C DEPARTMENT OF HEALTH 8:. HUMAN SERVICES Public Health Service
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`Date: _;(/7'
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`In response refer to File Numberpi2.ZZ2${]
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`in which you
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`HFD-19
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`AURO - EXHIBIT 1014
`0001
`
`

`
`foi FOl Services, Inc.
`
`12315 Wilkins Avenue
`Rockville MD 20852-1877 USA
`Phone: 301/881-0410
`301/881-0415
`Pax: (cid:9)
`
`FOOD & DRUG ADMINISTRATION (cid:9)
`FREEDOM OF INFORMATION STAFF
`5600 FISHERS LANE (cid:9)
`ROCKVILLE, MD 20857
`
`8/30/94
`
`CONTROL NUMBER 124176
`
`PURSUANT TO THE PROVISIONS OF THE FREEDOM OF INFORMATION ACT, PLEASE
`PROVIDE US WITH A PAPER COPY (NOT MICROFICHE) OF THE FOLLOWING
`DOCUMENTS. IF THE COST OF PROVIDING THESE DOCUMENTS WILL EXCEED
`100.00, PLEASE CALL US FIRST FOR AUTHORIZATION OF THE CHARGES,
`UNLESS INDICATED OTHERWISE BELOW.
`
`PLEASE REFER TO OUR CONTROL NUMBER IN YOUR REPLY.
`
`ATTENTION: CENTER FOR DRUGS
`
`COPY OF ALL DISCLOSABLE APPROVAL INFORMATION, INCLUDING APPROVAL LETTER
`AND LABELING FOR THE LABELING REVISION APPROVED 5/17/94 FOR MEVACOR
`TABLETS 10MG, 20MG & 40MG MANUFACTURED BY MERCK.
`
`C 4-34943
`RECEIVED
`
`SEP 0 1 1994
`
`FDA FOI STAFF (H -35)
`
`0002
`
`

`
`NDA 19-643/S-032
`NDA 19-643/S-033/ (cid:9)
`
`MAY 1 7 1994
`
`Merck & Co., Inc.
`Attention: Robert E. Silverman, M.D., Ph.D.
`Director, Regulatory Affairs
`BLA-30
`West Point, PA 19486
`
`Dear Dr. Silverman:
`
`Please refer to your March 1 (Supplement-032) and August 19, 1993, (Supplement-033)
`supplemental new drug applications submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act for Mevacor (lovastatin) Tablets.
`
`The supplemental applications provide for changes to the package insert regarding the
`following: Supplement-032 - Deletion of A.H.F.S. categories, editorial revisions to the
`"Clinical Studies" subsection of the CLINICAL PHARMACOLOGY section, additions
`to the "Hypersensitivity Reaction" and "Skin" subsections of the ADVERSE
`REACTIONS section, and class labeling revisions; and Supplement-033 - Revisions to
`the INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections
`based on the revised National Cholesterol Education Program (NCEP) Guidelines
`dated June 15, 1993, and includes the changes submitted in Supplement-032.
`
`We have completed our review of these supplemental applications and have concluded
`that adequate information has been presented to demonstrate that the drug product is
`safe and effective for use as recommended in the July 1993, final printed labeling
`submitted in Supplement-033 on August 19, 1993. Accordingly, the supplemental
`applications are approved effective on the date of this letter.
`
`Should additional information relating to the safety and effectiveness of the drug
`become available, revision of that labeling may be required.
`
`We remind you that you must comply with the requirements for an approved NDA
`set forth under 21 CFR 314.80 and 314.81.
`
`0003
`
`

`
`NDA 19-643/S-032 (cid:9)
`NDA 19-643/S-033
`
`Page 2
`
`Should you have any questions, please contact:
`
`Mr. Stephen T. Trostle
`Consumer Safety Officer
`Telephone: 301-443-3520.
`
`Sincerely yours,
`
`Solomon Sobel, M.D.
`Director
`Division of Metabolism and
`Endocrine Drug Products (HFD-510)
`Center for Drug Evaluation and Research
`
`cc:
`Original NDA
`HF-2 (with labeling)
`HFC-130/JAllen
`HFD-80 (with labeling)
`HFD-240 (with labeling)
`HFD-600 (with labeling)
`HFD-730 (with labeling)
`HFD-500/LRipper (with labeling)
`HFD-510
`HFD-510/SAurecchia/CNiu/EBarbehenn
`HFD-510/STrostle/05/12/94/ft/stt/05/16/94 \N19643AP.032
`Concurrence: (cid:9)
`EGalliers, SAurecchia 05.12; GTroendle, MRhee,
`YChiu, AJordan for EBarbehenn, AJordan 05.16.94
`
`SUPPLEMENT(S) APPROVAL (AP-032/AP-033)
`
`0004
`
`

`
`-34A;tr1/41-
`Severm,m, M 11
`
`11(Ther! (cid:9)
`Cireclic
`fiequ!atory Attnir.
