PDR”
`
`5 8
`
`EDITlON
`
`ISBN: 1-236363-4/176
`
`Drug Information Specialists: Greg Taliis, RPh; Min K0, PtiarniD
`Vice President, Sales and Marketing: Dikran N. Barsamian
`Senior Director of Pharmaceutical Sales: Anthony Sorce
`Project Editor: Harris Fleming
`National Account Manager: Marion Reid, RPh
`Senior Editor: Lori Murray
`Senior Account Manager: Frank Karkowsky
`Production Editor: Gwynned L. Kelly
`Account Managers: Marione A. Jaxel, Denise Kelley, Eileen Sullivan,
`Senior Director, Operations: Brian Holland
`Suzanne E. Yarrow, RN
`Director of PDR Operations: Jeffrey D. Schaefer
`Director of Trade Sales: Bill Gaffney
`Manager of Production Operations: Thomas Westburgh
`Senior Director, Marketing and Product Management:
`PDR Production Manager: Joseph F. Rizzo
`Valerie E. Berger
`Senior Production Coordinators: Gianna Caradonna, Christina Klinger
`Senior Product Manager: Jeffrey D. Dubin
`Finance Director: Mark S. Ritchin
`Production Coordinator: Yasmin Hernandez
`Senior Index Editor: Shannon Reilly
`Senior Director, Publishing Sales and Marketing: Michael Bennett
`Senior Marketing Manager: Jennifer M. Fronzaglia
`Index Editor: Noel Delougnery
`Direct Mail Manager: Lorraine M. Loening
`Format Editor: Michelle S. Guzman
`Manager of Marketing Analysis: Dina A. Maeder
`Production Associate: Joan K. Akerlind
`Promotion Manager: Linda Levine
`Production Design Supervisor: Adeline Rich
`Vice President, Regulatory Affairs: Mukesh Menta, RPl'i
`Electronic Publishing Designers: Bryan Dix, Rosalia Sbcrna, LiVio Udina
`Editorial Director: Lisette Bralow
`Digital Imaging Coordinator: Michael Labruyere
`Manager, Professional Data Services: Thomas Fleming, PharmD
`Director of Client Services: Stephanie Struble
`Manager, Editorial Services: Bette LaGow
`Fulfillment Manager: Louis J. Bolcik
`Manager, Concise Data Content: Tammy Chernin, RPh
`
`THOMSON Copyright © 2004 and published by Thomson PDR at Montvale, NJ 07645-1742. All rights reserved. None of the content of this publication
`*
`m may be reproduced, stored in a retrieval system, resold, redistributed, or transmitted in ary form or by any means (electronic, mechanical,
`photocopying, recording, or otherwise) without the prior written permission of the publisher. Physicians“ Desk Referencei PDFt ’, Pocket
`FDR
`PDFP, PDR Family Guide to Prescription Drugs‘, PDR Family Guide to Women's Health and Prescription Drugs ‘, and PDFt Family Guide to
`Nutrition and Health’e‘ are registered trademarks used herein urder license. PDR for Ophthalmic Medicines, PDR" for Nonprescriplion Drugs and Dietary Supplements, PDFt"
`Companion Guide, PDR" Pharmacopoeia, PDFi' for Herbal Medicines, PDR ‘ior Nutritional Supplements, PDR“ Medical Dictionary, PDFt’ Nurse's Drug Handbook, PDR
`Nurse's Dictionary, PDR ‘ Famin Guide Encyclopedia of Medical Care, PDR" Family Guide to Natural Medicines and Healing Therapies, PDFi" Family Guide to Common
`Ailments, PDRJ’ Family Guide to Over—lhe-Counter Drugs, PDP Family Goide to Nutritional Supplements, and FDR“ Electronic Library are trademarks used herein under
`license.
`
`2004
`
`PHYSICiANS’
`DESk
`REFERENCE
`
`
`Executive Vice President, Directory Services: David Duplay
`
`Officers of Thomson Healthcare,: Presrdcnt and Chief Executive Officer: Richard Noble; Chief Financial Officer: Paul Hilger; Executive Vice President, Clinical Trials: Toni Kelly;
`Executive Vice Presrdont, Medical Education: Jeff MacDonald; Executive Vice President, Clinical Solutions: Jeri Reihl; Executive Vice President, Directory Services: David Duplay;
`Senior Vice President, Business Development: William Gole; Vice President, Human Resources: Pamela M. Bilasn; President, Physmiaii’s World: Marty Cearnal
`
`NOVARTIS EXHIBIT 2072
`Par v. Novartis, IPR 2016-01479
`Page 1 of 32
`
`

`

`r'
`
`672/ASTFlAZEN ECA
`
`
`PHYSICIANS' DESK REFERENCE®
`fix
`
`Table 1: Demographic and Disease Characteristics
`
`012N
`
`ot recorded
`Tumor Histology
`Squamous
`Adcnocarcinoma
`Undifierentiated
`Large Cell
`Squamous & Adennr'urcinoma.
