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`
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`
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`
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`
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`gr/'4,
`
`our Fishman
`Se
`Freedom of Information Officer
`Center for Drug Evaluation
`and Research,
`HFD—19
`
`EXHIBIT
`
`Ex. 1014
`
`Sun-Amneal-lPR2016-01104
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:23)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:23)
`Ex.1014,p.10f14
`0001
`0001
`
`

`
`0 FOI Services, Inc.
`12315 Wilkins Avenue
`Ffockv/I/e MD 20852-1877 USA
`
`Phone: 301/881-0410
`Fax:
`301/881-0415
`
`‘_,é‘
`
`FOOD & DRUG ADMINISTRATION
`FREEDOM OF INFORMATION STAFF
`5600 FISHERS LANE
`
`ROCKVILLE, MD 20857
`
`8/30/94
`
`CONTROL NUMER 124176
`
`PURSUANT TO THE PROVISIONS OF THE FREEDOM OF INFOR.MATION 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
`
`INCLUDING APPROVAL LETTER
`COPY OF ALL DISCLOSABLE APPROVAL INFORMATION,
`AND LABELING FOR THE LABELING REVISION APPROVED 5/17/94 FOR MEVACOR
`1OMG,
`2OMG 8: 40MG MANUFACTURED BY MERCK.
`
`CM-3L&<3__g}3
`
`RECEIVED i
`
`SEP 0 1 1994
`
`FDA F01 STAFF (HESS)
`
`
`
`x
`
`«V,
`,
`\_ gn,
`V" I
`'
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`Sun-Amneal-|PR2016-01104
`(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:23)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:23)
`Ex. 1014,0,p_._2 of 14 ,_
`0002
`0002
`
`A
`
`

`
`NDA 19-643/S-O32
`NDA 19-643/s-o33/
`
`MAY 1 7 1994
`
`Merck 86 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-O33)
`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-O32 - 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-O32.
`
`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-O33 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.
`
`Sun-Amneal-|PR2016-01104
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:23)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:23)
`Ex. 1014, p. 3 of 14
`0003
`0003
`
`

`
`NDA 19-643/S-032
`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:
`
`EGalliers, SAurecchia 05.12; GTroendle, MRhee,
`YChiu, Ajordan for EBarbehenn, Ajordan 05.16.94
`
`SUPPI.EMENT(S) APPROVAL (AP-O32/AP-O33)
`
`Sun-Amneal-|PR2016-01104
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:23)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:23)
`Ex. 1014, p. 4 of 14
`0004
`0004
`
`

`
`.,,’<’Jo.11;—- cL;I24 04/i1l(r.3,
`
`ft,-9
`
`Rn M‘ I Silvrariiian M II W11
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`
`Mu».
`TI
`
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`0
`
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`
`'
`
`_
`119-WGSK Copaes.
`
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`
`4
`
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`
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`Wm 9mm PA isms
`lax 715 39/ 73351
`In‘
`2715 397 3044
`?‘;5 -35? 5000
`
`
`
`Researchtaboratnnes
`
`
`
`August 19,
`
`i9_é}i3.
`“.4-.z.um t.s..-..r4.
`
`Solomon Sobel, MD. - Director
`Division of Metabolism and Endocrine
`
`Drug Products HFD-510, Room 14B-O4
`Office of Drug Evaluation II (CDER)
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`x.
`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
`§ I4 50(c), we Submit, for your approval, a supplement to NDA I9-643.
`
`As indicated on the attached Form FDA 356h, the supplemental application provides for changes in
`Item 4.c.ii of the approved New Drug Application for Mevacor.
`
`Reference is made to our letter dated June 7, 1993 and your letter dated July 14, 1993 concerning
`incorporation ofthe 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, I993,
`
`The changes will become effective on or about October I, 1993 and will apply to all packages of
`Mevacor distributed from the company's manufacturing facilities at West Point, Pennsylvania.
`
`3
`
`I 4 Sun-Amneal-lPR2016-01104
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:23)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:23)
`Ex. 1014, p.5 of14
`0005
`0005
`
`

`
`Solomon Sobel, MD. — 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 fiiture 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.,
`PhD. (215/397-2944) or, in my absence, to Bonnie J. Goldmann, MD. (215/397-2383).