`
`N/6
`
`LIZ desk copies.
`
`-12 REF. NO. ,1)3.
`NrA (cid:9)
`A SUPPL FoR
`
`0s---(1`14,gy
`
`Merck & Co .
`REA 30
`West Point PA 19486
`fax 215 397 2335
`lel 215 397 2944
`2' 5 652 5000
`
`MERCK
`
`Research Laboratories
`
`August 19, 1993
`
`Solomon Sobel, M.D. - Director
`Division of Metabolism and Endocrine
`Drug Products HFD-510, Room 14B-04
`Office of Drug Evaluation II (CDER)
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`Dear Dr. Sobel:
`
`SPECIAL SUPPLEMENT - CHANGES BEING EFFECTED
`
`NDA 19-643: MEVACOR (Lovastatin)
`
`Pursuant to Section 505(b) of the Food Drug and Cosmetic Act and in accordance with 21 CFR
`;14 50(c), we submit, for your approval, a supplement to NDA 19-643.
`
`As indicated on the attached Form FDA 356h, the supplemental application provides for changes in
`Item 4.c.ii of the approved Ne w Drug Application for Mevacor.
`
`Reference is made to our letter dated June 7, 1993 and your letter dateJ July 14, 1993 concerning
`incorporation of the new NCEP Guidelines into the approved labeling for Mevacor.
`
`This supplement is being submitted in response to your July 14, 1993 letter and contains a summary of
`revisions, an annotated revised package circular, and twelve (12) copies of the final printed package
`circular (No. 7526525). The labeling has been revised under INDICATIONS AND USAGE and
`DOSAGE AND ADMINISTRATION based on new NCEP Guidelines dated June 15, 1993.
`
`the changes will become effective on or about October 1, 1993 and will apply to all packages of
`Mevacor distributed from the company's manufacturing facilities at West Point, Pennsylvania.
`
`0005
`
`

`
`Solomon Sobel, M.D. - Director
`NDA 19-643: MEVACOR (Lovastatin)
`Page 2
`
`We consider the filing of this Supplemental New Drug Application to be a confidential matter, and
`request the Food and Drug Administration not to make its content, nor any future communications in
`regard to it, public without first obtaining the written permission of Merck & Co., Inc.
`
`Questions concerning this supplemental application should be directed to Robert E. Silverman, M.D.,
`Ph.D.(215/397-2944) or, in my absence, to Bonnie J. Goldmann, M.D. (215/397-2383).
`
`Robert E. Silverman, M.D., Ph.D.
`Director, Regulatory Affairs
`
`Q:CAYWI AlezZCFIG
`
`Attachments
`
`Circular No. 7526525
`
`Federal Express No. 7470347150
`
`Desk Copy:
`
`Dr. S. Auerrechia, HFD-510, Room 14B-26
`
`Mr. S. Trostle, HFD-511, Room 14B-04
`
`0006
`
`

`
`NDA 19-643 (cid:9)
`MIGINAL
`c_
`
`10
`
`LaLabeling;'
`NDA No :
`
`Otsviewed by:
`
`Ro 'd. (cid:9)
`
`
`
`rdoi
`
`0 MERCK & CO., MC.
`West Point, PA 19486, USA
`
`TABLETS
`
`MEVACOR®
`
`(LOVASTATIN)
`
`7526525
`
`DESCRIPTION MEVACOR* (Lovastatin) is a cholesterol lowering agent isolated from a strain of AspergilloS temsus. Atter oral
`mgesnon. lovaStatin, winch is an inactive lacione. is hydrolyzed to the corresponding EfihYdroxyacid form, This is a pnnopal
`metabonte and an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the
`conversion of HMG-CoA to mevalonate. which tan early and rate limiting step on the biosynthesis of cholesterol.
`$-(1.(Fr).3u7(5,85(25-.45"). 81151)-1.2.3,7.8Ela-hexahydro-3.7-drmethyl-8-12-detrahyciro-4-hydroxy-6-oxo-
`Lovastatin (cid:9)
`2/4-pyran-2-ylethyll-l-naphthalenyl 2-methylbutanoate. The empirical formula 01 lowastatin in .2,H,.0, and as molecular weight
`is 4(14.55 Its structural formula is
`Lovastatin rs a white, nonhygroscopm crystalline powder that is insoluble in
`water and sparingly soluble In ethanol, methanol, and acetorttnle.