`Not Recorded
`Current Disease Status
`Locally advanced
`Metastatic
`
`IRESSA Dose
`250 mg/day
`500 mglday
`Characterisfic
`
`N = 66 l%) N = (76%)
`Age Group
`18—64 years
`43 (65)
`43 (57)
`64—74 years
`19 (29)
`30 (39)
`4 (6)
`75 years and above
`3 (4)
`Sex
`Male
`38 (58)
`41 (54:‘
`Female
`28 (42)
`35 (46)
`Race
`White
`68 (89}
`Black
`2 (3)
`Asian/Oriental
`2 (3)
`Hispanic
`3 (4)
`Other
`1 (1)
`Smoking History
`Yes (Previous or current smoker)
`62 (82)
`No (Never smoked)
`14 (18)
`Baseline WHO Performance Status
`9 (12)
`53 (70)
`14 (18)
`0 (0)
`ll (14)
`50 (66)
`4 (5)
`Z (3)
`7 (9)
`2 (3)
`5 (7)
`71 (93)
`
`Faslodex—Cont.
`
`After single use, discard in an approved sharps collector in
`accordance with applicable regulations and institutional
`policy.
`‘
`Becton Dickinson guarantees the contents of their un-
`opened or undamaged packages to be sterile, nontoxic and
`nonpyrogenic.
`
`Figure 1
`
`Activated
`After Use
`
`Figure 3
`
`\ Bevel Up : LeverArm Up
`
`HOW SUPPLIED
`One 5 mL clear neutral glass (Type 1) barrel containing
`250 rug/5 mL (50 mg/mL) FASLODEX Injection for intro,
`muscular injection and fitted with a tamper evident closure.
`The syringe is presented in a tray with polystyrene plunger
`rod and a safety needle (Safety/Glide“) for connection to the
`barrel.
`,
`NDC 0310—0720750 One 5 mL Prefllled Syringe
`Two 5 mL clear neutral glass (Type 1) barrels, each contain».
`ing 125 rug/2.5 niL (50 mg/mL) of FASLODEX Injection for
`intramuscular injection and fitted with a tamper-evident
`closure. The syringes are presented in a tray with polysty-
`rene plunger rod and safety noodles (SafetyGlide'm) for con-
`nection to the barrels,
`.
`NDC 0310-0720-25 Two 5 mL Prefillcd Syringes each con-
`taining 125 org/2.5 oil.
`storage
`REFRIGERATE, 2°—8°C (36°—46°F). TO PROTECT FROM
`LIGIIT, STORE IN THE ORIGINAL QARTON UNTIL
`TIME or USE.
`_
`'
`SafetyGlide‘“ is a trademark of Becton Dickinson and
`Company
`All other trademarks are the property of the AstraZuneca
`group
`© Asti'annecu 2002
`Distributed by:
`AstraZeneca Pharmaceuticals LP
`Wilmington, DE 19850
`Manufactured for:
`AstraZeneca UK Ltd.
`Mucclesfield, England
`By: Vctter Pharma-Fertigung Gnin & Co. KG
`Ravensburg, Germany
`22073-00
`Rev 07/02
`.
`Shown in Product Identification Guide, page 306
`
`IRESSA®
`lér' as-sa]
`(geliiimb tablets)
`250 mg
`FOR ONCOLOGY USE ONLY
`
`DESCRIPTION
`IRESSA® (gefitinib tablets) contain 250 mg of gefitinib and
`are available as brown film-coated tablets for daily oral
`administration.
`Gefitinib is an anilinoquinazoline with the chemical name
`4-Quinozolinamine, N—(S-chloro-4-fluorophenyl)-7-methoxy-
`6-[3747morpholin) propoxyl and the following structural
`formula:
`
`
`
`
`61 (92)
`1 (2)
`1 (2)
`0 (0)
`3 (5)
`45 (68)
`21 (32)
`14 (21)
`36 (55)
`15 (23)
`1 (2)
`9 (14)
`47 (71)
`6 (9)
`1 (2)
`3 (5)
`0(0)
`11 (17)
`55 (83)
`
`m I
`
`t has the molecular formula C22H24CIFN403 , a relative
`molecular mass of 446.9 and is a white-colored powder. Ge-
`fitinib is a free base. The molecule has pKas of5.4 and 7.2
`and therefore ionizes progressively in solution as the ,pH
`falls. Gefitinib can be defined as sparingly soluble at pH 1,
`but is practically insoluble above pH 7, with the solubility
`dropping sharply between pH 4 and pH 6. In non-aqueous
`solvents, gefitinib is freely soluble in glacial acetic acid and
`dii'nethylsulphoxideJ soluble in pyridine, sparingly soluble
`in tetrahydmfuran, and slightly soluble in methanol, etha
`nol (99.5%), ethyl acetate, propan-Z-ol and amtonitn‘le.