`
`Si
`
`e
`
`ours,
`
`J
`
`C? kg
`
`Robert E. Silverrnan, M.D., Ph.D.
`
`Director, Regulatory Affairs
`
`L_):C.>‘\'I'lWI.*Jv1&ZCH(§
`
`Attachments
`
`(‘ircular No. 7526525
`
`Federal Express No. 7470347150
`
`Desk Copy:
`
`Dr. S. Auerrechia, HFD—5lO, Room l4B—26
`
`Mr. S. Trostle, HFD-51 1, Room l4B—O4
`
`Sun-Amneal-|PR2016-01104
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:23)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:23)
`Ex. 1014, p. 6 of 14
`0006
`0006
`
`

`
`NDA 19-643”
`
`
`
`
`
`ilovlewed by: S 2
`
`0 MERCK&CO., INC.
`
`West Point, PA 19486, USA
`TABLETS
`
`7526525
`
`MEVACOR®
`(LOVASTATIN)
`DESCRIFHON MEVACOR‘ lLovastatin) is a cholesterol lowering agent isolated lroin a strain ol Asperglllus torreus. Alter oral
`ingestion. lcwastatiri. Mulch lS an inactive lactone, is hydrolyzed to the corresponding B'hYdl’0XY3CIU form. This is a principal
`metabolite and an inhibitor ol 3-hydraxy»3-methylglutarylcoenzyme A (HMG-CoA) reductase. This enzyme catalyzes trio
`conversion at HMG-COA to mevalonate. which is an early and rate limiting step in the blosynthesis ol cholesterol.
`Lovastatin is [1S-[1oi(Fl‘),3ix.7[5.8B(2S'.4S‘l. Satan-1,2.3,7.8.8avhexahydrpv3.7-dimetliyl»a-[2-(lecrahydro-4-liyoroxy-6-oxo~
`2l+pyranA2-yllcthyltvl-iiaprlthalenyl Zmethylbutanoate. The empirical tormula oi lovestatin is C,,H,.O, and its molecular weight
`is 404.55 Its stnictural lormula is
`Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in
`water and sparingly soluble in ethanol, methanol. and acetonitrile.
`Tablets MEVACOR are supplled as 10 mg. 20 mg and 40 mg tablets loi oral
`aomlnistration ln addition to the active ingredient lovastalin. each tablet
`contains the tollowing inactive ingredients’ cellulose. lactose, magnesium
`stearate. and starch. Butylated hydroiryanisole (BHA) is added as a preserva-
`tive Tablets MEVACOR ‘I0 mg also contain red lernc oxide and yellow ferric
`oxide. Tablets MEVACQR 20 mg also contain FD&C Blue 2 Tablets
`MEVACOFI 40 mg also contain DAC Yellow to and FD&C Blue 2
`
`HO
`
`0
`
`
`
`cUNlcAL PHARMACOLOGY The involvement at lowoensity iipopiotein
`(LDL) cholesterol in atherogenesis has been well-documented in clinical and
`palhologlcal studies. as well as in many animal experiments. Eploemiological
`studies have established that high LDL (lowoenstty llpoprotein) cholesterol
`and low HDL (hlgrwtleiisity lipoproteln) cholesterol are both nsk lactors lot
`coronary heart disease. The Llpld Research Cllnics Coronary Primafll P'eVBm*°" Tnal (LE6-CPPTT coordinated by the National
`Institutes at Health (NIH) studied men aged 35-59 irntn total cholesterol levels 265 m9IdL (6.8 mmol/L) or greater. LDL cholesterol
`values 175 mg/dL (4.5 rnmol/L) or greater ahd triglyceride levels not more than 300 mg/dL (3.4 mmol/Ll. This seven-year double—
`blind. piaoebo~coritiolleo study demonstrated that lowering LDL cholesterol with diet and cholestyramine decreased the cornblned '
`rate at coronary heart disease death plus non~latal myocardial infarction.
