58
`2004
`
`EDITION
`
`PHYSCANS'
`DESK
`REFERENCE@
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`

`
`2118/MERCK
`
`Zocor-Cont.
`
`Skin: alopecia, pruritus. A variety of skin changes (e.g.,
`nodules, discoloration, dryness of skin/mucous membraneS,
`changes to hair/nails) have been reported.
`loss of libido, erectile
`Reproductive: gynecomastia,
`dysfunction.
`Eye: progression of cataracts {lens opacities), ophthal(cid:173)
`moplegia.
`Laboratory Abnormalities: elevated transarninases, alka(cid:173)
`line phosphatase, -y-glutamyl transpeptidase, and bilirubin;
`thyroid function abnormalities.
`Laboratory Tests
`Marked persistent increases of serum transaminases have
`been noted (see WARNINGS, Liver Dysfunction). About 5%
`of patients had elevations of CK levels of 3 or more times
`the normal value on one or more occasions. This was attrib(cid:173)
`utable to th.e noncardiac fraction of CK. Muscle pain or dys~
`function usually was not reported (see WARNINGS, My(!p-
`·
`athy I Rhabdomyolysis).
`Concomitant Lipid·Lowering Therapy
`In controlled clinical studies iri which simvastatin was ad·
`minist~red concomitantly with cholestyramine, no advei'Se
`reactions peculiar to this concomitant treatment were ob(cid:173)
`served. The adverse reactions that occurred were limited
`reported previously with simvastatin or
`to
`those
`cholestyramin,e. The combined use of simvastatin ~t doseS
`exceeding 10 mg/day with gemfibrozil, other_ ~brates or
`lipid-lowering doses (~1 g/day) ofniaci~ should be avoided
`(see WARNINGS, Myopathy I Rhabdomyolysis).
`Adolescent Patients (ages 10-17 years)
`In a 48-week controlled study in adolescent boys and girls
`who were at least 1 year post-menarche, 10-17 years of age
`with heterozygous familial hypercholesterolemia (n~175),
`the safety and tolerability profile of the group treated with
`ZOCOR (10-40 mg daily) was generally similar to that of the
`gt:oup treated with placebo, with the most common adverse
`experiences obse~ed in both groups being upper respira(cid:173)
`tory infection, headache, abdominal pain, and nausea. (see
`CLINICAL PHARMACOLOGY," Clinical Studies in Adoles(cid:173)
`cents, and PRECAUTIONS, Pediatric Use).
`
`OVERDOSAGE
`Significant lethality was observed in mice after a single oral
`dose of9 g/m2
`. No evidence oflethality was observed in rats
`or dogs treated with doses of 30 and 100 g/m2
`, respectively.
`No specific diagnostic signs were observed in rodents. At
`these doses the only signs seen in dogs were emesis and mu(cid:173)
`coid stools.
`A few. cases of overdosage with ZOCOR have been reported;
`no patients had any specific symptoms, and all patients re(cid:173)
`covered without sequelae. The maximum dose taken was .
`450 mg. Until further experience is obtained, no specific
`treatment of overdosage with ZOCOR can be recommended.
`The dialyzability of simvastatin and its metabolites in man
`is not known at present.
`DOSAGE AND ADMINISTRATION
`The patient should be placed on a standard choleSterol(cid:173)
`lowering diet. In patients with CHD or at high risk of CHD,
`ZOCOR can be started simultaneously with diet. The dos(cid:173)
`age should be individualized according to the goals of ther·
`apy and the patient's response. (For the treatment of adult
`dyslipidemia, see NCEP Treatment Guidelines. For the re·
`duction in. risks of major coronary events, see CLINICAL
`PHARMACOLOGY, Clinical Studies in Adults.) The dosage
`range is 5·80 mg/day (see below).
`The recommended usual starting dose is 20 to 40 mg once a
`day in the evening. For patients at high risk for a CHD
`event due to existing coronary heart disease, diabetes, p_e(cid:173)
`ripheral vessel disease, history of stroke or other cerebrn::....
`vascular disease, the recommended sta1ting dose is 40 mg/
`daY. Lipid determinations should be performed after 4
`weeks of therapy and periodically thereafter. See below for
`dosage recommendations in special populations (i.e., homo(cid:173)
`zygous familial hypercholesterolemia, adolescents and renal
`insufficiency) or for patients receiving concomitant therapy
`(i.e., cyclosporine, amiodarone, verapamil, fibrates or
`niacin).
