`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`
`Center for Drug Evaluation and Research
`Office of Training and Communication
`
`Freedom ofInformation Stafi‘HFD-205
`
`5600 Fishers Lane
`
`12 B 05
`
`
`
`AUG 1 1
`
`August 9, 1999
`
`Rockville, Maryland
`
`20857
`
`In Response Refer to File : F99-10503
`
`F01 Services, Inc.
`11 Firstfield Road
`
`Gaitherburg, MD 20878-1703
`
`Dear Requester:
`
`This is in response to your request of May 4, 1999, in which you requested a copy of the
`approval package for NDA 20766. Your request was received in the Center for Drug
`Evaluation and Research on May 7, 1999.
`
`The documents you have requested are enclosed. “In order to help reduce processing time and
`costs, certain material has been deleted from the record(s) furnished to you because a
`preliminary review of the re-cord(s) indicated that the deleted information is not required to be
`publicly disclosed.
`If, however, you desire to review the deleted material, please make an
`additional request at the following address:
`
`Food and Drug Administration
`Freedom of Information Staff, I-lF[~35
`5600 Fishers Lane
`
`Rockville. MD 20857
`
`Should the Agency then deny this information, you would have the right to appeal such denial.
`Any letter of denial will explain how to make this appeal.” SMG 2460.7(3)
`
`This concludes the response for the Center for Drug Evaluation and Research.
`
`Computer time
`(Search $29.00, Review $261.00, Reproduction $
`Charges of $
`$0.00) will be included in a monthly invoice. DO NOT SEND ANY PAYMENT UNTIL YOU
`RECEIVE AN INVOICE.
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amneal-lPR2016-01104- Ex. 1013, p. 1 of 30
`
`EXHIBIT
`
`Ex. 1013
`
`0001
`0001
`
`

`

`If there are any problems with this response, please notify us
`problem(s). Please reference the above file number.
`
`of your specific
`
`Sincerely,
`
`y. 3an.¢Wz 7/u:/za-W, /em
`
`J. Santford Williams, R.Ph.
`Freedom of Information Officer
`
`Office of Training and Communications
`Freedom of Information Staff, HFD-205
`
`Direct Line (301)827-4583
`
`Enclosure:
`
`904 pages, approval package for NDA 20766
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amneal-IPR2016-01104- Ex. 1013, p. 2 of 30
`
`0002
`0002
`
`

`

`
`
`FOOD & DRUG ADMINISTRATION
`FREEDOM OF INFORMATION STAFF
`5600 FISKERS LANE
`ROCICVILLE, MD 20857
`
`5/’ 4799
`
`.
`
`CONTROL NUMBER 150380
`‘
`
`H510 }
`
`A
`
`PURSUANT TO TI-IE PROVISIONS OF THE FREEDOM OF INFORMATION ACT, PLEASE
`PROVIDE US WITH A PAPER COPY (PREFERABLY NOT MICROPICH) OF THE
`FOLLOWING S. IF THE COST OF PROVIDING THESE DOCUMENTS WILL
`Rxcnnn 100.00, ppnnsn CALL US FIRST FOR AUTHORIZATION or TI-IE CHARGES,
`UNLESS I1~lt)_IC.l\'J.‘ll.7*-0'-1'T,\IlIS annow.
`pnnsn
`‘I. IIIMBR. IN YOUR REPLY.
`
`
`ATTN: CENTER FOR DRUGS
`
`COPY OF THE DISCLOSABLE APPROVAL DOCUMENTATION FOR XENICAL (ORLISTAT)
`CAPSULES SPONSORED BY HOPFMANN-LAROCHE, APPROVED 4/ 26/ 99.
`
`
`
`WF$3oe: -6-)
`%
`
`comsonua 5/95
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amneal-IPR2016-01104- Ex. 1013, p. 3 of 30
`
`0003
`0003
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`v P:
`
`r:
`
`_A_gwcatioy_ Nggber: 020766
`
`Trade Name: XENICAL CAPSULES 120 MG
`
`Generic Name: ORLISTAT
`
`Sgonsor: HOFFMAN-LA ROCHE
`
`Aggroval Date: 04/23/99
`
`INDICATION]s[: FOR OBESITY MANAGEMENT
`INCLUDING VVEIGHT LOSS AND WEIGHT
`MAINTENANCE WHEN USED IN CONJUNCTION
`VVITH A REDUCED CALORIE DIET.
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amneal-IPR2016-01104- Ex. 1013, p. 4 of 30
`
`0004
`0004
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION: 020766
`
`CONTENTS
`
`Included
`
`Pending
`Comflefion
`
`Not
`Not
`Pregared Reguired
`
`X
`
`X
`X
`
`Apgroval Letter
`Tenative Amt-oval Letter
`Amgrovable Letter
`Printed Labeling
`Medical Reviewjsg
`Chemist_rx Reviewgsg
`EAIFONSI
`
`><><><><
`
`Phannacolog Reviewgs)
`Stafisfical Reviewgsg
`Microhiolog Reviewgsg
`Clinical Pharmacology
`Bioflarmaceutics Reviewgsg
`Bigggnivalence Reviewgsg
`Administrative]
`
`><><
`
`X
`
`Corresgondence Documentgs}
`
`X.
`
`X
`
`X
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`_Sun-ArI:|_nea|V_-IPR2016-01104- Ex. 1013, p. 5 of 30
`
`0005
`0005
`
`