`MEVACOFI has been shown to reduce both normal and elevated LDL cholesterol oonoentratioris. The ellect pl lovas1atin-
`induced changes in lipopiotein levels. including reduction ol serum cholesterol. on cardiovascular moioidrry or mortality has not
`been established
`LDL is lormed lrorn VLDL and is catatxtltzed predominantly try the high atliniiy LDL receptor. The mechanism at the LDL‘
`lowering ellect ol MEVACOR may involve both reduction ol VLDL cholesterol concentration. and induchon ol the LDL receptor,
`leading to reduced production aridioi increased cataoolism at LDL cholesterol. Apolipopiotein 5 also lalls substantially dimng ‘
`treatment with MEVACOR. Since each LDL particle contains one molecule ol aoolipoprotein B. and since little apolipopiotein B is
`found in other lipoprotalns. this strongly suggests that MEVACOR does not merely cause cholesterol to be lost lrorn LDL but also
`reduces the concentration of circulating LDL particles. In addition. MEVACOR can produce increases of variable magnitude in
`HDL cholesterol, and modestly reduces VLDL cholesterol and plasma triglycerides (see Tables l-IV under Clinical studies) The
`ellects ol MEVACOR on Lp(al. llhrinooen. and oenaln other independent biochemical risk manners lor coronary heart disease are
`llnkriown
`MEVACOR is a spealic inhibitor 01 HMG-CoA reductase. the enzyme which catalyzes the conversion of HMG~CoA to ,
`mevalonate. The conversion ol HMG-CoA to mevaloriate is an early step in the biosynthetic pathway lor cholesterol
`Prwminoolmerics Lovastatin is a lactone which is readily hydrolyzed in we to the corresponding B-hydfoxvacltt a D016"!
`inhibitor of HMG—CoA reouctasa. lnhioition ol HMG-CoA reductase is the basis for an assay in pharrnacolunetic studies of the
`B~hydrotryac:d metabolites (active inhibitors) and, lollowing base hyorplysis.ar.1~t plus latent inhibitors (total inhibitors) in plasma
`lollowing administration ol lovastatin,
`Following an oral dose or “C-labeled lovastaim in man. 10% ol the dose was excreted in urine and 83% ll’! leces The latter
`represents absorbed drug equivalents excreted in tile. as well as any unabsorbed drug Plasma concentrations ol
`total
`radioactivity (lovastatin plus ‘4C~metaoolites) peaked at 2 hours and declined rapidly to about 10% M peak by 24 hours postdose
`Absorption ol lovastatin. estimated relative to an intravenous relevance close. in each ol tour animal species tested. averaged
`about 30% or an oral dose ln animal studies. alter oral dosng, lovastatiri had high selectivity loi the liver. where it achieved
`substantially higher concentrations than in non-target tissues. Lovastann undorpols extensive first-pas extraaion in the liver, its
`primary site or action. with subsequent exuetion ol drug equivalent: “'1 the bile. As a ooriseouerlce ol extensive hepatic extraction .
`ol lcivaslatin, the availability ol drug to the general circulation is low and variable, lit a single dou stucy in Your hyperoholesten:ll-
`ernic patterns. it was estimated that less than 5‘/. ol an oral dose of lovastatin reaches the general csrculataon as active inhibitors.
`Following administration ol lovaslatin tablets the ooellicvent ol variation. based on behiiieerrsubioct vanabiloty. was approximately 1
`40%; tor in; area under the curve (AUC) ol total inriioiioiy activity in the general Drculahort.
`Both lovastatm and its B-hydroxyacrd metabolite are highly bound (>95'kl to human plasma proteins Animal studles
`demonstrated that lovastatin crosses the blood-brain and placental banners.
`The mayor active metabolites present in human plasma are the B-hydroxyaod pl lovaslatin, its 6'-hydroxy derivative. and two
`aoditlond metabolites Peak plasma concentrations of both active and total inhibitors were attained within 2 to 4 hours ol dose
`adrrllnrstration. While the recommended therapeutic dose range is 20 to B0 mglday. linearity of inhibitory activity in the general
`circulation was established by a single dose study employing lovastatin tablet dosages lrom so to as high as 120 mg. with a once
`a~day dosing regimen, plasma concentrations pl total inhibitors over a dosing interval achieved a steady state between the second
`and thlro days 0‘ therapy and were about 1 5 times those lollowing a single dose When lovastatin was given under lasting
`conditions. plasma concentrations at total
`inhibitors were on average about iwolhiro: those lound when l0V3S13lll'l was
`aclnrinisterecl immediately alter a aandaid test meal
`In a study pl patients with severe renal insulllclency (creatinine clearance 10-30 rnLJmin). the plasma ooncentranons cl total
`inhibitors alter a single dose ol Iovastatin were approximately two~lold higher than those in healthy volunteers.