`Patients with Homozygous Familial Hypercholesterolemia
`The recommended dosage for patients with hOmozygous fa(cid:173)
`milial hypercholesterolemia is ZOCOR 40 mg/day in the
`evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg,
`and an evening dose of 40 mg. ZOCOR should be used as an
`adjunct to other lipid-lowering treatments (e.g., LDL apher·
`esis) in these patients or if such treatments are unavailable.
`Adolescents {10-17 years of age) with Heterozygous Familial
`Hypercholesterolemia
`The recommended usual starting dose is 10 mg once a day
`in the evening. The recommended dosing range is 10-40 mg/
`day; the maximum recommended dose is 40 mg/day. Doses
`should be individualized according to the recommended goal
`of therapy (see NCEP Pediatric Panel Guidelines6 and
`CLINICAL PHARMACOLOGY). Adjustments should be
`made at intervals of 4 weeks or more.
`Concomitant Lipid-Lowering Therapy
`ZOCOR is effective alone or when used concomitantly with
`bile-acid sequestrants. If ZOCOR is used in combination
`with gemfibrozil, other fibrates or lipid-lowering doses
`(;d glday) of niacin, the dose of ZOCOR should not exceed
`10 mg/day (see WARNINGS, Myopathy I Rhabdomyolysis
`and PRECAUTIONS, Drug Interactions).
`
`Patients taking Cyclosporine
`In patients taking cyclosporine concomitantly with ZOCOR
`(see WARNINGS, MyopathyiRhabdomyolysis); therapy
`should begin with 5 mg/day and should not exceed 10 mgl
`day:
`Patients taking Amiodarone or Verapamil
`In patients taking amiodarone or verapamil concomitantly
`witb ZOCOR, the dose should not exceed 20 mglday (see
`WARNINGS, MyopathyiRhabdomyolysis and PRECAU·
`TIONS, Drug Interactions, Other drug interactionS).
`Patients with Renal Insufficiency
`Because ZOCOR does not undergo significant renal exCre(cid:173)
`tion, modification of dosage should not be necessary in pa·
`tients with mild to moderate renal insufficiency. However,
`caution should be exercised when ZOCOR is administered
`to patients with severe renal insufficiency; such patients
`should be started at 5 mg/day and be closely monitored (see
`CLINICAL PHARMACOLOGY, Pharmacohinetics and
`WARNINGS, Myopathy I Rhabdomyolysis).
`
`6 National Cholesterol Education Program (NCEP): High·
`lights of the Report of the Expert Panel on Blood Choles·
`terol Levels in Children and Adolescents. Pediatrics. 89(3):
`495-.501. 1992.
`HOW SUPPLIED
`No. 3588 -Tablets ZOCOR 5 mg are buff, shield-shaped,
`film-coated tablets, coded MSD 726 on one side and ZOCOR
`. on the other. They are supplied as follows:
`NDC 0006-0726-31 unit of use bottles of 30
`NDC 0006·0726-61 unit of use bottles of 60
`NDC 0006-0726-54 unit of use bottles of 90
`NDC 0006-0726-28 unit dose packages of 100
`NDC 0006-0726-82 bottles of 1000.
`No. 3589 - Tablets ZOCOR 10 mg are peach, shield·
`shaped, film-coated tablets, coded MSD 735 on one side and
`ZOCOR on the other. They are supplied as follows:
`NDC 0006-0735·31 unit of use bottles of 30
`NDC 0006-0735·54 unit of use bottles of 90
`NDC 0006·0735-28 unit dose packages of 100
`NDC 0006·0735-82 bottles of 1000
`NDC 0006-0735·87 bottles of 10,000.
`No." 3590- Tablets ZOCOR 20 mg are tan, shield-shaped,
`film-coated tablets, coded MSD 740 on one side and ZOCOR
`-on the other. They are supplied B.s follows:
`NDC 0006-0740·31 unit of use bottles of 30
`N.DC 0006-0740-61 unit of use bottles of 60
`NDC 0006-0740-54 unit of use bottles of90
`NDC OOQG-0740-28 unit dose packages of 100
`NDC·0006-0740·8Z bottles of 1000
`NDC 0006-0740-87 bottles of 10,000.
