pooled (10–40 mg).

205 -17 -25 -20 -23 -14 +7 Pooled data (All ZETIA + Pravastatin Doses) 204 -27 -39 -30 -36 -21 +8 TABLE 11: Response to ZETIA and Lovastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (MeanFor triglycerides, median % change from baseline.

% Change from Untreated BaselineBaseline – on no lipid-lowering drug.) Treatment (Daily Dose) N Total-C LDL-C Apo B Non-HDL-C TG HDL-C Placebo 64 +1 0 +1 +1 +6 0 ZETIA 72 -13 -19 -14 -16 -5 +3 Lovastatin 10 mg 73 -15 -20 -17 -19 -11 +5 ZETIA + Lovastatin 10 mg 65 -24 -34 -27 -31 -19 +8 Lovastatin 20 mg 74 -19 -26 -21 -24 -12 +3 ZETIA + Lovastatin 20 mg 62 -29 -41 -34 -39 -27 +9 Lovastatin 40 mg 73 -21 -30 -25 -27 -15 +5 ZETIA + Lovastatin 40 mg 65 -33 -46 -38 -43 -27 +9 Pooled data (All Lovastatin Doses)ZETIA + all doses of lovastatin pooled (10–40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of lovastatin pooled (10–40 mg).

220 -18 -25 -21 -23 -12 +4 Pooled data (All ZETIA + Lovastatin Doses) 192 -29 -40 -33 -38 -25 +9 Combination with Fenofibrate In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks.

Patients were randomized to receive placebo, ZETIA alone, 160-mg fenofibrate alone, or ZETIA and 160-mg fenofibrate in the 12-week study.

After completing the 12-week study, eligible patients were assigned to ZETIA coadministered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks.

ZETIA coadministered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone.

The percent decrease in TG and percent increase in HDL-C for ZETIA coadministered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 12 ).

TABLE 12: Response to ZETIA and Fenofibrate Initiated Concurrently in Patients with Mixed Hyperlipidemia (MeanFor triglycerides, median % change from baseline.

% Change from Untreated BaselineBaseline – on no lipid-lowering drug.

at 12 weeks) Treatment (Daily Dose) N Total-C LDL-C Apo B TG HDL-C Non-HDL-C Placebo 63 0 0 -1 -9 +3 0 ZETIA 185 -12 -13 -11 -11 +4 -15 Fenofibrate 160 mg 188 -11 -6 -15 -43 +19 -16 ZETIA + Fenofibrate 160 mg 183 -22 -20 -26 -44 +19 -30 The changes in lipid endpoints after an additional 48 weeks of treatment with ZETIA coadministered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above.

14.2 Homozygous Familial Hypercholesterolemia (HoFH) A study was conducted to assess the efficacy of ZETIA in the treatment of HoFH.

This double-blind, randomized, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg).

Patients were randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), ZETIA administered with atorvastatin or simvastatin (40 mg), or ZETIA administered with atorvastatin or simvastatin (80 mg).

Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7.4)], ezetimibe was dosed at least 4 hours before or after administration of resins.

Mean baseline LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the group randomized to ZETIA plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg.

ZETIA, administered with atorvastatin or simvastatin (40- and 80-mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%).

In those treated with ZETIA plus 80-mg atorvastatin or with ZETIA plus 80-mg simvastatin, LDL-C was reduced by 27%.

14.3 Homozygous Sitosterolemia (Phytosterolemia) A study was conducted to assess the efficacy of ZETIA in the treatment of homozygous sitosterolemia.

In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolemia with elevated plasma sitosterol levels (>5 mg/dL) on their current therapeutic regimen (diet, bile-acid-binding resins, statins, ileal bypass surgery and/or LDL apheresis), were randomized to receive ZETIA (n=30) or placebo (n=7).

Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7.4)], ezetimibe was dosed at least 2 hours before or 4 hours after resins were administered.

Excluding the one subject receiving LDL apheresis, ZETIA significantly lowered plasma sitosterol and campesterol, by 21% and 24% from baseline, respectively.

In contrast, patients who received placebo had increases in sitosterol and campesterol of 4% and 3% from baseline, respectively.