`

`CENTER FOR QEUG EVQUATION AND RESEARCH
`
`
`
`''on Number: 020766
`
`APPROVAL LETTER
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amnea|_-|mFfR2016-01104- Ex. 1013, p. 6 of 30
`
`0006
`0006
`
`

`

`NDA 20-766
`
`Hoflinann-La Roche
`
`Attention: Ms. Peggy Jack
`Program Director
`Drug Regulatory Affairs
`340 Kingsland Street
`Nutley, NJ 07110-1199
`
`Dear Ms. Jack:
`
`Please refer to your new drug application (NDA) dated November 26, 1996, received November
`27, 1996, submitted under section 505(b) ofthe Federal Food,‘Drug_. and Cosmetic Act for
`Xenical (orlistat) Capsules, 120 mg.
`
`We acknowledge receipt of your submissions dated May 12. 15, and 27, July 6, 15, I7, and 31,
`August 11, September 9, and October 7, 13, and 30, 1998; and January 6, 18, and 21(2). March
`2, ll, 12, 22(2). 23, 24, 26, and 30, and April 1. 5, 7, and 23(2), 1999. Your submission of
`January I8, 1999, constituted a complete response to our May 12, 1998. action letter. The goal
`date for this application is July 19. 1999.
`
`This new drug application provides for the use ofXenical (orlistat) Capsules for obesity
`management including weight loss and weight maintenance when used in conjunction with a
`reduced calorie diet. Xenical is also indicated to reduce the risk for weight regain after prior
`weight loss. Xenical is indicated for obese patients with an initial body mass index (BMI) 330
`kg/m2 or 327kg/tn’ in the presence of other risk factors (e.g., hypertension, diabetes,
`dyslipidemia).
`
`We have completed the review ofthis application, as amended, 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 agreed upon labeling text. Accordingly, the application is approved
`effective on the date of this letter.
`
`The final printed labeling (FPL) must be identical to the submitted drafi labeling (package insert
`submitted April 23, 1999, patient package insert submitted April 23. 1999, and immediate
`container label submitted April 5, 1999). Marketing the product with FPL that is not identical to
`the approved labeling text may render the product misbranded and an unapproved new drug.
`
`l’lease submit 20 copies ofthe FPL as soon as it is available. in no case more than 30_ days afier it
`IS printed. Please individually mount ten ofthe copies on heavy-weight paper or similar material.
`
`.
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:26)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amneal-IPRZO16-01104- Ex. 1013, p. 7 of 30
` - 0007
`0007
`
`