`Clrnrczl Studies MEVACOR has been shown to be highly ellective iri reoucmg total and LDL cholesterol in heterozygous tarrialial
`and l"lOfi~l3n1Il|3l lorrris ol primary hypercholesterolernia and in mixed hyporlioidemia, A maniac response was seen within 2
`weeks. and the maximum therapeutic response occurred wrthm 445 weeks The response was mamtalrted curing continua.
`,n dl
`therapy Single daily doses given in the evening were more ellective than the same dose given in the morning. perhaps because
`cholesterol is synthesized mainly at night.
`ln multioerlter. double-blind studies in patients with lamilial or non-lamilial hypercholesterolemla. MEVACOR adriiirilsiered in
`doses ranging lioiri 20 mg o.p.m to A0 mg t; ad, was compared to placebo. MEVACOR consistently and signiticantty decreased
`total plasma cholesterol (TOTAL-C), LDL cholesterol (l.DL»C). total cholesterol/HDL diolesterol (TOTAL-C/HDL-Cl, ratio and LDL
`cholesterol/HDL cholesterol (LDL-C/HDL-C) ratio.
`In addition. MEVACOR produced increases ol vanaole magriituoe in HDL
`cholestefcl ll-lDL~C) and modestly decreased VLDL cholesterol (VLDL-Cl and plasrru triglycerides iTRiG.) [see Tables I and IV
`‘or dose response resultsl
`
`.
`
`'
`
`TABLE I
`FAMILIAL HYPERCHOLESTEFIOLEMIA STUDY
`DOSE RESPONSE OF MEVACOR
`(Percent Change from BSSQIIFIE After 6 Weeks)
`LDL-C1
`HDL-C
`(mean)
`— i
`
`LDL—C
`(mean)
`— 2
`
`HDL-C
`lmeanl
`st
`
`DOSAGE
`Placebo
`MEVACOFI
`-7
`-24
`-26
`+10
`—i9
`-13
`20
`20rngq.prr-.
`-22
`-29
`-32
`no
`-27
`-24
`2t
`-Wmgciam
`—tl
`-25
`-25
`+5
`—25
`-22
`is
`lonqb-.0
`_ia
`-34
`—3a
`+12
`-31
`—27
`20
`Zomgold
`-12
`-33
`-43
`+3
`~39
`~34
`20
`40'r\t:tsid
`__ MEVACOR was compared to cholestyramine in a randomized Ollen parallel study and to prooucol in a double-blind, parallel
`$M'-lY 308’! studies were penoimed with patients with riyoorcholesteiolcrrna who were at high risk or rriyoardial niarction
`Summary results pl these two comparative studies are prcsorrlnd in Tables ti 5 m
`TABLE ll
`MEVACOR vs
`(Percent Change lrorri Baseline Alter i2 weeks)
`LDL—CJ
`YOTALCI
`HDL-C
`HDL-C
`(mean)
`(mean)
`
`ti
`Zl
`
`TOTAL-C
`trneanl
`—:
`
`TOTAL-O‘
`HDL~C
`lmeanl
`0
`
`TRIG
`imediziil
`+3
`
`TREATMENT
`MEVACOR
`20rrlgDld
`wmonic
`
`5
`
`TOTAL-C
`lmeanl
`
`LDL»C
`lmeafll
`
`HDL-C
`lmoafll
`
`VLDL-C
`(median)
`
`mic.
`(rngdian)
`
`85
`88
`
`-27
`~34
`
`-32
`-42
`
`+9
`+3
`
`-36
`-44
`
`-31
`.37
`
`-34
`gr
`
`-2|
`-27
`
`.
`l
`l
`
`Sun-Amneal-|PR2016-01104
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:23)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:26)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:23)
`Ex. 1014, p. 7 of 14
`0007
`0007
`
`

`
`\4-u-sn.u....m‘o-‘....-,<
`
`(
`
`DOSAGE
`
`(2
`
`(Porcem Change from Baselme Me: 5 Weeks)
`LDL-C‘
`LDL~C
`HDLvC
`TOTAL-C
`HDL-C
`(mean)
`(mean!