`No. 3591 - Tablets ZOCOR 40 mg are brick red, shield(cid:173)
`shaped, film-coated tablets, coded MSD 749 on one side and
`ZOCOR on the other. They-are supplied as follows:
`NDC 0006-0749·31 unit of use bottles of 30
`NDC 0006-0749-61 unit of use bottles of60
`NDC 0006-0749-54 unit of"use bottles of 90
`NDC 0006-0749-28 unit dose packages of 100
`.
`NDC 0006-0749-82 bottles of 1000.
`No. 6577 -Tablets ZOCOR 80 mg are brick r.ed, capsule(cid:173)
`shaped, film-coated tablets, coded 543 on one side and 80 on
`the other. They are supplied as follows:
`NDC 0006·0543-31 unit of use bottles of 30
`NDC 0006-0543-61 unit of use bottles of 60
`NDC 0006·0543-54 unit of use bottles of 90
`NDC 0006·0543-28 unit dose packages of 100
`NDC 0006-0543-82 bottles of 1000.
`Storage
`Store between 5-30'C (41-86'F). ·
`Tablets ZOCOR (simvastatin) 5 mg, 10 mg, 20 mg, ·and
`40 mg are manufactured by:
`MERCK & CO., INC.
`Whitehouse Station, NJ 08889, USA
`Tablets ZOCOR (simvastatin) 80 mg are manufactured for:
`MERCK & CO .• INC.
`Whitehouse Station, NJ 08889, USA
`By:
`MERCK SHARP & DOHME LTD,
`Cramlington, Northumberland, UK NE23 3JU
`·
`9556643
`Issued April 2003
`COPYRIGHT © MERCK & CO., Inc., 1991, 1995, 1998,
`2002
`All rights reserved
`Shown in Product Identification Guide, page 325
`
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`
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`PHYSICIANS' DESK REFERENCE®
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`information,
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`healthcare
`
`ZETIATM
`[zet' e a]
`(ezetimibe)
`TABLETS
`
`DE.SCRIPTION
`ZETIA (ezetimibe) is in a class of 1ipid-lowering compounds
`that selectively inhibits the intestinal absorption of choles(cid:173)
`terol and related phytosterols. The chemical name of
`ezetimibe is 1-(4-fltioropheny))-3(R)-[3-(4-fluoropheny!)·
`3(S)-hydroxypropyl] -4(S).( 4·hydroxyphenyl)-2-azetidinone.
`The empirical formula is C24H21F2N0 3. 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, a.nd acetorie a~d practi·
`cally insoluble in water. ~zetimibe has a melting point of
`about 163oC and is stable at ambient temperature. ZETIAis
`avaPf!ble as a tabl~t for oral atiministration containing
`10 mg of ezetimibe and the following inactive ingt·edien\s:
`croscarmellose sodium NF, lactose monohydrate NF, magne·
`sium stearate" NF, microcrystalline cellulose NF, povidone
`USP, and sodium lauryl sulfate NF.
`CLINICAL PHARMACOLOGY
`Background
`Clinical studies have demonstrated that elevated levels of
`total cholesterol (total-C), low density lipoprotein choles·
`terol (LDL-C) and apolipoprotein B (Apo B), the major pro·
`tein constituent of LDL, promote human atherosclerosis. In
`addition, decreased levels of high density lipoprotein cho\es·
`terol <HDL-C) are associated with the development of ath·
`erosclerosis. 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 rem·
`nants, can also promote atherosclerosis. The independent
`effect of raising HDL-C or lowering triglycerides (TG) on the
`risk of coronary and cardiovascular morbidity and mortality
`has not been determined.
`ZETIA reduces total-C, LDL-C, Apo B, and TG, and in(cid:173)
`creases HDL·C in patients with hypercholesterolemia. Ad·
`ministration of ZETIA with an HMG-CoA reductase inhibi·
`tor is effective in improving serum total-C, LDL-C, Apo B,
`· TG, and HDL-C beyond either treatment alone. The effecls
`of ezetimibe given either alone or in addition to an HMG·
`CoA reductase inhibitor on cardiovascular morbidity and
`mortality have not been established.
`Mode of Action
`Ezetimibe reduces blood cholesterol by inhibiting lhe ab·
`sorption of cholesterol by the small intestine. In a 2-week
`clinical study in 18 hypercholesterolemic patients, ZETIA
`jnhibited intestinal cholesterol absorption by 54%, com·
`pared with placebo. ZETIA had no clinically meaningful er(cid:173)
`fect on the plasma concentrations of the fat-soluble vita·
`rnins A, D, and E (in a study of 113 patients), and did no!