`Tablets MEVACOR are supplied as 10 erg. 20 mg and 40 mg tablets for oral
`adthirkstratron. In aglitter, Is the active ingredient lovastatm, each tablet
`contains the following Inactive ingredients, cellulose, lactose, magnesium
`stearate. and starch. Bulylated hydroxyansole (BHA) is added as a Preserva-
`tive. Tablets MEVACOR 10 mg also contain red ferric oxide and yellow ferric
`oxide. Tablets MEVACOR 20 mg also contain FD&C Blue 2. Tablets
`MEVACOR 40 mg also contain DEC Yellow 10 and FD&C Blue 2
`
`HO
`
`CHs
`
`
`
`HsC
`
`CUNICAL PHARMACOLOGY The invoNernern of low-density hpoprotern
`(LDL) cholesterol in atherogeness has been wet-documented n clinical and
`pathological studies. as well as 0 many animal experiments. Egdemiologmat (cid:9)
`studies have established that high LDL (low-density lipoprotein) cholesterol
`and low HDL (high-density lipoprotein) cholesterol are both risk factors for
`coronary heart disease. The Liprol Research Clinics Coronary Primary Prevention Teal (LRC-CPPT), coordinated by the National
`Institutes of Health (NIH) studied men aged 35-59 with total cholesterol levels 265 mg/dL (6,8 mmol/ Li or greater. LDL cholesterol
`values 175 rnigroL (45 mmol/L) or greater aid tnglyceribe levels not more than 300 mg/dL (3.4 rnmoUL). This seven-year. double-
`tdind. placebo-controlled study demonstrated that lowenng LDL cholesterol with diet and chulektyramine decreased the combined
`rate of coronary heart disease death plus non-fatal myocardial infarction.
`MEVACOR has been shown to reduce both norrral and elevated LDL cholesterol concentrations. The effect ol rovastatrn-
`induced changes In lipoprotein levels, including reduction of serum cholesterol, on cardiovascular morbidity or mortally nas not
`been established
`LDL is formed from VLDL and s catabolized predominantly by the high aft inny LDL receptor. The mechanism of the LDL.
`lowenng effect of MEVACOR may involve both reduction of VLDL cholesterol concentration, and incluctron 01 the LDL receptor,
`leading to reduced production and/or increased catabolism of LDL cholesterol. Aparporprolein B also falls substantially dunng •
`treatment with MEVACOR. Since each LDL particle contains one molecule of apoirpotxotein B. and since little apolpoprotein B ts
`found in other lipoproteins, this strongly suggests that MEVACOR does not merely cause cholesterol 10 be lost from LDL. but also
`reduces the concentration of orcularting LDL particles. In addition. MEVACOR can produce Increases of variable magnitude in
`HOL cholesterol and modestly reduces VLDL cholesterol and plasma tnglycerides (see Tables I-1V under Clinical Studies/. The
`Vent biochemical esk markers Ion coronary heart disease are
`effects of MEVACOR on Lp(a), fibnnogen, and certain other nidispe
`unknown.
`MEVACOR s a specific inhibitor of HMG-COA reductase, the enzyme which catalyzes the conversion of I-IMG-CoA to
`rrevaionate. The conversion of HMG-CoA to rnevalonale is an early step re the biosyrrilmta, pathway for cholesterol.
`
`Pharmacokirretics Lovastatin is a redone which is readily hydrolyzed in woo to Me corresponding B-hydroxyacd. a potent
`,nhrbilor of HMG-Cat reductase. Inhibition ol HMG-CoA reductase is the bout for an assay in pharmacokinelc studies of the
`13-nydroxyacd metabolites (active inhibitors) and. lolloving base hydrolysis. active plus latent inhibitors (total inhibitors) in plasma '
`blowing administration of lovastatin
`Foltmeng an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in unne and 83% in feces. The latter
`represents absorbed drug equivalents excreted in bile, as wet as any unabsorbed drug. Plasma concentrations of total
`radroactmly devastate plus 14C-rnetabolnes) peaked at 2 hours and declined rapidly to about 10% ol peak by 24 hours postoose
`Absorption of lovastattn, estimated reiative to an intravenous reference dose, rn each of lour animal species tested. averaged
`about 30% of an oral dose. In animal studies, aver oral dosing. lovastatte had high Wed.-fly for the liver. where it achieved
`substantially higher concentrations than in non-target tssueS. Lovastatin undergoes extensive fest-pass extraction in the hver. its
`pnrhary sae of action, with subsequent excretion of drug equivalents in the bee As a consequence of extensive hepauc extraction .