`The inactive ingredients of IRESSA tablets are: Tablet core:
`Lactose (nionohydrate, microcrystallinc cellulose, croscar-
`mellcse sodium, povidono, sodium lauryl sulfate and mag-
`nesium stool-ate. Coating: Hydroxypropyl inetliylcelluluse,
`polyethylene glycol 300, titanium dioxide, rcd ferric oxide
`and yellow ferric oxide,
`CLINICAL PHABIVIACOLOGY
`Mechanism of Action
`The mechanism of the clinical antitllmor action of gefitinib
`is not fully characterized. Geiitinib inhibits the intracellular
`phosphorylation of numerous tyrosine kinases associated
`with transmembrane cell surface receptors, including the
`tyrosine kinascs associated with the epidermal growth fac-
`lur receptor (EGFR-TK). EGFR is expressed on the cell suit
`face of many normal cells and cam-er cells. No clinical stud-
`ies have been performed that demonstrate a correlation
`between EGFR receptor expression and response to
`gefitinib.
`Pharmacokinetics
`Gefitinib is absorbed slowly after oral administration with
`mean bioavailability of 60%. Elimination is by metabolism
`(primarily CYP3A4) and excretion in feces. The elimination
`half-life is about 48 hours. Daily oral administration of ge~
`fltinib to cancer patients resulted in a Zefold accumulation
`compared to single dose administration. Steady state
`plasma concentrations are achieved within 10 days.
`Absorption and Distribution:
`Gefitinib is slowly absorbed, with peak plasma levels occur-
`ring 3—7 hours after closing and mean oral bioavailability of
`60%. Bio-availability is not significantly altered by food. Ge-
`fitinib is extensively distributed throughout the body with a
`mean steady state volume of distribution of 1400 L follow—
`ing intravenous administration. I:1, nitro binding of gefitinib
`to human plasma proteins (scrum albumin and ell-acid gly-
`coproiein) is 90% and is independent of drug concentrations.
`Metabolism and Elimination:
`Gefitinib undergoes extensive hepatic metabolism in
`humans, predominantly by CYP3A4. Thrcc sites of bio~
`transformation have been identified: metabolism of the N7
`propoxymorpholino-group, demmiiylaliun of the methoxy-
`substituent on the quinazoline. and oxidative defluorination-
`of the halogenated phenyl group.
`Five metabolites were identified in human plasma. Only 0-
`deemethyl geiitinib has exposure comparable to gefitinib.
`Although this metabolite has similar EGFR—TK activity to
`gefitinih in the isolated enzyme assay, it had only 1/14 of the
`potency of gefltinib in one of the cell~based assays.
`Gefitinib is cleared primarily by the liver, with total plasma
`clearance and elimination half-life values of 595 mL/min
`and 48 hours, respemively, after intravenous administra-
`tion. Excretion is predominantly via the feces (86%), with
`renal elimination of drug,r and metabolites accounting for
`less than 4% of the administered dose.
`
`Special Populations:
`In population based data analyses, no relationships were
`identified between predicted steady state trough concentra-
`tion and patient age, body weight, gender, ethnicity or
`creatinine clearance.
`Pediatric:
`There are no pharmacokinetic data in pediatric patients.
`Hepatic Impairment:
`The influence of hepatic metastases with elevation of serum
`aspurtote aminotransferase (AST/SGOT), alkaline phospha-
`tase, and bilirubin has been evaluated in patients with nor-
`mal (14 patients), moderately elevated (13 patients) and se
`verer elevated (4 patients) levels of one or more of these
`biochemical parameters. Patients with moderately and se-
`verely elevated biochemical liver abnormalities had gefi-
`tinib pharmacokinetics similar to individuals without liver
`abnormalities (see PRECAUTIONS section).
`Renal Impairment:
`No clinical studies were conducted with IRESSA in patients
`with severely compromised renal function (see PRECAU-
`TIONS section), Gefltinib and its metabolites are not sig-
`nificantly excreted via the kidney ((4%).
`Drug-Drug Interactions:
`In human liver microsome studies, gefitinib had no inhibi-
`tory effect on CYP1A2, CYP2C9, and CYP3A4 activities at
`concentrations ranging from 2—5000 ng/mL. At the highest
`concentration studied (5000 ng/mL), gefitinib inhibited
`CYPZCI9 by 24% and CYP2D6 by 43%. Exposure to ineto-
`prolol, a substrate of CYPZDB, was increased by 30% when
`it was given in combination with gefitinib (500 mg daily {01"
`28 days) in patients with solid tumors.
`Rifampicm, an inducer of CYP3A4, reduced mean AUU 0f
`gefitinib by 86% in healthy male volunteers (see PRECAU'
`TIONS—Dmg Interactions and DOSAGE ANnAnivnNIS-
`TRATION-r Dosage Adjustment sections).
`Concomitant administration of iti'aconazolo (200 m2 QD for
`12 days), an inlrbitor of CYP3A4, with gefitinib (250 mg ain-
`glc dose) to healthy male volunteers, increased mean gefl'
`tinib AUC by 88% (see PRECAUTIONS—Drug Interac-
`tions section).