For patients treated with ZETIA, mean plasma levels of plant sterols were reduced progressively over the course of the study.

The effects of reducing plasma sitosterol and campesterol on reducing the risks of cardiovascular morbidity and mortality have not been established.

Reductions in sitosterol and campesterol were consistent between patients taking ZETIA concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).

Limitations of Use The effect of ZETIA on cardiovascular morbidity and mortality has not been determined.

HOW SUPPLIED

16 /STORAGE AND HANDLING No.

3861 — Tablets ZETIA, 10 mg, are white to off-white, capsule-shaped tablets debossed with “414” on one side.

They are supplied as follows: Overbagged with 10 tablets per bag, NDC 55154-5034-0 Storage Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F).

[See USP Controlled Room Temperature.] Protect from moisture.

GERIATRIC USE

8.5 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 Coadministration 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)].

DOSAGE FORMS AND STRENGTHS

3 10-mg tablets are white to off-white, capsule-shaped tablets debossed with “414” on one side.

•Tablets: 10 mg (3)

MECHANISM OF ACTION

12.1 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)].

INDICATIONS AND USAGE

1 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.

ZETIA is an inhibitor of intestinal cholesterol (and related phytosterol) absorption indicated as an adjunct to diet to: •Reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary hyperlipidemia, alone or in combination with an HMG-CoA reductase inhibitor (statin) (1.1) •Reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate (1.1) •Reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin (1.2) •Reduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia) (1.3) Limitations of Use (1.4) •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.

1.1 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.

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.

PEDIATRIC USE

8.4 Pediatric Use The effects of ZETIA coadministered 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 coadministered 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 coadministered with simvastatin group compared to 219 mg/dL (range: 149–336 mg/dL) in the simvastatin monotherapy group.

The patients received coadministered ZETIA and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, coadministered ZETIA and 40-mg simvastatin or 40-mg simvastatin monotherapy for the next 27 weeks, and open-label coadministered 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.

TABLE 3: Mean Percent Difference at Week 6 Between the Pooled ZETIA Coadministered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia Total-C LDL-C Apo B Non-HDL-C TG For triglycerides, median % change from baseline.

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 coadministered 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 coadministered 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 coadministered 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.

Coadministration 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.

PREGNANCY

8.1 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).]

NUSRING MOTHERS

8.3 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.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS •ZETIA is not recommended in patients with moderate or severe hepatic impairment.

(5.4, 8.7, 12.3) •Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur when ZETIA is added to a statin.

Therefore, when ZETIA is added to statin therapy, monitor hepatic transaminase levels before and during treatment according to the recommendations for the individual statin used.

(5.2) •Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): •Cases of myopathy and rhabdomyolysis have been reported in patients treated with ZETIA coadministered with a statin and with ZETIA administered 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.

(5.3, 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 coadministered 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.

5.3 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 coadministered 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).]

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information).

Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.

17.1 Muscle Pain All patients starting therapy with ezetimibe should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

The risk of this occurring is increased when taking certain types of medication.

Patients should discuss all medication, both prescription and over-the-counter, with their physician.

17.2 Liver Enzymes Liver tests should be performed when ZETIA is added to statin therapy and according to statin recommendations.

17.3 Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using ZETIA added to statin therapy.

Discuss future pregnancy plans with your patients, and discuss when to stop combination ZETIA and statin therapy if they are trying to conceive.

Patients should be advised that if they become pregnant they should stop taking combination ZETIA and statin therapy and call their healthcare professional.

17.4 Breastfeeding Women who are breastfeeding should be advised to not use ZETIA added to statin therapy.

Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professionals.

Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA For patent information: www.merck.com/product/patent/home.html Copyright © 2001-2012 MSD International GmbH, a subsidiary of Merck & Co., Inc.

uspi-mk0653-t-1308r026

DOSAGE AND ADMINISTRATION

2 •One 10-mg tablet once daily, with or without food (2.1) •Dosing of ZETIA should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.

(2.3, 7.4) 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 Coadministration 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)].

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)].

2.6 Geriatric Patients No dosage adjustment is necessary in geriatric patients [see Clinical Pharmacology (12.3)].