" ")’¢.="
`
`
`
`
`
`
`
`EDITION
`
`2003
`
`PHYSICIANS’
`DESK
`i?EFEPEi\lCE®
`
`FOLEY, HOAB 5i ELIOT
`LIBRARY CGPV
`
`Executive Vice President, Directory Services: Paul M. Walsh
`
`Vice President, Sales and Marketing: Dikran N. Barsamian
`Director, PDR Pharmaceutical Sales: Anthony Sorce
`Senior Account Managers: Frank Karkowsky, Elaine Musco,
`Marion Reid, RPh
`Account Managers: Lawrence C. Keary, Lois Smith, Eileen Sullivan,
`Suzanne E. Yarrow, RN
`Director of Trade Sales: Bill Gaffney
`Director of Product Management: Valerie E. Berger
`Senior Product Manager: Jeffrey D. Dubin
`finance Director: Mark S. Ritchin
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`Direct Mail Managers: Jennifer M. Fronzaglia, Lorraine M. Loening
`Senior Marketing Analyst: Dina A. Maeder
`Promotion Manager: Linda Levine
`Vice President, clinical Communications and
`Strategic Initiatives: Mukesh Mehta, RPh
`Manager, Professional Data Services: Thomas Fleming, RPh
`Manager, Concise Data content: Christine Wyble, PharmD
`Drug information Specialists: Maria Deutsch, MS, PharmD;
`Anu Gupta, PharmD
`Editor, Directory Services: David W. Sifton
`
`Project Manager: Edward P. Connor
`Senior Associate Editor: Lori Murray
`Associate Editor: Gwynned L. Kelly
`Senior Director, Operations: Brian Holland
`Senior Data Manager: Jeffrey D. Schaefer
`Manager of Production Operations: Thomas Westburgh
`Project Manager: Amy B. Brooks
`Senior Production coordinator: Gianna Caradonna
`
`Production Coordinators: DeeAnn DeRuvo, Christina Klinger
`Index Supervisor: Joseph F. Rizzo
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`V
`Digital Imaging coordinator: Frank J. McElroy, lll
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`
`Cupyrigl1t© 2l:i03 and published by Thomson PDFI at Montvale, NJ tTr‘6-15-1 M2. All rights reserved. None at the content of this publication
`T I-I 3 IVIS C)[\|
`W may be reproduced. stored in a retrieval system. resold. redistributed. or transmitted in any form or by any means (electronic. mechanical.
`#5
`photocopying. recording. or otherwise] without the prior written permission of the publisher. PHYSICIANS’ DESK REFERENCE’, PDR‘.
`Pocket PDR‘. The F-‘DH’ Family Guide to Prescription Drugs‘, The PDR‘ Family Guide to Women's Health and Prescription Drugs’. and
`PDR
`The PDFt' Family Guide to Nutrition and Health” are registered trademarks used herein under license. PDR for Oplilhairnic Mediclnesifl, PDR tor Nonprescription Drugs and
`Dietary Supplements”. F'DFt Companion Guide“. PDH Pharmacopoeia” Pocket Dosing Guide, PDR‘ for Herbal Medicines“, PDR’ for Nutritional Supplements“, PDR“
`Medical Dictionary”, PDR‘ Nurse's Drug I-inndbcoki", PDR’ Nurse's Dictionary“, The PDR‘ Family Guide Encyclopedia of Medical Care”, The PDR’ Family Guide to
`Natural Medicines and Healing Therapiesi", The PDR" Family Guide to Common Ailments“, The PDR‘ Family Guide to Over-Uievcounter Drugs“. The PDFI‘ Family Guide
`to Nutritional Supplements”. and PDR’ Electronic t.ibrsry"" are trademarks used herein under license.
`
`officers of Thomson Heaithcare: President and Chief Executive Offlcen Richard Noble; Chief Hnancial Officer and Executive Vice President, Finance: Paul J. Hilger;
`Executive i/ice President, Directory Services: Paul M. Walsh; Senior Vice President, Planning and Business Development: William J. Gole; Senior Vice President and
`Chief Technology Officer: Jeff Reihl; Vice President, Corporate Human Resources: Pamela M. Bilash
`KOIOS Exhibit 1022 I
`Page 1 of 7
`
`Page 1 of 7
`
`KOIOS Exhibit 1022
`
`

`
`*
`
`for either the 21-day or the 28-day
`
`I.
`'
`«
`.
`_
`,
`2- YOU Will not need to use a back-up method of birth con-
`pr;_li’0:lnce Y0“ are Stamng the pill at the beginning of your
`SUNDAY START;
`These instnictions are
`pill pack.
`1. Take the first
`“active” white pill of the first pack on the
`sunda
`t
`in
`H3’ af" 3’°‘_”P9"Ud starts. even if you are still bleed~
`‘ 8-
`your period begins on Sunday, start the pack that
`same day.
`2. Use another method of birth control as a back-up method
`lfym‘ have 59* anytime from the Sunday you start your first
`pack “mil me '19“ Sunday (7 (lays). Condoms, spermicide
`°r the 5P°“E9 are good back-up methods of birth control.