`al rovastatm, the avatar:Arty of drug to the general emulation S low and variable. In a single dose study in four hypercholesterd- •
`emc patents. It was estimated that less than 5% of an oral dose of lovastalm reaches Me general circulation as active rehrtirtors.
`Followng adminestration of lovastaun tablets the coefficient Of variation. based on between-subject variability, was approximately
`40% `Or rte area under the curve (AOC) of total inhibitory active/ in the general proulation.
`Both lovaStatin and it 13-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins Anmal studies
`demonstrated that lovastatin crosses the blood-brain and placental barriers
`The major active metabolites present in human plasma are the 13-hydroxyacKI of tovaslahn, its 6'-hyd,uxy derivative. and two
`additional metabolites Peak plasma concennabons of both active and total rntilbetterS were attained within 2 to 4 hours of dose
`admrnistration. While the recommended therapeutic dose range t 20 to SO ring/day, linearity of inhibitory activity in the general
`circulation was established by a single dose study employing lovastabn tablet dosages tram 60 to as high as 120 mg. Wits a once-
`aroay dosing regimen. plasma toncentrabons of total inhibitors over a dosing Interval &Okayed a steady stale between the second
`and thee clays of therapy and were about 1 5 times those following a ante* dose. When lovastann was given under tasting
`conditions, plasma concentrations of total inhibitors were on average about two-thirds those found when lovastahn was
`administered immediately utter a standard lest meal
`In a study of patients won severe renal rnsufficency forearm,* clearance 10-30 mUmtn), the plasma concentrations of total
`inhibitors alter a single dose of lovastann were approximately two-fold higher than those in healthy volunteers.
`
`Clinical Studios MEVACOR has been shown to be hghly effective in reducing total and LDL cholesterol in heterozygous familial
`and non-familial torms of pnmary nypercholesterolernks and in mixed hypenlikteleina A marked response was seen within 2
`weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during continua. .n of
`therapy. Single daily doses given in the evening were more effective than the same close given in the morning, perhaps because
`cholesterol s synthesized mainly at night.
`In munrcenter, double-blind studies in patients with larrskal or non-fanlike' hyperchoeswolema, MEVACOR. administered
`doses ranging horn 20 mg ()p.m. to 40 mg bid., was compared to placebo. MEVACOR consistently and significantly decreased
`total plasma cnolesterol (TOTAL-C). LDL cholesterol (LDL-C). total cholesterol/HEX cholesterol (TOTAL-C/HDL-C) ratio and LDL
`cholesterol/HDL cholesterol (LOL-C/HDL-C) ratio In addition. MEVACOR produced rncreases of vanabie reagnnuce in HDL
`cnolesleroi 0-10L.C). and modestly decreased VLDL cholesterol (VLDL-CI and plasma trtglycendes (TRIG.) (see Tabes I and IV
`lot- dose response results).
`
`TABLE I
`FAMILIAL HYPERCHOLESTEROLEMIA STUDY
`DOSE RESPONSE OF MEVACOR
`
`DOSAGE
`
`Placebo
`MEVACOR
`20 mg q.p.rn
`to -rig q p.m
`10 mg b i.d.
`20 mg b.i.d
`40 mg [Lid.
`
`N
`
`21
`
`20
`21
`19
`20
`20
`
`(Percent Change from Baseline After 6 Weeks)
`LDL-C/
`HDL-C
`(mean)
`- 1
`
`LOL-C
`(mean)
`- 2
`
`HDL-C
`(Mean)
`4-1
`
`TOTAL-C
`(mean)
`-1
`
`TOTAL-C!
`HDL-C
`(mean)
`0
`
`TRIG
`I elegem
`+3
`
`-18
`-24
`-22
`-27
`-34
`
`-19
`-27
`-25
`-31
`-39
`
`+10
`+10
`-+6
`+12
`+8
`
`-26
`-32
`-28
`-38
`-43
`
`-24
`-7
`-22
`-29
`-it
`-25
`-ma
`-34
`-38
`-12
`MEVACOR toes compared to cholestyrarnine in a randomized open parallel study and to StrObbCot re a double- kind. parallel
`-Sway Both studies were performed with patients with hyperChOleStevolerrea who were at high risk of myocardial rtarchon
`Summary results or these two comparative studies are presented in Tables 11 & III
`
`TABLE II
`MEVACOR vs Ovierstyramine
`
`TREATMENT
`
`N
`
`(Percent Change from Baseline Mat 12 WOOS)
`TOTAL-C/
`HDL-C
`(mean)
`
`HDL-C
`imean)
`
`HOL-C
`(mean)
`
`TOTAL-C
`(mean)
`
`LDL-C
`rowan,
`
`VLDL-C
`median)
`
`TRIG.