`(mean)
`(mean)
`+1
`-1
`42
`
`TOTAL—C/
`HDL-C
`(mean)
`0
`
`TRIG.
`(meo-an)
`+3
`
`Placebo
`MEVACOFI
`-7
`-24
`-26
`H0
`-19
`20 mg q.p m.
`-22
`-29
`H0
`-32
`-27
`40 mg qAp_m.
`-11
`-25
`-29
`+6
`—25«as
`10 mg mo.
`~18
`- 34
`-35
`+12
`20 mg (3.: d
`-12
`-33
`+5
`-39
`-43
`to mg b LU
`MEVACOR was compared 10 cnolcstyramme m a randomized open parallei sludy and lo pvobucol In a doub(e»bhnd_ parallel
`sluoy Both studses were performed mm patients mm rvyperchotesterolemua who were al hsgh nsk of myocardial mfannvon
`Summary resurzs of these two comparalnve stud-es ale plesenled nn Tables H 8 III
`TABLE II
`MEVACOR vs. Cgfizamnr-e
`(Peroem Change from Basehne Mia: 12 Weeks)
`LDL-(‘J
`TOTAL»CI
`TOTAL-C
`LDL-C
`HDL-C
`HDL-C
`HDL-C
`(mean)
`(mean;
`(mean;
`(mean)
`(moan)
`
`TREATMENT
`MEVACOR
`20 mg b.) d.
`40 mg b.x.d.
`Cholesgxramme
`12 9 In a
`
`TREATMENT
`
`(Z
`
`88’-
`
`!Z
`
`MEVACOR
`°0m9cwrn
`somgqprn
`domgbxd
`Probuwi
`soomgnm
`3neg.s(eraa uaoeman. 0| MERCK a co.
`
`47
`49£7
`97
`
`-25
`A30
`-33
`-10
`
`— 27
`-34
`
`— 32
`-42
`
`+9
`+8
`
`— 36
`-4“
`
`— 31
`-37
`
`-17
`
`-23
`
`-27
`
`-21
`
`+5
`TABLE III
`MEVACOH vs Pvobucel
`(Percent Change Irom Basehne After (4 weeks)
`LOL~C/
`TOYAL-0'
`TOTAL-C
`LDL—C
`HDL-C
`HDL-C
`HDL-C
`(mean)
`(-neam
`(mean!
`(mean)
`(mean)
`
`VLDLAC
`(mod-an)
`
`TRIG
`(rnednan)
`
`— 34
`-31
`
`+2
`
`- 21
`-27
`
`+11
`
`VLDLC
`lmedtan)
`
`TRIG
`(medxan)
`
`-31
`-33
`+9
`-32
`-36
`~t2
`+21
`-37
`-39
`~45
`+12
`4-40
`+23
`+26
`-23
`-8
`COPVFIIGHT 6 MERCK 5. CO Inc 198179831991
`
`-15
`-37
`—|7
`-27
`-25
`-40
`+1
`-13
`All nqhls reserved
`
`INC
`
`Sun-Amneal-|PR2016-01104
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:23)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:27)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:23)
`Ex. 1014, p. 8 of 14
`0008
`0008
`
`

`
`7525525
`Mt=.vAcon- (LDvastatIrtl
`Expanded Clinical Evaluation of Lovasutin (EXCEL) Study MEVACOR was compared to placebo In 8 245 pattehts wlth
`nyoercholesterolemta (total cholesterol 2&0-300 rrt dL [6 2 mmolIL - 7.6 mmol/L]. LDL cholesterol >160 mg/dL [41 mmolIL]) In
`the randomized. dcluble—b|tr\d, parallel, A8-week E CEL stu
`. All changes In the IIp.a measurements (Table W) m MEVACOR
`treated patlonts were ooseralated and stgntttcantly dttlerertt
`rom place00 (D50 001). These results were suslalrled Wolllihoul
`the study
`TABLE IV
`MEVACOR vs. Placebo
`(Percent Change trom Baseline -
`Average Values Between Weeks 12 and 48)
`LDL-C!