`

`For administrative purposes, this submission should be designated "FPL for approved NDA
`20-766." Approval of this submission by FDA is not required before the labeling is used.
`
`Validation ofthe regulatory methods has not been completed. At the present time, it is the policy
`ofthe Center not to withhold approval because the methods are being validated. Nevertheless.
`we expect your continued cooperation to resolve any problems that may be identified.
`
`We remind you of your Phase 4 cormnitment specified in your submission dated April 23. 1999,
`to provide monthly updates of breast cancer diagnoses from the ongoing studies that were
`included in your January l8, 1999, submission. These updates will continue until these studies are
`completed.
`
`As ofApril 1, 1999, all applications for new active ingredients, new dosage forms, new
`indications, new routes of administration, and new dosing regimens are required to contain an
`assessment ofthe safety and effectiveness ofthe product in pediatric patients unless this
`requirement is waived or deferred (63 FR 66632). We note that you have not fulfilled the
`requirements of 2] CFR 314.55. We are deferring submission of your pediatric studies until
`l2/2;'00. However, in the interim, please submit your pediatric drug development plans within
`120 days from the date ofthis letter unless you believe a waiver is appropriate.
`
`Ifyou believe that this dmg qualities for a waiver ofthe pediatric study requirement. you should
`submit a request for a waiver with supporting information and documentation in accordance with
`the provisions of21 CFR 314.55 within 60 days from the date ofthis letter. We will notify you
`within 120 days of receipt of your response whether a waiver is granted. if a waiver is not
`granted, we will ask you to submit your pediatric drug development plans within 120 days from
`the date of denial of the waiver.
`
`Pediatric studies conducted under the terms of section 505A of the Federal Food, Drug, and
`Cosmetic Act may result in additional marketing exclusivity for certain products (pediatric
`exclusivity). You should refer to the Guidancefor Indusn-_v on Quaiijjzingjbr Pediatric
`Erclusivity (available on our web site at www.fda.gov.cder/pediatric) for details. Ifyou wish to
`qualify for pediatric exclusivity, you should submit a "Proposed Pediatric Study Request" in
`addition to your plans for pediatric drug development described above. Ifyou do not submit a
`Proposed Pediatric Study Request within I20 days from the date ofthis letter, we will presume
`that you are not interested in obtaining pediatric exclusivity [NOTE: You should still submit 21
`pediatric drug development plan] and will notify you ofthe pediatric studies that are required
`under section 21 CFR 314.55. Please note that satisfaction ofthe requirements in 2] CFR 314.55
`alone may not qualify you for pediatric exclusivity.
`
`Please submit one market package ofthe drug productwhen it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 314.80 and 314.81.
`.
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:27)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`un-Amnea|-|PR2016-01104- EX. 1013, p. 3 Of 30
`
`0008
`
`

`

`Ifyou have any questions, contact Maureen Hess, MPH, RD, Regulatory Health Project
`Manager, at (301) 827-6411.
`
`Sincerely,
`
`James Bilstad, MD.
`Director
`
`Office of Drug Evaluation 1}
`Center forDrug Evaluation and Research
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:28)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amneal-IPRZO16-01104- Ex. 1013, p. 9 of 30
`
`0009
`0009
`
`

`

`CENTER FOR QRUG EVQQA _I_ !0N AND RESEABCH
`
`APPLICATION NUMQER: 020766
`
`Pflfl TED LQELING
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:19)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amnejal-|PR2016-01104- Ex. 1013, p. 10 of 30
`
`0010
`0010
`
`