`
`WHAT TO DO DURING THE MONTH
`
`I. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL
`THE PACK IS EMPTY.
`Do not skip pills even if you are spotting or bleeding be-
`tween monthly periods or
`feel sick to your stomach
`(nausea).
`Do not skip pills even if you do not have sex very often
`2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND
`OF PILLS:
`21 pills: Wait 7 days to start the next pack. You will proba-
`bly have your period during that week. He sure that no more
`ma“. 7 days Pass between 21-day packs.
`21? pills: Start the next pack on the day afier your last “re
`minder" pill. Do not wiiit any days between packs,
`
`WHAT TO DO IF YOU MISS PILLS
`
`The pill may not be as effective if you miss white “active”
`pills, and particularly if you miss the first few or the last
`few white “active” pills in a pack.
`If you MISS 1 white “active” pill:
`1. Take it as soon as you remember. Take the next pill at
`your regular time. This means you may take 2 pills in 1 day.
`2. You do not need to use a back-up birth control method if
`you have sex.
`It‘ you MISS 2 white “active” pills in a row in WEEK 1 OR
`WEEK 2 of your paclc
`1. Take 2 pills on the day you remember and 2 pills the next
`day.
`2. Then take 1 pill a day until you finish the pack.
`3. You MAY BECOME PREGNANT if you have sex in the 7
`days afier you miss pills. You MUST use another birth con-
`trol method (such as condoms, spermicide, or sponge) as a
`back-up for those 7 days.
`Ifyou MISS 2 white "active" pills in a row in THE 3rd WEEIC
`The Day 1 Startlr instructions are for the 21-day pill pack
`only. The 28-day pill pack does not accommodate a DAY 1
`START dosage regimen. The Sunday Starter instructions
`are for either the 21-day or 28-day pill pack.
`1. If you are a Day 1 Starter:
`THROW OUT the rest of the pill pack and start a new pack
`that same day.
`If you are a Sunday Starter:
`Keep taking 1 pill every day until Sunday.
`On Sunday, TI-[ROW OUT the rest of the pack and start a
`new packofpillsthatsame day.
`2. You may not have your period this month but this is ex-
`pected. However,ifyoumissyourperiod2monthsinnmw,
`call your doctor oirclinic because you might be pregnant.
`3. You MAY BECOME PREGNANT ifyou have sex in the 7
`days afler you miss pills. You MUST use another birth am-
`trol method (such as condoms, spermidde, or sponge) as.a
`back-up for those 7 days.
`Ifyou MISS 3 OR MORE white “active” pills in a raw (during
`the first 3 weeks):
`The Day 1 Starter instructions are for the 21-day pill pack
`only. The 28-day pill pack does not accommodate 8 DAY 1
`START dosage regimen. ‘The Sunday sum: instructions
`are for either the 21-day or 28-day pill pack.
`1. If you an I Day 1 Starla:
`'
`THROW OUT the rest ofthe pill pack and start a new pack
`that same day.
`If you no I Sunday Starter:
`Keep taking 1 pill every day until Sund8Y-
`0nSunday,'I'HRDWOUTtherestofthepackands1.arta
`new pack of pills that same day.
`.
`_
`_
`2. You may not have your period tlus month but
`is ex-
`pected. However, ifyou miss your period 2 months in a row,
`can your doctor or clinic because you might be pregnant.
`3. You MAY BECOME PREGNANT ifyou have sex in the 7
`.141. gfigr-you miss pills. You MUST use another birth Don-
`tml method (such as condoms, fipefmifildey 01’ 3P°n£°) 15 3
`bgckqip for those 7 days.
`
`A REMINDEKFOR THOSE ON 28-DAY PACKS
`Ifyou forget any of the 7 pink ‘reminder’ pills in Week 4:
`THROW AWAY.the pills you missed.
`Keeptalringlpilleachduyuntilthepackisempty.
`Youdgnotneedabgck-upmethodifyoustartyoin-next
`pack on time.
`'
`--
`
`FIHALLY, IF YOU ARE STILL NOT SURE WHAT TO DO
`ABOUT TIE PILLS YOU HAVE IISSED
`Use A BACK-UP METHOD anytime you have sex.
`KEEPTAKING ONEPILLEACH DAY until yuumni-veach
`your doctor or clinic
`
`_
`_
`_
`Pregnancy due to pill failune
`The incidence of pill failure resulting in Dfegnancl’ ‘5 3?‘
`proidmately less than 1.07: if taken every day as dl1'9C1'Bd~
`‘ but average failure rates are 5%. Ifyou do become FY8833-lib
`the risk to the fetus is minimal, but you should stop taking
`your pills and discuss the pregnancy with your doctor.
`Pregnancy after stopping the pill
`There may be some delay in becoming pregnant afier you
`stop using oral contraceptives. especially ifyrm had irregu-
`lar menstrual cycles before you used oral contraceptives. It
`may be advisable to postpone conception until you begin
`menstruating regularly once you have stopped taking the
`pill and desire pregnancy.