`HDL-C
`(mean)
`+0.2
`
`TOTAL-CI
`HDL~C
`(mean)
`+0.6
`
`TRK5
`(rnedlartl
`+4
`
`E
`1663
`
`TOTALvC
`[meant
`+0 7
`
`LDL»C
`(mean)
`+0 4
`
`HDL-C
`(mean)
`+2.0
`
`posacg
`Placebo
`MEVACOR
`zomgqpm.
`40 mg q.p.m
`20mg b.Id.
`Aon-Ig:IIa
`‘Patterns enrolled
`Eye There was a htgrt prevalence of baseline lenucular opactttes In the patent populatron Included In the early cltnlcal trials wtth
`Iovastattn. Durtng these trtals the appearance ol new opacittes wasnoted In both the lovastattn and placebo groups. There was no
`cltmcalty srgntrtcant change in vrsual acutty In the pattents who had new opacrttes reported not was any pahent, Includtng those
`wtth opactttes noted at baselme. dlSC0l'llInuEd trom therapy because at a decrease In vtsuat acutty
`An tntenrn analysrs was pertormed at 2 years In 192 hypercrtolesterolemic pattents who panrctpated In a placebo—controlled.
`parallel. double-bltnd study to assess the ehect ol Iovastatrn on the human lens. There were no dtntcatly srgntlicant drttererlces
`between the lovastattn and placebo groups In the Inodence. type. or progresstort ol lerttrculal‘ clpaattes
`
`I542
`1645
`1646
`I649
`
`-—t7
`-22
`-24
`-29
`
`—24
`—-30
`-34
`-40
`
`+5.6
`+7.2
`+8.5
`+9.5
`
`-27
`-34
`-38
`-44
`
`—2t
`-26
`-29
`-34
`
`~10
`-14
`-16
`-19
`
`INDICATIONS AND USAGE Therapy wrlh ttpto-altermg agents should be a component of multiple nslt lador Interventron In those
`lndtvlduals at stgnihcantly Increased nsk tor atherosclerottc vascular cltsease due to hypercholesterolerrtta MEVACOFI is Indtcated
`as art adtunct to dtet tor the reauctron or elevated total and LDL cholesterol levels In pattenu vvrth pnrnary rrypercholosteroletnta
`(Types lla and not). when the response to dtet restrtcted In saturated rat and cholesterol and to other nol'lDTl3"“3C°l°9l¢3'
`measures alone has been Inadequate.
`Poor to Intttattng therapy wtth lovastattn, secondary causes lot hypercholesterolemta le.g.. poorly controlled dtabotes mellttus.
`nypotnyrotdtsm. nephrotrc syndrome, dysprotetnemtas. ocstmctrve ltver dtsease other drug therapy. aloohohsm) should be
`excluded. and a ltptd profile performed to measure TOTALC. HDL-C. and tnglycendes (TG) For patterns Iutth TG less than 400
`rt-IgIoL (<4 5 rrtmol:’L), LDL-C can be estrrhated uslng the toltowmg equatton,
`LDL—C : Total cholesterol - [0 2 x (tnglycendes) + HDL-C]
`For TG levels >400 mgIdL r>-1.5 rnrnoVL). thus oquatton Is less accurate and LDL-C cortoerttratrorls should be deterrntned by
`In ltypertnglycetldemrc patrertts. LDL-C may be low or normal desonte elevated TOTAL-C.
`ultracamrttuganort
`In such cases,
`MEVACOR Is not ll’\dlC3leG.
`The effect ol
`lOV3!sIa|lnvlf\dUG2O changes In ltpoprotctn levels, Including reductton of serum cholesterol. on cardtovascular
`mortndrty or mortaltty has not been astabtlshecl
`The Nauonal Cholesterol Educatton Program ENCEP) Treatment Guroellnes are summartzed below
`LDL-Cholesterol
`mg1dL (mrnol/Ll
`
`Deltntte
`Atherosc-lerottc
`DIsease'
`NO
`NO
`VES
`
`~
`
`Two or More
`Other FlIsk
`Factors"
`NO
`YES
`YES 0rNO
`
`tmttattcn
`Level
`: l 90
`(’_-4 9)
`.-160
`t :4 t]
`.430
`\ :3 4l
`‘Coronary heart dtsease or pcrtpheral vascular cltsease ltrtcludlng symptorhabc carotrd artery dxseasel
`"Other nsk lactors tor coronary heart dtsease lCHDl Include age (males >45 years. lemales‘ :55 years or premature
`menopause wtthout estrogen replacement therapy). lamtly hrstory ol premature CHD. current ctgarette smolung: hypenenslon.