`Co-administration of high doses of ranitidine with sodium
`bicarbonate (to maintain the gastric pH above pH 50) re'
`duced mean gefitinib AUC by 44% (See PRECAUTIONS’
`Drug Interactions section).
`International Normalized Ratio (INR) elevations and!“
`bleeding events have been reported in some pa2ients taking
`warfarin while on IRESSA therapy. Patients taking \Vfilfa'
`iin should be monitored regularly for changes in prothram‘
`bin time or INR (see PRECAUTIONS—Drug Interaction’
`and ADVERSE REACTIONS sections).
`‘
`I
`Clinical Studies
`Non-Small Cell Lung Cancer {NSCLC)—A inulticenter Cllm‘
`cal trial in the United States evaluated the tumor response
`rate of IRESSA 250 and 500 mg/doy in patients with ad‘
`vanced non-small cell lung cancer whose disease had PTD'
`grossed after at least two prior chemotherapy regimens 1“
`eluding a platinum drug and docetaxeli IRESSA was taken
`once daily at approximately the same time each day.
`Two hundred and sixteen patients received IRESSA. 192
`(47%) and 114 (53%) receiving 250 mg and 500 mg and”
`doses, respectively. Study patient demographics and disefls’.e
`characteristics are summarized in Table 1. Forty-one Pel'
`cent of the patients had received two prior treatment I‘HZ“
`mens, 33% three prior treatment regimens, and 25% four 0"
`more prior treatment regimens. Effectiveness 0:" IRESSA as
`
`Information will be superseded by supplements and subsequent editions
`
`NOVARTIS EXHIBIT 2072
`Par v. Novartis, IPR 2016-01479
`Page 2 of 32
`
`

`

`PHODUCT-INFORMATION
`
`ASTRAZENECA/673
`
`Table 2: Efficacy Results
`
`Evaluable Patients
`
`Objective Tumor Response Rate ('12)
`95% CI (%)
`Median Duration of Objective
`6.9
`Response (months)
`.
`7.0.I
`4.5
`
`4.6-18.6+
`4.4-18.6+
`4.4—7.6
`Range (months)
`+ =data are ongoing
`
`500 mg (N=76)
`7.9
`3.0—1.6.4
`
`Combined (N=142)
`10.6,
`65.0-16.8
`
`250mg (N=66)
`13.6
`EBA—24.3
`
`_
`Geriatric Use
`0f the total number ofpatients participating in trials of sec-
`ond and thirdelino IRESSA treatment ofNSCLC, 65% were
`aged 64 years or less, 30.5 % were aged 65 to 74 years, and
`5% ofpatients were aged ’75 years or olden-No differences in
`safety or eificacy were observed between younger and older
`patients.
`‘
`Patients with Severe Renal Impairment
`The effect of severe ranal impairment on the phama‘coki-
`notice of'gefitinib is not known. Patients with severe renal
`impairment should be treated with caution when given
`IRESSA.
`ADVERSE REACTIONS
`The safety database includes 941 patients from clinical tri-
`als and-approximately 23,000 patients in the Expanded Ac—
`cess Program.
`A
`Table 3 includes drug~related adverse events with an inci-
`dcnco of 25% for the 216 patients who received either
`250 mg or 500 mg of IRESSA monotherapy for treatment of
`NSCLC, The most common adverse events reported at the
`recommended 250 mg daily dose were diarrhea,‘rash, acne,
`dry skin, nausea, and vomiting (see PRECAUTIONS—
`Information for Patients and DOSAGE AND ADMINIS-
`TRATIONADosage Adiustnient. sections). The 600,mg
`dose showed a higher rate for most of these adverse events.
`Table 41provides drug-related adverse events with an inci-
`dence of 25% by CTC grade, for the patients who received
`the 250 mg/day dose of IRESSA monotherapy for treatment
`of NSCLC. Only 2% of patients stopped therapy due to an
`adverse drug reaction (ADR). The onset of these ADRs
`occurred within the first month of therapy.
`Table 3: Drug-Related Adverse Evontswiih an Incidence
`of 25% in either 250 mg or 500 mg Dose Group
`Number (Wu) of Patients
`
`500 nig/day
`250 rag/day
`Drug-related adverse event“
`(N=114)
`(N=102)
`9b
`%
`
`Diarrhea
`'76 (67)
`49 (4s)
`Rash
`61 (54)
`44 (43)
`Acne
`25 (25)
`‘37 (33)
`13 (13)
`30 (26)
`Dry. skin
`Nausea
`13 (13)
`20 (18)
`12 (12)
`10 (9)
`Vomiting
`Pruritus
`8 (8)
`10 (9)
`Anorexia
`11 (10)
`7 <7).
`Asthenia‘
`6 (6)
`'5 (4)
`6 (5)
`3 (a)
`Weight loss
`
`“A patient may have had more than 1 drug-related adverse
`event.