`There does not appear to be any increase in birth defects in
`‘ newborn babies when pregnant)‘ occurs soon afier stopping
`the pill.
`‘
`_
`Overdosage
`Serious ill elfects have not been reported following Ingestion
`I of large doses of oral contraceptives by young children.
`Overdosage may cause nausea and withdrawal bleeding in
`females. In case ofoverdosage, contact your health-care pro-
`vider or pharmacist.
`V
`Other information
`Your health-care provider will take a medical and family
`history before prescribing oral contraceptives and will ex-
`amine you. The physical examination may be delayed to an-
`other time ifyou request it and the health-care provider be-
`lieves that it is appropriate to postpone it. You should be
`reexamined at least once a year. Be sure to inform your
`health-care provider if there is a family history of any of the
`conditions listed previously in this leaflet. Be sure to keep
`all appointments with your health-care provider. because
`this is a time to determine if there are early signs of side
`effects of oral-contraceptive use.
`Do not use the drug for any condition other than the one for
`which it was prescribed. This drug has been prescribed spe-
`cifically for you; do not give it to others who may want birth-
`control pills.
`HEALTH BENEFITS FROM ORAL CONTRACEP'I'l'\'ES
`In addition to preventing pregnancy, use of oral contraoep
`tives may provide certain benefits. They are:
`' Menstnial cycles may become more regular.
`0 Blood flow during menstruation may be lighter. and less
`iron may be lost. Therefore. anemia due to iron deficiency
`is less likely to occur.
`° Pain or other symptoms during menstruation may be en-
`countered less frequently.
`0 Ovarian cysts may occur less frequently.
`I Ectopic (tubal) pregnancy may occur less frequently.
`0 Noncanoerous cysts or lumps in the breast may occur less
`frequently.
`0 Acute pelvic inflammatory disease may occur less fre-
`quently.
`0 Oral-contraceptive use may provide some protection
`against developing two forms of canoei-. cancer of the ova-
`ries and cancer ofthe lining of the menu.
`If you want more information about birth-control pills. ask
`your doctor or pharmacist. They have a more technical leaf-
`let called the Professional Labeling which you may wish to
`read.
`Manufactured by:
`Wyeth Laboratories
`A Wyeth-Ayerst Company
`Philadelphia, PA 19101
`Revised Novanba 30, 2001
`CI 4259-7
`_
`Shown in Product n Guide. 131$ -137
`
`B
`METHOTREXATE SODIUM TABLETS.
`METHOTBEXATE SODIUM FOR INJECTION, B
`ME11'lOTIIEXATE LPFO SODIUM
`(ME‘I'l-IOTBEXATE SODIUM INJECTION) AND
`METHOTREXATE SODIUM INJECTION
`
`
`WARNINGS
`METHOTREXATE SHOULD BE USED ONLY BY
`PHYSICIANS WHOSE KNOWLEDGE AND ii:xPEm.
`ENCE INCLUDE THE USE or ANTIMETABOLITE
`THERAPY. BECAUSE or THE POSSIBILITY or SE-
`RIOUS TOXIC REACTIONS (WHICH CAN BE
`FATAL):
`_
`METHDTREXATE SHOULD BE USED ONLY IN
`LIFE THnEATENnvc NEoPLAsrIc msniism,
`on D: PATIENTS WITH PSORIASIS on unnum-
`TOID AR’l'H‘.RI'I‘IS wrrn sxvsns. RECAIJCL
`TRANT, DISABLING nismss wmon is NOTAB-
`EQUATELY RESPONSIVE '10 0i'flER FORMS OF’
`THERAPY.
`‘
`DEATHS fi.AVEBEENREPOR'I'EBWl'I'H'l‘EEI&c
`OF ME'I‘H0'l'R$XA'!E IN THE '.I'REKfllEN'l‘ OF
`MALIGNANCY, PSORIASIS, AND D
`AR'l'HRI'I'IS.
`PATIENTS SHOULD BE CLOSELY MONITORS!)
`FOR BONE MARROW, LIVER. LUNGANDKIDNEY
`TOXICITIES. (Set: PRECAUHOE.)
`PATIENTS SHOULD BE INFORMED BY THEIR
`PHYSICIAN OF THE RISKS INVOLVED AND BE
`UNDER A PHYSICIANS CARE THBOUGI-lOU'l‘
`THERAPY.
`
`.
`
`Continued on next page
`
`Consul! 2003 PDR° supplements and future editions for ievisiom
`
`PRODUCT INFORMATION
`
`21 active tablets, NDC 000
`80078‘ while, round tablet
`marked “WYETH" and “78"_
`'
`7 inert tablets. NDC 0008-
`0436» Pmk. round tablet marked
`‘WYETH" and ‘‘48e».
`Store at controlled room tem
`77“F).
`Deraturo 20°C to 25°C (68eF ‘O
`
`References available upon request
`Brief Summary Patient Pack;
`S L0/0
`Qelnsert:
`DETAILED PATIENT LABELIN
`G: See i.o/oiiEAL, VRAL
`HOW TO TAKE THE PILL
`
`IMPORTANT POINTS To REMEMBER
`
`'
`
`BEFORE YOU START TAKING YOUR PILLS’
`.