`conrtrmed HDl_—C -:35 mgIoL (<0 91 mrt-toIILl: and dlabetes mellttus Subtract one rtslt lactor It HDL«C Is 260 rrIgldL (at.6
`rnmol/L)
`Strtce the goal ol treatment Is to lower LDL-C. the NCEP recommends that LDL~C levels be used to Inmate and assess
`treatment response. only It LDL-C levels are not avarlable. should the TOTALAC he used to monrtor therapy
`Although MEVACOR may be useful to reduce elevated LDL cholesterol levels In patrertts vrrth cornbtned hy-porcholesterolernta
`and hypertnglyoortdamta whore hyperdtotestorolemta Is the major aboormaltty (Type llb hyperlrpobroletnemlal
`It has not been
`Qudted In condtttons where the mater aonorrrtaltty Is alevanort at chylorrtlcrons. VLDL or lDL (I e . hyper1rooproteInernIa tybes l. Ill.
`IV. or V).l
`
`
`
`CONTRAINDICATIONS Hypersenstttvrt-y to any component of tho medlcatlon.
`Actwe ttver osease or unexplamoa perststent elevattorts ol serum tIarIsarnInases (see WARNINGS)
`Pregnancy and lactauon Atherosclerosrs Is a dtronrc process and the dtsconttnuatlon or lipid-lawerlflg drugs aunng pregnancy
`should have Itttte Impact on the outcome ol long-term therapy at ortrnary hypercholesterolett-Ita. Moreover. cholesterol and other
`products at the cholesterol btosynthests pathway are esserttlal components lor letal development Including synthesrs at steroods
`and cell membranes Because ol the abttrty at Inhtortors or HMG-COA raductase such as MEVACOFI to decrease the syrtthests at
`cholesterol and posslbly other products ol the cholesterol htosynthests pathway MEVACOR may cause letal hartn when
`admrmstered to a pregnant woman Therefore. lovastatm Is contratndtcated dumg pregnancy Lovzstattn should be admonis-
`tered to women 0! chtldbeanng age only when such pattern: are highly unltituty to coocerva. It the Dattertt becomes pregnant
`whtle taltmg thts drug, lovastatrn should be drsooltttnued and the pattent should be aporlsed ol the Dotentlal hazard to the letus.
`
`WARNINGS Lrvorbyslunction Martted persistent Incteaes no morvthan Jtimosthouppor limit oloormal) ‘Inserum
`tr'ansamInasesoccurIledIn1.9%oradmtpaourswtnncewodbvastatittorathastmnyoutnomyctiucalbtuslsoa
`ADVERSE REACTIONS). when the drug was Interrupted or dtsconttnued In these patlents. the transamrtasa levels usually tell
`slowly to pretreatment levels The Increases usually abtleared 3 to 12 months alter the start ol therapy wrth lovastattn. and were
`not assoctated wtth Iaundtce or other clrnucal stgns or symptoms. There was no evldence or hyporsenstttvtty. tn the EXCEL study
`(see CLINICAL PHARMACOLOGY GImIcaI Stuarts). the Inctdence ol marked Derststent lflC'l3S€S In scrum trartsamtnases over
`48 weeks was 0.1% tor placebo. O W. at 20 mg/day. 0.9‘/. at 40 rrtglday. and 1 5% at 80 mglday In patterrts on lovastattn, However.
`In post-marltetlng expanence wrth MEVACOR, symptomatrc Itver dtsease has been reported rarery at all dosages (see ADVERSE
`naAcrIo~s).
