`
`EDITION
`
`
`
`
`
`
`
`
`
`
`2001
`Pl—IVSICIANS'
`DESK ‘
`REFERENCE
`
`
`
`
`Senior Vice President, Directory Services: Paul Walsh
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`MEDICAL ECONOMICS Copyright© 2001 and published by Medical Economics Company, Inc. at Montvale. NJ 07645-1742. All rights reserved. None of
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`NOVARTIS EXHIBIT 2025
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`NOVARTIS EXHIBIT 2025
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`

`ww-
`
`PRODUCT INFORMATION
`
`
`
`WVETH—AYERST/3443
`
`phosphoro-
`SYSTOX®—diethyl—(2-ethylmercaptoethyl)
`thionabe
`
`TEE—see TEPP
`
`TEPP—Itetmothylpyro phosphate
`THIOPH018®~sce PARATHION
`
`TIGUVONisee FENTHION
`
`
`TRICHLOROF‘ON~rdimetliyl»1;hydroxy-2,2,2-trichloroeth—
`
`ylphusphonate
`
`VAPONAfi—see DICHLORVOS
`VAPOPHOSAsee PARATHION
`
`VINYLPHOS—dlethyl-2-chloro-vinylphnsphate
`
`
`tive, against poisoning by:
`PRO’I‘OPAM appea1s to be ineflective, or marginally effec-
`CIODRIN® (alplia--methylbenzyl3[dimethoxyphu$phinyl-
`oxyl-ciscrotonate)
`DIMEFOX (tetramethylphosphorodiamidic fluoride)
`DIMETHOATE
`(dimethyl-S-[N-methylcarbamoylmeth-
`yl]phosphorodithioate)
`METHYL DIAZINON (dimethyl-[2‘isopropyl-4-methylpy»
`rimidyll-phosphorofliionate)
`METHYL PHENCAPTON (dimethyl-S—[2,5-dichlorophe-
`nylmercaptomethyllphosphorodithioate)
`PHORATE
`(diethyl-S~ethylmercaptomethylphospho-
`rodithioate)
`SCHRADAN (octamethylpyrophosphoramide)
`WEPSYN® (Ex-amino-1-[bis-(dimethylamino) phosphinyl]3-
`phenyl-1,2,4-triazole)
`The use of Protopam should. nevertheless, be considered"1n
`any life-threatening situation resulting fi'om poisoning by
`these compounds, since the limited and arbitrary conditions
`of pharmacologic screening do not alwaysaccurately reflect
`the usefulness of Protopam'1n the clinical situation.
`CLINICAL STUDIES
`The use of Protopam (pralidoxime) has been reported in the
`treatment ofhuman cases of poisoning by' the following sub-
`stances:
`Asodrin
`Diazinon
`Dichlorvos (DDVP) with chlordane
`Disulfoton
`EPN
`lsoflurophate
`_
`Malathion
`Metasystox I® and Fenthion
`Methyldemeton
`Methylparathion ,
`Mevinphos
`Parathion
`Parathion and Mevinphos
`Phosphamidon
`San‘n
`Systox®
`TEPP
`Of these cases, over 100 were due to parathion, about a
`dozen each to malathion, diazinon, and mevinphos, and a
`few to each of the other compounds.
`REFERENCES
`1. LANDAUER, W.: Cholinomimetic teratogens. V. The ef-
`fect of oximes and related cholinesterase reactivators
`Thratolngy 15:88 (Feb) 1977.
`~
`2. MOLLER, K0., JENSENHOLM, J. and LAUSEN,
`H.H.: Ugcskr Laeg 123 :501, 1961.
`3. NAMBA, T., NOLTE, CT, JACKREL, J. and GROB, D1:
`Poisoning due to orgonophosphote insecticides. Acute and
`chronic manifestations, Amer. J. Med. 50 :475 (Apr),
`1971.-
`4. ARENA, J.M.: Poisoning, Toxicology Symptoms, Treat-
`ments, ed. 4, Springfield, IL, Charles C. Thomas, 1979, p.
`133.
`5. BRACHFELD, J., and ZAVON, M.R.: Organic phosphate
`(Phosdrln®) intoxication. Report of a case and the results
`of treatment with Z-PAM, Arch. Environ. Health 11 :859,
`1965.
`6. HAYES, W.J., Jr; Toxicology ofPesticides, Baltimore, The
`Williams 8: Wilkins Company, 1975, p. 416.
`7. AMA Department of Drugs: AMA Drug Evaluations, ed.