`
`Table 4: Drug Related Adverse Events 25% at 250 mg
`dose by Worst OTC Grade (n=102I.
`% of Patients
`All
`Adverse
`event
`Grades
`
`CTC
`CTC
`are ‘
`Grade Grade Grade
`Z
`3
`4
`
`crc
`Grade
`1
`
`Consdt 20 04 I’DRfl supplements and future editions for revisions
`
`
`
`third line therapy was determined in the 142 evaluable pa~
`fientswith documented disease progression on platinum
`and dacetaxel therapies or who had had‘unacceptable tox-
`icity on these agents.
`.
`[See fable 1 at top of preVious page]
`.
`Table 2 shows tumor responserates and response duration.
`The overall response rate for the 250 and 500 mg doses com~
`bmad was 10.6% (95% CI: 6%, 16.8%). Response rates up
`poured to be highly Variable in subgroups ofthe treated pop.
`“lotion: 5.1% (4/79) in males, 17.5% (11/63) in females, 4.6%
`(5/108) in *prevrous or current smokers, 29.4% (10/34) in
`nbnmokers, 12.4% (12/97) with adenocarcin‘oma histology,
`“d 6.7% (3/45) with other NSCLC histologies. Similar dif-
`ferences were seen in amultinational study in patients who
`had received 1 or 2 prior chemotherapy regimens, at least 1
`of which was platinum-based. In responders, the median
`fime from diagnosis to study randomization was 16.7
`months (range 8 to‘34 months).
`[see table 2 above]
`.
`Namsmall Cell Lung Cancer (NSL‘LL‘); Studio: of Filer-line
`Tmflment In Combination with Chemotherapy—1WD large
`trials were conducted in chemotherapy-naive patients ‘with
`stage III and IV non-small cell lung cancer. Two thousand
`one hundred thirty patients were randomized to receive
`IRESSA- 250 mg daily, IRESSA 500 mg daily, or placebo‘in
`combination with platinum-based chemotherapy regimens.
`The chemotherapies given in these first-line trials were
`gemcitabine and tie-platinum (N=1093) or carboplatin and
`paclitaxel (N=1037). The addition of [RESSA did not dem-
`onstrate any increase, or trend toward such an increase, in
`tumor- response rates, time to progression, or overall
`survival.
`p
`INDICATIONS AND USAGE
`IRESSA is indicated as monotherapy for thetreatment of
`patients with locally advanced or metastatic non-small cell
`lung cancer after failure of both platinum-based and ‘
`docetnxel chemotherapies.
`,
`The effectiveness of IRESSA is based on objective response
`rates (see CLINICAL PHARMACOLOGY—Cllnlcal Stud-
`los section). There are no controlled trials demonstrating a
`clinical benefit,.such as improvement in disease—related
`symptoms or increased survival.
`Results from two large, controlled, randomized trials in
`first-line treatment of non-small cell lung cancer showed no
`benefit from adding IRESSA to doublet, platinumrbased
`chemotherapy. Therefore. IRESSAis not indicated for use in
`this setting.
`CONTRAINDICATIONS -
`IRESSAI'is contraindicated in patients with severe hyper-
`sensitivity to gefitinib or to any other component of
`IRESSA.
`WARNINGS
`Pulmonary Toxicity
`Cases of interstitial lung disease, (ILD) have been, observed
`in patients receiving IRESSA at an overall incidence of
`about 1%. Approximately 1/3 ofthe cases have been fatal.
`The reported incidence of ILD was about 2% inthe Japa-
`nese post-marketing experience, about 0.3% in approxi-
`mately 23,000 patients treated with IRESSA in a US
`expanded access program and about 1% in the studies of
`first-line use in NSCLC (but: with similar rates in both
`treatment and placebo groups). Reports have described the
`adverse event as interstitial pneumonia, pneumonitis and
`alveolitis. Patients often present with the acute .onset of
`dyspnea, sometimes associated with cough or low-grade fe-
`yer, often becoming severe within ashort time and requir—
`"JE hospitalization. ILD has occurred inpatients who have
`IFeceived prior radiation therapy (31% of reported cases),
`P1101 chemotherapy (57% of reported patients), and no pre»
`:2“? therapy. (12% ofreported cases). Patients with concur-
`wfi‘flldmpéthic pulmonary fibrosis whose condition worsens
`ere e recon/mg IRESSA have been observed to have an in
`,0 35951 mortality compared to those without concurrent id-
`pafl’“? pulmonary fibrosis.
`33m :3 Went of acute onset or worsening of pulmonary
`e if}:ng (dyspnea, cough, fever), IRESSA therapy should
`ms sampled and a prompt investigation of these symp-
`IRESSAOPM occur. If interstitial lung disease is confirmed,
`propr'i
`tfihould be discontinued and the patient treated ap-
`‘ima TEE/1886 PRECAUTIONS- -|nlormation for P3-
`mlml‘_r-RSE REACTIONS and DOSAGE AND AD-
`ragn
`t1"ION—Dosage Adjustment sections).
