Getting started with. For treating RA, pjia, and psoriasis with a single, weekly injection under the skin

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1 Getting started with Fr treating RA, pjia, and psriasis with a single, weekly injectin under the skin What is Rasuv (methtrexate) injectin? Rasuv (methtrexate) injectin is a single-dse aut-injectr cntaining a prescriptin medicine, methtrexate. Methtrexate is used t: Treat certain adults with severe, active rheumatid arthritis, and children with active plyarticular juvenile idipathic arthritis (pjia), after treatment with ther medicines including nn-steridal anti-inflammatry (NSAIDS) have been used and did nt wrk well. Cntrl the symptms f severe, resistant, disabling psriasis in adults when ther types f treatment have been used and did nt wrk well. Rasuv shuld nt be used fr the treatment f cancer. Rasuv shuld nt be used fr the treatment f children with psriasis. Rasuv is available in dses f 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, and 30 mg. Yur dctr will prescribe a different way t take methtrexate if yu need t take methtrexate by muth r in sme ther way. Imprtant Safety Infrmatin, including Bxed Warning, fr Rasuv What is the mst imprtant infrmatin I shuld knw abut Rasuv? This prduct includes the fllwing Bxed Warning: Rasuv can cause serius side effects that can lead t death, including: Organ system txicity. Peple wh use methtrexate fr the treatment f cancer, psriasis, r rheumatid arthritis, have an increased risk f death frm rgan txicity. Please see additinal Imprtant Safety Infrmatin, including Bxed Warning, cntinued n next page and full Imprtant Safety Infrmatin n pages Please see Patient Infrmatin in pcket fr cmplete infrmatin abut Rasuv.

2 Imprtant Safety Infrmatin, Including Bxed Warning Bxed Warning (cntinued) Types f rgan txicity can include: gastrintestinal, nerve, bne marrw, lung, liver, kidneys, immune system, and skin. Yur dctr will d bld tests and ther types f tests befre yu take and while yu are taking Rasuv t check fr signs and symptms f rgan txicity. Call yur dctr right away if yu have any f the fllwing symptms f rgan txicity: vmiting, neck stiffness, diarrhea, paralysis, muth sres, irritability, fever, sleepiness, cnfusin, prblems with crdinatin, weakness, dry cugh, temprary blindness, truble breathing, seizures, severe skin rash, headache, and back pain. Wmen wh are pregnant are at increased risk fr death f the baby and fr birth defects in the baby. Wmen wh are pregnant r wh plan t becme pregnant must nt take Rasuv. A pregnancy test shuld be perfrmed befre starting Rasuv. Cntraceptin shuld be used by bth females and males while taking Rasuv. Pregnancy shuld be avided if either partner is receiving Rasuv: fr a minimum f 3 mnths after treatment with Rasuv fr males. during and fr at least 1 menstrual cycle after treatment with Rasuv fr females. What are the pssible side effects f Rasuv? Rasuv may cause serius side effects, including: Fertility prblems. Methtrexate, the active ingredient in Rasuv, may affect yur ability t have a baby. Males may have a decreased sperm cunt, and females may have changes t their menstrual cycle. This can happen while taking Rasuv and fr a shrt perid f time after yu stp. Certain cancers. Sme peple wh have taken methtrexate have had a certain type f cancer called Nn-Hdgkin s lymphma and ther tumrs. Yur dctr may tell yu t stp taking Rasuv if this happens. Tissue and bne prblems. Taking methtrexate while having radiatin therapy may increase the risk f yur tissue r bne nt receiving enugh bld. This may lead t death f the tissue r bne. 2

3 Cmmn side effects f Rasuv include: nausea, stmach pain, indigestin (dyspepsia), muth sres, and rash. Wh shuld nt take Rasuv? D nt take Rasuv if yu: Are pregnant r planning t becme pregnant Are breastfeeding; Rasuv can pass int yur breast milk and may harm yur baby. Have alchl prblems (alchlism) Have liver prblems Have prblems fighting infectin (immundeficiency syndrme) Have been tld yu have (r think yu have) a bld disrder, such as lw levels f white bld cells, red bld cells (anemia), r platelets Have had an allergy t methtrexate r any f the ingredients in Rasuv What shuld I tell my dctr befre taking Rasuv? Befre yu take Rasuv, tell yur dctr if yu have any ther medical cnditins. Tell yur dctr abut all f the medicines yu take, including prescriptin medicines, ver-the-cunter medicines, vitamins, and herbal supplements. Rasuv may affect hw ther medicines wrk, and ther medicines may affect hw Rasuv wrks, causing side effects. Ask yur dctr r pharmacist fr a list f medicines if yu are nt sure. Tell yur dctr if yu have any side effect that bthers yu r that des nt g away. These are nt all the pssible side effects f Rasuv. Fr mre infrmatin, ask yur dctr r pharmacist. Fr additinal infrmatin abut Rasuv, please refer t the Patient Infrmatin Leaflet and Instructins fr Use, which can be fund at r call MEDAC ( ). Yu are encuraged t reprt negative side effects f prescriptin drugs t the FDA. Visit r call FDA Please see additinal Imprtant Safety Infrmatin, including Bxed Warning, n cver, and full Imprtant Safety Infrmatin n pages Please see Patient Infrmatin in pcket fr cmplete infrmatin abut Rasuv. Reliability Redefined 3

4 Intrductin The gal f this brchure is t prvide yu with infrmatin fr getting started with Rasuv (methtrexate) injectin, a treatment ptin fr RA, pjia, and psriasis. It will cver what Rasuv is, hw t use it, what side effects may ccur, and ther imprtant infrmatin yu shuld cnsider. Advantages f Rasuv One treatment ptin fr RA, the drug methtrexate, is currently the mst frequently used RA drug in the wrld. Patients wh take methtrexate by swallwing a pill (rally) may nt respnd well because f side effects. Patients wh switch frm methtrexate taken by a pill t methtrexate taken by injectin (subcutaneusly) may experience benefits. Yu may experience fewer certain side effects and a better respnse t treatment. 4

5 Imprtant Infrmatin t knw abut Rasuv Serius side effects, including death, in patients taking Rasuv include rgan system txicity and increased risk f death r birth defects in the baby when taken by a pregnant wman. Other serius side effects include fertility prblems, certain cancers, and tissue and bne prblems. The mst cmmn side effects f Rasuv are nausea, stmach pain, indigestin, muth sres, and rash. Please see full Imprtant Safety Infrmatin, including Bxed Warning, n pages Please see Patient Infrmatin in pcket fr cmplete infrmatin abut Rasuv. Reliability Redefined 5

6 Designed with patients in mind Rasuv (methtrexate) injectin is a patient friendly ptin fr taking methtrexate by injectin under the skin. Rasuv cmes as a prefilled aut-injectr, eliminating the need t use a vial, needle, and syringe preparatin. Rasuv is available in mre dses than any ther ptin fr taking methtrexate by injectin under the skin. This makes it easy fr yur dctr t find the dse that is right fr yu thrughut the curse f yur treatment. 7.5 mg 10 mg 12.5 mg 15 mg 17.5 mg 20 mg 22.5 mg 25 mg 27.5 mg 30 mg Each Rasuv dsage amunt is clr cded fr easy identificatin. Rasuv ffers 10 dsage strengths, mre than any ther subcutaneus methtrexate delivery system. 6

7 Patients find Rasuv simple t use In a study f 104 adult patients with RA, ver 95% f patients reprted n difficulties using Rasuv. Rasuv nly needs t be injected nce a week. Once yu start n Rasuv, yur dctr may adjust the amunt ne r mre times t determine the right amunt fr yu % Patients have rated Rasuv an average f 9.8 r higher n ease f use (1=very difficult and 10=very easy; range 8 t 10) 98% f patients had a psitive verall impressin f Rasuv Patients indicated ne f the things they liked best abut Rasuv was that it was relatively pain free. T learn mre abut Rasuv, please visit Please see full Imprtant Safety Infrmatin, including Bxed Warning, n pages Please see Patient Infrmatin in pcket fr cmplete infrmatin abut Rasuv. Reliability Redefined 7

8 Rasuv (methtrexate) injectin instructins a c b d Parts f Rasuv Aut-injectr a) Yellw injectin buttn b) Handling area c) Transparent cntrl zne d) Yellw cap Befre using: Check Rasuv befre yu inject it. The liquid inside the Abdmen transparent cntrl zne shuld be clear and yellw t brwn in clr and shuld nt have any lumps r Thigh particles in it. D nt use Rasuv if the liquid is cludy, disclred, r cntains particles. Wash yur hands with sap and warm water, and wipe area t be injected with alchl (abdmen r upper thighs). D nt inject within 2 inches f belly buttn. 1. Remve yellw cap Hld the Rasuv aut-injectr with ne hand, and use yur ther hand t pull the yellw cap straight ff. (D nt twist the cap.) The Rasuv Dispsal Prgram is a free prgram fr patients t safely dispse f Rasuv aut-injectrs after use. T jin, sign up nline at r call MEDAC (6-3322). 8

9 2. Prepare the injectin With yur thumb and frefinger f yur free hand, pinch a pad f skin surrunding the cleaned injectin site by gently squeezing. Be sure t hld the skin pinched until Rasuv is remved frm the skin after the injectin. Psitin the uncapped transparent end f the Rasuv aut-injectr perpendicular (at a 90-degree angle) t the fld f skin. Withut pressing the buttn, push Rasuv firmly nt yur skin until yu feel the stp pint in rder t unlck the yellw injectin buttn. 3. Inject Rasuv While still hlding Rasuv firmly against pinched skin, press the yellw injectin buttn with yur thumb t inject. Once yu hear a click, which indicates start f injectin, keep hlding Rasuv against the pinched skin until all f the medicine is injected. This can take up t 5 secnds (slwly cunt 1, 2, 3, 4, 5). Lk at the transparent cntrl zne while yu are injecting t make sure that the entire dse is injected. When the mvement stps, the injectin is cmpleted. After cmpleting injectin, release skin and remve Rasuv frm skin by pulling straight up (perpendicular t the skin). If there is liquid left, cntact yur dctr r healthcare prfessinal. D nt use anther Rasuv. After using: After injectin, the prtective needle shield will autmatically mve int place and lck ver the needle. Put Rasuv in an FDA-cleared sharps dispsal cntainer (nt husehld trash). T learn mre abut using Rasuv, please view the Rasuv Administratin Vide r dwnlad a cpy f the cmplete Rasuv Injectin Instructins at Please see full Imprtant Safety Infrmatin, including Bxed Warning, n pages Please see Patient Infrmatin in pcket fr cmplete infrmatin abut Rasuv. Reliability Redefined 9

10 Imprtant Safety Infrmatin, Including Bxed Warning What is Rasuv (methtrexate) injectin? Rasuv (methtrexate) injectin is a single-dse aut-injectr cntaining a prescriptin medicine, methtrexate. Methtrexate is used t: Treat certain adults with severe, active rheumatid arthritis, and children with active plyarticular juvenile idipathic arthritis (pjia), after treatment with ther medicines including nn-steridal anti-inflammatry (NSAIDS) have been used and did nt wrk well. Cntrl the symptms f severe, resistant, disabling psriasis in adults when ther types f treatment have been used and did nt wrk well. Rasuv shuld nt be used fr the treatment f cancer. Rasuv shuld nt be used fr the treatment f children with psriasis. Rasuv is available in dses f 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, and 30 mg. Yur dctr will prescribe a different way t take methtrexate if yu need t take methtrexate by muth r in sme ther way. Imprtant Safety Infrmatin, including Bxed Warning, fr Rasuv What is the mst imprtant infrmatin I shuld knw abut Rasuv? This prduct includes the fllwing Bxed Warning: Rasuv can cause serius side effects that can lead t death, including: Organ system txicity. Peple wh use methtrexate fr the treatment f cancer, psriasis, r rheumatid arthritis, have an increased risk f death frm rgan txicity. Types f rgan txicity can include: gastrintestinal, nerve, bne marrw, lung, liver, kidneys, immune system, and skin. Yur dctr will d bld tests and ther types f tests befre yu take and while yu are taking Rasuv t check fr signs and symptms f rgan txicity. Call yur dctr right away if yu have any f the fllwing symptms f rgan txicity: vmiting, neck stiffness, diarrhea, paralysis, muth sres, irritability, fever, sleepiness, cnfusin, prblems with crdinatin, weakness, dry cugh, temprary blindness, truble breathing, seizures, severe skin rash, headache, and back pain. Wmen wh are pregnant are at increased risk fr death f the baby and fr birth defects in the baby. Wmen wh are pregnant r wh plan t becme pregnant must nt take Rasuv. A pregnancy test shuld be perfrmed befre starting Rasuv. Cntraceptin shuld be used by bth females and males while taking Rasuv. Pregnancy shuld be avided if either partner is receiving Rasuv: fr a minimum f 3 mnths after treatment with Rasuv fr males. during and fr at least 1 menstrual cycle after treatment with Rasuv fr females. What are the pssible side effects f Rasuv? Rasuv may cause serius side effects, including: 10