`4, Chicago, American Medical Association, 1980, p. 1455.
`Manufactured by:
`Ayerst Laboratories Inc.
`A Wyeth-Ayerst Company
`Philadelphia, PA 19101
`CI 3799b
`
`Revised June 25, 1996
`
`
`' RAPAMUNE® ORAL SOLUTION
`[nip 'd-man]
`sirolimus
`
`Br
`
` WARNING:
`Increased susceptibility to infection and the possible de—
`velopment of lymphoma may result from immunosup.
`pression. Only physicians experiencedin immunusup-
`Continued on next page
`
`- Consult 2 0 01 FDR” supplements and future editions for revisions
`
`NOVARTIS EXHIBIT 2025
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 7
`
`
`
` 1
`
`‘
`
`DRUG ABUSE AND DEPENDENCE
`Pralidoximc chlorideis not subject to abuse and possesses
`
`no known potential for dependence.
`OVERDOSAGE
`MANIFESTATIONS OF OVERDOSAGE
`Observedin normal subjects only: dizziness, blurred vision,
`diplopia, headache,
`impaired accommodation, nausea,
`slight tachycardia. In therapy it has been difiicult to difi'er-
`entiate side efi‘ects due to the drug from'those due to the
`effects of the poison.
`TREATMENT OF OVERDOSAGE
`Artificial respiration and other supportive therapy should
`be administered as needed.
`ACUTE TOXICITY
`IV—man TDLo'. 14 mg/kg (toxic effects: CNSIV
`IV—rat LD50: 96 mglkg
`IM—rat LD50: 150 mg/kg
`ORAL—mouse LD50: 4100 mg/kg
`IPfimouse‘LD50: I55 rug/kg
`W’vmouse LD50: 90 mg/kg
`IM—mouse LD50: 180 mg/kg
`IV—rabbit LD50: 95 mg/kg
`IM—guinea pig LD50: 168 mg/kg
`DOSAGE AND ADMINISTRATION
`ORGANOPHOSPHATE POISONING
`“Pralidoxime is most effective if administered immediately
`after poisoning. Generally, little is' accomplished if the drug
`is given more than 36 hours alter termination of exposure.
`When the poison has been ingested, however, exposure may
`continue for some time due to slow absorption from the
`lower bowel, and fatal relapses have been reported after in-
`itial improvement. Continued administration for several
`days may be useful in such patients. Close supervision of
`the patient is indicated for at least 48 to 72 hours. If dermal
`exposure has occurred, clothing should be remdved and the
`hair and skin washed thoroughly with sodium bicarbonate
`or alcohol as soon as possible. Diazepam may be given cau-
`tiously if convulsions are not controlled by atropine.”7
`Severe poisoning (coma, cyanosis, respiratory depression)
`requires intensive management. This includes the removal
`of secretions, airway management, the. correction of acido-
`sis, and hypoxemia.
`Atropine should be given as soon as possible alter hypoxe-
`min is improved. Atropine should not be given in the pres-
`~ ence of significant hypoxia due to the risk of atropineiine
`duced ventricular fibrillation. In adults, atropine may be
`given intravenously in doses of 2 to 4 mg. This should be
`repeated at 5— to 10»minuto intervals until full atropiniz'a-
`tion (secretions are inhibited) 01‘ signs of atropine toxicity
`appear (delirium, hyperthermia, muscle twitching).
`Some degree of atropinization should be maintained for at
`least 48 hours and until any depressed blood cholinesterase
`activity is reversed.
`Morphine theophylline, aminophylline, and succinylcholine
`are contraindicated. Tranquilizers of the reserpine or phe-
`nothiazine type are to be avoided.
`After the clients of atropine become apparent, Protopam
`may be administered.
`PROTOPAM CHLORIDE INJECTION
`Parenteral drug products should be inspected visually for
`particulate matter and discoloration prior to administra-
`tion, whenever solution and container permit.
`Discard unused solution after a dose has been withdrawn.
`In adults, inject an initial dose of 1 to 2 g of Protopam, pref-
`erably, as an infusion in 100 mL of saline, over a 15 to 30»
`minute period. Ifthis is not practical or if pulmonary edema
`is present, the dose should be given slowly by intravenous
`injection as a 5 percent solution in water over not less than
`five minutes. After about an hour, a second dose of 1 to 2 3
`will be indicated if muscle weakness has not been relieved.
`Additional doses may be given cautiously if muscle weak-
`ness persists.