`S:
`1. BE SURE TO READ THESE DIRECTION
`Before you start taking your pins,
`;‘“¥‘t;IlE9 Y0“ are not sure what to do
`.
`RIGHT wAY TO TAKE
`ONE PILL EVERY DAY AT THE
`To TAKE
`'
`‘
`If you miss pills you could get pregnant Th‘
`mg th
`k I
`‘eh Th
`_
`.
`.
`is includes start-
`llmi arialtdcgecapregnaiilimre plus you miss’ the m°"9 likely
`mlswoii vwl§l‘i‘?3§'E‘i“s‘§l:§Pl”§¥§§1§R “G” MED’
`ING THE FIRST 1-3 PACKS or PILLSSTOMACH DUE"
`¥hy°“ fag Slck
`your stomach, do not stop taking the pill_
`che°c1:"":itiglofilgogtsfiailycfiffigway. If it doesn‘t go away,
`4. MISSING PILLS CAN ALSO CAUSE SPO'l'I‘ING OR
`I£iI1$vsHT BLEEDING, even when you make up these missed
`0“ the days YOU lake 2 pills to make up for missed pills, you
`could also feel a little sick to your stomach.
`5. IF YOU
`VOMITING (within 3 to 4 hours after you
`take your pill), you should follow the instructions for WHAT
`TO DO [F YOU MISS PILLS. IF YOU HAVE DIARRHEA or
`IEYOU TAKE SOME MEDICINES, including some antibi-
`otics, your pills may not work as well. Use a back-up method
`(such as condoms, spermicide, or sponge) until you check
`with your doctor or clinic.
`6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE
`THE PILL, talk to your doctor or clinic about how to make
`pill-taking easier or about using another method of birth
`control.
`»
`7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE
`ABOUT THE INFORMATION IN THIS LEAFLET, call
`your doctor or clinic.
`'
`L0/OVRALO AND L0/OVRALO-28 lnaryostnl and athinyl
`ostradiol tablets).
`
`BE@HE_YOU START TAKING YOUR PILLS
`1. DECIDE WHAT TIME OF DAY YOU WANT TO TAIQI
`YOUR PILL.
`It is important to take it at about the same time every day.
`2. LOOK AT YOUR PILL PACK TO SEE IF IT HAS 21 OR
`28 PILLS:
`The 21-pillpack has 21 “active” white pills (with hormones)
`to take for 3 weeks, followed by 1 week without pills.
`The 28-pill pack has 21 “active” white pills (with hormones)
`to take for 3 weeks, followed by 1 week, of reminder pink
`pills (without hormones).
`_
`_
`3. ALSO FIND:
`1) where on the pack to start taking pills. and
`2) in what order to take the pills (follow the arrows).
`
`YtR>Ilp>VNu>llU> )g>s4~>‘iusvi>n_4(>-Io
`'
`“O00000000 Odin-an:
`.o00000550Qfl
`III
`-.4 mica:-< -no-<1
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`
`
`
`0550.05E300000
`
`-i_.—
`0000000000000 I
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`
`
`
`
`§1$ Ig3gg:hE g mn®m.
`sfehlfidde, or EPDDE9) t° ‘me 3‘ “ backup In case you mu
`i!NnsEX‘I'R.A, FULL PILL PACK.
`
`WIEN TO START THE HRST PACK OF PILLS
`:j
`go: the 214sv;I;l11rPffl‘;§’!;‘;‘;kh§fV;gti'Il:<se;°IiAv 1 S‘I'Aifl'|'
`5-"»"°A'-STA"? °“'°°“°“‘ '°°‘°"""’°“'i‘~‘I.?’..".2§1‘i.l§v"L'iu lick
`orciinicwiiichiu.iiebeatdayfnU'°“-
`.'
`. Wk
`pivsixaiiiiflartdais/w1Ii¢1='*“"““"""°""°"'.'.°"'
`.,
`DKYISTT.
`3.
`’
`-
`ken] 111928-
`afcoommorthe 2...I.¢.i”°"’."I'ilIi'1”sriiI’z‘rdouse
`'1°:i,fl;-];tLtm.fimt._me.whi,,,m,riheanI.,..ckauins
`theifizat 24 hour: ofyour perm
`
`Page 2 of 7
`
`KOIOS Exhibit 1022
`
`Page 2 of 7
`
`KOIOS Exhibit 1022
`
`

`
`
`
`1
`
`if».
`
`3416/WYETH
`
`Methotrexate-—Cont.
`
`THE USE or METHOTREXATE HIGH DosE REGI-
`MENs RECOMMENDED FOR OSTEOSARCOMA RE-
`QUIRES METICULOUS CARE. (See DOSAGE AND
`ADMINISTRATION.) HIGH DOSE REGIMENS FOR
`OTHER NEOPLASTIC DISEASES ARE INVESTIGA-
`TIONAL AND A THERAPEUTIC ADVANTAGE HAS
`NOT BEEN ESTABLISHED.