11 Bxed Warning (cntinued) Fertility prblems. Methtrexate, the active ingredient in Rasuv, may affect yur ability t have a baby. Males may have a decreased sperm cunt, and females may have changes t their menstrual cycle. This can happen while taking Rasuv and fr a shrt perid f time after yu stp. Certain cancers. Sme peple wh have taken methtrexate have had a certain type f cancer called Nn-Hdgkin s lymphma and ther tumrs. Yur dctr may tell yu t stp taking Rasuv if this happens. Tissue and bne prblems. Taking methtrexate while having radiatin therapy may increase the risk f yur tissue r bne nt receiving enugh bld. This may lead t death f the tissue r bne. Cmmn side effects f Rasuv include: nausea, stmach pain, indigestin (dyspepsia), muth sres, and rash. Wh shuld nt take Rasuv? D nt take Rasuv if yu: Are pregnant r planning t becme pregnant Are breastfeeding; Rasuv can pass int yur breast milk and may harm yur baby. Have alchl prblems (alchlism) Have liver prblems Have prblems fighting infectin (immundeficiency syndrme) Have been tld yu have (r think yu have) a bld disrder, such as lw levels f white bld cells, red bld cells (anemia), r platelets Have had an allergy t methtrexate r any f the ingredients in Rasuv What shuld I tell my dctr befre taking Rasuv? Befre yu take Rasuv, tell yur dctr if yu have any ther medical cnditins. Tell yur dctr abut all f the medicines yu take, including prescriptin medicines, ver-the-cunter medicines, vitamins, and herbal supplements. Rasuv may affect hw ther medicines wrk, and ther medicines may affect hw Rasuv wrks, causing side effects. Ask yur dctr r pharmacist fr a list f medicines if yu are nt sure. Tell yur dctr if yu have any side effect that bthers yu r that des nt g away. These are nt all the pssible side effects f Rasuv. Fr mre infrmatin, ask yur dctr r pharmacist. Fr additinal infrmatin abut Rasuv, please refer t the Patient Infrmatin Leaflet and Instructins fr Use, which can be fund at r call MEDAC ( ). Yu are encuraged t reprt negative side effects f prescriptin drugs t the FDA. Visit r call FDA Please see Patient Infrmatin in pcket fr cmplete infrmatin abut Rasuv. Reliability Redefined 11

12 CORE Cnnectins: The Rasuv Patient Supprt Prgram Persnalized Pharmacy Supprt: Prviding patients with assistance btaining Rasuv thrugh hme delivery by ur pharmacy partner Administratin Vide: Develped t help patients learn hw t self-inject C-pay Assistance: Savings n ut-f-pcket expenses fr eligible patients Dispsal Prgram: Free prgram fr patients t safely dispse f Rasuv after use Patient Assistance Prgram: Helping eligible patients affrd their Rasuv prescriptin Benefits Supprt: Fr help with insurance questins. Available at MEDAC (6-3322), 8:00 am-8:00 pm ET Mnday- Friday (excluding hlidays) T learn mre abut CORE Cnnectins, please visit Please see full Imprtant Safety Infrmatin, including Bxed Warning, n pages Please see Patient Infrmatin in pcket fr cmplete infrmatin abut Rasuv. Reliability Redefined Rasuv is a trademark f Medac Pharma, Inc Medac Pharma, Inc. All rights reserved. MP-Q September 2014

13 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights d nt include all the infrmatin needed t use. RASUVO safely and effectively. See full prescribing infrmatin fr RASUVO. RASUVO (methtrexate) injectin, fr subcutaneus use Initial U.S. Apprval: 1953 WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO- FETAL TOXICITY AND DEATH See full prescribing infrmatin fr cmplete bxed warning. Serius txic reactins and death have been reprted with the use f methtrexate. Patients shuld be clsely mnitred fr bne marrw, liver, lung, skin, and kidney txicities (5.1). Methtrexate has been reprted t cause fetal death and/r cngenital anmalies and is cntraindicated in pregnancy (4, 5.2). Unexpectedly severe (smetimes fatal) bne marrw suppressin, aplastic anemia, and gastrintestinal txicity have been reprted with cncmitant administratin f methtrexate (usually in high dsage) alng with sme nnsteridal anti-inflammatry drugs (NSAIDs) (5.1). Hepattxicity, fibrsis, and cirrhsis may ccur after prlnged use (5.1). Methtrexate may cause interstitial pneumnitis at any time during therapy and has been reprted at lw dses. Pulmnary symptms (especially a dry, nnprductive cugh) may require interruptin f treatment and careful investigatin (5.1). Diarrhea, ulcerative stmatitis, hemrrhagic enteritis, and death frm intestinal perfratin may ccur (5.1). Severe, ccasinally fatal, skin reactins have been reprted (5.1). Ptentially fatal pprtunistic infectins may ccur (5.1) INDICATIONS AND USAGE Rasuv is a flate analg metablic inhibitr indicated fr the: Management f patients with severe, active rheumatid arthritis (RA) and plyarticular juvenile idipathic arthritis (pjia), wh are intlerant f r had an inadequate respnse t first-line therapy (1.1) Symptmatic cntrl f severe, recalcitrant, disabling psriasis in adults wh are nt adequately respnsive t ther frms f therapy (1.2) Limitatin f Use Rasuv is nt indicated fr the treatment f neplastic diseases ( 1.3) DOSAGE AND ADMINISTRATION Rasuv is fr nce weekly subcutaneus use nly. Administer Rasuv in the abdmen r thigh. (2.1) Use anther frmulatin f methtrexate fr patients requiring ral, intramuscular, intravenus, intra-arterial, r intrathecal dsing, dses less than 7.5 mg per week, dses abve 30 mg per week, high-dse regimens, r dse adjustments f less than 2.5 mg increments (2.1) Starting dses f methtrexate: RA: 7.5 mg nce weekly f an ral r subcutaneus frmulatin (2.2) pjia: 10 mg/m 2 nce weekly (2.2) Psriasis: 10 t 25 mg nce weekly f an ral, intramuscular, subcutaneus, r intravenus frmulatin (2.3) Adjust dse gradually t achieve an ptimal respnse (2.2, 2.3) DOSAGE FORMS AND STRENGTHS Injectin: Single-dse manually-triggered aut-injectr delivering methtrexate in the fllwing dsage strengths: 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, and 30 mg (3) CONTRAINDICATIONS Pregnancy (4) Nursing mthers (4) Alchlism r liver disease (4) Immundeficiency syndrmes (4) Preexisting bld dyscrasias (4) Hypersensitivity t methtrexate (4) WARNINGS AND PRECAUTIONS Organ system txicity: Ptential fr serius txicity. Only fr use by physicians experienced in antimetablite therapy (5.1). Embry-fetal txicity: Exclude pregnancy befre treatment. Avid pregnancy if either partner is receiving Rasuv. Advise males t avid pregnancy fr a minimum f three mnths after therapy and females t avid pregnancy fr at least ne vulatry cycle after therapy (5.2). Effects n reprductin: May cause impairment f fertility, ligspermia and menstrual dysfunctin (5.3) Labratry tests: Mnitr cmplete bld cunts, renal functin and liver functin tests (5.4). Risks frm imprper dsing: Mistaken daily use has led t fatal txicity (5.5) Patients with impaired renal functin, ascites, r pleural effusins: Eliminatin is reduced (5.6). Dizziness and fatigue: May impair ability t drive r perate machinery (5.7) ADVERSE REACTIONS Cmmn adverse reactins are: nausea, abdminal pain, dyspepsia, stmatitis/muth sres, rash, naspharyngitis, diarrhea, liver functin test abnrmalities, vmiting, headache, brnchitis, thrmbcytpenia, alpecia, leukpenia, pancytpenia, dizziness, phtsensitivity, and burning f skin lesins (6). T reprt SUSPECTED ADVERSE REACTIONS, cntact Medac at r FDA at FDA-1088 r DRUG INTERACTIONS Aspirin, NSAIDs, and sterids: cncmitant use may elevate and prlng serum methtrexate levels and cause increased txicity (7.1) Prtn pump inhibitrs: cncmitant use may elevate and prlng serum methtrexate levels and cause increased txicity (7.2) USE IN SPECIFIC POPULATIONS Pediatric use: Safety and efficacy f methtrexate, including Rasuv, have nt been established in pediatric patients with psriasis. Safety and efficacy f Rasuv have nt been established in pediatric patients with malignancy (8.4) Geriatric use: Use cautin in dse selectin (8.5) See 17 fr PATIENT COUNSELING INFORMATION and FDA-apprved patient labeling. Revised: 07/2014 FULL PRESCRIBING INFORMATION: CONTENTS WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO- FETAL TOXICITY AND DEATH 1 INDICATIONS AND USAGE 1.1 Rheumatid Arthritis including Plyarticular Juvenile Idipathic Arthritis 1.2 Psriasis 1.3 Limitatin f Use 2 DOSAGE AND ADMINISTRATION 2.1 Imprtant Dsing Infrmatin 2.2 Rheumatid Arthritis including Plyarticular Juvenile Idipathic Arthritis 2.3 Psriasis 2.4 Administratin and Handling 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Organ System Txicity 5.2 Embry-Fetal Txicity 5.3 Effects n Reprductin 5.4 Labratry Tests 5.5 Risks frm Imprper Dsing 5.6 Patients with Impaired Renal Functin, Ascites, r Pleural Effusins 5.7 Dizziness and Fatigue 5.8 Malignant Lymphmas 5.9 Tumr Lysis Syndrme 5.10 Cncmitant Radiatin Therapy

14 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Other Adverse Reactins 7 DRUG INTERACTIONS 7.1 Aspirin, Nnsteridal Anti-Inflammatry Drugs, and Sterids 7.2 Prtn Pump Inhibitrs (PPIs) and H 2 Blckers 7.3 Oral Antibitics 7.4 Hepattxins 7.5 Thephylline 7.6 Flic Acid and Antiflates 7.7 Mercaptpurine 7.8 Other Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mthers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Females and Males f Reprductive Ptential 8.7 Renal Impairment 8.8 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism f Actin 12.2 Pharmacdynamics 12.3 Pharmackinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility 14 CLINICAL STUDIES 14.1 Rheumatid Arthritis 14.2 Plyarticular Juvenile Idipathic Arthritis 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sectins r subsectins mitted frm the full prescribing infrmatin are nt listed