`IRESQXW category D
`nan, “Quay cause fetal harm when'administered to a preg-
`timb em all. A single dose study in rats showed that gen-
`(30 m “$2393 the placenta after an oral dose of 5 mg/kg
`mug/h a about 1/5 the recommended human dose on a
`5 rug/kg t3513)- When pregnant rats were treated with
`Weaning mm 11.16 beginning of orgnnngensnis to the end-of
`0 Mug?” blll‘th, there was a reduction in the number of '
`, m alive. This eflect was more severe at 20 mg/kg
`mmpanied by high neonatal mortality soon afizer
`m-SIII this study a dose of 1 mg/kg caused no ad-
`,Jfifi dose of so mg/kglday (240 mg/mz, about twice
`d f ended dose in humans on 3 mg/m2 basis) caused
`eta] Weight.
`“lie?” aClotmate and well-controlled studies in preg-
`I if: “Sing IRESSA. II‘IRESSA is used during preg-
`shthfl patient becomes pregnant while receiving
`us 0r 9 should be apprised ofthe potential hazard to
`P°tential risk for loss of the pregnancy
`
`HCDOOOOCO
`
`Newman-Imam
`
`HCDHHOOOH
`
`41
`48
`Diarrhea
`39
`43
`Rash
`19
`25
`Acne
`12
`13
`Dry Skin
`7
`13
`Nausea
`9
`12
`Vomiting
`7
`8
`Pruritus .
`3
`7
`Anorexia .
`2
`6.
`Asthenia
`Other adverse events reported at an incidence of <5% iri
`patients who received either 250 mg or ,500 mg as mono-
`therapy for treatment of NSCLC (along with their fre-
`quenoyat the 250 mg recommended dose) include the fol-
`lowing: poriphcrol edema (2%);‘nmblyopio (2%), dyspnea
`(2%), conjunctivitis (1%),‘vesiculobulloup rash (1%), and
`mouth ulceration (1%).
`'
`Interstitial Lung Disease
`1
`Cases of interstitial lung disease (ILD) have been observed
`in patients receiving IRESSA at an overall incidence of
`about 1%. Approximately 1/3,of the cases have been fatal.
`The reported incidence of ILD was about 2% in the Japa-
`nese post-marketing experience, about 03% in approxi-
`mately 23,000 patients treated with IRESS‘A in a US
`expanded access. program and about 1% in the studies of
`first-line use in NSCLC (but with similar rates in both
`
`Continued on next page
`
`
`
`PRECAUTIONS
`Hepototoxicity
`Asymptomatic increases in liver transaminascs have been
`observad in IRESSA treated patients; therefore, periodic
`liver function (transaminases, bilirubin, and alkaline phos-
`phatase) testing should be considered. Discontinuation of
`IRESSA should be considered if changes are severe.
`Patients with Hepatic Impairment
`In vitro and in vivo evidence suggest that gcfitinib is cleared
`primarily by the liver. Therefore, gefitinib exposure may be
`increased in patients with hepatic dysfunction. In patients
`with liver metastases and moderately to severely elevated
`biochemical liver abnormalities, however, gefitinib pharma-
`cokinetics were similar to the pharm'acokinetics of individu-
`als without liver abnormalities (sec CLINICAL PHARMA-
`COLOGY—Pharmacokinetles—Spoclal
`.
`' Populations
`Section). The influence ofnon-cancer related hepatic impair:
`ment on the pharmacokinetics of gefitinib has not been
`evaluated.
`Information for Patients
`1
`Patients should be advised to seek medical advice promptly
`if they develop 1) severe or persistent diarrhea, nausea, an- I
`orexia, or vomiting, as these have sometimes been associ-
`ated with dehydration; 2) an onset or worsening of pulmo-
`nary symptoms, is, shortness of breath or cough: 3) an eye
`irritation; or, 4) any other new symptom (see WARN-
`INGS—Pulmonary Toxicity, ADVERSE REACTIONS and
`DOSAGE AND ADMINISTRATION—Dosage Adjust-
`ment sections).
`Women of childbearing potential must be advised to avoid
`becoming pregnant (see WARNINGS—Pregnancy Cate-
`gory D).
`Drug Interactions
`Substances that are inducers of CYP3A4 activity increase
`the metabolism of gefitinib and decrease its plasma concen—
`trations. In patients receiving a potent CYP3A4 inducer
`such as rifampicin or phenytuin, a dose increase to 500 mg
`daily should he considered in the absence of severe adverse
`drug reaction, and clinical response and adverse events
`should be carefully monitored (see CLINICAL PHARMA-
`COLOGYwPharmacokineticSTDrug-Drug
`Interactions
`and DOSAGE AND ADMINISTRATION—Dosage Adiust-
`ment sections).
`_
`.