`Too~rapid administration may result in temporary worsen-
`ing of cholinergic manifestations. Injection rate should not
`exceed 200 rug/minute. Ifintravenous administration is not
`feasible, intramuscular or subcutaneous injection should be
`used.
`In severe cases, especially alter ingestion of the poison, it
`may be desirable to monitor the effect of therapy electrocar-
`diographically because of the possibility of hcart block due
`to the anticholinesterase. Where the poison has been in-
`gested, it is particularly important to take into account the
`likelihood of continuing absorption from-the lower bowel
`since this constitutes new exposure. Insuch cases, addi-
`tional doses of Protopam (pralidoxime) may be needed every
`three to eight hours. In effect, the paticnt should be “titratr
`ed” with Protopam as long as signs of poisoning recur. As in
`all cases of organophosphate poisoning, care should be
`taken to keep the patient under observation for at least 24
`hours.
`If convulsions interfere with respiration, they may be con-
`trolled by the slow intravenous injection of diazepam, up to
`20 mg in adults.
`ANTICHOLINESTERASE OVERDOSAGE
`As an antagonist to such anticholinesterases as neostig—
`mine, pyridcstigmine, and ambenonium, which are used in
`the treatment ofmyasthenia gravis, Protopam may be given
`in a dosage of 1 to 2 g intravenously followed by increments
`of 250 mg every five minutes.
`HOW SUPPLIED ,
`NDC 0046-0374—06—Hospital Package: This contains six 20
`mL vials of 1 g each of sterile Protopam Chloride (preli-
`
`
`
`
`
`‘doxime chloride) white to ofi‘iwhiie porous cake*, without
`diluent or syringe. Solution may be prepared by adding 20
`mL of Sterile Water'for Injection, USP These are single-
`duse vials for intravenous injection or for intravenous infu-
`sion alter further dilution with physiologic saline. Intra-
`muscular or subcutaneous injection may be used when in-
`travenous injection is not feasible.
`*thn necessary, sodium hydroxide is added during pro-
`‘ ceasing to adjust the pH.
`
`Stor'e at room temperature lapproxlmately 25°C).
`ANIMAL PHARMACOLOGY AND TOXICOLOGY
`The following table lists chemical and trade or generic
`names of pesticides, chemicalshand drugs against which
`Protopam (usually administered in conjunction with atro—
`pine) has been found to have 'antidotal activity on the basis
`of animal experiments. All compounds listed are organe-
`phosphates having anticholinesterase activity. A great
`many additional substances are in industrial use but have
`been omitted because of lack of special information.
`AAT—see PARATHION
`
`AFLlX®-—See FORMOTHION
`
`ARROW—See PARATHION
`AMERICAN CYANAMID 3422—see PARATHION
`AMITON—diethyl-S—(Zdiethylaminoethylmhosplio-
`rcthiolate
`
`ANTHIoo—see FORMOTHION .
`APHAMIWMe PARATHION.
`ARMIN—ethyl-4-nitrophenylethylphosphonate
`AZINPHQS-METHYL—dimethyl-S- [(4-oxo1,2,3,-benzotri-
`azin-S (4H)—yl)n1ethyll phosphorodithioate
`MORPHOTHION—dimethyl-S-2—kcto-2-(N-morphnlylleth-
`ylphosphorodithioate
`NEGUVON®~see TRICHLOROFON
`NIRAN®r~scc PARATHION
`
`NITROSTIGMINE—see PARATHIQN
`0,0-DIETHYL—O—p-NITROPHENYL PHOSPHOROTIIIQ-
`ATE—v—see PARATHION
`-
`
`O,Q-DIETHYL-O-p-NITROPHENYLTHIO PHOSPHATE—
`see PARATHION
`0R 1191—see PHOSPHAMIDON
`OS 1836-see VINYLPHOS
`OXYDEMETONMETHYL—dimethyl—S-Z—(cthylsulflnyl)
`ethyl phosphorotbiolate
`
`PHOSPHOROTHIQIC ACID, 0,0~DIETHYL»O-p—NITRO-
`PHENYL ESTER—see PARATHION
`PLANTHION—see PARATHION
`QUELETOX~see FENTHION
`RHODIATOX®—soe PARATHION
`
`RUELENE®—4-tert-butyl-2-chlcrophenylmethyl-N-meth—
`ylphosphoroamidate
`
`SARIN—isoptopyl-methylphosphonofluoridate
`Isl-ELL OS 1836—see VINYLPHOS
`SHELL 2046—see MEVINPHOS
`
`SNP—see PARATHXON
`
`S0MAN—pinacolylvmethylphosphanofl111iridate
`
`PARAOXON—diethyl (4-nitrophcnyl) phosphate
`PARATHION—diethyl (4-nitrophenyl) phosphorothionate
`PENPHOS—see PARATHION
`PHENCAPTONwdiethylei2,57111chlorophenylmercaptom-
`: ethyl) phosphorodithioate
`PHOSDRIN®—see MEVINPHOS
`PHOS-KlL—see PARATHION
`PHOSPHAMIDON—1-chloro-1-disthylcarbamoyl-1-propen-
`\
`2-yl-dimethylphosphate
`PHOSPHOLINE IODIDE®—-see echothiophate iodide
`
`NOVARTIS EXHIBIT 2025
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 7
`
`

`

`3444/WYETH-AYERST
`
`PHYSICIANS’ DESK REFERENCE®
`
`_________.___.__i___
`Rapamune—Cont.