`impair adrenocortical steroid hormone production (in a
`study of 118 patients).
`The cholesterol content of the liver is derived predomi·
`nantly from three sources. The liver can synthesize choles(cid:173)
`terol, take up cholesterol from the blood from circulating lip·
`oproteins, 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 {HMG·
`CoA reductase inhibitors, bile acid sequestrants [resins!,
`fibric acid derivatives, and planL stanols).
`
`

`
`PRODUCT INFORMATION
`
`MERCK/SCHERING-PLOUGH/2119
`
`Table 1
`Response to ZETIA in Patients with Primary Hypercholesterolemia
`(Meana % Change from Untreated Baselineb)
`Treatment group
`Totai-C
`LDL-C
`N
`
`Apo B
`
`TG'
`
`HDL-C
`
`Study 1c
`
`Study 2'
`
`Pooled Datac
`(Studies 1 & 2}
`
`Placebo
`
`Ezetimibe
`
`Placebo
`
`Ezetimibe
`
`Placebo
`
`+1
`
`-12
`
`+1
`
`-12
`
`205
`
`622
`
`226
`
`666
`
`431
`
`Ezetimibe
`
`1288
`
`-13
`
`+1
`
`-18
`
`+1
`
`-18
`
`+1
`
`-18
`
`-1
`
`-15
`
`-1
`
`-16
`
`-2
`
`-16
`
`-1
`
`-7
`
`+2
`
`-9
`
`-8
`
`a For triglycerides, median % change from baseline
`b Baseline - 6n no lipid-lowering drug
`' ZETIA significantly reduced total·C, LDL-C, Apo B, and TG, and increased HDL-C compared to placebo.
`
`-1
`
`+1
`
`-2
`
`+1
`
`-2
`
`+1
`
`HDL-C
`
`+1
`
`+3
`
`Ezetimibe does not inhibit cholesterol synthesis in the liver,
`or increase bile acid excretion. Instead, ezetimibe localizes
`and appears to act at the brush border of the small intestine
`and inhibits the absorption of cholesterol, leading to a de(cid:173)
`crease in the delivery of intestinal cholesterol to the liver.
`This causes a reductiOn of hepatic chOlesterol stor~s and an
`increase in Clearance of cholesterol from the "blood; this dis(cid:173)
`tinct mechanism is complementary to that of HMG-CoA
`reductase inhibitors (see CLINICAL STUDIES).
`Pharmacokinetics
`Absorption
`After oral administration, ezetimibe is absorbed and exten(cid:173)
`sively conjugated to a pharmacologically active phenolic
`glucuronide (ezetimibe-glucuronide). After a single 10-rng
`dose ofZETIA 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 (T max>· There was no substantial deviation from
`dose proportionality between 5 and 20 mg. The absolute bio-.
`availability of ezetimibe cannot be determined, as the com(cid:173)
`pound is virtually insoluble in aque~?US media suitable for
`injection. Ezetimibe has variable bioavailability; the coeffi(cid:173)
`cient of variation, based on inter-subject variability, was 35
`to 60% for AUC values.
`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 Cm~ 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 i~t.estine
`and liver via glucuronide conjugation (a phase II reaction)
`with subsequent biliary and renal excretion. Minimal oxida(cid:173)
`tive 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, consti(cid:173)
`tuting approximately 10 to 20% and 80 to 90% of the total.
`·drug in plasma, respectively. Both ezetimibe and ezetimibe(cid:173)
`glucuronide are slowly eliminatecl from plasm~. with a half(cid:173)
`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-eietimibe (20 mg) to
`human subjects; total ezetimibe (ezetimibe + ezetimibe(cid:173)
`glucuronide) accounted for approximately 93% of the total
`radioactivity in plasma. After 48 hours, there were no de(cid:173)
`tectable levels of radioactivity in the plasma.
`Approximately 78% and 11% of the administered radioactiv(cid:173)
`itY were recovered in the feces and urine, respectively, over
`a 10-day collection period. )Szetimibe was the major compo(cid:173)
`nent 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.
`Special Populations
`Geriatric Patients
`Iri a multiple dose study with ezetimibe given 10 rug once
`daily for 10 days, plasma concentrations for total ezetimibe
`were about 2-fold higher in older (265 years) healthy sub(cid:173)
`jects compared to younger subjects.