`(rnedan)
`
`MEVACOR
`20 mg o d
`40 mg bit
`
`85
`88
`
`-27
`--34
`
`-32
`-42
`
`+9
`+13
`
`-36
`-44
`
`-31
`-37
`
`-34
`-31
`
`-2t
`-27
`
`0007
`
`(cid:9)
`(cid:9)
`

`
`DOSAGE (cid:9)
`
`Placebo
`MEVACOR
`20 rng qp.rn
`40 '110 cl.P.m
`10 mg bt.d_
`20 mg bed.
`40 mg b.td.
`
`N (cid:9)
`
`21
`
`20
`21
`19
`20
`20
`
`(Percent Change horn Baseline After 6 Weeks)
`LDL-C, (cid:9)
`HDL-C (cid:9)
`(mean) (cid:9)
`-1
`
`TOTAL-C (cid:9)
`(mean) (cid:9)
`- .
`
`LOL-C (cid:9)
`(mean) (cid:9)
`-2
`
`HDL-C (cid:9)
`(mean) (cid:9)
`4-1
`
`-18
`-24
`-22
`-27
`-34
`
`-19
`-27
`-25
`-31
`-39
`
`+10
`+10
`+6
`+12
`+8
`
`-26
`-32
`-28
`-38
`-43
`
`TOTAL-Ci
`HOL-C (cid:9)
`(mean) (cid:9)
`0
`
`-24
`-29
`-25
`-34
`-38
`
`TRIG
`(metian)
`+3
`
`-7
`-22
`-11
`-18
`-12
`
`MEVACOR was compared to cholestyramine in a randomized open parallel study and to probucol m a double-blind. parallel
`study. Both studies were performed with patients with hypertholesterolernia who were at high nsk of myocardial I niarctron
`Summary results of these two comparaine studies are presented in Tables II 8 Ill
`
`TABLE LI
`MEVACOR vs. Chltestyramele
`
`TREATMENT
`
`MEVACOR
`20 mg b., d.
`40 mg D.J.0.
`Cholestyramtne
`12 gbid
`
`(Percent Change from Baseline Alter 12 Weeks)
`LDL-C/ (cid:9)
`TOTAL-C!
`HDL-C (cid:9)
`HOL.0
`(mean) (cid:9)
`(mean)
`
`TOTAL-C (cid:9)
`(mean) (cid:9)
`
`LDL-C (cid:9)
`(mean) (cid:9)
`
`HOL.0 (cid:9)
`(mean) (cid:9)
`
`VLDL-C
`(median)
`
`TRIG
`(median)
`
`85
`68
`
`88
`
`-27 (cid:9)
`-34 (cid:9)
`
`-17 (cid:9)
`
`-32 (cid:9)
`-42 (cid:9)
`
`-23 (cid:9)
`
`+9 (cid:9)
`+8 (cid:9)
`
`*8 (cid:9)
`
`-36 (cid:9)
`-44 (cid:9)
`
`-27 (cid:9)
`
`-31
`-37
`
`-21
`
`-34
`-31
`
`+2
`
`-21
`-27
`
`+11
`
`TABLE Ill
`MEVACOR vs. Protkicol
`(Percent Change from Baseline After 14 Weeks)
`TOTAL-C:
`LDL-C/ (cid:9)
`HDL-C (cid:9)
`HDL-C
`(mean) (cid:9)
`(mean)
`
`TOTAL-C (cid:9)
`(meal) (cid:9)
`
`LDL C (cid:9)
`
`HDL-C (cid:9)
`rnean) (cid:9)
`
`VLDL-C
`(meclan)
`
`TRIG
`(medan)
`
`TREATMENT
`
`6(
`
`MEVACOR
`40 rng q.p.m.