`METHOTREXATE FORMULATIONS AND DlLU-
`ENTS CONTAINING PRESERVATIVES MUST NOT
`BE USED FOR INTRATI-IECAL OR HIGH DOSE
`METHOTREXATE THERAPY.
`1. Methotrcxate has been reported to cause fetal death
`and/or congenital anomalies. Therefore, it is not rec-
`ommended for women of childbearing potential un-
`less there is clear medical evidence that the benefits
`can be expected to outweigh the considered risks,
`Pregnant women with psoriasis or rheumatoid ar-
`thritis should not receive rnetliotrexate. (See CON-
`TRAINDICATIONS.)
`2. Methotrexate elimination is reduced in patients
`with impaired renal function, ascites, or pleural ef-
`fusio_ns._ Such patients require especially careful
`monitoring for toxicity, and require dose reduction
`or, in some cases, discontinuation of methotrexate
`administration.
`3. Unexpectedly severe (sometimes fatal) bone marrow
`suppression, aplastic anemia, and gastrointestinal
`toxicity have been reported with concomitant ad-
`ministration of methotrexate (usually in high dos-
`age) along with some non-steroidal anti-infiamma-
`tory drugs (NSAIDS). (See PRECAUTIONS. Drug
`Interactions.)
`4. Methotrexate causes hepatotoxicity, fibrosis and cir-
`rhosis, but generally only after prolonged use.
`Acutely. liver enzyme elevations are Frequently
`seen. These are usually transient and asymptom-
`atic, and also do not appear predictive of subsequent
`hepatic disease. Liver biopsy after sustained use of-
`ten shows histologic changes, and fibrosis and cir-
`rhosis have been reported; these’ latter lesions may
`not be preceded by‘ symptoms or abnormal liver
`function tests in the psoriasis population. For this
`reason, periodic liver biopsies are usually recom-
`mended ibr psoriatic "patients who are under long-
`term treatment. Persistent abnormalities in liver
`function tests may precede appearance of fibrosis or
`cirrhosis in the'rheumatoid arthritis population.
`(See PRECAUTIONS, Organ System Toxicity, He-
`patio.)
`5. Methotrexate-induced lung disease is a potentially
`dangerous lesion, which may occur acutely at any
`time during therapy and which has been reported at
`doses as low as 7.5 mg/week. It is not always fully
`reversible. Pulmonary symptoms (especially a dry,
`nonproductive cough) may ‘require ii_itei-ruption of
`treatment and careful investigation. "
`“J
`6. Diarrhea and ulcerainve stomatitis r‘equii'-e inbe'ri-'up-
`tion of therapy; otherwise, hemorrhagic enteritis
`and death from intestinal perforation may occur.
`7. Malignant lymphomas, which may regress following “
`withdrawal of methotrexate, may occur in patients
`receiving low-dose methotrexate and, thus, may not
`require cytotoxic treatment. Discontinue metho-
`trexate first and. if the lymphoma does not regress,
`appropriate treatment should be instituted.
`8. Like other cytotoxic drugs, niethotrexate may in-
`duoe “tumor lysis syndrome” in patients with rap-
`idly growing tI;u'nors.‘App’ropriate supportive and
`pharmacologic mé‘dsures‘may prevent or alleviate‘
`this complication: V
`‘
`‘
`-
`9. Severe,- occasionally fatal, skin reactions have been
`reported’-‘following single‘ or multiple doses’ of
`methotrexate. Reactions have occurred within days
`of oral, intramuscular, intravenous, or intrathecal
`methotrexate administration. Recovery has been re-
`ported with discontinuation of therapy. (See PRE-
`CAUTIONS, Q gun System Toxicity, Skin.)
`10. Potentially fat
`opportunistic infections. especially
`I Pneumocyslis carinii‘ pneumonia, may occur
`methotrexate therapy.
`_
`'
`V
`‘,
`11. Methotrexategiven concomitantly with radiother-
`apy niay increase the risk of soft tissue necrosis and
`'
`‘ osteonecrosis.
`
`DESCRIPTION
`.
`Methotrexate (formerly Amethopterin) is an antimetabolite
`used in the treatment of certain neoplastic diseases, severe
`psoriasis, and adult rheumatoid 81'i.I’ll'ltlS.'
`_
`‘
`_
`Chemically methotiexata is N-l4-ll(2,4-diamino-6-poendr
`nyl)methyIlmethyI—aniinolbenzoyll-L-glutamlc 803- The
`structural formula is:
`
`‘
`
`nated as the RHEUMA'l'REX® Methotrexate Sodium Dose
`Pack for therapy with a weekly dosing schedule of 5 mg,
`7.5 mg, 10 mg. 12.5 mg and 15 mg. Methotrexate Sodium
`Tablets contain an amount of mothotrexate sodium equiva-
`lent to. 2.5 mg of methotrexate and the following inactive
`ingredients: Lactose, Magnesium Stenratc and Pregelati-
`nized Starch. May also contain Corn Starch.