`ntsncommondadmnliwrlmtcuathstsbepedornnddunngfltuapywnhlovastntin.Scrumtrvtnmmasos,rIclt.Io6ng
`ALT(SGPT).shouldbemonitorodbetmuunummbo§rls.way6wooludunnguuhrst3rnonttn.w~ry8wuksduingme
`llfllllndof or the l'Irs1 you and pot-Ioatcatry thonarter la.g.. It approximatoly s rncrtth intervals). specs artentIorI should be
`patd to patrertts who develop elevated serum transamtnase levels. and In these pahents. meisurort-toms should be rppaalea
`promptly and then peflorrned more lrequenrly ll the U'af\$3fT1IF‘-35¢ levels show evldence cl progresslorx partIcularty If they rtse to
`three ttmes the upper ltmtt at normal and are perststerrl. the drug should be dtscorlttrtued Lrver DIODSV should be oonsadered ll
`elevattons are Derststertt beyond the dtsconttnuatton at the drug
`The drug should be used wtth cauoon In patterns who consume suostantral quantvtres cl alcohol andlor have a past htstory at
`lrver dlsease. Acttve lrver dnsease or unexplatrted transatntrlase elevahons are corttratrldtcatlorts to the use 11 lovastatm
`As vrrth other lIpId—Iawenng agents. moderate (less than three B11105 the utter Itrnrt of normal) olovatnons 01 serum trans-
`amtnascs have been reported lollowtng therapy wtth MEVACOR (see ADVERSE FIEACWONS). These changes appeared soon
`altar Inttaauon of therapy with MEVACOR. wert often transtent. were not aocompamec oy any syntatoms and Interruptton ol
`treatment was not mounted.
`Skohfllllt/sci: Rtabda'wowsuhubemnsodaodmmlwasumm«'&yl0m,whmcutbiwdMmmnnmosup-
`ycsuvomuwyitafirgwcmpamma¢xuInutttmunB.uw%mcunuwdmrut-hmphmmbummm
`emugrnfibrbuwifid-bV¢'WWusl21WMy)dnm&xmo.SumMwmxudpnumhwuu4uwrqmU
`hndfiamcytmasyunwruoqtmmdut9nzt«n¢abnnAwtImuhlmnunmwdawuyishuumum
`tmmurmuwfimmobvnum-9urmMoaIcunumom.adhuflwbomI1mmdntuuuunpmonunuMm
`Fthaboornyplysts mm or wttnout renal tmpatrrnent has been roponed Ifl senousty tll patmts Ieoetvm ervlhrorrrycm condom»
`lwllr wllh ‘M/Islzll-'1 Therelore. pat-ems re-.--_-v-ng cor-cr.vn.I:tr~v lcvastarm and erytfirnmyon atoms be cammtty momtoma
`Fmmmunmfidawoqmrnsbnnumuetwumuwnumuirmmmdourbwwdmrtpywnhgwfluoflun
`tovastatirnbtnmuybosocrtafternovorralmonthsFortheurnasorts.nrstvttthna.mrnostsubject:wttohav¢hadun
`wsafifluctaylpHnsomuowavmawmm.memmbwmnofimmcmmmwmuwywmb~aumuugumuou
`®nmamfighflbmbdnvmmwpmmfluboamoNsa.ummmomwtihn.Whhnarmkrvwnwhwwmn
`nwmfiwtwmnwmfihmtnomrmmmnfiuudhmwpwwznmmourwowasmvoxcanmdymmnowud
`wIththat.tsootothorfIbntoIdonI.tr\cluIdinqdofibrutI.Ttnrofom.tMcombvndt.nootbvuxztmwtmo|fnrfibrmushould
`gornralryboavoodod.
`PrryslctanscorttornolatinqcorrtbortoothoraoywrtnlovastzttrtandltprddawenrtgdosesotrbcotttvcnctdorwtthImrntnou:p-
`-
`I
`.
`.
`.,... I....,..4..I» ——m»,nmn=~Io~r<lrvanvs-onsnrvd
`
`Sun- mneal-|PR2016-01104
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:3)
`(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:23)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:28)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:23)
`Ex.1014,p.90f14
`0009
`0009
`
`

`
`Placebtr
`MEVACOR
`no
`qprri
`lo 33 q.p m
`zorriquia
`Id
`
`-mi
`
`lsa"
`lea?
`W46
`We
`
`«ti
`
`
`
`+04
`
`-2-:
`-30
`-34
`-40
`
`+20
`
`+66
`+7.2
`+56
`+95
`
`+34:
`
`-2"
`-34
`-38
`—-u
`
`+06
`
`—2l
`-26
`~29
`-3:
`
`+4
`
`-10
`-14
`-16
`-