`80 rng q p.m
`40 mg bi.d
`Protitcot
`500 mg bt.0
`
`47
`49
`47
`
`97
`
`-25 (cid:9)
`-30 (cid:9)
`-33 (cid:9)
`
`- 10 (cid:9)
`
`-32 (cid:9)
`-37 (cid:9)
`-40 (cid:9)
`
`+9 (cid:9)
`+11 (cid:9)
`+12 (cid:9)
`
`-8 (cid:9)
`
`-23 (cid:9)
`
`-38 (cid:9)
`-42 (cid:9)
`-45 (cid:9)
`
`+26 (cid:9)
`
`-31
`-36
`-39
`
`+23
`
`-37
`-27
`-40
`
`-13
`
`-18
`-17
`-25
`
`'Reg stered trademark of MERCK 8 CO NC (cid:9)
`
`COPYRIGHT tz MERCK 8 CO Inc 1987 1989. 1991 (cid:9)
`
`All rights reserved
`
`0008
`
`

`
`MEVACOR" (LOvastatin) (cid:9)
`
`7526525
`
`Expanded Clinical Evaluation of Lovastattn (EXCEL) Study MEVACOR was compared to placebo in 8245 patients with
`hypercholesterolemia (total cholesterol 240-300 mpidL (6.2 mmol/L - 7.6 mmobl], LDL cholesterol >160 rngicIL 14.1 mrnolit)) In
`the raNlornized, double-blind, parallel. 48-week EXCEL study. All changes in the lipid measurements (Table IV) in MEVACOR
`treated patients were dose-related and significantly different hom placebo (ps0.001). These results were sustained throughout
`the stirdy
`
`TABLE IV
`MEVACOR vs. Placebo
`(Percent Change from Baseline —
`Average Values Between Weeks 12 and 48)
`LOL-CI (cid:9)
`1-4DL-C (cid:9)
`I mean) (cid:9)
`
`LDL-C (cid:9)
`_
`(mean) (cid:9)
`
`HDL-C (cid:9)
`(mean) (cid:9)
`
`TOTAL-C (cid:9)
`(mean) (cid:9)
`
`TOTAL-Cl
`HDL-C (cid:9)
`(mean) (cid:9)
`
`DOSAGE (cid:9)
`
`la- (cid:9)
`
`1663
`
`1642
`1645
`1646
`1649
`
`-.0 7
`
`-17
`-22
`-24
`-29
`
`+0.4
`
`-24
`-30
`-34
`-40
`
`+2_0
`
`+66
`+7.2
`+8.6
`+9.5
`
`+02
`
`-27
`-34
`-38
`-44
`
`+0 6
`
`-21
`-26
`-29
`-34
`
`Placebo
`MEVACOR
`20 rng cl-Pm
`40 mg OP-m
`20 mg bid.
`40 ing b fid.
`'Patents enrolled
`Eye (cid:9) There was a high prevalence of baseline lenticular opacities in the patient population included in the early clinical trials with
`lovathatin. During these trials the appearance of new opacities wasnoted in both the lovastatin and placebo groups. There was no
`clinically significant change in visual acuity in the patients who had new opacities reposed nor was any patient, including those
`with opacities noted at baseline, discontinued from therapy because of a decrease in visual acuity.
`An interim analysis was performed at 2 years in 192 hypercholesterdemic patients who pad/Created in a placebo-controlled,
`parallel. double-blind study to assess the effect of lovastatin on the human lens. There were no clinically significant differences
`between the lovastatin and placebo coups in the incidence. type, or progression of lenticular opacities
`
`TRIG.
`(median)
`+4
`
`-t0
`-14
`-16
`-19
`
`INDICATIONS AND USAGE Therapy with lied-altering agents should be a component of multiple risk factor intervention in those
`individuals at significantly increased nsk for atherosclerotic vascular disease due to hypercholesterolentia. MEVACOR is indicated
`as an adjunct to del for the reduction of elevated total and LDL cholesterol levels in patients with comary hyperCholesterolemia
`(Types Ile and 11b1). when the response to diet restricted in saturated tat and cholesterol and to other nonPharmacological
`measures alone has been inadequate.
`Prior to inioasng therapy with lovastatin. secondary causes for hypercholesterdemd (e.g., poorly controlled diabetes mellitus.
`hypothyrodsm, nephrotic syndrome. dysprotememias, obstructive liver disease. other drug therapy. alcoholism) should be
`est:WOW. and a lipid profile performed to measure TOTAL-C. HDL-C. and triglycencles (TG). For patients with TG less than 400
`rnigioL (<4.5 mmoll). LDL-C can be estimated using the following equation:
`LDL-C = Total cholesterol - [0.2 x (triglyCerictes) + HDL-C)
`concentrations should be determined by
`For TG levels >400 mgldL (>4.5 mmoVL). this equation Is less accurate and (cid:9)
`offracentritugation. In hypenriglycendernic patients. LDL-C may be low or normal despite elevated TOTAL-C. In such cases.
`MEVACOR is not indicated.