`
`SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN iSD) IN RENAL
`TRANSPLANT PATIENTS (MULTIPLE DOSE)” h
`
`Owls“
`t...
`.i.
`AUC “
`CLIF/WT"
`(ng/mL)
`(l?)
`(ng-himsL)
`(mL/h/kg)
`Dose
`n
`
`12.2 t 6.2
`3.01 .4: 2.40
`153 a 70
`182 + 72'
`2 mg
`19
`
`
`37.4 r 21 1.84 t 1.30 396 t 1935 mg 221 £143
`
`
`23
`a: Sirolimns administered four hours after cyclosporine oral solution (MODIFIED) (e.g., Neoral® Oral Soluti
`closporinc capsules (MODIFIED) (e.g., Neoral® Soft Gelatin Capsules).
`'
`on) my" “y‘
`b: As measured by the Liquid Chromatographic/Tandem Mass Spectrometric Method (LC/Ms/M$)
`c: These parameters were dose normalized prior to the statistical comparison.
`d: CLIP/WT = oral dose clearance.
`__________________————__—‘
`
`SIRDLIMUS PHARMACOIHNETIC PARAMETERS (MEAN :SD) IN 18 HEALTHY SUBJECTS AND 18
`PATIENTS WITH ‘HEPATIC IMPAIRMENT (15 MG SINGLE DOSE)
`
`Cm;
`tn
`AUCM
`CL/F/WT
`W,fl
`(ng/mL)
`{ngoh/mL)
`(mI/h/kg)
`Population
`ax
`Healthy subjects
`78.2 i 18.3
`0.82 i 0.17
`970 i 272
`215 1‘ 76
`Hepatic impairment
`
`0.34 1' 0.17 1567 r 61677.9 1 23.1 144 E 02
`
`
`
`a: As measured by (LC/MS/MS)________—__———-_————.
`
`pressive therapy and management of renal transplant
`patients should use Rapamune® Patients receiving the
`drug should be managed in facilities equipped and
`staffed with adequate laboratory and supportive medi-
`cal resources. The physician responsible for mainte-
`nance therapy should have complete information requi-
`site for the follow-up of the patient.
`
`DESCRIPTION ‘
`Rapamune® (sirolimus) is an immunosuppressive agent.
`Sirolimus is a macrocyclic lectone produced by Stmptamyces
`hygroscopicus. The chemical name of sirolimus (also known
`as
`rapamycin)
`is (3S,6R,7E,9R,10R,12R,14S,1516,1719,
`19E,21$,23S,26R,27R,348$) - 9,10,12,13,14,2l,22,23,24,
`25.,26,27,32,'33,34,34a— hexadecahydrc -9,27-dihydroxy-3—
`[(151)-2—l(18,3R.4.R)-4-hydroxy-3~methoxycyclohexyl]—1-me»
`thylethyll-10,21-dimethoxy-6,8,1244,2026 7 hexamethyl-
`23,27-epoxy-3H-pylido [2,1-c] [1,4] oxaazacyclohentriacon-
`tine-1,5,11528,29 (4H,6H,31H)-pentone. Its molecular for-
`mula is CHI-179N013 and its molecular weight is 914.2. The
`structural formula of sirolimus is shown below.