15 FULL PRESCRIBING INFORMATION WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH Rasuv shuld be used nly by physicians whse knwledge and experience include the use f antimetablite therapy. Because f the pssibility f serius txic reactins (which can be fatal), Rasuv shuld be used nly in patients with psriasis r rheumatid arthritis with severe, recalcitrant, disabling disease which is nt adequately respnsive t ther frms f therapy. Deaths have been reprted with the use f methtrexate in the treatment f malignancy, psriasis, and rheumatid arthritis. Patients shuld be clsely mnitred fr bne marrw, liver, lung, skin, and kidney txicities. Patients shuld be infrmed by their physician f the risks invlved and be under a physician s care thrughut therapy [see Warnings and Precautins (5.1)]. 1. Methtrexate has been reprted t cause fetal death and/r cngenital anmalies. Therefre, Rasuv is nt recmmended fr females f childbearing ptential unless there is clear medical evidence that the benefits can be expected t utweigh the cnsidered risks [see Warnings and Precautins (5.2)]. Rasuv is cntraindicated in pregnant wmen [see Cntraindicatins (4)]. 2. Methtrexate eliminatin is reduced in patients with impaired renal functins, ascites, r pleural effusins. Such patients require especially careful mnitring fr txicity, and require dse reductin r, in sme cases, discntinuatin f Rasuv administratin [see Warnings and Precautins (5.6)]. 3. Unexpectedly severe (smetimes fatal) bne marrw suppressin, aplastic anemia, and gastrintestinal txicity have been reprted with cncmitant administratin f methtrexate (usually in high dsage) alng with sme nnsteridal antiinflammatry drugs (NSAIDs) [see Warnings and Precautins (5.1) and Drug Interactins (7.1)]. 4. Methtrexate causes hepattxicity, fibrsis and cirrhsis, but generally nly after prlnged use. Acutely, liver enzyme elevatins are frequently seen. These are usually transient and asymptmatic, and als d nt appear predictive f subsequent hepatic disease. Liver bipsy after sustained use ften shws histlgic changes, and fibrsis and cirrhsis have been reprted; these latter lesins may nt be preceded by symptms r abnrmal liver functin tests in the psriasis ppulatin. Fr this reasn, peridic liver bipsies are usually recmmended fr psriatic patients wh are under lng-term treatment. Persistent abnrmalities in liver functin tests may precede appearance f fibrsis r cirrhsis in the rheumatid arthritis ppulatin [see Warnings and Precautins (5.1)]. 5. Methtrexate-induced lung disease, including acute r chrnic interstitial pneumnitis, is a ptentially dangerus lesin, which may ccur acutely at any time during therapy and has been reprted at lw dses. It is nt always fully reversible and fatalities have been reprted. Pulmnary symptms (especially a dry, nnprductive cugh) may require interruptin f treatment and careful investigatin [see Warnings and Precautins (5.1)]. 6. Diarrhea and ulcerative stmatitis require interruptin f therapy: therwise, hemrrhagic enteritis and death frm intestinal perfratin may ccur [see Warnings and Precautins (5.1)]. 7. Malignant lymphmas, which may regress fllwing withdrawal f methtrexate, may ccur in patients receiving lwdse methtrexate and, thus, may nt require cyttxic treatment. Discntinue Rasuv first and, if the lymphma des nt regress, apprpriate treatment shuld be instituted [see Warnings and Precautins (5.8)]. 8. Like ther cyttxic drugs, methtrexate may induce tumr lysis syndrme in patients with rapidly grwing tumrs [see Warnings and Precautins (5.9)]. 9. Severe, ccasinally fatal, skin reactins have been reprted fllwing single r multiple dses f methtrexate. Reactins have ccurred within days f ral, intramuscular, intravenus, r intrathecal methtrexate administratin. Recvery has been reprted with discntinuatin f therapy [see Warnings and Precautins (5.1)]. 10. Ptentially fatal pprtunistic infectins, especially Pneumcystis jirveci pneumnia, may ccur with methtrexate therapy [see Warnings and Precautins (5.1)]. 11. Methtrexate given cncmitantly with raditherapy may increase the risk f sft tissue necrsis and stenecrsis [see Warnings and Precautins (5.10)].

16 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Rheumatid Arthritis including Plyarticular Juvenile Idipathic Arthritis Rasuv is indicated in the management f selected adults with severe, active rheumatid arthritis (RA) (ACR criteria), r children with active plyarticular juvenile idipathic arthritis (pjia), wh have had an insufficient therapeutic respnse t, r are intlerant f, an adequate trial f first-line therapy including full dse nnsteridal anti-inflammatry agents (NSAIDs). 1.2 Psriasis Rasuv is indicated in adults fr the symptmatic cntrl f severe, recalcitrant, disabling psriasis that is nt adequately respnsive t ther frms f therapy, but nly when the diagnsis has been established, as by bipsy and/r after dermatlgic cnsultatin. It is imprtant t ensure that a psriasis flare is nt due t an undiagnsed cncmitant disease affecting immune respnses. 1.3 Limitatin f Use Rasuv is nt indicated fr the treatment f neplastic diseases. 2 DOSAGE AND ADMINISTRATION 2.1 Imprtant Dsing Infrmatin Rasuv is a single-dse manually-triggered aut-injectr fr nce-weekly subcutaneus use nly [see Warnings and Precautins (5.5)]. Administer Rasuv in the abdmen r the thigh. Rasuv is nly available in dses between 7.5 t 30 mg in 2.5 mg increments. Use anther frmulatin f methtrexate fr alternative dsing in patients wh require ral, intramuscular, intravenus, intra-arterial, r intrathecal dsing, dses less than 7.5 mg per week, dses mre than 30 mg per week, high-dse regimens, r dse adjustments f less than 2.5 mg increments. 2.2 Rheumatid Arthritis including Plyarticular Juvenile Idipathic Arthritis Recmmended starting dse f methtrexate: Adult RA: 7.5 mg as a single ral r subcutaneus dse nce weekly. pjia: 10 mg/m 2 nce weekly. Fr patients switching frm ral methtrexate t Rasuv, cnsider any differences in biavailability between ral and subcutaneusly administered methtrexate [see Clinical Pharmaclgy (12.3)]. Dsages may be adjusted gradually t achieve an ptimal respnse. Limited experience shws a significant increase in the incidence and severity f serius txic reactins, especially bne marrw suppressin, at dses greater than 20 mg/wk in adults. Althugh there is experience with dses up t 30 mg/m 2 /wk in children, there are t few published data t assess hw dses ver 20 mg/m 2 /wk might affect the risk f serius txicity in children. Experience des suggest, hwever, that children receiving 20 t 30 mg/m 2 /wk (0.65 t 1.0 mg/kg/wk) may have better absrptin and fewer gastrintestinal side effects if methtrexate is administered either intramuscularly r subcutaneusly. Therapeutic respnse usually begins within 3 t 6 weeks and the patient may cntinue t imprve fr anther 12 weeks r mre. The ptimal duratin f therapy is unknwn. Limited data available frm lng-term studies in adults indicate that the initial clinical imprvement is maintained fr at least tw years with cntinued therapy. When methtrexate is discntinued, the arthritis usually wrsens within 3 t 6 weeks. The patient shuld be fully infrmed f the risks invlved and shuld be under cnstant supervisin f the physician. Assessment f hematlgic, hepatic, renal, and pulmnary functin shuld be made by histry, physical examinatin, and labratry tests befre beginning, peridically during, and befre reinstituting Rasuv therapy [see Warnings and Precautins (5.4)]. Females f childbearing ptential shuld nt be started n Rasuv until pregnancy is excluded [see Cntraindicatins (4) and Warnings and Precautins (5.2)].

17 All schedules shuld be cntinually tailred t the individual patient. An initial test dse may be given prir t the regular dsing schedule t detect any extreme sensitivity t adverse effects. Maximal myelsuppressin usually ccurs in seven t ten days. 2.3 Psriasis Recmmended starting dse f methtrexate: Psriasis: mg as a single ral, intramuscular, subcutaneus, r intravenus dse nce weekly. Fr patients switching frm ral methtrexate t Rasuv, cnsider any differences in biavailability between ral and subcutaneusly administered methtrexate [see Clinical Pharmaclgy (12.3)]. Dsage may be gradually adjusted t achieve ptimal clinical respnse; 30 mg/week shuld nt rdinarily be exceeded. Once ptimal clinical respnse has been achieved, the dsage shuld be reduced t the lwest pssible amunt f drug and t the lngest pssible rest perid. The use f Rasuv may permit the return t cnventinal tpical therapy, which shuld be encuraged. 2.4 Administratin and Handling Rasuv is a manually-triggered aut-injectr intended fr subcutaneus use under the guidance and supervisin f a physician. Patients may self-inject with Rasuv if a physician determines that it is apprpriate, if they have received prper training in hw t prepare and administer the crrect dse, and if they receive medical fllw-up, as necessary. Rasuv is injected nce weekly. The patient must be explicitly infrmed abut the nce weekly dsing schedule. It is advisable t determine an apprpriate fixed day f the week fr the injectin. Visually inspect Rasuv fr particulate matter and disclratin prir t administratin. D nt use Rasuv if the seal is brken. Handle and dispse f Rasuv cnsistent with recmmendatins fr handling and dispsal f cyttxic drugs 1. 3 DOSAGE FORMS AND STRENGTHS Rasuv is an injectin cntaining methtrexate at a cncentratin f 50 mg/ml available as a manually-triggered aut-injectr that administers a single dse f methtrexate slutin in the fllwing dsage strengths: 7.5 mg 10 mg 12.5 mg 15 mg 17.5 mg 20 mg 22.5 mg 25 mg 27.5 mg 30 mg 4 CONTRAINDICATIONS Rasuv is cntraindicated in the fllwing: Pregnancy Rasuv can cause fetal death r teratgenic effects when administered t a pregnant wman. Rasuv is cntraindicated in pregnant wmen. If this drug is used during pregnancy, r if the patient becmes pregnant while taking this drug, the patient shuld be apprised f the ptential hazard t the fetus [see Warnings and Precautins ( 5.2) and Use in Specific Ppulatins (8.1)]. Nursing Mthers Because f the ptential fr serius adverse reactins frm methtrexate in breast fed infants, Rasuv is cntraindicated in nursing mthers [see Use in Specific Ppulatins ( 8.3)].

18 Alchlism r Liver Disease Patients with alchlism, alchlic liver disease r ther chrnic liver disease [see Warnings and Precautins ( 5.1)]. Immundeficiency Syndrmes Patients wh have vert r labratry evidence f immundeficiency syndrmes [see Warnings and Precautins ( 5.1)]. Preexisting Bld Dyscrasias Patients wh have preexisting bld dyscrasias, such as bne marrw hypplasia, leukpenia, thrmbcytpenia, r significant anemia [see Warnings and Precautins ( 5.1)]. Hypersensitivity Patients with a knwn hypersensitivity t methtrexate. Severe hypersensitivity reactins have been bserved with methtrexate use [see Warnings and Precautins ( 5.1) and Adverse Reactins (6.1 and 6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Organ System Txicity Rasuv shuld be used nly by physicians whse knwledge and experience include the use f antimetablite therapy. Because f the pssibility f serius txic reactins (which can be fatal), Rasuv shuld be used nly in patients with psriasis r rheumatid arthritis with severe, recalcitrant, disabling disease which is nt adequately respnsive t ther frms f therapy. Deaths have been reprted with the use f methtrexate in the treatment f malignancy, psriasis, and rheumatid arthritis. Patients shuld be clsely mnitred fr bne marrw, liver, lung and kidney txicities. Rasuv has the ptential fr serius txicity. Txic effects may be related in frequency and severity t dse r frequency f administratin but have been seen at all dses. Because they can ccur at any time during therapy, it is necessary t fllw patients n Rasuv clsely. Mst adverse reactins are reversible if detected early. When such reactins d ccur, the drug shuld be reduced in dsage r discntinued and apprpriate crrective measures shuld be taken. If necessary, this culd include the use f leucvrin calcium and/r acute, intermittent hemdialysis with a high-flux dialyzer [see Overdsage (10)]. If Rasuv therapy is reinstituted, it shuld be carried ut with cautin, with adequate cnsideratin f further need fr the drug and increased alertness as t pssible recurrence f txicity. The clinical pharmaclgy f methtrexate has nt been well studied in lder individuals. Due t diminished hepatic and renal functin as well as decreased flate stres in this ppulatin, relatively lw dses shuld be cnsidered, and these patients shuld be clsely mnitred fr early signs f txicity [see Use in Specific Ppulatins (8.5)]. Gastrintestinal: Diarrhea and ulcerative stmatitis require interruptin f therapy: therwise, hemrrhagic enteritis and death frm intestinal perfratin may ccur. If vmiting, diarrhea, r stmatitis ccur, which may result in dehydratin, Rasuv shuld be discntinued until recvery ccurs. Rasuv shuld be used with extreme cautin in the presence f peptic ulcer disease r ulcerative clitis. Unexpectedly severe (smetimes fatal) gastrintestinal txicity has been reprted with cncmitant administratin f methtrexate (usually in high dsage) alng with sme nnsteridal anti-inflammatry drugs (NSAIDs) [see Drug Interactins (7.1)]. Hematlgic: Rasuv can suppress hematpiesis and cause anemia, aplastic anemia, pancytpenia, leukpenia, neutrpenia, and/r thrmbcytpenia. In patients with preexisting hematpietic impairment, Rasuv shuld be used with cautin, if at all. In cntrlled clinical trials cnducted with anther frmulatin f methtrexate in rheumatid arthritis (n=128), leukpenia (WBC <3000/mm 3 ) was seen in 2 patients, thrmbcytpenia (platelets <100,000/mm 3 ) in 6 patients, and pancytpenia in 2 patients.