`

`KENICAI. 0-vlflfl
`
`XENICAL’
`
`(orlistat)
`CAPSULES
`
`DESCRIPTION: XENICAL (orlistat) is a lipase inhibitor for obesity management that acts by inhibiting
`the absorption of dietary fats.
`
`Orlistat is (S)-2-formylamino—’l-methyl-penhanoic acid (S)-l-[[(2S, 3S)-3—hexyl-4-oxo-2-oxetanyll
`methyl]-dodecyl ester. Its empirical formula is C;9H53NO5, and its molecular weight is 495.7. It is a single
`diastereomeric molecule that contains four chiral centers, with a negative optical rotation in ethanol at
`529 nm. The structure is:
`
`D
`
`gt!‘
`
`i°‘?°
`
`
`Oriistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, fieely soluble in
`chloroform, and very soluble in methanol and ethanol. Orlistat has no pK.within the physioiogical pH
`range.
`
`XENICAL is available for oral administration in dark-blue, hard-gelatin capsules, with light-blue
`imprinting. Each capsule contains I20 mg ofthe active ingredient, orlistat. 'l'hc capsules also contain the
`inactive ingredients microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone.
`and talc. Each capsule shell contains gelatin, titanium dioxide, and FD&C Blue No.1, with printing of
`pharmaceutical glaze NF, titanium dioxide. and FD&C Blue No.1 aluminum lake.
`
`CLINICAL PHARMACOLOGY: Mechanism ofAction: Orlistat is a reversible inhibitor of lipases. It
`exerts its therapeutic activity in the lumen ofthe stomach and small intestine by forming a covalent bond
`with the active serine residue site of gastric and pancreatic lipases. The inactivated enzymes are thus
`unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable flee fatty acids and
`monoglycericles. As undigested triglycerides are not absorbed, the resulting caloric deficit may have a
`positive effect on weight control. Systemic absorption ofthe dntg is therefore not needed for activity. At
`the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by
`approximately 30%.
`
`PIrarmacolrim:tt'cs.-Absorption: Systemic exposure to orlistat is minimal. Following oral dosing with 360
`mg "C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations ofintact
`orlistat were near the limits ofdetection (<5 ng/rnL). In therapeutic studies involving monitoring ofplasma
`samples. detection ofintact orlistat in plasma was sporadic and concentrations were low (<10 nymt. or
`0.02 ttM), without evidence of accumulation, and consistent with minimal absorption.
`
`h:\20?66Ib|. doc
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amneal-IPRZO16-01104- Ex. 1013, p. 11 of 30
`
`_
`
`.-
`
`0011
`
`

`

`XIJHICAL H1399
`
`XENICAL‘ (Orlistat)
`
`The average absolute bioavailability of intact orlistat was assessed in studies with male rats at oral
`doses of I50 and 1000 mg/kg/day and in male dogs at oral doses of 100 and i000 mg/kg/day and
`found to be 0.12%, 0.59% in rats and 0.7%, 1.9% in dogs, respectively.
`
`Distribution.‘ In vitro crlistat was >99% bound to plasma proteins (lipoproteins and albumin were major
`binding proteins). Orlistat minimally partitioned into er_vtl'u-ocytes.
`
`Melabolr'sm.' Based on animal data, it is likely that the metabolism ofoilistat occurs mainly within the
`gastrointestinal wall. Based on an oral "C-orlistat mass balance study in obese patients, two metabolites,
`M 1 (4-member lactone ring hydrolyzed) and M3 (Ml with N-fonnyl leucine moiety cleaved), accounted
`for approximately 42% oftotal radioactivity in plasma. MI and M3 have an open B-lactone ring and
`extremely weak lipase inhibitory activity (l000- and 2500-fold less than orlistat, respectively). In view of
`this low inhibitory activity and the low plasma levels at the therapmtic dose (average of26 ng/ml, and I08
`ng/ml. for M1 and M3, respectively, 2 to 4 hours alter a dose), these metabolites are considered
`phannaeologically inconsequential. The primary metabolite Ml had a short half-life (approximately 3
`hours) whereas the secondary metabolite M3 disappeared at a slower rate (half-life approximately l3.S
`hours). In obese patients, steady‘-state plmma levels ofM], but not M3, increased in proportion to orlistat
`doses.
`
`El:‘mt'narr‘on: Following a single oral dose of360 mg “C-orlistat in both nonnal weight and obese
`subjects, fecal excretion ofthe unabsorbed drug was found to be the major route ofelimination. Orlistat
`and its Ml and M3 membolites were also subject to biliary excretion. Approximately 97% ofthe
`administered radioactivity was excreted in feces: 83% ofthat was found to be unchanged orlistat. The
`cumulative renal excretion of total radioactivity was Q% of the given dose of360 mg “C-Orlistat. The
`time to reach complete excretion (fecal plus urinary) was 3 to 5 days. The disposition oforlistat appeared
`to be similar between normal weight and obese subjects. Based on limited data, the half-life of the
`absorbed orlistat is in the range of I to 2 hours.
`
`Special Populations.‘ Because the drug is minimally absorbed, studies in special populations (geriatric.
`pediatric, different races, patients with renal and hepatic insufiiciency) were not conducted.
`
`Drug-Drug Interactions.‘ Drug-drug interaction studies indicate that XENICAL had no effect on
`phannacolcinetics and/or phamiacodynamies ofalcohol, digoxin, glyburide, nifedipine (extended-release
`tablets), oral contraceptives, phenytoin, or warfarin. XENICAL induced a modest increase ofthe
`bioavailability and lipid—lowering effect ofpravastatin (sec CLINICAL STUDIES and PRECAUTIONS).
`Alcohol did not affect the pharmacodynamics of orlistat.
`
`were no clinically significant changes observed in gallbladder motility, bile composition or lithogenicity, or
`colonic cell proliferation rate, and no clinically significant reduction ofgastric emptying time or gastric
`acidity. In addition, no effects on plasma triglyceride levels or systemic lipases were observed with the
`administration ofXENICAL in these studies. in a 3-week study of28 healthy male volunteers, XENICAL
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amneal-lPR2016-01104- Ex. 1013, p. 12 of 30
`
`0012
`
`0012
`
`