`Pediatric Patients
`In a multiple dose study with ezetimibe given 16 rug once
`daily for 7 days, the absorption and metabolism of ezetimibe
`were similar in adolescents (10 to 18 years) and adults.
`Based on total ezetimibe, there are no pharmacokinetic dif(cid:173)
`ferences between adolescents and adults. Pharmacokinetic
`data in the pediatric population <10 years of age are not
`available.
`Gender
`\n 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, thei·e were no pharmacokinetic differences between
`Blacks and Caucasians. There were too few patients in
`other racial or ethnic groups to permit further pharmacoki(cid:173)
`netic comparisons.
`Hepatic Insufficiency
`After a single 10-mg dose of ezetimibe, the mean area unde~·
`the curve (AUC) for total ezetimibe was increased approxi(cid:173)
`mately 1.7-fold in patients with mild hepatic insufficiency
`(Child-Pugh score 5 to 6), compared to healthy subjects. The
`meanAUC values for total ezetimibe and ezetimibe were in(cid:173)
`creased approximately 3-4 fold and 5-6 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 insufficiency, the mean AUC values for total
`ezetimibe and ezetimibe were increased approximately
`Hold 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 insuf(cid:173)
`ficiency, ZETIA is not recommended in these patients (see
`CONTRAINDICATIONS and PRECAUTIONS, Hepatic
`Insufficiency).
`
`Table 2
`Response to Addition ·of ZETIA to On~going HMG-CoA Reductase Inhibitor Thera pya in
`Patients with Hypercholesterolemia
`(Meanb % Change from Treated Baselinecl
`Apo B
`LDL-C
`
`N
`
`Totai-C
`
`TGb
`
`Treatment
`(Daily Dose}
`
`On-going HMG-CoA
`reductase inhibitor
`+Placebo•
`
`On-going HMG-CoA
`reductase inhibitor
`+ZET!Ad
`
`390
`
`379
`
`-2
`
`-4
`
`-3
`
`-3
`
`-17
`
`-25
`
`-19
`
`-14
`
`a Patients receiving each HMG-CoA reductase inhibitor: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin,
`ftuVastatin," cerivasfatin, lovastatin)
`'
`h For triglycerides, median % change from baseline
`c Baseline • on an HMG-CoA reductase inhibitor alone.
`d ZETIA + HMG-CoA reductase inhibitor significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C
`compared to HMG-CoA reductase inhibitor alone.
`
`Renal Insufficiency
`After a single 10-mg dose of ezetimibe in patients with se(cid:173)
`ver·e renal disease (n::::;8; inean CrCl :530 mUmin/1.73 m2
`),
`the mean AUC values for total ezetiroibe,· ezetimibe-gluc(cid:173)
`uronide, and ezetiinibe were increased approximately 1.5-
`fold, compared to healthy subjects (n=9).
`Drug Interactions (See also PRECAUTIONS, Drug Interac(cid:173)
`tions)
`ZETJA had no sigllificant effect on a series of probe drugs
`(caffeine, dextromethorphan, tolbutamide, and rv··midazo(cid:173)
`lam) 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 in(cid:173)
`hibitor 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.
`Warfarin: Concomitant administration of ezetimibe (10 mg
`once daily) had no significant effect on,.bioavailability of
`warfarin and prothrombin time in a study of twelve healthy
`adult males.
`Digoxin: Concomitant administration of ezetimibe (10 mg
`once daily) 4ad no significap.t effect on ~he bioavailability of
`digoxin and the ECG parameters (HR, PR, QT, and QTc in(cid:173)
`tervals) in a study of twelve healthy adult males.
`In a study of twelve healthy adult males, con(cid:173)
`Gemfibrozil:
`comitant administration of gemfibrozil (600 mg twice daily)
`significantly increased the oral bioavailability of total
`ezetimibe by a factor ofl.7. Ezetimibe (10 mg once daily) did
`not significantly affect the bioavailability of gemfibrozil.
`Oral Contraceptives: Co-administration of ezetimibe
`(10 mg once daily) with oral contraceptives had no signifi(cid:173)
`cant effect on the bioavailability of ethinyl estradiol or
`levonorgestrel in a study of eighteen healthy adult females.
`Cimetidine: Ml,lltiple doses of cirnetidine (400 rug twice
`daily) had no significant effect on the oral bioavailability of
`ezetimibe and total ezetirnibe in a study of twelve healthy
`adults.