`
`“IN
`
`0
`" ‘GH,
`
` 0
`
`H23
`
`‘CHQ
`
`
`
`
`
`SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN 1 SD) IN PEDIATRIC PATIENTS WITH
`STABLE CHRONIC RENAL FAILURE MAINTAINED ON HEMODIALYSIS OR PERITONEAL DIALYSIS
`(1, 3, e, 15 Mel/M2 SINGLE DOSE)
`
`
`
` 12m, (11) in (h) CLIP/WT (mL/h/kg)
`n
`Age Group (y) '
`‘
`1.1 I 0.5
`71 1' 40
`530 1 450
`9
`5—11
`11
`12—18
`0.79 i 0.17
`55 + 18
`450 t 232
`____________________———-—
`tients with severe hepatic dysfunction is unknown. Dosage
`variability, Rapamune should be. taken consistently with or
`..adjustment is recommended for patients with mild to mod-
`without food (s‘e'e DOSAGE ANerDMINISTRA’l‘ION).
`eratehepatic impairment (see DOSAGE AND ADMINIS-
`Distribution
`‘
`'
`'
`TRATION).
`‘
`The mean ('t SD) blood-to-plasma ratioof sirolimus was 36
`Renal impairment: The eifect of renal impairment on the
`(t 17.9) in stable renal allograil.‘ recipients, indicating that
`pharmacokinctics of sirolimus is not known-However, there
`sirolimus is extensively partitioned into formed blood else
`is minimal (2.2%) renal excretion of the drug or its metab—
`'ments. The mean volume of distribution (VSS/F) of sirolimus
`elites.
`is 12 I 7.52 L/kg. Sirolimus is extensively bound (approxi-
`Pediatric: Limited pharmacokinetic data are available in
`mately 92%) to human plasma proteins. In man, the binding
`of sirolimus was shown mainly to be associated with serum
`pediatric patients. The table below summarizes pharmaco»
`kinetic data obtained in pediatric dialysis patients with
`albumin (97%), all-acid glycoprotein, and lipoproteins.
`Metabolism
`chronically impaired renal function.
`Sirolimus is a substrate for both cytochrome P450 IIIA4
`[See third table above]
`‘
`Geriatric: Clinical studies of Rapamune did not include a
`(CYP3A4) and P»glycoprotein. Sirolilnus is extensively me-
`sufficient number of patients > 65 years of age to determine
`tabolized by O—demethylation and/or hydroxylation. Seven
`whether they will respond differently than younger pa-
`(7) major metabolites, including hydroxy, demethyl, and hy-
`tients:Sirolimus trough concentration data in 35 renal
`droxydemethyl, are identifiable in whole blood. Some of
`these metabolites are also detectable in plasma, fecal, and
`transplant patients > 66 years of age were similar to those
`urine samples, Glucuronidc and sulfate conjugates are not
`in the adult population (n=822) from 18 to 65 years of age.
`vGender:
`.Siroliruus oral dose clearance in males was 12%
`present in any ofthe biologic‘matricesnSil-olimus is the ma-
`lower than that in females; male subjects had a significantly
`jor component in human wholerblood and contributes to
`greater than 90% of the immunosuppressive activity.
`longer tug than did female subjects (72.3 hours versus 61.3
`Excretion
`hours). These pharmacokinetic differences do not require
`Alters single dose of [MCISirolimus in healthy volunteers,
`dose adjustment based on gender.
`the majority (91%) of radioactivity was recovcrcd from the
`Race:
`In large phase 111 trials using Rapamune and W.
`feces, and only'e. minor amount (22%) was excreted in
`urine.
`closporine oral solution (MODIFIED) (e.g., Neoral® Oral
`Solution) and/or cyclosporine capsules (MODIFIED) (cg,
`Pharmacokinetics in renal transplant patients
`Neoral® Soft Gelatin Capsules), there were no significant
`Pharmacokinetic parameters for sirolimus oral solution
`differences in mean trough sirolimus concentrations over
`given daily in combination with cyclos'porine and cortices
`time between black (n = 139) and non~black (n = 724) pa-
`steroids in renal transplant patients are summarized below
`tients during the first 6 months after transplantation at
`based on data collected at months 1, 3, and 6 alter trans-
`sirolimus doses of 2 Trig/day and 5 mg/day.
`plantation. There were no signiflcant difl'erences in any of
`CLINICAL STUDIES
`these parameters with respect to treatment group or month.
`[See first table above]
`-
`The safety and efficacy of Rapamune for the prevention of
`Whole blood sirolimus trough concentrations, as measured
`organ rejection following renal transplantation were as
`sessed in two randomized, double—blind, multicenter, con-
`by immunoassay, (mean 1 SD) for the 2 mgjday and 5 mg/
`day dose groups were 8.59 _+ 4.01 (n = 226) and 17.3 t 7.4 (n
`trolled trials. These studies compared two dose levels'of
`= 219), respectively Whole blood trough sirolimus concen-
`Rapamune oral solution (2 mg and 5 mg, once dolly) with
`trations, as measured by LC/MS/MS, were significantly cor-
`azathiopiine (Study lllor placebo (Study 2) when admlmS—
`related (r2 = 0.96) with AUCW Upon repeated twice daily
`tered in combination with oyclosporine and corticosteroids.