`

`XIMCAL It-41.399
`
`XENICAL“ (orlistat)
`
`(120 mg three times a day) did not significantly atfect the balance ofcalcium, magnesium, phosphorus.
`zinc, copper, and iron.
`.
`
`Dose-response Relationship.‘ A simple maximum efi'ect (E...) model was used to define the dose-
`response curve ofthe relationship between XENICAL daily dose and fecal fat excretion as representative
`ofgastrointestinal lipase inhibition. The dose-response curve demonstrmed a steep portion for doses up to
`approximately 400 mg daily, followed by a plateau for higher doses. At doses greater than 120 mg three
`times a day, the percentage increase in efiect was minimal.
`
`CLINICAL STUDIES: Observational epidemiologic studies have established a relationship between
`obesity and visceral fat and the risks for cardiovascular disease, type 2 diabetes, certain forms of cancer,
`gallstones, certain resphatory disorders, and an increase in overall morta|ity.'Thesc studies suggest that
`weight loss, ifmaintained, may produce health benefits for obese patients who have or are at risk of
`developing weight-related comorbidities. The long-term effects oforllstat on morbidity and mortality
`associated with obesity have not been established.
`
`The efi'ects_ ofXENICAL on weight loss, weight maintenance, and weight regain and on a number of
`comorbidities (cg, type 2 diabetes, lipids, blood pressure) were assemed in seven long-term (1- to 2-years
`duration) multicenter, double-blind, placebo-controlled clinical trials. During the first year oftherapy,
`weight loss and weight maintenance were assessed. During the second year oftherapy, some studies
`assessed continued weight loss and weight maintenance and others assessed the effect oforlistat on weight
`regain. These studies included over 2800 patients treated with XENICAL and I400 patients treated with
`placebo. The majority ofthese patients had obesity-related risk factors and comorbidities. in these 7
`studies, treatment with XENICAL and placebo designates treatment with XENICAL plus diet and
`placebo plus diet, respectively.
`
`During the weight loss and weight maintenance period. a well—balanced, reduced-calorie diet that was
`intended to result in an approximate 20% decrease in caloric intake and provide 30% ofcalories ii-om fat
`was recommended to all patients. in addition. all patients were offered nutritional counseling.
`
`One—year Results.‘ Weight Loss, Weight Maintenance. rmdRr's)'c Factors: Weight loss was observed within
`2 weeks ofinitiation oftherapy and continued for 6 to 12 months. '
`
`During the 4-week placebo lead-in period of’the studies, an additional 5 to 6 lb weight loss was also
`observed in the same patients. Ofthe patients who completed I year oftreatment, 57% ofthe patients
`treated with XENICAL (120 mg three times a day) and 3 l% ofthe placebo-treated patients lost at least
`5% of their baseline body weight.
`
`Thepercentages ofpatients achieving 25% and 210% weight loss after 1 year in five large multicenter
`studies for the intent-to-treat populations are presented in Table 1.
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amneal-IPR2016-01104- Ex. 1013, p. 13 of 30
` -T
`
`.
`
`0013
`
`0013
`
`