`The effect of lovastatin-induced changes in lipoprotein levels, including reduction of serum cholesterol. on cardiovascular
`morbidity or modality has not been established.
`The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below.
`
`Delinde
`Atherosclerotic
`Disease'
`NO
`
`NO
`
`YES
`
`Two or More
`Other Risk
`Factors--
`NO
`
`YES
`
`YES or NO
`
`LDL-Cholesterol
`rrya/oL immoVI-1
`
`initiation
`Level
`
`Goal
`
`-(160
`(<4.1)
`
`(<3.41
`
`"3 p- (cid:9) 0 1
`
`03
`(<26)
`
`1-:-4' 9°9i
`, 760
`I na 1)
`z 130
`( -,341
`'Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease!
`"Other risk factors for coronary heart disease (CHD) include: age (males( «45 years: 'senates :55 years or premature
`menopause without estrogen replacement therapy). family history of premature CND. current cigarette smoking: hypertension:
`confirmed HDIC <35 rng/dL (<0.91 mmol/L). and diabetes mellitus Subtract one risk factor 4 HDL-C is :60 mai& ( <1 6
`rnmial&).
`Since one goal of treatment s to diver LDL-C. the NCEP recommends that LDL-C levels be used to initiate and assess
`treatment response_ Only if LDL-C levels are not available_ should the TOTAL-C be used to monitor therapy.
`Although MEVACOR may be useful to reduce elevated LDL cholesterol levels in patients with combined hypercholesterdemia
`and hypertnglycendemd where hyPercholesterotema is the major abnormality (Type Ilb hyperldoprotenerma). it has not been
`studied in conditions where the major abnormality is elevation of chylomicrons, VLDL or IDL 0 e . hypethooprotetherma types I, Ill,
`IV or V).1
`
`CONTRAINDICATIONS NYPerSensitivity to any component of this medication.
`Active liver disease or unetpianed persistent elevations 01 serum transaminases (see WARNINGS)
`Pregnancy and lactate:in. Atherosclerosis is a chronic process and the discontinuation of lipicl.lowerirg drugs Suing pregnancy
`should have little impact on the outcome of long-term therapy el primary hypercholesterOlernm- Moreover. cholesterol and other
`products of the cholesterol biosynthesis pathway are essential components for fetal development. including synthesis of steroids
`and cell membranes Because or the ability of inhibitors of HMG-CoA reductase Such as MEVACOR to decrease the synthesis of
`cholesterol and possibly other products of the cholesterol biosynthesis pathway. MEVACOR may cause fetal harm when
`administered to a pregnant woman. Therefore, lovastatin is comrainclicated during pregnancy LOVastaen should be adminis-
`tered to women of childbearing age only when such patients are highly unlikely to conceive. It the patient becomes pregnant
`while taking this drug lovastatin should be discontinued and the patient should be apprised of the potential hazard to the fetus.
`
`thief Dysfunction Marked persistent increases (to more than 3 times the upper tins of nom al) n son,m
`WARNINGS
`transamenases occurred in 1.99n of adult patients who reclined lovastatin for at least one year in early clinical trials (See
`ADVERSE REACTIONS). When the drug was interrupted or discontnued in these patients. One Pansamsnase levels usually tell
`slowly to pretreatment levels. The increases usually appeared 3 to 12 months after the start of therapy with lovastatin and were
`not askinnated with iaundce or other clinical signs or symptoms. There was no evidence of hycersensamty. In the EXCEL study
`(see CLINICAL PHARMACOLOGY, Clinical Stuckes), the incidence of marked persistent increases in serum transarninaSes over
`48 weeks was 0.191, for placebo, 0 1% at 20 mg/day. 0.9% at 40 mg/day, and 1.5% at 80 migiclay in patients on lovastatin. However.
`in post.rnarketing experience with MEVACOR, symptomatic liver disease has been reported rarely at at: dosages (see ADVERSE
`REACTIONS).
`b is recommended that liver function tests be performed during therapy with Icnrastetin. Serum transaminases, including
`ALT (sGar), should be monitored before treatment begins, every 6 weeks during the first 3 months. every 8 weeks during the
`remainder of the first year, and penodically thereafter log., at approximately 6 month intervals). Special attention should be
`paid to patients who develop elevated serum transaminase levels, and in these patients. measurements Should be repeated
`promptly and thee Performed more frequently It the transaminase ievels show ev4enbe of progresthon, particularly if they rise to
`three times the upper limit of normal and are persrstem. the drug should be discontinued. Liver biopsy shroud be considered it
`elevations are persistent beyond the discontinuation of the drug.