`administration'without an initial loading [dose in a multiple-
`Study 1 was conducted in the United States at 38. sites.
`dose study, the average trough concentration of sirolimus
`Seven hundred nineteen (719) patients were enrolled in this
`increases approximately 2 to 3—fold over the initial 6 days of
`trial and randomized following transplantation; 284 were
`therapy at which time steady stoic is reached. A loading
`randomized to receive Rapamune 2 mg/day, 274 were ran-
`dose of 3 times the maintenance dose will provide near
`domized to receive Rapamune 5 m‘g/day, and 161 to receive
`steady state concentrations within 1 day in most patients.
`.
`azathioprine 2—3 mg/kg/day. Study 2 was conducted in A‘us-f
`The mean ’t SD'tel-minal elimination half life (tug) of siroli-
`tralia, Canada, Europe, and’tlle United States, at a tota 0
`, mus after multiple dosing'in stable renal transplant pa-
`3‘4» sites. Five hundred seventy—six (576) patients were Ian:
`tients was estimated to be about 62 i 16 hours.
`rolled in this trial and randomized before transplantationg,
`Special Populations
`'
`227 were randomized to receive Rapamune 2 mg/day, gm
`Hepatic impairment: Sirolimus (15 mg) was administered
`were randomized to receive Rapamune 5 mgiday, and}? yte
`as a single oral dose to 18 subjects with normal hepatic
`receive placebo. -In both studies, the use of antllympt 0:195
`function and to 18 patients with Child-Pugh classificationA
`antibody induction therapy was prohibited. In both 5 u
`l
`’
`failure
`or B hepatic impairment, in which hepatic impairment was
`the primn‘ry efficacy endpoint was the rate of efficacy failure
`'
`fie trans lantatlon. Efficacy '
`primary and not related to an underlying systemic disease.
`1n the first 6 months a
`r
`P of an acute ”199““ BP—
`Shown- below are the mean : SD pharmacokinetic param—
`was defined as the first occurrerge‘
`death
`eters following the administration of sirolimus oral solution.
`isode (confirmed by biopsy), gra
`ass, or
`.
`.
`of-
`~
`t doses 0
`[Sec second table above]
`The tables below summarize the results of the primaryf 2
`Compared with the values in, the normal hepatic group, the
`flcacy analyses from these'trials. Rapamune, 2, cidencc 0
`hepatic impairment group had higher mean values for
`mg/day and 5'mg/day, Significantly reduced:fill:13025 level;
`sirolimus AUG (61%) and tm (43%) and hadlower mean val-
`eflicac failure (statistically significant at
`.
`dose
`ues for sirolimus CUF/WT (33%). The mean tm increased
`nominil significance level adjusted for mullmfijtibzrl corn-
`from 79 t 12 hours in subjects with normal hepatic function
`comparisons) at 6 months followmg transp an
`to 113 i 41 hours in patients With impaired hepatic func-
`pared to both azathioprine and placebo.
`tion. The-rate of absorption of sirolimus was not altered by
`[See first & second table at top of next page]
`rima
`hepatic disease, as evidenced by CH,“ and tmu values. How-
`Patient and graft survival at 1 year were Eire-r1; survival d4-
`ever, hepatic diseases with varying etiologies may show dif-
`ferent effects and the pharmacokinetice of simlimus in pa-
`points. The table below shows graft and Pa 1
`
`
`
`NOVARTIS EXHIBIT 2025
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 7
`
`Sirolimus is a white to ofi-wldte powder and is insoluble in
`water but freely soluble in benzyl alcohol, chloroform, ace—
`tone, and acetonitrile.
`Each mL of Rapamune® Oral Solution contains 1 mg siroli-
`mus; inactive ingredients arePhosal 50 PG® (phosphatidyl-
`choline, propylene glycol, monodiglycerid‘es, ethanol, soy
`fatty acids, and ascorbyl palmitate) and Polysorbate 80, NF.
`Rapemune Oral Solution contains 1579—2570 ethanol.