`

`XINICAL(H1399
`
`XE.NICAL°(orI'ntat)
`
`Table 1. Percentage of Patients Losing 2570 and 210% of Body Weight From Randomization
`After I-Year Treatment*
`
`Intent-to-Treat Po « ahtiont
`25% w c Loss —'—210'/o Weiht Loss
`
`'11
`
`.
`
`
`
`XENICAL ll@
`
`
`
`Study
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`[EEK <o.oo1
`
`J9
`
`The diet utilized during year 1 was a reduced-calorie diet.
`* Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet
`1' Last observation carried forward
`_
`r
`I All studies, with the exception of H161, were conducted at centers specialized in treating obesity
`and complications of obesity. Study 1416] was conducted with primary care physicians.
`
`-9% 223
`
`
`The relative changes in risk factors associated with obesity following 1 year oftherapy with XENICAL
`and placebo are presented for the population as a whole and for the population with abnonnal values at
`randomization.
`
`Population as a Whole: The changes in metabolic. cardiovascular and anthropometric risk factors
`associated with obesity based on pooled data for five clinical studies, regardless of the patient’s risk
`factor status at randomization, are presented in Table 2. One year of therapy with XENICAL
`resulted in relative improvement in several risk factors.
`
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
` nea|-|PR2016-01104- Ex. 1013, p. 14 of 30
`
`0014
`
`

`

`XENICAL M1399
`
`XENICAL°"(or-listat)
`
`Tab]: 2, Man Change In Risk Factors From Randomization Following 1-Year Treattnent*
`Population as a Whole
`
`
`
`+5-0%
`
`lI.E
`
`
`
`IEE£i_
`m
`
`mil:
`
`
`
`
`——
`s
`olic Biood Pressure, mm H Ti
`
`
`T1
`
`
`
`—I
`
`
`
`
`
`
`
`Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus
`diet
`
`'1‘
`
`lntent—to-treat population at week 32. observed data based on pooled data
`from 5 studies
`
`Population With Abnomml‘ Risk Factors at Randornizatian.‘ The changes fiom randomization following
`1-year treatment in the population with abnormal lipid levels (LDL 2130 mg/dL, LDL/HDL 23.5,
`I-1DL <35 mg/dL) were greater for XENICAL compared to placebo with respect to LDL-cholesterol
`(-7.83% vs +1.14%) and the LDL/HDL ratio (-0.64 vs -0.46). HDL increased in the placebo group by
`20.1% and in the XENICAL group by 18.8%. In the population with abnormal blood pressure at baseline
`(systolic BP 2140 mm Hg), the change in SBP fi*om randomization to 1 year was greater for XENICAL
`(-10.89 mm Hg) than placebo (-5.07 mm Hg). For patients with a diastolic blood pressure 290 mm Hg,
`XENICAL patients decreased by -7.9 mm Hg while the placebo patients decreased by -5.5 mm Hg.
`Fasting insulin decreased more for XENICAL than placebo (~39 vs -I 6 pmol/L) trom randomization to 1
`year in the population with abnormal baseline values (2120 pmol/L). A greater reduction in waist
`circumference for XJENICAL vs placebo (-7.29 vs -4.53 cm) was observed in the population with
`abnormal baseline values (2100 cm).
`
`Effect on Weight Regain: Three studies were designed to evaluate the effects ofXENICAL
`compared to placebo in reducing weight regain after a previous weight loss achieved following either
`diet alone (one study, 14302) or prior treatment with XENICAL {two studies, 141 19C and 14185).
`The diet utilized during the 1-year weight regain portion ofthe studies was a weight-maintenance
`diet, rather than a weight-loss diet, and patients received less nutritional counseling than patients in
`weight-loss studies. For studies 14] 19C and 14185, patients’ previous weight loss was due to 1 year
`
`5
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amneal-IPR2016-01104- Ex. 1013, p. 15 of 30
` --
`
`0015
`
`0015
`
`