19 Rasuv shuld be stpped immediately if there is a significant drp in bld cunts. Patients with prfund granulcytpenia and fever shuld be evaluated immediately and usually require parenteral brad-spectrum antibitic therapy. Unexpectedly severe (smetimes fatal) bne marrw suppressin and aplastic anemia have been reprted with cncmitant administratin f methtrexate (usually in high dsage) alng with sme nnsteridal antiinflammatry drugs (NSAIDs) [see Drug Interactins (7.1)]. Hepatic: Rasuv has the ptential fr acute (elevated transaminases) and chrnic (fibrsis and cirrhsis) hepattxicity. Chrnic txicity is ptentially fatal; it generally has ccurred after prlnged use (generally tw years r mre) and after a ttal dse f at least 1.5 grams. In studies in psriatic patients, hepattxicity appeared t be a functin f ttal cumulative dse and appeared t be enhanced by alchlism, besity, diabetes and advanced age. An accurate incidence rate has nt been determined; the rate f prgressin and reversibility f lesins is nt knwn. Special cautin is indicated in the presence f preexisting liver damage r impaired hepatic functin. In psriasis, liver functin tests, including serum albumin, shuld be perfrmed peridically prir t dsing but are ften nrmal in the face f develping fibrsis r cirrhsis. These lesins may be detectable nly by bipsy. The usual recmmendatin is t btain a liver bipsy at 1) pretherapy r shrtly after initiatin f therapy (2 t 4 mnths), 2) a ttal cumulative dse f 1.5 grams, and 3) after each additinal 1.0 t 1.5 grams. Mderate fibrsis r any cirrhsis nrmally leads t discntinuatin f the drug; mild fibrsis nrmally suggests a repeat bipsy in 6 mnths. Milder histlgic findings such as fatty change and lw grade prtal inflammatin are relatively cmmn pretherapy. Althugh these mild changes are usually nt a reasn t avid r discntinue Rasuv therapy, the drug shuld be used with cautin. In rheumatid arthritis, age at first use f methtrexate and duratin f therapy have been reprted as risk factrs fr hepattxicity; ther risk factrs, similar t thse bserved in psriasis, may be present in rheumatid arthritis but have nt been cnfirmed t date. Persistent abnrmalities in liver functin tests may precede appearance f fibrsis r cirrhsis in this ppulatin. There is a cmbined reprted experience in 217 rheumatid arthritis patients with liver bipsies bth befre and during treatment (after a cumulative dse f at least 1.5 g) and in 714 patients with a bipsy nly during treatment. There are 64 (7%) cases f fibrsis and 1 (0.1%) case f cirrhsis. Of the 64 cases f fibrsis, 60 were deemed mild. The reticulin stain is mre sensitive fr early fibrsis and its use may increase these figures. It is unknwn whether even lnger use will increase these risks. Liver functin tests shuld be perfrmed at baseline and at 4 t 8 week intervals in patients receiving Rasuv fr rheumatid arthritis. Pretreatment liver bipsy shuld be perfrmed fr patients with a histry f excessive alchl cnsumptin, persistently abnrmal baseline liver functin test values r chrnic hepatitis B r C infectin. During therapy, liver bipsy shuld be perfrmed if there are persistent liver functin test abnrmalities r there is a decrease in serum albumin belw the nrmal range (in the setting f well cntrlled rheumatid arthritis). If the results f a liver bipsy shw mild changes (Renigk, grades I, II, IIIa), Rasuv may be cntinued and the patient mnitred as per recmmendatins listed abve. Rasuv shuld be discntinued in any patient wh displays persistently abnrmal liver functin tests and refuses liver bipsy r in any patient whse liver bipsy shws mderate t severe changes (Renigk grade IIIb r IV). Infectin r Immunlgic States: Rasuv shuld be used with extreme cautin in the presence f active infectin, and is cntraindicated in patients with vert r labratry evidence f immundeficiency syndrmes. Immunizatin may be ineffective when given during Rasuv therapy. Immunizatin with live virus vaccines is generally nt recmmended. There have been reprts f disseminated vaccinia infectins after smallpx immunizatins in patients receiving methtrexate therapy. Hypgammaglbulinemia has been reprted rarely. Ptentially fatal pprtunistic infectins, especially Pneumcystis jirveci pneumnia, may ccur with Rasuv therapy. When a patient presents with pulmnary symptms, the pssibility f Pneumcystis jirveci pneumnia shuld be cnsidered.

20 Neurlgic: There have been reprts f leukencephalpathy fllwing intravenus administratin f methtrexate t patients wh have had cranispinal irradiatin. Serius neurtxicity, frequently manifested as generalized r fcal seizures, has been reprted with unexpectedly increased frequency amng pediatric patients with acute lymphblastic leukemia wh were treated with intermediate-dse intravenus methtrexate (1 gm/m 2 ). Symptmatic patients were cmmnly nted t have leukencephalpathy and/r micrangipathic calcificatins n diagnstic imaging studies. Chrnic leukencephalpathy has als been reprted in patients wh received repeated dses f high-dse methtrexate with leucvrin rescue even withut cranial irradiatin. Discntinuatin f methtrexate des nt always result in cmplete recvery. A transient acute neurlgic syndrme has been bserved in patients treated with high dse regimens. Manifestatins f this strke-like encephalpathy may include cnfusin, hemiparesis, transient blindness, seizures and cma. The exact cause is unknwn. After the intrathecal use f methtrexate, the central nervus system txicity which may ccur can be classified as fllws: acute chemical arachniditis manifested by such symptms as headache, back pain, nuchal rigidity, and fever; sub- acute myelpathy characterized by paraparesis/paraplegia assciated with invlvement with ne r mre spinal nerve rts; chrnic leukencephalpathy manifested by cnfusin, irritability, smnlence, ataxia, dementia, seizures and cma. This cnditin can be prgressive and even fatal. Pulmnary: Methtrexate-induced lung disease, including acute r chrnic interstitial pneumnitis, is a ptentially dangerus lesin, which may ccur acutely at any time during therapy and has been reprted at lw dses. It is nt always fully reversible and fatalities have been reprted. Pulmnary symptms (especially a dry nnprductive cugh) r a nn-specific pneumnitis ccurring during Rasuv therapy may be indicative f a ptentially dangerus lesin and require interruptin f treatment and careful investigatin. Althugh clinically variable, the typical patient with methtrexate induced lung disease presents with fever, cugh, dyspnea, hypxemia, and an infiltrate n chest X-ray; infectin (including pneumnia) needs t be excluded. This lesin can ccur at all dsages. Renal: Rasuv may cause renal damage that may lead t acute renal failure. High dses f methtrexate used in the treatment f stesarcma may cause renal damage leading t acute renal failure. Nephrtxicity is due primarily t the precipitatin f methtrexate and 7- hydrxymethtrexate in the renal tubules. Clse attentin t renal functin including adequate hydratin, urine alkalinizatin and measurement f serum methtrexate and creatinine levels are essential fr safe administratin. Skin: Severe, ccasinally fatal, dermatlgic reactins, including txic epidermal necrlysis, Stevens- Jhnsn syndrme, exfliative dermatitis, skin necrsis, and erythema multifrme, have been reprted in children and adults, within days f ral, intramuscular, intravenus, r intrathecal methtrexate administratin. Reactins were nted after single r multiple lw, intermediate, r high dses f methtrexate in patients with neplastic and nn-neplastic diseases. Lesins f psriasis may be aggravated by cncmitant expsure t ultravilet radiatin. Radiatin dermatitis and sunburn may be recalled by the use f methtrexate. Other precautins: Rasuv shuld be used with extreme cautin in the presence f debility. Methtrexate exits slwly frm third space cmpartments (e.g., pleural effusins r ascites). This results in a prlnged terminal plasma half-life and unexpected txicity. In patients with significant third space accumulatins, it is advisable t evacuate the fluid befre treatment and t mnitr plasma methtrexate levels. 5.2 Embry-Fetal Txicity Methtrexate has been reprted t cause fetal death and/r cngenital anmalies. Therefre, Rasuv is nt recmmended fr females f childbearing ptential unless there is clear medical evidence that the benefits can be expected t utweigh the cnsidered risks. Rasuv is cntraindicated in pregnant wmen with psriasis r rheumatid arthritis.

21 Females f childbearing ptential shuld nt be started n Rasuv until pregnancy is excluded and shuld be fully cunseled n the serius risk t the fetus shuld they becme pregnant while underging treatment. Apprpriate steps shuld be taken t avid cnceptin during Rasuv therapy. Pregnancy shuld be avided if either partner is receiving Rasuv; during and fr a minimum f three mnths after therapy fr male patients, and during and fr at least ne vulatry cycle after therapy fr female patients. 5.3 Effects n Reprductin Methtrexate has been reprted t cause impairment f fertility, ligspermia and menstrual dysfunctin in humans, during and fr a shrt perid after cessatin f therapy. The risk f effects f reprductin shuld be discussed with bth male and female patients taking Rasuv. 5.4 Labratry Tests Patients underging Rasuv therapy shuld be clsely mnitred s that txic effects are detected prmptly. Baseline assessment shuld include a cmplete bld cunt with differential and platelet cunts, hepatic enzymes, renal functin tests and a chest X-ray. During therapy, mnitring f these parameters is recmmended: hematlgy at least mnthly, renal functin and liver functin every 1 t 2 mnths [see Warnings and Precautins (5.1)]. During initial r changing dses, r during perids f increased risk f elevated methtrexate bld levels (e.g., dehydratin), mre frequent mnitring may als be indicated. Liver Functin Tests Transient liver functin test abnrmalities are bserved frequently after methtrexate administratin and are usually nt cause fr mdificatin f methtrexate therapy. Persistent liver functin test abnrmalities, and/r depressin f serum albumin may be indicatrs f serius liver txicity and require evaluatin [see Warnings and Precautins (5.1)]. A relatinship between abnrmal liver functin tests and fibrsis r cirrhsis f the liver has nt been established fr patients with psriasis. Persistent abnrmalities in liver functin tests may precede appearance f fibrsis r cirrhsis in the rheumatid arthritis ppulatin. Pulmnary Functin Tests Pulmnary functin tests may be useful if methtrexate-induced lung disease is suspected, especially if baseline measurements are available [see Warnings and Precautins (5.1)]. 5.5 Risks frm Imprper Dsing Bth the physician and pharmacist shuld emphasize t the patient that Rasuv is administered nce weekly and that mistaken daily use has led t fatal txicity [see Dsage and Administratin (2)]. 5.6 Patients with Impaired Renal Functin, Ascites, r Pleural Effusins Methtrexate eliminatin is reduced in patients with impaired renal functin, ascites, r pleural effusins. Such patients require especially careful mnitring fr txicity and require dse reductin r, in sme cases, discntinuatin f Rasuv administratin. 5.7 Dizziness and Fatigue Adverse reactins, such as dizziness and fatigue, may affect the ability t drive r perate machinery. 5.8 Malignant Lymphmas Nn-Hdgkin s lymphma and ther tumrs have been reprted in patients receiving lw-dse ral methtrexate. Hwever, there have been instances f malignant lymphma arising during treatment with lwdse ral methtrexate, which have regressed cmpletely fllwing withdrawal f methtrexate, withut requiring active anti- lymphma treatment. Discntinue Rasuv first and, if the lymphma des nt regress, apprpriate treatment shuld be instituted. 5.9 Tumr Lysis Syndrme Like ther cyttxic drugs, methtrexate may induce tumr lysis syndrme in patients with rapidly grwing tumrs Cncmitant Radiatin Therapy Methtrexate given cncmitantly with raditherapy may increase the risk f sft tissue necrsis and stenecrsis.