`In a study of twelve healthy adults, a single dose
`Antacids:
`of antacid (Supralox TM 20 mL) administration had no signif(cid:173)
`icant effect on the oral bioavailability of total ezetimibe,
`ezetimibe-glucuronide, or ezetimibe based on AUC values.
`The Cmax value of total ezetimibe was decreased by· 30%.
`Glipizide:
`In a study of twelve healthy adult males, steady(cid:173)
`state levels of ezetimibe (10 rug once daily) had no signifi(cid:173)
`cant effect on the pharmacokinetics and pharmacodynamics
`of glipizide. A single dose of glipizide (10 mg) had no signif·
`icant effect on the exposure to total ezetimibe or eZetimibe.
`HMG-CoA reductase inhibitors:
`In studies of healthy hy(cid:173)
`percholesterolemic (LDL-C 2130 mg/dL) adult subjects,
`concomitant administration of ezetimibe (10 rug once daily)
`had no significant effect on the bioavailability of either lov(cid:173)
`astatin, si~vastatin, prav.astatin, atorvastatin, or fluvasta(cid:173)
`tin. No significant effect on the bioavailability of total
`ezetimibe and ezetimibe was demonstrated by either lovas(cid:173)
`tatin (20 mg once daily), pravastatin (20 mgoncedaily ), atorva(cid:173)
`statin (10 mg once daily), or ftuvastatin (20 mg once daily).
`In a study of thirty-two healthy" hypercholes(cid:173)
`Fenofibrate:
`terolemic (LDL-C 2130 mg/dL) adult subjects, concomitant
`fenofibrate (200 mg once daily) administration increased
`the mean Cmax and AUC values of total ezetimibe approxi-
`
`mately 64% and 48%, respectively. Pharmacokinetics of
`fenofibr"ate. were not significantly affected by ezetimibe
`(10. mg once daily)."
`Cholestyramine: In a study of forty he~lthy hypercholes"(cid:173)
`terolemic (LDL-C 2130 mg/dL) adult subjects, concomitant
`cholestyramine (4 g twice daily) administration decreased
`the mean AUC values of total ezetimibe and ezetimibe ap(cid:173)
`proximately 55% and 80%, respectiVely.
`ANIMAL PHARMACOLOGY
`The hypocholes.terolemic effect of ezetimibe was ev3.1uat€d
`in cholesterOl-fed Rhes~s monkeys, dogs, rats, and mouse
`models· of human cholesterol metabolism. Ezetimibe waS
`found to have an ED 50 value of 0.5 J.lg/kg/day for inhibiting
`tJ:le rise in plasma chOlesterol levels in monkeys. The ED50
`values in dogs, rats, and inice were 7, 30, and 700 ]lgikg/day,
`respectively. These resultS· are consistent with ZETIA being
`a potent cholesterol absorption inhibitor.
`In a r·at · model, where the glucuronide metabolite of
`ezetimibe (SCH 60663) was administered intraduodenally,
`the .metabolite was as potent as the parent compound (SCH
`58235) in inhibiting the absorption of cholesterol, suggest(cid:173)
`ing that the gluCuronide metabolit~ had activity similaf to
`the parent drUg.
`In 1-month studies in dogs given ezetimibe (0.03-300 mg/
`kg/day), the concentration of cholesterol in gallbladder bile
`increased ~2- to 4-fold. However, a dose of 300 mg/kg/day
`administered to dogs for one year did not result in gallstone·
`formation or any other adverse hepatobiliary effects. In a
`14-day study in mice given ezetimibe (0.3-5 mg/kg/day) and
`the concentration of
`fed a low-fat or c~olesterol-rich di€t,
`cholesterol in gallbladder bile was either unaffected· or re(cid:173)
`duced to normal levels, respectively.
`A series of acute preclinical studies was performed to deter(cid:173)
`mine the selectivity of ZETIA for inhibiting cholesterol ab(cid:173)
`sorption. Ezetirnibe inhibited the absorption of 14C choles(cid:173)
`terol with no effect on the absorption of triglycerides, fatty
`acids, 'bile acids, progesterone, ethyl estradiol, or the fat(cid:173)
`solUble vita'mins A and D.