`The drug should be used with caution in patients who consume 544:15Larta 01.(4.111,5 cl aicohd WOO( have a past history ol
`liver ditwase. Active liver disease or unexpianed transaminase elevations are cone-din: Matrons to the use 01 lovastavn.
`As with other lipid-lowering agents. moderate resit than three times the upper lend of normal) elevations Of serum trans-
`an...ruses have been repotted folowing therapy with MEVACOR (see ADVERSE REACTIONS). These changes appeared soon
`alter initiation of therapy with MEVACOR. were ones transient. were not accompanied by any srigtunis and intenoption of
`treatment was not required.
`Skeletal Muscle RhabdomYolVars has been associated with lovastatin therapy alone, when combined with 'indium:sup-
`wmirve therapy including cyclosporine in cardiac transplant patients, and when calibrate] in non-transplant patients with
`either gem(rbrozif or lipid-lowenng doses Izt g/day) of flexitime acid. Some of the affected patients had pre-existing renal
`insufficiency, usually as a consequence of long-standing diabetes. Acute renal failure from rhabdornyolysis lies been seen
`more oomenonly with the lovastatmegembOvonl comtanabon, and has also been reported in treneCasht pabsnts receiving
`await:gin plus cyclosponne.
`Rhabdnrnyolysis with or without renal impairment has been reported in seriously ill patents receivng erythromycin condom,
`Wetly with .ovastzen. Therefore. patients •eceiving concnimitani imiadnon and erythromycin mould tie carefully monitored
`Fulivenent Mabdornyolysis has been mon as tarty as three weeks after irWation of combined theraPy with 9.mPa...a end
`10VaitillOrt, but may be seen after sewer* months. For these reasons, it is tett that, in meat subject* vino have had an
`unsatisfactory lipid response to either drug alone, the possible benefits of combined therapy weh leveatatm end gereffbrOhl
`do not outweigh the risks of severe myooathy. rhabdornyoarso. and acute renal hikes, While it is not known whether dm
`interaction occurs with fibrates other than gernfibroral, thyopathy and rtiabdornyolysis MY* occasionally been 114,043112.1
`with the use of other fibrates alone, including clofibrate Therefore, the combined use of lovastatin with other fibears sMud
`generally be avoided.
`physicians contemplating combined therapy with lovestabn and lipid-lowering doses of nicotinic acid Or with ann....sup.
`
`0009
`
`

`
`rnapenii
`ME VAGOR
`20 mg q pm
`40 mg q to in
`20 mg 0 1 d
`40 mg a i d
`Patents enrolled
`
`663
`
`1642
`1645
`1646
`1649
`
`"
`
`--17
`-22
`-24
`- 29
`
`+0 4
`
`-24
`-30
`-34
`-ao
`
`+2 1.
`
`+66
`+7 2
`+86
`+9 5
`
`••
`
`34
`
`.0.6
`
`-21
`-26
`-29
`- 34
`
`+4
`
`-10
`-14
`- 16
`- 19
`
`eye (cid:9) There was a high prevalence of baseline lenticular cpaCittieS in Me pabent population indude0 in the early clinical Mats with
`X.Tastahn• During these trials the appearance 0/ new opacities weaseled in both the lovastabn and placebo groups. There was no
`clinically signficant change in visual acuity el the patents who had new opacities reported nor was any patient, mckeing those
`with opadbes noted al baseline. disConenued horn therapy because of a decrease in visual acuity
`An mum analysts was performed at 2 years in 192 hypercholesterolemic patients who p.vbcpated in a 02CM:0-00MP:teed.
`paranei coupe-bond study to assess the effect of lovastabn on the human lens. There were no clinically significant differences
`tetwer, he lovastatin and placebo groups in the Incacience. yore, or progression of lenticular °Decrees
`
`INDICATIONS AND USAGE Therapy with lipid-altering agents should be a component of multiple nsk factor intervention in those
`.ndividuals at significantly increased risk for atherosclerotic vascular disease due to hyperchoesterolerna. MEVACOR is indicated
`as an adjunct 10 del for the reduction of elevated total and LDL cholesterol levels in patients with primary hypercholesterolemo
`• Tydes Ila and lib' I. when the response to diet restricted in saturated fat and cholesterol and to other nonpharrnacological
`Treasures alone raS been iranequale
`Pnor (cid:9)
`initiating therapy with Icvastatin, secondary causes torn trfpercnoieSterOlemla le g., poorly controlled diabetes mellitus.
`prpolnyididsm, nephiotic synororne, dyspoteinernas obstructive liver disease, other drug therapy