22 6 ADVERSE REACTIONS The fllwing adverse reactins are discussed in mre detail in ther sectins f the labeling. Organ System Txicity [see Warnings and Precautins (5.1)] Embry-Fetal Txicity [see Warnings and Precautins (5.2)] Effects n Reprductin [see Warnings and Precautins (5.3)] Malignant Lymphmas [see Warnings and Precautins (5.8)] The mst frequently reprted adverse reactins include ulcerative stmatitis, leukpenia, nausea, and abdminal distress. Other frequently reprted adverse reactins are malaise, undue fatigue, chills and fever, dizziness and decreased resistance t infectin. 6.1 Clinical Trials Experience This sectin prvides a summary f adverse reactins reprted in subjects in clinical studies cnducted with Rasuv as well as with methtrexate injectin and ral methtrexate. Because clinical trials are cnducted under widely varying cnditins, adverse reactin rates bserved in the clinical trials f a drug cannt be directly cmpared t rates in the clinical trials f anther drug, and may nt reflect the rates bserved in practice. Rheumatid Arthritis The apprximate incidences f methtrexate-attributed (i.e. placeb rate subtracted) adverse reactins in 12 t 18 week duble-blind studies f patients (n=128) with rheumatid arthritis treated with lw-dse ral (7.5 t 15 mg/week) pulse methtrexate, are listed belw. Virtually all f these patients were n cncmitant nnsteridal anti- inflammatry drugs and sme were als taking lw dsages f crticsterids. Hepatic histlgy was nt examined in these shrt-term studies. Incidence greater than 10%: Elevated liver functin tests 15%, nausea/vmiting 10%. Incidence 3% t 10%: Stmatitis, thrmbcytpenia (platelet cunt less than 100,000/mm 3 ). Incidence 1% t 3%: Rash/pruritis/dermatitis, diarrhea, alpecia, leukpenia (WBC less than 3000/mm 3 ), pancytpenia, dizziness. Tw ther cntrlled trials f patients (n=680) with Rheumatid Arthritis n 7.5 mg t 15 mg/wk ral dses shwed an incidence f interstitial pneumnitis f 1%. Other less cmmn reactins included decreased hematcrit, headache, upper respiratry infectin, anrexia, arthralgias, chest pain, cughing, dysuria, eye discmfrt, epistaxis, fever, infectin, sweating, tinnitus, and vaginal discharge. Plyarticular Juvenile Idipathic Arthritis The apprximate incidences f adverse reactins reprted in pediatric patients with pjia treated with ral, weekly dses f methtrexate (5 t 20 mg/m 2 /wk r 0.1 t 0.65 mg/kg/wk) were as fllws (virtually all patients were receiving cncmitant nnsteridal anti-inflammatry drugs, and sme als were taking lw dses f crticsterids): elevated liver functin tests, 14%; gastrintestinal reactins (e.g., nausea, vmiting, diarrhea), 11%; stmatitis, 2%; leukpenia, 2%; headache, 1.2%; alpecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Althugh there is experience with dsing up t 30 mg/m 2 /wk in pjia, the published data fr dses abve 20 mg/m 2 /wk are t limited t prvide reliable estimates f adverse reactin rates. Psriasis There are tw literature reprts (Renigk, 1969, and Nyfrs, 1978) describing large series (n=204, 248) f psriasis patients treated with methtrexate. Dsages ranged up t 25 mg per week and treatment was administered fr up t fur years. With the exceptin f alpecia, phtsensitivity, and burning f skin lesins (each 3% t 10%), the adverse reactin rates in these reprts were very similar t thse in the rheumatid arthritis studies. Rarely, painful plaque ersins may appear (Pearce, HP and Wilsn, BB: Am Acad Dermatl 35: , 1996).

23 6.2 Other Adverse Reactins Other adverse reactins that have been reprted with methtrexate in nclgy, RA, pjia, and psriasis patients are listed belw by rgan system. Alimentary System: gingivitis, pharyngitis, stmatitis, anrexia, nausea, vmiting, diarrhea, hematemesis, melena, gastrintestinal ulceratin and bleeding, enteritis, pancreatitis. Bld and Lymphatic System Disrders: suppressed hematpiesis, anemia, aplastic anemia, pancytpenia, leukpenia, neutrpenia, thrmbcytpenia, agranulcytsis, esinphilia, lymphadenpathy and lymphprliferative disrders (including reversible). Hypgammaglbulinemia has been reprted rarely. Cardivascular: pericarditis, pericardial effusin, hyptensin, and thrmbemblic events (including arterial thrmbsis, cerebral thrmbsis, deep vein thrmbsis, retinal vein thrmbsis, thrmbphlebitis, and pulmnary emblus). Central Nervus System: headaches, drwsiness, blurred visin, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and cnvulsins have als ccurred fllwing administratin f methtrexate. Fllwing lw dses, there have been ccasinal reprts f transient subtle cgnitive dysfunctin, md alteratin r unusual cranial sensatins, leukencephalpathy, r encephalpathy. Hepatbiliary Disrders: hepattxicity, acute hepatitis, chrnic fibrsis and cirrhsis, hepatic failure, decrease in serum albumin, liver enzyme elevatins. Infectin: There have been case reprts f smetimes fatal pprtunistic infectins in patients receiving methtrexate therapy fr neplastic and nn-neplastic diseases. Pneumcystis jirveci pneumnia was the mst cmmn pprtunistic infectin. There have als been reprts f infectins, pneumnia, Cytmegalvirus infectin, including cytmegalviral pneumnia, sepsis, fatal sepsis, ncardisis, histplasmsis, cryptcccsis, Herpes zster, Herpes simplex hepatitis, and disseminated Herpes simplex. Musculskeletal System: stress fracture. Ophthalmic: cnjunctivitis, serius visual changes f unknwn etilgy. Pulmnary System: respiratry fibrsis, respiratry failure, alvelitis, interstitial pneumnitis deaths have been reprted, and chrnic interstitial bstructive pulmnary disease has ccasinally ccurred. Skin: erythematus rashes, pruritus, urticaria, phtsensitivity, pigmentary changes, alpecia, ecchymsis, telangiectasia, acne, furunculsis, erythema multifrme, txic epidermal necrlysis, Stevens-Jhnsn syndrme, skin necrsis, skin ulceratin and exfliative dermatitis. Urgenital System: severe nephrpathy r renal failure, aztemia, cystitis, hematuria, prteinuria; defective genesis r spermatgenesis, transient ligspermia, menstrual dysfunctin, vaginal discharge, and gynecmastia; infertility, abrtin, fetal death, fetal defects. Other rarer reactins related t r attributed t the use f methtrexate such as ndulsis, vasculitis, arthralgia/myalgia, lss f libid/ imptence, diabetes, steprsis, sudden death, lymphma, including reversible lymphmas, tumr lysis syndrme, sft tissue necrsis and stenecrsis. Anaphylactid reactins have been reprted. 7 DRUG INTERACTIONS 7.1 Aspirin, Nnsteridal Anti-Inflammatry Drugs, and Sterids Nnsteridal anti-inflammatry drugs (NSAIDs) shuld nt be administered prir t r cncmitantly with the high dses f methtrexate, such as used in the treatment f stesarcma. Cncmitant administratin f sme NSAIDs with high dse methtrexate therapy has been reprted t elevate and prlng serum methtrexate levels, resulting in deaths frm severe hematlgic and gastrintestinal txicity [see Warnings and Precautins (5.1)]. Cautin shuld be used when NSAIDs and salicylates are administered cncmitantly with lwer dses f methtrexate, including Rasuv. These drugs have been reprted t reduce the tubular secretin f methtrexate in an animal mdel and may enhance its txicity.

24 Despite the ptential interactins, studies f methtrexate in patients with rheumatid arthritis have usually included cncurrent use f cnstant dsage regimens f NSAIDs, withut apparent prblems. It shuld be appreciated, hwever, that the dses used in rheumatid arthritis (7.5 t 15 mg/week) are smewhat lwer than thse used in psriasis and that larger dses culd lead t unexpected txicity. Aspirin, NSAIDs, and/r lw dse sterids may be cntinued, althugh the pssibility f increased txicity with cncmitant use f NSAIDs including salicylates has nt been fully explred. Sterids may be reduced gradually in patients wh respnd t methtrexate. 7.2 Prtn Pump Inhibitrs (PPIs) and H 2 Blckers Use cautin if high-dse methtrexate is administered t patients receiving prtn pump inhibitr (PPI) therapy. Case reprts and published ppulatin pharmackinetic studies suggest that cncmitant use f sme PPIs, such as meprazle, esmeprazle, and pantprazle, with methtrexate (primarily at high dse), may elevate and prlng serum levels f methtrexate and/r its metablite hydrxymethtrexate, pssibly leading t methtrexate txicities. In tw f these cases, delayed methtrexate eliminatin was bserved when high-dse methtrexate was c-administered with PPIs, but was nt bserved when methtrexate was c-administered with ranitidine. Hwever, n frmal drug interactin studies f methtrexate with ranitidine have been cnducted. 7.3 Oral Antibitics Oral antibitics such as tetracycline, chlramphenicl, and nnabsrbable brad spectrum antibitics, may decrease intestinal absrptin f methtrexate r interfere with the enterhepatic circulatin by inhibiting bwel flra and suppressing metablism f the drug by bacteria. Penicillins may reduce the renal clearance f methtrexate; increased serum cncentratins f methtrexate with cncmitant hematlgic and gastrintestinal txicity have been bserved with high and lw dse methtrexate. Use f Rasuv with penicillins shuld be carefully mnitred. Trimethprim/sulfamethxazle has been reprted rarely t increase bne marrw suppressin in patients receiving methtrexate, prbably by decreased tubular secretin and/r an additive antiflate effect. 7.4 Hepattxins The ptential fr increased hepattxicity when methtrexate is administered with ther hepattxic agents has nt been evaluated. Hwever, hepattxicity has been reprted in such cases. Therefre, patients receiving cncmitant therapy with Rasuv and ther ptential hepattxins (e.g., azathiprine, retinids, and sulfasalazine) shuld be clsely mnitred fr pssible increased risk f hepattxicity. 7.5 Thephylline Methtrexate may decrease the clearance f thephylline; thephylline levels shuld be mnitred when used cncurrently with Rasuv. 7.6 Flic Acid and Antiflates Vitamin preparatins cntaining flic acid r its derivatives may decrease respnses t systemically administered methtrexate. Preliminary animal and human studies have shwn that small quantities f intravenusly administered leucvrin enter the CSF primarily as 5-methyltetrahydrflate and, in humans, remain 1 t 3 rders f magnitude lwer than the usual methtrexate cncentratins fllwing intrathecal administratin. Hwever, high dses f leucvrin may reduce the efficacy f intrathecally administered methtrexate. Flate deficiency states may increase methtrexate txicity. Trimethprim/sulfamethxazle has been reprted rarely t increase bne marrw suppressin in patients receiving methtrexate, prbably by decreased tubular secretin and/r an additive antiflate effect. 7.7 Mercaptpurine Methtrexate increases the plasma levels f mercaptpurine. The cmbinatin f Rasuv and mercaptpurine may therefre require dse adjustment. 7.8 Other Drugs Methtrexate is partially bund t serum albumin, and txicity may be increased because f displacement by certain drugs, such as salicylates, phenylbutazne, phenytin, and sulfnamides. Renal tubular transprt is als diminished by prbenecid; use f Rasuv with this drug shuld be carefully mnitred.