`Methotrexate Sodium Injection and for Injection products
`are sterile and non-pyrogenic and may be given by the in-
`tramuscular,
`intravenous,
`intra-arterial or intrathecal
`route. (See DOSAGE AND ADMINISTRATION.) How-
`ever, the preservative formulation contains Benzyl Alcohol
`and must not be used for intrathecal or high dose therapy.
`Mcthotrexatc Sodium Injection, lsotomc Liquid, Contains
`Prcservatiue is available in 25 mg/mL, 2 mL (50 mg) and
`10 mL (250 mg) vials.
`Each 25 mg/mL, 2 mL and 10 mL vial contains metho-
`trexate sodium equivalent to 50 mg and 250 mg methotrex-
`ate respectively, 0.90% w/v of Benzyl Alcohol as a preserva-
`tive. and the following inactive ingredients: Sodium
`Chloride 0.260% w/v and Water for Injection qs at 100% v.
`Sodium Hydroxide and, if necessary, Hydrochloric Acid are
`added to adjust the pH to approximately 8.5.
`Metliotrexate LPF® Sodium (methotrcxate sodium injec-
`tion), Isotonic Liquid, Preseruative Free, for. single use only,
`is available in 25 mg/mL, 2 mL (50 mg), 4 mL (100 mg), and
`10 mL (260 mg) vials.
`Each 25 mg/mL, 2 mL, 4 mL, and 10 mL vial contains
`methotrexate sodium equivalent to 50 mg, 100 mg, and
`250 mg methotrexate respectively, and the following inac-
`tive ingredients: Sodium Chloride 0.490% w/v and Water for
`Injection qs ad 100% v. Sodium Hydroxide and, if necessary,
`Hydrochloric Acid are added to adjust the pH to approxi-
`mately 8.5. The 2 mL, 4 mL, and 10 mL solutions contain
`approximately 0.43 mEq, 0.86 mEq, and 2.15 mEq of So-
`dium per vial, respectively. and are isotonic solutions.
`Methotrexate Sodium for Injection, Lyophilized, Presermztive
`Free, for single use only, is available in 20 mg and 1 gram
`vials.
`Each 20 mg and 1 g vial oflyophilized powder contains
`methotrexate sodium equivalent
`to 20 mg and 1 g
`methotrexate respectively. Contains no preservative. So-
`dium Hydroxide and, if necessary, Hydrochloric Acid are
`added during manufacture to adjust the pH. The 20 mg vial
`contains approximately 0.14 mEq of Sodium and the 1 gvial
`contains approximately 7 mEq Sodium.
`CLINICAL PHARMACOLOGY
`Methotrexate inhibits dihydrofolic acid reductase. Dihydro-
`folates must be reduced to tetrahydrofolates by this enzyme
`before they can be utilized as carriers of one-carbon groups
`in the synthesis of purine nucleotides and thymidylate.
`Therefore, nlethotrexate interferes with DNA synthesis, re-
`pair, and cellular replication. Actively proliferating tissues
`such as malignant cells,-bone marrow, fetal cells, buccal and
`intestinal mucosa, and cells of the urinary bladder are .in
`general more sensitive to this effect of methotrexate. When
`cellular proliferation in malignant tissues is greater than in
`most normal tissues, methotrexate may impair malignant
`growth without irreversible damage to normal-tissues.
`The mechanism of action in rheumatoid arthritis is un-
`known; it may aifect immune function. 'I\vo reports describe
`in uitm methotrexate inhibition ofDNA precursor uptake by
`stimulated mononuclear cells, and another describes in an-
`imal polyarthritis partial correction by methotrexate of
`spleen cell hyporesponsiveness and suppresed IL 2 produc-
`tion. Other laboratories, however, have been unable to dem-
`onstrate similar efiects. Clarification of lmethotrexateb
`efi‘ect.on immune activity and its relation to rheumatoid. im-
`munopathogenesia await furthsrstudies...
`- nu.
`'
`I
`In patients with rheumatoid arthritis, effects of metho-
`trexnte on articular swelling and tei‘idert1es‘s.nin".be‘seen as
`early as 3 to 6 weeks. Although methotroxate clearly
`amelioraws symptoms ofinflammation. (pain. swelling; skilf-
`nesé), there is no evidence that it induces rem‘issionr6I‘rhau-
`matoid arthritis nor has a beneficial elfect hood‘
`etrnted on bone erosions and other radiologicnhnngssxwhich
`mit .
`.
`N
`~
`‘
`-
`'
`result in impaired joint use, functional disability. and-dd’I"o!1
`Mosyt studies of methotrexate in patients with rhnumalioid
`arthritis are relatively short term (8 to 6 niuitlis). Limited
`data from long-ternutudies indicate that an initial clinical
`improvement is maintained for at least two years with con-
`tinued therapy.
`I
`-
`A
`'
`-
`-
`In paorinlis, tlisnate of production of epithelial cells in the
`skin is greatly increased over normal skin. This-difierenhial
`in proliferation rates is the basis for the use ofmdliliotrsnto
`to control the psorintic process.
`<
`'
`I
`-
`Methotrsxste in high dose; followed by leuouvorin rescue.