`'
`International Normalized‘Ratio (I'NR) elevations and/or
`bleeding events have been reported in some patients taking
`warfarin while on IRESSA therapy. Patients. taking warfa-
`rin should be monitored regularly for changes in prothrom-
`bin time or' INR (see CLINICAL PHARMACOLOGY“
`Pharmaookinoticsw—Drug-Drug Interactions and ADVERSE
`REACTIONS sections).
`Substancesvthat are'potent inhibitors of CYP3A4 activity
`(eg, ketoconazole and itraconazole) decrease gefitinib mei
`tabolism and increase gefitinib plasma concentrations. This
`increase may be clinically relevant as adverse experiences
`are related to dose and exposure; therefore, caution should
`he used when administering CYP3A4 inhibitors with
`IRESSA (see CLINICAL PHARMACOLOGY—Pharmaco-
`kinetios—Drug-Drug Interactions and ADVERSE REAC-
`TIONS sections).
`Drugs that cause significant sustained elevation in gastric
`pH (histamine Hg-receptor antagonists suchas ranitidine or
`cimetidine) may reduce plasma concentrations of IRESSA
`and therefore potentially may reduce eflioaCy (sec CLINI-
`CAL PHARMACOLOGY—Drug-Drug Intoractlons sec-
`tion).
`Carcinogenesis, Muta’genesis, Impairment of Fertility
`Gefibinib has been tested for genotoxicity in a series of in
`vitro (bacterial mutation, mouse lymphoma, and human
`lymphocyte) assays and an‘ in. viva rat micronucleusjsst.
`Under the conditions of these assays, geiitinib did not cause
`genetic damage.
`Carcinogenicity studies have not been conducted with
`gefitinib.
`Pregnancy
`Pregnancy Category D (seo WARNINGS and PRECAU-
`TIONS—Information for Patients sections).
`Nursing Mothers
`It is not known whether IRESSA is excreted in human milk.
`Following oral administration of carbon—14 labeled gefitinib
`to rats 14 days postpartum, concentrations of radioactivity
`in milk were higher than in blood. Levels ofgefitinib and its
`metabolites were 11—to—19—fold higher in milk than in blood,
`after oral exposure of lactating rats to a dose‘ of 5 mglkg.
`Because many drugs are excreted in human milk and be-
`cause of the potential for serious adverse reactions in nurs—'
`ing infants, women should be advised against breast-
`feeding while receiving IRESSA therapy.
`Pediatric Use
`'
`Safety and effectiveness of IRESSA in pediatric patients
`have not been studied.
`
`NOVARTIS EXHIBIT 2072
`Par v. Novartis, IPR 2016-01479
`Page 3 of 32
`
`

`

`674IASTRAZENECA
`
`PHYSICIANS' DESK REFERENCE:I“a
`
`Bottles of 3U.Tab1ets (NDC 0310-0482-30)
`Siorage
`U P].
`Sign at controlled room temperature 20-25°C (GB-77°F) [see
`All trademarks are the property of the AstraZeneca group
`©AsIIaZeneca 2003
`'
`Manufactured for:
`AstraZeneca Pharmaceuticals LP
`Wilmington, DE 19850
`By: AstraZeneca UK Limited
`Macclesfield, Cheshire, England
`Made in theAUnited Kingdom
`Rev 05-03
`_
`Shown in Product Identification Guide, 'page 306
`
`.
`
`MERREM® I.V.
`meropenem for injection '
`For Intravenous Use Only
`DESCRIPTION
`MERREM® I.V. (ineropenem for injection) is a sterile, pyror
`gen-free, synthetic, owed-spectrum, carbapenem antibiotic
`for intravenous administration. It is (4R,ES,GS)-3-[[(3S,ES)-
`5-,(Dimethylcarbamoyl)>3—pyrrolidinyl]thio]-6-[(lR)-1»hy~
`droxyethyl] -4-methyl-7-oxo- l-azabicyclo [3.2.0]hept-2-ene-2—
`carboxylic. acid trihydrate.
`Its empirical
`formula is
`CNHQ§N305508H20 with a molecular weight of 437.52. Its
`structural formula is:
`
`MERREM I.V. is a white to pale yellow crystalline'powder.
`The solution varies from colorless to yellow depending on
`the concentration. The pH offreshly constituted solutions is
`between 7.3 and 8.3.- Mero'penem is soluble in 5% monobasic
`potassium phosphate solution, sparingly soluble in water,
`very slightly soluble in hydrated ethanol, and practically in-
`soluble in acetone or ether.
`r‘
`When constituted as instructed (see DOSAGE AND AD-
`MINISTRATION; PREPARATION OF SOLUTION), each 1 g
`MERREM I.V. vial will deliver 1 g of merop‘enem and
`90.2 mg of sodium as sodium -carbonate'(3;92 mEq). Each
`500 mg MERREM I.V. Vial will deliver 500 mgrmcropcncm
`and 45.1 mg of sodium as sodium carbonate (1.96 mEq).