25 Cmbined use f methtrexate with gld, penicillamine, hydrxychlrquine, sulfasalazine, r cyttxic agents, has nt been studied and may increase the incidence f adverse effects. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Categry X [see Cntraindicatins (4)] Methtrexate has been reprted t cause embrytxicity, fetal death, cngenital anmalies, and abrtin in humans and is cntraindicated in pregnant wmen. 8.3 Nursing Mthers Because f the ptential fr serius adverse reactins frm methtrexate in breast fed infants, methtrexate is cntraindicated in nursing mthers. Therefre, a decisin shuld be made whether t discntinue nursing r discntinue the drug, taking int accunt the imprtance f the drug t the mther. Methtrexate has been detected in human breast milk. The highest breast milk t plasma cncentratin rati reached was 0.08: Pediatric Use The safety and effectiveness f methtrexate, including Rasuv, have nt been established in pediatric patients with psriasis. The safety and effectiveness f Rasuv have nt been established in pediatric patients with neplastic diseases. The safety and effectiveness f methtrexate have been established in pediatric patients with plyarticular juvenile idipathic arthritis [see Clinical Studies (14.2)]. Published clinical studies evaluating the use f methtrexate in children and adlescents (i.e., patients 2 t 16 years f age) with pjia demnstrated safety cmparable t that bserved in adults with rheumatid arthritis [see Adverse Reactins (6.1)]. Rasuv des nt cntain a preservative. Hwever, methtrexate injectable frmulatins cntaining the preservative benzyl alchl are nt recmmended fr use in nenates. There have been reprts f fatal gasping syndrme in nenates (children less than ne mnth f age) fllwing the administratins f intravenus slutins cntaining the preservative benzyl alchl. Symptms include a striking nset f gasping respiratin, hyptensin, bradycardia, and cardivascular cllapse. Serius neurtxicity, frequently manifested as generalized r fcal seizures, has been reprted with unexpectedly increased frequency amng pediatric patients with acute lymphblastic leukemia wh were treated with intermediate-dse intravenus methtrexate (1 gm/m 2 ) [see Warnings and Precautins (5.1)]. 8.5 Geriatric Use Clinical studies f methtrexate did nt include sufficient numbers f subjects age 65 and ver t determine whether they respnd differently frm yunger subjects. In general, dse selectin fr an elderly patient shuld be cautius reflecting the greater frequency f decreased hepatic and renal functin, decreased flate stres, cncmitant disease r ther drug therapy (i.e., that interfere with renal functin, methtrexate r flate metablism) in this ppulatin [see Warnings and Precautins (5.1) Drug Interactins (7.7) and Use in Specific Ppulatins (8.7)]. Since decline in renal functin may be assciated with increases in adverse reactins and serum creatinine measurements may ver estimate renal functin in the elderly, mre accurate methds (i.e., creatinine clearance) shuld be cnsidered. Serum methtrexate levels may als be helpful. Elderly patients shuld be clsely mnitred fr early signs f hepatic, bne marrw and renal txicity. In chrnic use situatins, certain txicities may be reduced by flate supplementatin. Pst-marketing experience suggests that the ccurrence f bne marrw suppressin, thrmbcytpenia, and pneumnitis may increase with age [see Warnings and Precautins (5.1)].

26 8.6 Females and Males f Reprductive Ptential Rasuv is nt recmmended fr females f childbearing ptential unless there is clear medical evidence that the benefits can be expected t utweigh the cnsidered risks. Females f childbearing ptential shuld nt be started n methtrexate until pregnancy is excluded and shuld be fully cunseled n the serius risk t the fetus shuld they becme pregnant while underging treatment [see Use in Specific Ppulatins (8.1)]. Apprpriate steps shuld be taken t avid cnceptin during Rasuv therapy. Pregnancy shuld be avided if either partner is receiving methtrexate; during and fr a minimum f three mnths after therapy fr male patients, and during and fr at least ne vulatry cycle after therapy fr female patients. Methtrexate has been reprted t cause impairment f fertility, ligspermia and menstrual dysfunctin in humans, during and fr a shrt perid after cessatin f therapy. 8.7 Renal Impairment Methtrexate eliminatin is reduced in patients with impaired renal functin. Such patients require especially careful mnitring fr txicity and require dse reductin r, in sme cases, discntinuatin f Rasuv administratin. 8.8 Hepatic Impairment The effect f hepatic impairment n methtrexate pharmackinetics has nt been studied. Rasuv is cntraindicated in patients with alchlic liver disease r ther chrnic liver disease. Patients with besity, diabetes, hepatic fibrsis r steathepatitis are at increased risk fr hepatic injury and fibrsis secndary t methtrexate, and shuld be mnitred clsely [see Warnings and Precautins (5.1)]. 10 OVERDOSAGE Leucvrin is indicated t diminish the txicity and cunteract the effect f inadvertently administered verdsages f methtrexate. Leucvrin administratin shuld begin as prmptly as pssible. As the time interval between methtrexate administratin and leucvrin initiatin increases, the effectiveness f leucvrin in cunteracting txicity decreases. Mnitring f the serum methtrexate cncentratin is essential in determining the ptimal dse and duratin f treatment with leucvrin. In cases f massive verdsage, hydratin and urinary alkalinizatin may be necessary t prevent the precipitatin f methtrexate and/r its metablites in the renal tubules. Generally speaking, neither hemdialysis nr peritneal dialysis has been shwn t imprve methtrexate eliminatin. Hwever, effective clearance f methtrexate has been reprted with acute, intermittent hemdialysis using a high-flux dialyzer (Wall, SM et al: Am J Kidney Dis 28 (6): , 1996). Accidental intrathecal verdsage may require intensive systemic supprt, high-dse systemic leucvrin, alkaline diuresis and rapid CSF drainage and ventricullumbar perfusin. In pstmarketing experience, verdse with methtrexate has generally ccurred with ral and intrathecal administratin, althugh intravenus and intramuscular verdse have als been reprted. Reprts f ral verdse ften indicate accidental daily administratin instead f weekly (single r divided dses). Symptms cmmnly reprted fllwing ral verdse include thse symptms and signs reprted at pharmaclgic dses, particularly hematlgic and gastrintestinal reactin. Fr example, leukpenia, thrmbcytpenia, anemia, pancytpenia, bne marrw suppressin, mucsitis, stmatitis, ral ulceratin, nausea, vmiting, gastrintestinal ulceratin, gastrintestinal bleeding. In sme cases, n symptms were reprted. There have been reprts f death fllwing verdse. In these cases, events such as sepsis r septic shck, renal failure, and aplastic anemia were als reprted. Symptms f intrathecal verdse are generally central nervus system (CNS) symptms, including headache, nausea and vmiting, seizure r cnvulsin, and acute txic encephalpathy. In sme cases, n symptms were reprted. There have been reprts f death fllwing intrathecal verdse. In these cases, cerebellar herniatin assciated with increased intracranial pressure, and acute txic encephalpathy have als been reprted. There are published case reprts f intravenus and intrathecal carbxypeptidase G2 treatment t hasten clearance f methtrexate in cases f verdse.

27 11 DESCRIPTION Rasuv cntains methtrexate, a flate analg metablic inhibitr. Chemically, methtrexate is [N-[4-[[(2,4-diamin-6-pteridinyl)methyl]methylamin]benzyl]-Lglutamic acid. The structural frmula is: C 20 H 22 N 8 O 5 M.W.= Rasuv cntains methtrexate in a sterile, preservative-free, nn-pyrgenic slutin fr a single subcutaneus injectin. Rasuv is an istnic, clear, yellw t brwn slutin. Rasuv cntains the fllwing inactive ingredients: sdium chlride 0.4% w/v; water fr injectins, sdium hydrxide and, if necessary, hydrchlric acid are added t adjust the ph t apprximately CLINICAL PHARMACOLOGY 12.1 Mechanism f Actin Methtrexate inhibits dihydrflic acid reductase. Dihydrflates must be reduced t tetrahydrflates by this enzyme befre they can be utilized as carriers f ne-carbn grups in the synthesis f purine nucletides and thymidylate. Therefre, methtrexate interferes with DNA synthesis, repair, and cellular replicatin. Actively prliferating tissues such as malignant cells, bne marrw, fetal cells, buccal and intestinal mucsa, and cells f the urinary bladder are in general mre sensitive t this effect f methtrexate. The mechanism f actin in rheumatid arthritis is unknwn; it may affect immune functin Pharmacdynamics Tw reprts describe in vitr methtrexate inhibitin f DNA precursr uptake by stimulated mnnuclear cells, and anther describes in animal plyarthritis partial crrectin by methtrexate f spleen cell hyprespnsiveness and suppressed IL 2 prductin. Other labratries, hwever, have been unable t demnstrate similar effects. Clarificatin f methtrexate s effect n immune activity and its relatin t rheumatid immunpathgenesis await further studies. In psriasis, the rate f prductin f epithelial cells in the skin is greatly increased ver nrmal skin. This differential in prliferatin rates is the basis fr the use f methtrexate t cntrl the psriatic prcess. Methtrexate in high dses, fllwed by leucvrin rescue, is used as a part f the treatment f patients with nn- metastatic stesarcma. The riginal ratinale fr high dse methtrexate therapy was based n the cncept f selective rescue f nrmal tissues by leucvrin. Mre recent evidence suggests that high dse methtrexate may als vercme methtrexate resistance caused by impaired active transprt, decreased affinity f dihydrflic acid reductase fr methtrexate, increased levels f dihydrflic acid reductase resulting frm gene amplificatin, r decreased plyglutamatin f methtrexate. The actual mechanism f actin is unknwn Pharmackinetics Absrptin In adults, ral absrptin appears t be dse dependent. Peak serum levels are reached within ne t tw hurs. At dses f 30 mg/m 2 r less, methtrexate is generally well absrbed with a mean biavailability f abut 60%. The absrptin f dses greater than 80 mg/m 2 is significantly less, pssibly due t a saturatin effect.