`In 4- to 12-week toxicity studies in mice, ezetimibe did not
`induce cytochrome P450 drug metabolizing enzymes. In
`toxicity studies, a pharmacokinetic interaction of ezetimibe
`with HMG-CoA reductase inhibitors (parents or their active
`hydroxy acid metabolites) was seen in rats, dogs, and rab(cid:173)
`bits.
`CLINICAL STUDIES
`Primary Hypercholesterolemia
`ZETIA reduces total-C, LDL·C, Apo B, and TG, and in(cid:173)
`creases HDL-C in patients with hypercholesterolemia. Max(cid:173)
`imal to near maximal response is generally achieved within
`2 weeks and maintained during chronic therapy.
`ZETIA is effective in patients with hypercholesterolemia, in
`men and women, in younger and older patients, alone or ad(cid:173)
`ministered with an HMG-CoA reductase inhibitor. Exper(cid:173)
`ience in pediatric and adolescent patients (ages 9 to 17) has
`been limited to patients with homozygous familial hyper(cid:173)
`cholesterolemia (HoFH) or sitosterolemia.
`
`Continued on next page
`
`Consult 2 0 0 4 POR® supplements and future editions for revisions
`
`

`
`2120/MERCK/SCHERING-PLOUGH
`
`PHYSICIANS' DESK REFERENCE®
`
`Zetia-Cont.
`
`Treatment
`(Daily Dose)
`
`Placebo
`
`ZETIA
`
`Atorvastatin 10 mg
`
`ZETIA+
`Aton'astatin 10 mg
`
`Atorvastatin 20 mg
`
`ZET)A+
`Atorvastatin 20 mg
`
`Atorvastatin 40 mg
`
`ZETIA +
`Aforvastatin 40 mg
`
`Atorvastatin 80 mg
`
`ZETIA+
`Atorvastatin 80 mg
`
`Pooled data (All
`Atorvastatin Doses)c
`
`Pooled data (All ZETIA +
`Atorvastatin Doses)~
`
`Table 3
`Response to ZETIA and Atorvastatin Initiated Concurrently
`in Patients with Primary Hypercholesterolemia
`(Mean 8 % Change from Untreated Baselineb)
`N
`Totai-C
`Apo B
`LDL-C
`
`60
`
`65
`
`60
`
`65
`
`60
`
`62
`
`66
`
`65
`
`62
`
`63
`
`248
`
`255
`
`+4
`
`-14
`
`-26
`
`-38
`
`-30
`
`-39
`
`-32
`
`-42
`
`-40
`
`-46
`
`-32
`
`-41
`
`+4
`
`-20
`
`-37
`
`-53
`
`-42
`
`-54
`
`-45
`
`-56
`
`-54
`
`-61
`
`-44
`
`+3
`
`-15
`
`-28
`
`-43
`
`-34
`
`-44
`
`-37
`
`-45
`
`-46
`
`-50
`
`-36
`
`TG'
`
`-6
`
`-5
`
`-21
`
`-31
`
`-23
`
`-30
`
`-24
`
`-34
`
`-31
`
`-40
`
`-24
`
`HDL-C
`
`+4
`
`+4
`
`+6
`
`+9
`
`+4
`
`+9
`
`+4
`
`+5
`
`+3
`
`+7
`
`+4
`
`+7
`
`-56
`
`-45
`
`-33
`
`a For triglycerides, median % change from baseline
`b Baseline - on no lipid-lowering drug
`' ZETIA + all doses of atorvastatin pooled (10-80 mg) significantly reduced total-C, LDL-C, Apo B, and TG, and increased
`HDL-C compared to all doses of atorvastatin pooled (10-80 mg).
`
`N
`
`Experience in non-Caucasians is limited and does not per(cid:173)
`mit a precise estimate of the magnitude of the effects Of
`ZETIA.
`Monotherapy
`In two, multicenter, double-blind, placebo-controlled, 12-
`week studies in 1719 patients with primary hypercholester(cid:173)
`olemia, ZETIA significantly lowered total-C, LDL-C, Apo B,
`and TG, and increased HDL-C compared to placebo (see
`Table 1). Reduction in LDL-C was consistent across age,
`sex, and baseline LDL-C.
`[See table 1 at top of previous page!
`Combination with HMG-CoA Reductase Inhibitors
`ZETIA Added to On-going HMG-CoA Reductase Inhibitor
`Therapy
`In a multicenter, double-blind, placebo-controlled, 8-week
`study, 769 patients with primary hypercholesterolemia,
`known coronary heart disease o