`is used as a part of the treatment of patients with ‘non-
`metastatic osteosarcoma. The original rationale for high
`dose methotrexate therapy was based on the concept of se-
`lective rescue of normal tinq91by__1eucovorip, More
`evidence suggest: that high dose’ methotrexdte may also
`overcome methotrexaté resistance caused by impaired ac-
`tive transport, decrea.se‘d"nflfity of diliydmfolic acid reduc.
`tase for methotrexate. increamd levels oi‘ diliydrotbllc acid
`reductase resulting from gene amplification,‘ or decreased
`polyglutamation of methotrexate. The actual niechanisni of
`action is unknown.
`-
`1
`’
`‘ HO0CCH;CH-3--C---COOH
`lsccbo-coiittolled
`In a 6-month, double-bllfinil
`T27
`l
`-
`pediatric patients wIiIiT)Iivdri§!‘I'houmnbaid'ar_tI1fi|JS(-IRA)
`MoloculnIwslgh1‘454.45 CaoH:2Nc°5
`(mean age, 10.1 yesrl; IKOTIMV 35 VA?” Wli'5/,‘|,1*‘3P;d“'
`ration of disease, 6.d‘'.ysi!‘d) 0"! ‘lJI°l=8'5'“h3‘B'°|'°*€_"°'d‘1
`blleflaotrexato Sodium 'l_.‘nblebs for oral administration are
`Iwliillllnitaiivttlsn bfdvfllhldin a packaging system desig-
`Anti-inflammatory drug: (NSAJDI) nndlorvpndnrsono,
`1% .
`
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`”“rorg>i..;~=
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`
`PHYSICIANS’ DESK REFERENCEC4
`‘
`.
`x
`meth
`my pm.
`....d°:§§..?£§.€IZ‘Zl.?l:.‘il‘i¥.‘;.i:‘;.2.’:‘3,."°* M -A
`Wired to pla:,p,i,,,
`as measured by either the physicians gcliigi] . ..
`by a patient composite 125'/7 reduction in ‘lli:f::1m.m qr
`severity score plus improvement in parent and
`h],L_'7]l.ar‘
`global assessments of disease ac-tivityr. 1')»-9, t“.,f"}}gma"
`the patients in this trial had pulyarticulur-course .ll{|X5d‘) of
`the numerically greatest response was seen in this -and
`group treated with 10 mg/mt‘/wk metliotrexave,
`'['he'[:.ub‘
`whelming majority of the remaining patients had syst:_-mm.»
`course JRA. All patients were Ul'lI‘€bp()l'l.'a'l\'E.‘
`to .\':SA1[:(‘
`approximately one-third were using low dose cortico=ie:-
`at Sig.
`oids. Weekly methotrexate at a dose of 5 mg/ml was n I
`‘
`nificantly more efibctive than placebo in this trial,
`Two Pediatric Oncology Group studies (one randomized and
`one non-randomized) demonstrated a significant improve»
`ment
`in relapse-free survival
`in patients with non-
`metastatic osteosarcoma, when high dose methutrexagg.
`with leucovorin rescue was used in combination with other
`chemotherapeutic agents following surgical resection of the
`primary tumor. These studies were not designed to demon-
`strate the specific contribution of high dose methotrexaw
`leucovorin rescue therapy to the eificacy of the wmbination
`However, a contribution can be inferred from the reports of
`objective responses to this therapy in patients with meta.
`static osteosarcoma, and from reports of extensive tumor
`necrosis following preoperative administration of this ther.
`apy to patients with non-metastatic osteosarcoma.
`Pharmacokinetics
`Absorption—ln adults, oral absorption appears to be dose
`dependent. Peak serum levels are reached within one to two
`hours. At doses of 30 mg/ml or less, methotrexate is gener-
`ally well absorbed with a mean bioavailability of about 60'}
`The absorption of doses greater than 80 mg/m2 is signifi-
`cantly less, possibly due to a saturation effect.
`In leukemic pediatric patients, oral absorption of metho-
`trexate also appears to be dose dependent and has been re-
`ported to vary widely (23% to 95%). A twenty fold difierencc
`between highest and lowest peak levels (Cum: 0.11 to 23
`micromolar after a 20 mg/m2 dose) has been reported. Sig-
`nificant interindividual variability has also been noted in
`time to peak concentration (Tum: 0.67 to 4 hrs afier a
`15 mg/m dose) and fraction of dose absorbed. The absorp-
`tion of doses greater than 40 mgmz has been reported to be
`significantly less than that of lower doses. Food has been
`shown to delay absorption and reduce peak concentration.