28 In a relative biavailability study in healthy subjects, the systemic expsure f methtrexate (AUC) frm Rasuv at dses f 7.5 mg, 15 mg, 22.5 mg, and 30 mg, was higher than that f ral methtrexate administered at the same dses by 35%, 49%, 51%, and 68%, respectively. In a relative biavailability study in psriasis patients, the systemic expsure (AUC) f methtrexate frm Rasuv at a dse f 30 mg, was similar t that f methtrexate administered at the same dse by the intramuscular rute. In leukemic pediatric patients, ral absrptin f methtrexate als appears t be dse dependent and has been reprted t vary widely (23% t 95%). A twenty fld difference between highest and lwest peak levels (C max : 0.11 t 2.3 micrmlar after a 20 mg/m 2 dse) has been reprted. Significant interindividual variability has als been nted in time t peak cncentratin (T max : 0.67 t 4 hrs after a 15 mg/m 2 dse) and fractin f dse absrbed. The absrptin f dses greater than 40 mg/m 2 has been reprted t be significantly less than that f lwer dses. Fd has been shwn t delay absrptin and reduce peak cncentratin. Methtrexate is generally cmpletely absrbed frm parenteral rutes f injectin. After intramuscular injectin, peak serum cncentratins ccur in 30 t 60 minutes. As in leukemic pediatric patients, a wide interindividual variability in the plasma cncentratins f methtrexate has been reprted in pediatric patients with JIA. Fllwing ral administratin f methtrexate in dses f 6.4 t 11.2 mg/m 2 /week in pediatric patients with JIA, mean serum cncentratins were 0.59 micrmlar (range, 0.03 t 1.40) at 1 hur, 0.44 micrmlar (range, 0.01 t 1.00) at 2 hurs, and 0.29 micrmlar (range, 0.06 t 0.58) at 3 hurs. Distributin After intravenus administratin, the initial vlume f distributin is apprximately 0.18 L/kg (18% f bdy weight) and steady-state vlume f distributin is apprximately 0.4 t 0.8 L/kg (40 t 80% f bdy weight). Methtrexate cmpetes with reduced flates fr active transprt acrss cell membranes by means f a single carrier-mediated active transprt prcess. At serum cncentratins greater than 100 micrmlar, passive diffusin becmes a majr pathway by which effective intracellular cncentratins can be achieved. Methtrexate in serum is apprximately 50% prtein bund. Labratry studies demnstrate that it may be displaced frm plasma albumin by varius cmpunds including sulfnamides, salicylates, tetracyclines, chlramphenicl, and phenytin. Methtrexate des nt penetrate the bld-cerebrspinal fluid barrier in therapeutic amunts when given rally r parenterally. High CSF cncentratins f the drug may be attained by intrathecal administratin f ther parenteral frms f methtrexate. In dgs, synvial fluid cncentratins after ral dsing were higher in inflamed than uninflamed jints. Althugh salicylates did nt interfere with this penetratin, prir prednisne treatment reduced penetratin int inflamed jints t the level f nrmal jints. Metablism After absrptin, methtrexate underges hepatic and intracellular metablism t plyglutamated frms which can be cnverted back t methtrexate by hydrlase enzymes. These plyglutamates act as inhibitrs f dihydrflate reductase and thymidylate synthetase. Small amunts f methtrexate plyglutamates may remain in tissues fr extended perids. The retentin and prlnged drug actin f these active metablites vary amng different cells, tissues and tumrs. A small amunt f metablism t 7-hydrxymethtrexate may ccur at dses cmmnly prescribed. Accumulatin f this metablite may becme significant at the high dses used in stegenic sarcma. The aqueus slubility f 7-hydrxymethtrexate is 3 t 5 fld lwer than the parent cmpund. Methtrexate is partially metablized by intestinal flra after ral administratin. Half-Life The terminal half-life reprted fr methtrexate is apprximately three t ten hurs fr patients receiving treatment fr psriasis, r rheumatid arthritis r lw dse antineplastic therapy (less than 30 mg/m 2 ). Fr patients receiving high dses f methtrexate, the terminal half-life is eight t 15 hurs.

29 In pediatric patients receiving methtrexate fr acute lymphcytic leukemia (6.3 t 30 mg/m 2 ), r fr JIA (3.75 t 26.2 mg/m 2 ), the terminal half-life has been reprted t range frm 0.7 t 5.8 hurs r 0.9 t 2.3 hurs, respectively. Excretin Renal excretin is the primary rute f eliminatin and is dependent upn dsage and rute f administratin. With IV administratin, 80% t 90% f the administered dse is excreted unchanged in the urine within 24 hurs. There is limited biliary excretin amunting t 10% r less f the administered dse. Enterhepatic recirculatin f methtrexate has been prpsed. Renal excretin ccurs by glmerular filtratin and active tubular secretin. Nnlinear eliminatin due t saturatin f renal tubular reabsrptin has been bserved in psriatic patients at dses between 7.5 and 30 mg. Impaired renal functin, as well as cncurrent use f drugs such as weak rganic acids that als underg tubular secretin, can markedly increase methtrexate serum levels. Excellent crrelatin has been reprted between methtrexate clearance and endgenus creatinine clearance. Methtrexate clearance rates vary widely and are generally decreased at higher dses. Delayed drug clearance has been identified as ne f the majr factrs respnsible fr methtrexate txicity. It has been pstulated that the txicity f methtrexate fr nrmal tissues is mre dependent upn the duratin f expsure t the drug rather than the peak level achieved. When a patient has delayed drug eliminatin due t cmprmised renal functin, a third space effusin, r ther causes, methtrexate serum cncentratins may remain elevated fr prlnged perids. When ther frms f parenteral methtrexate are administered during cancer chemtherapy, the ptential fr txicity frm high dse regimens r delayed excretin is reduced by the administratin f leucvrin calcium during the final phase f methtrexate plasma eliminatin. Pharmackinetic mnitring f methtrexate serum cncentratins may help identify thse patients at high risk fr methtrexate txicity and aid in prper adjustments f leucvrin dsing. 13 NONCLINICAL TOXICOLOGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility Methtrexate has been evaluated in a number f animal studies fr carcingenic ptential with incnclusive results. Althugh there is evidence that methtrexate causes chrmsmal damage t animal smatic cells and human bne marrw cells, the clinical significance remains uncertain. Data are available regarding the risks fr pregnancy and fr fertility in humans [see Use in Specific Ppulatins (8.1 and 8.6)]. 14 CLINICAL STUDIES 14.1 Rheumatid Arthritis Clinical trials in patients with rheumatid arthritis were perfrmed using ther frmulatins f methtrexate. In patients with rheumatid arthritis, effects f methtrexate n articular swelling and tenderness can be seen as early as 3 t 6 weeks. Mst studies f methtrexate in patients with rheumatid arthritis are relatively shrt term (3 t 6 mnths). Limited data frm lng-term studies indicate that an initial clinical imprvement is maintained fr at least tw years with cntinued therapy Plyarticular Juvenile Idipathic Arthritis Clinical trials in patients with plyarticular juvenile idipathic arthritis were perfrmed using ther frmulatins f methtrexate.

30 In a 6-mnth duble-blind, placeb-cntrlled trial f 127 pediatric patients with pjia (mean age, 10.1 years; age range, 2.5 t 18 years; mean duratin f disease, 5.1 years) n backgrund nnsteridal anti-inflammatry drugs and/r prednisne, methtrexate given weekly at an ral dse f 10 mg/m 2 prvided significant clinical imprvement cmpared t placeb as measured by either the physician s glbal assessment, r by a patient cmpsite (25% reductin in the articular-severity scre plus imprvement in parent and physician glbal assessments f disease activity). Over tw-thirds f the patients in this trial had plyarticular-curse JIA, and the numerically greatest respnse was seen in this subgrup treated with 10 mg/m 2 /wk methtrexate. The verwhelming majrity f the remaining patients had systemic-curse JIA. All patients were unrespnsive t NSAIDs; apprximately ne-third were using lw dse crticsterids. Weekly methtrexate at a dse f 5 mg/m 2 was nt significantly mre effective than placeb in this trial. 15 REFERENCES 1. Hazardus Drugs. OSHA HOW SUPPLIED/STORAGE AND HANDLING Rasuv cntains methtrexate in a preservative-free sterile slutin fr a single subcutaneus injectin in the fllwing cnfiguratins. Strength Pack Cnfiguratin* NDC mg per 0.15 ml mg per 0.20 ml mg per 0.25 ml mg per 0.30 ml mg per 0.35 ml mg per 0.40 ml mg per 0.45 ml mg per 0.50 ml mg per 0.55 ml mg per 0.60 ml *Single unit cnfiguratins are nt fr sale. Sample nly. Nt all pack sizes may be marketed.

31 Stre at cntrlled rm temperature, 25 C (77 F); excursins permitted t 15 t 30 C (59 t 86 F). PROTECT FROM LIGHT. Handling and Dispsal Handle and dispse f Rasuv cnsistent with recmmendatins fr handling and dispsal f cyttxic drugs PATIENT COUNSELING INFORMATION See FDA-apprved patient labeling (Patient Infrmatin and Instructins fr Use) Risk f Organ Txicity Infrm patients f the risks f rgan txicity, including gastrintestinal, hematlgic, hepatic, infectins, neurlgic, pulmnary, renal and skin as well as pssible signs and symptms fr which they shuld cntact their healthcare prvider. Advise patients f the need fr clse fllw-up, including peridic labratry tests t mnitr txicity [see Warnings and Precautins (5.1 and 5.4)]. Imprtance f Prper Dsing and Administratin Bth the physician and pharmacist shuld emphasize t the patient that the recmmended dse is taken nce weekly and that mistaken daily use f the recmmended dse has led t fatal txicity [see Dsing and Administratin (2)]. Rasuv is intended fr use under the guidance and supervisin f a physician. Patients shuld nt self- administer until they receive training frm a healthcare prfessinal. The patient s r caregiver s ability t administer Rasuv shuld be assessed. Patients shuld be instructed t use administratin sites n the abdmen r the thigh. Administratin shuld nt be made within 2 inches f the navel. Instruct patients nt t administer Rasuv t the arms r any ther areas f the bdy, as delineated in the Rasuv Instructins fr Use [see Instructins fr Use]. Risks f Pregnancy and Reprductin Advise patients that Rasuv can cause fetal harm and is cntraindicated in pregnancy. Advise wmen f childbearing ptential that Rasuv shuld nt be started until pregnancy is excluded. Wmen shuld be fully cunseled n the serius risk t the fetus shuld they becme pregnant while underging treatment. Infrm patients t cntact their physician if they suspect that they are pregnant. Advise patients that pregnancy shuld be avided if either partner is receiving Rasuv; during and fr a minimum f three mnths after therapy fr male patients, and during and fr at least ne vulatry cycle after therapy fr female patients [see Warnings and Precautins (5.2)]. Discuss the risk f effects n reprductin with bth male and female patients taking Rasuv. Infrm patients that methtrexate has been reprted t cause impairment f fertility, ligspermia and menstrual dysfunctin, during and fr a shrt perid after cessatin f therapy [see Use in Specific Ppulatins (8.6)]. Nursing Mthers Infrm patients that Rasuv is cntraindicated in nursing mthers [see Use in Specific Ppulatins (8.3)]. Ability t Drive r Operate Machinery Infrm patients that adverse reactins such as dizziness and fatigue may affect their ability t drive r perate machinery. Prper Strage and Dispsal Advise patients t stre Rasuv at rm temperature (68 t 77 F r 20 t 25 C). Infrm patients and caregivers f the need fr prper dispsal after use, including the use f a sharps dispsal cntainer. Manufactured fr: Medac Pharma Inc. 29 N Wacker Drive, Suite 704 Chicag, IL 60606

32 Manufactured by: Onctec Pharma Prduktin GmbH Am Pharmapark D Dessau-Rßlau Germany

33 What is Rasuv? PATIENT INFORMATION RASUVO (ruh-soo-vh) (methtrexate) injectin, fr subcutaneus use Rasuv is a single-dse manually-triggered aut-injectr cntaining a prescriptin medicine, methtrexate. Methtrexate is used t: treat certain adults with severe, active rheumatid arthritis (RA), and children with active plyarticular juvenile idipathic arthritis (pjia), after treatment with ther medicines including nn-steridal anti-inflammatry (NSAIDS) have been used and did nt wrk well. cntrl the symptms f severe, resistant, disabling psriasis in adults when ther types f treatment have been used and did nt wrk well. Rasuv is available in dses f 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5 and 30 mg. Yur dctr will prescribe a different way t take methtrexate if yu need t take methtrexate by muth r in sme ther way. Yur dctr may als change yur prescriptin if yur dse des nt match the available Rasuv dses, such as dses f less than 7.5 mg, mre than 30 mg, r dses in between the available Rasuv dses. Rasuv shuld nt be used fr the treatment f cancer. Rasuv shuld nt be used fr the treatment f children with psriasis. What is the mst imprtant infrmatin I shuld knw abut Rasuv? Rasuv can cause serius side effects that can lead t death, including: 1. Organ system txicity. Peple wh use methtrexate fr the treatment f cancer, psriasis, r rheumatid arthritis, have an increased risk f death frm rgan txicity. Types f rgan txicity can include: gastrintestinal bne marrw liver immune system nerve lung kidneys skin Yur dctr will d bld tests and ther types f tests befre yu take and while yu are taking Rasuv t check fr signs and symptms f rgan txicity. Call yur dctr right away if yu have any f the fllwing symptms f rgan txicity: vmiting diarrhea muth sres fever cnfusin weakness neck stiffness paralysis irritability sleepiness prblems with crdinatin dry cugh