`CLINICAL PHARMACOLOGY
`Mechanism -of Action
`Sirolimus inhibits T lymphocyte activation and proliferation
`that occur-sin response to:antigenic and cytokine (Interleu-
`kin l‘lLl-Z, IL-4, and IL-15) stimulation by a mechaniSm
`that is distinct from that of other immunosuppressants.
`Sirolimus also inhibits antibody production. In cells, siroli-
`mus binds to the, immunophilin, FK Binding Protein-12
`(F‘KBP»12), to generate an immunosuppressivc complex.
`The sirolimus: FKBP—12 complex has no effect on cal-
`cineurin activity. This complex binds to and inhibits the ac-
`tivation of the mammalian Target Of Rapamycin (mTOR), a
`key regulatory kinase. This inhibition suppresses cytokine»
`driven T—cell proliferation, inhibiting the progression from
`the G1 to the S phase of the cell cycle.
`Studios in experimental models show that sirolimus pro-
`longs allografi (kidney, heart, skin, islet, small bowel, pan-
`creatico—duodenal, and bone marrow) survival in mice, rats,
`pigs, and/or primates. Sirolimus reverses acute rejection of
`heart and kidney allogratts in rats and prolonged the graft
`survival in presensitizcd rats. In some studies, the immu-
`nosuppressive effect of sirolimus lasted up to 6 months after
`discontinuation of therapy. This tolerization efiect is alien-
`tigen specific.
`In rodent models of autoimmune disease, sirolimus sup-
`presses imrm‘me-mediated events associated-with systemic
`lupus erythematosus, collagen-induced arthritis, autoim-
`mune type I‘ diabetes, autoimmune myocarditis, experimen»
`tal allergic encephalomyelitis, graft-versus-host disease,
`and- autoimmune uveoretinitis.
`Pharmacokinetics
`Sirolimus pharmacokinetic activity has been determined
`following oral administration in healthy subjects, pediatric
`dialysis patients, hepatically-impaired patients and renal
`transplant patients.
`Absorption
`.
`Following oral administration, sirolimus is rapidly ab-
`sorbed, with a mean‘time-to-peak concentration of approxi-
`mately 1. hour after a single dose in healthy subjects and
`approximately 2 hours after multiple oral doses in renal
`transplant recipients. The systemic availability of eirolimue
`was estimated to be approximately 14%. Sirolimus concen-
`trations in stable renal transplant patients are dose propor-
`tional between 3 and 12 mg/m2.
`Food effects:
`In 22 healthy volunteers, 9. high fat break-
`fast (1.88 kcal, 54.7% fat) altered the bioavailability charac-
`teristics of sirolimus. Compared to fasting, a 34% decrease
`in the peak blood sirolimus concentration (0,“), a 35-fold
`increase in the time-to-peak concentration (tmm), and a 35%
`increase. in mml exposure (AUG) was observed. ’Ib minimize
`lnlormnfinn will be xlmundod l“. “mummy.“ “.7 summon... um
`
`NOVARTIS EXHIBIT 2025
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 7
`
`

`

`a W
`
`Azathiopr-ine
`Rapamune®
`Rapamune®
`2—3 mg/kg/day
`2 Ins/day
`5 mg/day
`
`(n = 161)
`(n = 284)
`(n = 274)
`32;;
`18.7
`16.8
`Efficacy failure at 6 months
`Components ofe/ficacy failure
`29.2
`16,5
`11.3
`Eiopsyproven acute rejection
`2.5
`. 1.1
`2.9
`Graft loss
`0
`0.7
`1.8
`Death
`.
`
`
`0.4 0.7Lost to follow-up 0.6
`
`a: I’atiehts received cyclospurine and corticosteroids.
`INCIDENCE (%) OF THE PRIMARY ENDPOINT AT 6 MONTHS: STUDY 2‘
`Rapamune®
`Repamune®
`2 mg/day
`5 rug/day
`Placebo
`
`(n = 219)
`(n = 180)
`(n = 227)
`25.6
`47,7
`30 0
`
`Efficacy failure at 6 months
`Components ofelficacy failure
`41.5
`19.2
`24.7
`Eiopsy-proven acute rejection
`3.9
`3.7
`3.1
`Grafi loss
`2.3
`2.7
`2.2
`Death
`.
`
`
`0Lost to follow-up 0
`3: Patients received 'cycloeporiuc and corticosteroids,
`
`1 YEAR .GRAF'I‘ AND PATIENT SURVIVAL (752)“
`
`Placebo
`
`Azathioprine
`2—3 mglkg/day
`(n = 161)
`93.8
`98.1
`
`PRODUCT INFORMATION
`YETH >AYERST/3445
`m—fi—fi
`INCIDENCE (76) OF THE PRUVIARY ENDPOINT AT 6 MONTHS: STUDY 1‘
`1 year in Study 1 and Study 2. The graft and patient sur—
`vival rates at 1. year were similar in the Rapamune~ and
`comparator-treated patients.