`Methotrexate is generally completely absorbed from parsn-
`teral routes of injection. Alter intramuscular injection, peak
`serum concentrations occur in 30 to 60 minutes. As in leu-
`kemic pediatric patients. a wide interindividual variability
`in the plasma concentrations of methotrexat/2 has been re-
`ported in pediatric patients with JRA Following oral ad-
`ministration of methotrexate in doses of 6.4 to 11.2 ll‘lg/l?l12/
`week in pediatric patients with JRA, mean serum concen-
`trations were 0.59 micromolar (range, 0.03 to 1.40) at 1
`hour, 044 micromolar (range, 0.01 to 1.00) at 2 hours, and
`0.29 micromolar (range 0.06 to 0.58) at 3 hours. In pediatric
`patients receiving inetliotrexate for acute lymph0C.VClV 19"‘
`kemia (6.3 to so mg/m2), or for JRA (3.75 to 26 mg/mi». the
`terminal half-life has been reported to range from 0.7 to 5.8
`hours or 0.9 to 2.3 hours, respectively.
`_
`Distribution—After intravenous administration, the initial
`volume of distribution is approximately 0.18 llkg (13% of
`body weight) and steady-state volume of distribution is ap
`proximately 0.4 to 0.3 I./kg (40% to 80% of body weigl}t*-
`Methotrexate competes with reduced folates for active
`transport across cell membranes by means of a single carn-
`sr-rnedisted active transport process. At serum concentra-
`tions greater than 100 micromolar, passive diffusion be-
`comes 'a major pathway by which eifective intracellular
`concentrations can be achieved. Methotrexate in serum 15
`approximately,50% protein bound. Laboratory studies dem-
`onstrate that it may be displaced from plasma albumin b.\'
`various compounds including sulfonamides, sslicylates. tet-
`rscyclinos, chloramphenicol, and phenylzoin.
`‘
`Mothotrexate does not penetrate the blood-cerebrospinal
`fluid barrier in therapeutic amounts when given orally 0'
`pnrenterally. High CSF concentrations of the drug may be
`attained by intratheoal administration.
`In dogs, synovinl fluid concentrations nflzer oral dosinl "9"
`higher in inflamed than uninflained joints. Although salicyl-
`ates did not interfere with this penetration, prior Pfldm‘
`sane treatment reduced penetmfion into inflamed J03“-5 W
`the level of normal joints.
`Metabolism—Aiter absorption, methotrenta underiws h°‘
`patio Ind intracellular metabolism to polyglutnmahod 5|?‘
`which can be converted back to metlioia-suite by h.Vd-01"‘
`enzymes. Those polyglutamntos act as inhibit/_.n'a 01' dim"
`drofolato roduotuu ondtllynildylaie 'synnlietane- Sn!"
`amounts of niothotrcxntc polyglntuiintu 11:17 "mm ”'
`unsqesommndad periods.-’I‘hs intuition and i=n3lw=°‘:
`druguiaion mam active metabolites my man: d1‘.‘°“"“‘
`cells, uuuounduumors.Au:s.uammmtormatabo1im°°
`1-hydmaoniisthotroxato inly docuir‘ at doses o0mm°°l"
`proscribed. Ascumuiuuan drums metabolite our W”
`
`significant at uic Iit¢h dons ulod in‘osteoE0jnl¢ *'‘N°’‘’‘_8 his
`The aqueous solubility of 7-hydw!yIn6'-'h°t"“'”’, “.
`Rild laworahiin rho pusnt uompound.Mofls1uuxne_igi::
`finlly mehbiilinedfizy intwflnllflon aileron] aélflms
`tinn.
`Half-lufi=-d'ho«hrnnnnl half-life reported for In
`is approximately three to tan Iintmfot 173'-Wu“ '°°d E
`
`Page 3 off
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`KOIOS Exhibit 1022
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`Page 3 of 7
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`KOIOS Exhibit 1022
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`

`
`PRODUCT INFORMATION
`WYETH/3417
` ;
`treatment for psoriasis or m
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`tion and is dependent upon do ‘L pnmary mute of elimina-
`Ci00- with TV administration Sage and “Jute of administra-
`tered dose is excreted unchanigl/l -to 90% 0f_ the adminis.
`
`evels. Excellent correla.
`n inet
`hotrexate clearance and
`endogenous creatimne clearance
`Methotrexate clearance rates, v
`ary widely and are gene]-a]]y
`§le°r°§‘5ed 3‘ higher doses. Del
`Eyed drug clearance has been
`identified as one of the m
`
`upon the duration of exp
`.
`t‘
`peak level achieved. Wh
`ination due to compromi::darl);idlel;|:Il1C:?0rIilelaa¥.le1‘iirgrs|;)g slimy-
`fu -
`ace e -
`J
`mm’ or lnher “USES, methotrexate serum concentrations
`may remain elevated for prolonged periods_
`The P°‘e“"?1 f°r mxicity from high dose regimens or de.
`klyed e’5°’et‘°“ ls "3d“°€d by the administration of leucovo-
`"1? °_5]c“}m during 319 fi_na1 phase of methotrexate plasma
`a imination. Pharmacolunetic monitoring of methon-exafi;
`serum concentrations may help identify those patients at
`high risk for methotrexate toxicity and aid in proper acfiugt.
`ment of leucovor-in dosing. Guidelines for monitoring serum
`F‘9‘h°‘7“‘-Kate levels. and for adjustment of leucovorin dos-
`ing to reduce the risk of methotraxate to