34 temprary blindness seizures headache back pain 2. Wmen wh are pregnant are at increased risk fr death f the baby and birth defects. Wmen wh are pregnant r wh plan t becme pregnant must nt take Rasuv. A pregnancy test shuld be perfrmed befre starting Rasuv. Cntraceptin shuld be used by bth females and males while taking Rasuv. Pregnancy shuld be avided if either partner is receiving Rasuv: fr a minimum f 3 mnths after treatment with Rasuv fr males. during and fr at least 1 menstrual cycle after treatment with Rasuv fr females. Wh shuld nt take Rasuv? D nt take Rasuv if yu: are pregnant r planning t becme pregnant. See What is the mst imprtant infrmatin I shuld knw abut Rasuv? are breastfeeding. Rasuv can pass int yur breast milk and may harm yur baby. D nt breastfeed while taking Rasuv. Talk t yur dctr abut the best way t feed yur baby if yu take Rasuv. have alchl prblems (alchlism) have liver prblems have prblems fighting infectin (immundeficiency syndrme) have been tld yu have (r think yu have) a bld disrder such as lw levels f white bld cells, red bld cells (anemia), r platelets. have had an allergy t methtrexate r any f the ingredients in Rasuv. See the end f this leaflet fr a cmplete list f ingredients in Rasuv. Talk t yur dctr befre taking this medicine if yu have any f these cnditins. What shuld I tell my dctr befre taking Rasuv? Befre yu take Rasuv, tell yur dctr if yu have any ther medical cnditins. Tell yur dctr abut all f the medicines yu take, including prescriptin, ver-the-cunter medicines, vitamins, and herbal supplements. Rasuv may affect hw ther medicines wrk, and ther medicines may affect hw Rasuv wrks causing side effects. Ask yur dctr r pharmacist fr a list f medicines if yu are nt sure. Knw the medicines yu take. Keep a list f them t shw yur dctr and pharmacist when yu get a new medicine. truble breathing severe skin rash infectin

35 Hw shuld I take Rasuv? Read the Instructins fr Use that cme with Rasuv. Take Rasuv exactly as yur dctr tells yu t take it. Inject Rasuv nly 1 time each week. D nt take Rasuv every day. Taking Rasuv every day may cause death frm txicity. Yur dctr will shw yu r yur caregiver hw t inject Rasuv. Yu shuld nt inject Rasuv until yu have been trained n the right way t use it. Check Rasuv befre yu inject it. Rasuv shuld be yellw t brwn in clr and shuld nt have any lumps r particles in it. Rasuv shuld be injected under the skin f the abdmen r thigh. D nt inject Rasuv within 2 inches f the belly buttn (navel) Use a different site each time yu inject. This may help t decrease any reactins at the injectin site. D nt inject Rasuv in the arms r any ther areas f the bdy. D nt inject Rasuv in areas where the skin is tender, bruised, red, scaly, hard, r has scars r stretch marks. If yu are nt sure if Rasuv was injected, r if yu have hard time giving the injectin, d nt inject anther dse. Call yur pharmacist r dctr right away. If yu inject t much Rasuv, call yur dctr r g t the nearest hspital emergency rm right away. What shuld I avid while taking Rasuv? D nt drink alchl while taking Rasuv. Drinking alchl can increase yur chances f getting serius side effects. Rasuv can cause dizziness and tiredness. D nt drive a car, perate machinery, r d anything that needs yu t be alert until yu knw hw Rasuv affects yu. Certain vaccinatins shuld be avided while taking Rasuv. Talk t yur dctr befre yu r members f yur husehld receive any vaccines. What are the pssible side effects f Rasuv? Rasuv may cause serius side effects, including: See What is the mst imprtant infrmatin I shuld knw abut Rasuv? fertility prblems. Methtrexate, the active ingredient in Rasuv, may affect yur ability t have a baby. Males may have a decreased sperm cunt, and females may have changes t their menstrual cycle. This can happen while taking Rasuv and fr a shrt perid f time after yu stp. certain cancers. Sme peple wh have taken methtrexate have had a certain type f cancer called Nn-Hdgkin s lymphma and ther tumrs. Yur dctr may tell yu t stp taking Rasuv if this happens. tissue and bne prblems. Taking methtrexate while having radiatin therapy may increase the risk f yur tissue r bne nt receiving enugh bld. This may lead t death f the tissue r bne.

36 Cmmn side effects f Rasuv include: nausea stmach pain indigestin (dyspepsia) muth sres rash stuffy r runny nse and sre thrat diarrhea abnrmal liver functin tests vmiting headache brnchitis lw red, white, and platelet bld cell cunt hair lss dizziness sensitivity t light burning skin lesins lung prblems Tell yur dctr if yu have any side effect that bthers yu r that des nt g away. These are nt all the pssible side effects f Rasuv. Fr mre infrmatin, ask yur dctr r pharmacist. Call yu dctr fr medical advice abut side effects. Yu may reprt side effects t FDA at FDA Hw shuld I dispse f Rasuv? D nt thrw away in the husehld trash. Put used Rasuv in a FDAcleared sharps dispsal cntainer right away after use. If yu d nt have a FDA-cleared sharps dispsal cntainer, yu may use a husehld cntainer that is: made f a heavy-duty plastic can be clsed with a tight-fitting, puncture-resistant lid, withut sharps being able t cme ut upright stable during use leak-resistant prperly labeled t warn f hazardus waste inside the cntainer When yur sharps dispsal cntainer is almst full, yu will need t fllw yur cmmunity guidelines fr the right way t dispse f yur sharps dispsal cntainer. There may be state r lcal laws abut hw yu shuld thrw away used needles and syringes. Fr mre infrmatin abut the safe sharps dispsal, and fr specific infrmatin abut sharps dispsal in the state that yu live in, g t the FDA s website at: D nt dispse f yur used sharps dispsal cntainer in yur husehld trash unless yur cmmunity guidelines permit this. D nt recycle yur used sharps dispsal cntainer. Safely dispse f Rasuv that is ut f date r is n lnger needed. Hw shuld I stre Rasuv? Stre Rasuv at rm temperature between 68 F t 77 F (20 C t 25 C) D nt freeze Keep Rasuv ut f the light.

37 Keep Rasuv and all medicines ut f the reach f children. General infrmatin abut the safe and effective use f Rasuv. Methtrexate is smetimes prescribed fr purpses ther than thse listed in Patient Infrmatin leaflet. D nt use Rasuv fr a cnditin fr which it was nt prescribed. D nt give Rasuv t ther peple, even if they have the same symptms that yu have. It may harm them. This Patient Infrmatin leaflet summarizes the mst imprtant infrmatin abut Rasuv. If yu wuld like mre infrmatin, talk t yur dctr. Yu can ask yur dctr r pharmacist fr infrmatin abut Rasuv that is written fr health prfessinals. Fr mre infrmatin, please cntact Medac Pharma, Inc. at ur number What are the ingredients in Rasuv? Active ingredient: methtrexate Inactive ingredients: sdium chlride, sdium hydrxide and water fr injectin, USP, and if necessary hydrchlric acid, USP. This Patient Infrmatin has been apprved by the U.S. Fd and Drug Administratin. Manufactured fr: Medac Pharma, Inc. 29 N Wacker Drive, Suite 704 Chicag, IL Issued: 07/2014

38 Read this Instructins fr Use befre using Rasuv (ruh-soo-vh) (methtrexate) injectin, fr subcutaneus use Fllw these instructins each time yu use Rasuv. Parts f yur Rasuv aut-injectr Yellw injectin buttn Handling area Transparent cntrl zne Yellw cap (Figure A) (Figure B) a) Pre-filled aut-injectr with cap befre injectin b) Pre-filled aut-injectr after cap remval befre injectin c) Pre-filled aut-injectr after injectin Prepare t Use Rasuv Wash yur hands well with sap and warm water.

39 Select a clean, well-lit, flat wrk surface, such as a table. Place the Rasuv cartn cntaining the aut-injectr n yur flat wrk surface. Be sure that the dse, either 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5 r 30 mg, stated n the cartn is the same as the dse prescribed by yur dctr. Check the expiratin date n the label. D nt use if expired. Remve ne Rasuv aut-injectr frm the packaging. If the Rasuv appears t be damaged d nt use it. Use anther Rasuv. In additin t Rasuv, yu will need the fllwing items: ne alchl swab and ne cttn ball r gauze and small adhesive bandage strip, if desired. Check the Liquid (Figure C) Lk at the transparent cntrl zne (see Figure C). The prefilled syringe is visible within the transparent cntrl zne. Examine the cntents f the syringe carefully. If the syringe is cracked r brken, d nt use it. Use anther aut-injectr. The liquid shuld be clear and yellw t brwn in clr and shuld nt have any lumps r particles in it. D nt use Rasuv if the liquid is cludy, disclred r cntains particles. Yu may see an air bubble. This is nrmal. If yu are nt able t see r t check the Rasuv aut-injectr crrectly prir t injectin, ask a caretaker fr assistance. D nt remve the yellw cap frm the aut-injectr until yu are ready t use Rasuv. Chse an Injectin Site Rasuv shuld be injected int the stmach (abdmen) r the upper thigh. D nt inject Rasuv within 2 inches f the belly buttn (navel) (see Figure D). D nt inject Rasuv in the arms r any ther areas f the bdy.

40 D nt inject Rasuv in areas where the skin is tender, bruised, red, scaly, hard, r has scars r stretch marks. Use a different site each time yu inject. This may help t decrease any reactins at the injectin site. Wipe the area with an alchl swab (see Figure E). Allw the skin t dry and d nt tuch this area again befre giving Rasuv. D nt fan r blw n the clean area. (Figure D) (Figure E) Give yur Injectin STEP 1: Remve the Yellw Cap (see Figure F) Hld the Rasuv aut-injectr with ne hand in the handling area.

41 Use yur ther hand t pull the yellw cap straight ff (see Figure F). D nt twist the cap. If yu are unable t remve the cap, ask a caretaker fr assistance. Cautin! (Figure F) D nt tuch the needle end with yur hands r fingers. This culd inject the medicine int yur hand. T avid any injury, never insert yur fingers in the pening f the prtect tube cvering the needle. D nt replace the cap after it has been remved. After the cap is remved Rasuv must be used withut delay r dispsed f safely. D nt press the yellw injectin buttn until yu are ready t inject Rasuv. STEP 2: Prepare the Injectin Pinch a pad f skin surrunding the cleaned injectin site with yur thumb and frefinger f yur free hand by gently squeezing. Patients with rheumatid arthritis wh are unable t pinch the skin can inject directly int the thigh withut pinching if needed. Hld the skin pinched until Rasuv is remved frm the skin after the injectin. Psitin the uncapped transparent end f the Rasuv aut-injectr perpendicular (at a 90 degree angle) t the skin (see Figure G). Withut pressing the buttn, push Rasuv firmly nt yur skin until yu feel the stp pint in rder t unlck the yellw injectin buttn (see Figure G). If yu are unable t push Rasuv t the stp-pint, ask a caretaker fr assistance.

42 (Figure G) STEP 3: Inject Rasuv While still hlding Rasuv firmly against the skin, press the yellw injectin buttn with yur thumb (see Figure H). Yu will hear a click which indicates the start f the injectin. Hld Rasuv against the skin until all f the medicine is injected. This can take up t 5 secnds (slwly cunt 1, 2, 3, 4, 5). T avid an incmplete injectin, d nt remve the Rasuv frm the skin befre the end f the injectin. Lk at the transparent cntrl zne while yu are injecting t make sure that the entire dse is injected. When the mvement stps, the injectin is cmpleted. If yu have prblems with yur hearing, slwly cunt t 5 secnds frm the mment yu have pressed the buttn. It is nt necessary t keep the buttn f the Rasuv pressed dwn with yur thumb after the injectin has begun. Figure H After cmpleting the injectin, remve Rasuv frm the injectin site by pulling straight up (perpendicular t the skin). The prtective needle shield autmatically mves int place and lcks ver the needle.