`[See third table above]
`The reduction in the incidence of first biopsy~confirmed
`acute rejection episodes in Rapamune-treated patients com-
`pared to the control groups included a reduction in all
`grades of rejection.
`[See fourth table above]
`In Study 1, which was prospectively stratified by race
`within center, efficacy failure was similar for Rapamune 2
`rug/day and lower for Rapamune 5 mglday compared to aza-
`thiopn'ne in black patients. In Study 2, which was not pro-
`spectively stratified by race, eflicacy failure was similar for
`both Rapamune doses compared to placebo in black pa-
`tients. The decision to use the higher dose of Rapamune in
`black patients must be weighed‘against the increased risk
`of dose dependent adverse events that were observed with
`the Rapamune 5 mg dose (see ADVERSE REACTIONS).
`[See fifih table above]
`Mean glomerular filtration (GFR) at one year post trans-
`plautworo calculated using the Nankivell equation for all
`subjects in Studies 1 and 2 who hail serum creatinine mea-
`sured at 12 months. In Studies 1 and 2 mean GFR, at 12
`months, were lower in patients treated with cyclosporine
`and Rapamune compared to those treated with cyclosporine
`and the respective azathioprinecr placebo control.
`.
`Within each treatment group in Studios 1 and 2, mean GFR
`at one year post transplant -waslower in patients who ex-
`perienced at least 1 episode ofbiopsy-proven acute rejection,
`compared to those who did not.
`Renal function should be monitored and appropriate adjust-
`ment of the immunosuppression regimen should be consid-
`ered in patients with elevated serum creatinine levels (see
`PRECAUTIONS).
`INDICATIONS AND USAGE '
`Repamune is indicated for the prophylaxis of organ rejec»
`tion in patients receiving renal transplants. It is recom-
`mended that Rapomune be used in a regimen with cyclospo-
`rine and corticosteroids.
`CONTRAINDICATIONS
`Rapamune is contraindicated in patients with a hypersen-
`sitivity to sirolimus or its derivatives or any Component of
`the drug product.
`WARNINGS
`Increased susceptibility to infection and the possible devel-
`opment of lymphoma and other malignancies, particularly
`of the skin, may result from immunosuppression (see ADr
`VERSE REACTIONS). Oversuppression of the immune
`system can also increase susceptibility to infection includ-
`ing opportunistic infections, fatal infections, and sepsis.
`Only'physicians experienced in immunosuppressive ther-
`apy and management of organ transphint patients should
`use Rapernuue. Patients receiving the drug should be manL
`aged in facilities equipped and stafi‘e‘d with adequate labo-
`ratory and supportive medical resources. The physician re-
`sponsiblezfor maintenance therapy shouldhave completein»
`formation requisite for the followup of the patient.
`As usual for patients with increased risk for skin cancer,
`exposure to sunlight and UV light should be limited by
`wearing protective clothing and using sunscreen with a
`high protection factor.
`Increased serum cholesterol and triglycerides that may re-
`quire treatment occurred. more frequently in patients
`treated with Rapemune compared to azathioprine or plan -
`cebo controls. (see PRECAUTIONS).
`In phase III studies,.mean serum creatinine was increased
`and mean glomerular filtration rate wasdecreased in pa— ‘
`tients treated with Rapamune and cyclosporine compared to
`those treated with cyclosporine and placebo or azathioprine
`controls (see CLINICAL STUDIES). Renal function should
`be monitored during the administration of maintenance im-
`munosuppression regimens including Rapamune in combi-
`nation with cyclosporine, and appropriate adjustment ofthe
`immunosuppression regimen should be considered in pa-
`tients with elevated serum creatinine levels. Caution should
`be exercised when using agents which are known to impair
`renal function (see PRECAUTIONS).
`In clinical trials, Rapamune has been administered concur.-
`rontly with corticosteroids and with the following formula-
`tions of cyclosporine:
`.
`Sandimmune® Injection (oyclosporine injection
`Sandimmunc® Oral Solution (cyclosporine oral solution)
`Neoral® Soft Gelatin Capsules (cyclosporine capsules
`[MODIFIEDD
`,
`Ncoral® Oral Solution (cyclosporine’oralvsolution [MODI-
`