`

`.\'ENlCAI. 041399
`
`XENICAL°(orlistat)
`
`of treatment with XENICAL in conjunction with a mildly hypocaloric diet. Study 14302 was
`conducted to evaluate the effects of 1 year oftreatment with XENICAL on weight regain in patients
`who had lost 8% or more of their body weight in the previous 6 months on diet alone.
`
`In study 14] 19C, patients treated with placebo regained 52% ofthe weight they had previously lost while
`the patients treated with XENICAL regained 26% ofthe weight they had previously lost (p<0.00l). In
`study 14185. patients treated with placebo regained 63% ofthe weight they had previously lost while the
`patients treated with XENICAL regained 35% ofthe weight they had lost (p<0.00l). In study 14302,
`patients treated with placebo regained 53% ofthe weight they had previously lost while the patients
`treated with XENICAL regained 32% ofthe weight that they had lost (p<0.00l).
`
`Two-year Results.’ Lang-term Weight Control and Risk Factors: The treatment effects ofXENICAL
`were examined for 2 years in four of the five 1-year weight management clinical studies previously
`discussed (see Table 1). At the end ofyear 1, the patients’ diets were reviewed and changed where
`necessary. The diet prescribed in the second year was designed to maintain patient’s current weight.
`XENICAL was shown to be more efiective than placebo in long-term weight control in four large,
`multicenter, 2-year double-blind, placebo-controlled studies.
`
`Pooled data from four clinical studies indicate that 40% ofall patients treated with 120 mg three times a
`day cfXENICAL and 24% ofpatients treated with placebéfwho completed 2 years ofthe same therapy
`had 25% loss of body weight ii-om randomization.‘Pooled data from four clinical studies indicate that
`the relative weight loss advantage between XENICAL 120 mg three times a day and placebo treatment
`groups was the same afier 2 years as for 1 year, indicating that the pharmacologic advantage of
`XENICAL was maintained over 2 years. In the same studies cited in the One-year Results (see Table 1),
`the percentages ofpatients achieving a 25% and 210% weight loss after 2 years are shown in Table 3.
`
`Table 3. Percentage of Patients Losing 25% and 210% of Body Weight From Randomization
`After 2-Year Treatment"'
`
`
`
`Intent-to-Treat Population“
`
`'
`
`Study
`
`
`210% Wei 1 ht Loss
`V
`
`
`
`<0.001
`5.5% 123
`23.5% 12324.s% 133
`45.1% 133
`14r19c
`0.025
`9.5% 158
`27.2% 153
`0.002
`18.0% 178
`43.3% 173
`14149
`3.5% 113
`15.0% 113
`0.049
`16.9% 143
`25.0%
`MB
`141011
`27.9% 1221r.s% 122
`0.154
`34.0% 147
`14185
`The diet utilized during year 2 was designed for weight maintenance and not weight loss.
`
`* Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet
`** Last observation carried forward
`'i‘ All studies, with the exception of 14161 were conducted at centers specializing in treating obesity
`or complications of obesity. Study 1416] was conducted with primary care physicians.
`The relative changes in rnsk factors associated with obesity following 2 years oftherapy were also assessed
`in the population as a whole and the population with abnormal risk factors at randomization.
`
`(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:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:22)(cid:19)
`Sun-Amneal-IPRZO16-01104- Ex. 1013, p. 16 of 30
`.
` 1
`
`0016
`
`0016
`
`

`

`XENICAI. M2399
`
`XENICALO (orlistat)
`
`Population as a Whole: The reluive differences in risk factors between treatment with XENICAL and
`placebo were similar to the results following 1 year oftherapy for total cholesterol, LDL-cholesterol.
`LDUHDL ratio.
`f9§t;na_insuln' diasto_l_is=_
`pressure. waist
`circumference, and hip circumference. The relative differences between treatment groups for HDL
`cholesterol and systolic blood pressure were less than that observed in the year one results.
`
`Population With Abnormal Risk Factors at Randomization: The relative difierences in risk factors
`between treatmem with XENICAL and placebo were similar to the results following 1 year of therapy for
`LDL- and HDL-cholesterol, triglycerides, fasting insulin, diastolic blood pressure, and waist
`circumference. The relative differences between treatment groups for LDIJHDL ratio and isolated systolic
`blood pressure were less than that observed in the year one results.
`
`Study ofPatients With Type 2 Diabetes.‘ A l-year double-blind, placebo-controlled study in type 2
`diabetics (N=321) stabilized on sulfonylureas was conducted. Thirty percent ofpatients treated with
`}ENlCA.L achieved at least a 5% orgteater reduction in body weight fipm randomization compared to
`13% ofthe placebo-treated patients (p<0.00l). Table 4 describes the changes over 1 year oftreatment
`with