`MERREM I.V. in the ADD-Vantagei vial is intended for in-
`travenous use only alter dilution with the‘appropiiate vol-
`ume of diluent solution in the Abbott ADD-Vantage® dilu-
`ent container. (See DOSAGE AND ADMINISTRATION;
`PREPARATION OF SOLUTION.) MERREM I.V. in the ADD;
`Vantage'vialrisavailsble in two Strengths. Each 1'g ADD-
`Vantage vial ofMERREM I.V. will deliver-90,2 mg of sodium
`as sodium carbonate (3.92 mEq), and each 500 mg ADDJ
`Vantage vial will deliver 45.1 mg of sodium as sodium' car-
`bonate (1.96 mquu
`’
`CLINICAL PHARMACOLOGY I
`At the endpof a 30-minute intravenous infusion of a single
`dose of MERREM I.V. in normal yolunteers, mean peak
`
`
`
`plasma. concentrations are approximately 23 uglmL (ran
`14—26)-for the 500 mg dose and 49 ug/mL (range 39—58) E
`the 1 g dose. A 5-minute intravenous bolus injection of
`MERREM I.V. in normal volunteers results in mean 1,
`plasma concentrations of'npproximntely 45 ug/mL (ran
`18—65) for the 500 mg dose and 112 ug/mL (range 837140)
`for the 1 g dose.»
`.
`,
`Following intravenous doses of 500 mg, mean plasma cam
`centrations of meropenem usually decline to approximately
`1 pglmL at 6 hours otter administration.
`I
`In subjects with normal renal function, the elimination ham
`life of MERREM I.V. .is approximately 1 “hour. Apprmd~
`mately 70% ofthe intravenously administered dose is rem“
`ered as unchanged merupenen'i in_ the urine over 12 hours.
`after whichlitble further urinary excretion isrdetecmhle’
`Urinary concentrations of meropenem in excess of 10 ug/mI:
`are maintained for up to 5 hours after a 500 mg dose, Ncl
`accumulation of meropenem in plasma-or urine was ob
`served with regimens using 500 mg administered every 8
`hours or 1 g administered every-6 hours in volunteers with
`normal renalfunction.
`Plasma protein binding of meropenem is approximately 2%
`There is one metabolite which is microbiologically inactive:
`Meropeneni‘penetr‘ates well into most body fluids and tis_
`sues including cerebrospinal fluid, achieving concentrations
`matching or exceeding those required to inhibit most 'gus.
`ceptible bacteria. After a single intravenous dose of
`MERREM' I.V.,
`the highest mean concentrations of
`meropenem were found in tissues and fluids at 1 hour (0_5
`to 1.5- hours) after the start of infusion, except where indi.
`cated in the tissues and fluids listed in the table below.
`[See table below]
`The pharmacokinetics of MERREM,I.V. in pediatric pa.
`tients 2 years of age or older are essentially similar to those
`in adults. The elimination half'life for meropenem was ap.
`proximately 1.5 hours in pediatric patients of age 3 months
`to 2 years. The pharmacokinetics are linear over the dose
`range from 10 to 40 rug/kg.
`'
`'
`‘
`Pharmacokinetic studies with MERREM I.V. in patients
`with renal insufficiency have shown that thc plasma Clear—
`ance of meropenem correlates with creatinine clearance.
`Dosage adjustments‘are necessary in subjects with renal
`impairment. (Sec DOSAGE AND ADMINISTRATION—-
`Use in Adults ‘with Renal Impalvmenl.) A phamacokineiic
`study with MERREM I.V. in elderly patients with renal in-
`suificicncy has shown a reduction in plasma clearance of
`meropenem that correlates with age-associated reduction in
`creatinine clearance.
`Moropencm I.V. is hemodiolyzoblc. However, there is no in—
`formation on the usefulness of hemodialysis to treat over-
`dosage. (See OVERDOSAGE.)
`A pharmacokinetic study with MERREM I.V. in patients
`with hepatic impairment has shown no eflects of liver dis-
`ease on the pharmacokinetics of meropenem.
`Microbiology
`The bactericidal activity of meropeneni results \from the
`inhibition of cell Wall synthesis. Meropenem readily
`penetrates the cell wall of most gram-positive and gram-
`negative bacteria to reach penicillin-bindingmrotein (PEP)
`targets. Its strongest affinities are toward PBPs 2, 3 node of
`Escherichia coli and Pseudomonas aerugirioso; and PBPS 1,
`2 and 4 of Staphylocdccus oureus. Bactericidal concentra-
`tions (defined as a 3 log10 reduction in cell counts within 12
`to 24 hours) are typically 1—2 times the bacteriostatic con-
`centrations of meropencm, with the exception of Listeria
`monocytogenes, against which lethal activizy is not ob-
`served.
`M‘el‘openem has significant stability to hydrolysis by B-lacr
`tamases of most categories, both penicillinases and cepha-
`losporinases produced by gram-positive and gram-negative
`
`Meropenem Concentrations in Selected Tlssues
`(Highest Concentrationsfleportedl
`Number of