ALIMTA Frequently Asked Questions

Transcription

1 Frequently Asked Questions Here re the nswers to some frequently sked questions out. Tlk to your dotor if you need more informtion. Question: Wht is dvned nonsqumous NSCLC? Answer: There re two min types of lung ner: non-smll ell lung ner (lso known s NSCLC) nd smll ell lung ner (SCLC). Within NSCLC, there re three min histologil sutypes. The sutypes re lssified y the type of ells tht mke up the tumor. Your dotor my hve told you tht you hve type of ner lled denorinom, or mye it ws lled lrge ell rinom. Both of these fll under lrger tegory lled dvned nonsqumous non-smll ell lung ner. This is the type of ner tht therpy is pproved for. It is not pproved for nother type of dvned non-smll ell lung ner lled squmous ell. Question: Wht is histology nd why does it mtter? Answer: Histology is lssifition of the ellulr omposition of tumor. Within NSCLC, the mjor lssifitions re nonsqumous (inluding denorinom nd lrge ell rinom) nd squmous ell rinom. Histology is importnt euse reserh hs shown tht there is link etween histology nd the effetiveness of in NSCLC. is not pproprite for ptients who hve squmous ell rinom. n suppress one mrrow funtion, whih my use low lood ell ounts. Question: How will I know wht my histology is? Answer: Your dotor will let you know wht your histology is sed on your pthology report. Question: When should I ontt my dotor right wy? Answer: Cll your dotor right wy if you hve fever (temperture ove. F), hills, dirrhe, or mouth sores. These symptoms ould men you hve n infetion, whih my e severe nd ould led to deth. For more informtion out ll of the side effets of, plese see the Importnt Sfety Informtion on pges -, the ompnying Ptient Presriing Informtion, nd Presriing Informtion; visit or ll You re enourged to report negtive side effets of presription drugs to the FDA. Visit or ll --FDA-. is pproved y the FDA in omintion with ispltin (nother hemotherpy drug) for the initil tretment of dvned nonsqumous non-smll ell lung ner (NSCLC), speifi type of NSCLC. is pproved y the FDA for the tretment of ptients with dvned nonsqumous non-smll ell lung ner (NSCLC), speifi type of NSCLC, to mintin the effet of initil tretment with hemotherpy nd whose disese hs not worsened. is pproved y the FDA s single gent (used lone) for the tretment of ptients with dvned nonsqumous non-smll ell lung ner (NSCLC), speifi type of NSCLC, fter prior hemotherpy. is not indited for ptients who hve different type of NSCLC lled squmous ell. is tretment for mlignnt pleurl mesotheliom (MPM), whih is ner tht ffets the inside lining of the hest vity. is given with ispltin, nother ntiner mediine (hemotherpy), when surgery is not n option. n suppress one mrrow funtion, whih my use low lood ell ounts. Selet Importnt Sfety Informtion If you know you re llergi to (pemetrexed for injetion), tell your dotor immeditely euse you should not reeive it. Prior to tretment with nd on speifi dys throughout tretment, you must tke foli id y mouth, nd you will reeive vitmin B injetions to help redue the severity of ertin side effets. Your dotor will lso presrie mediine lled ortiosteroid, whih you must tke for dys during eh tretment with.

2 Frequently Asked Questions Question: Wht ftors n impt my outome or hne of lung ner reurrene? Answer: The possile outome nd tretment options for people with NSCLC depend upon the following: The stge of the ner when it is found. This is determined y the size of the tumor nd whether it is in the lung only or hs spred to other ples in the ody Your type of lung ner, whih inludes the histology of the NSCLC Whether ertin symptoms re present, suh s oughing or troule rething Your generl helth Question: How muh does ost? Answer: The ost of therpy vries y insurne pln. Your helthre tem or insurne ompny will hve more informtion for you. Question: Will my insurne over? Answer: Your helthre tem or insurne ompny n help you determine your overge. For insurne verifition ssistne, you n lso ontt Lilly PtientOne t --PtOne (--7-). Question: I don t hve helth insurne. Is there ny finnil ssistne for? Answer: Lilly PtientOne is reimursement nd ptient ssistne progrm tht my e le to help. Cll the Lilly PtientOne hotline t --PtOne (--7-).. Wht Is Lung Cner? Cner Support Community wesite. Aessed June,.. Lung Cner (Non-Smll Cell). Amerin Cner Soiety wesite. Aessed June 7,.. Sgliotti GV, et l. J Clin Onol. ;():-.. (pemetrexed for injetion) [pkge insert]. Indinpolis, IN: Eli Lilly nd Compny;.. Generl Informtion Aout Non-Smll Cell Lung Cner (NSCLC). Ntionl Cner Institute wesite. Aessed June,. For more informtion out ll of the side effets of, plese see the Importnt Sfety Informtion on pges -, the ompnying Ptient Presriing Informtion, nd Presriing Informtion; visit or ll You re enourged to report negtive side effets of presription drugs to the FDA. Visit or ll --FDA-. is pproved y the FDA in omintion with ispltin (nother hemotherpy drug) for the initil tretment of dvned nonsqumous non-smll ell lung ner (NSCLC), speifi type of NSCLC. is pproved y the FDA for the tretment of ptients with dvned nonsqumous nonsmll ell lung ner (NSCLC), speifi type of NSCLC, to mintin the effet of initil tretment with hemotherpy nd whose disese hs not worsened. is pproved y the FDA s single gent (used lone) for the tretment of ptients with dvned nonsqumous non-smll ell lung ner (NSCLC), speifi type of NSCLC, fter prior hemotherpy. is not indited for ptients who hve different type of NSCLC lled squmous ell. is tretment for mlignnt pleurl mesotheliom (MPM), whih is ner tht ffets the inside lining of the hest vity. is given with ispltin, nother ntiner mediine (hemotherpy), when surgery is not n option. n suppress one mrrow funtion, whih my use low lood ell ounts. Selet Importnt Sfety Informtion n suppress one mrrow funtion, whih my use low lood ell ounts. This my mke you feel tired, pper ple, eome short of reth, nd my give you greter hne for infetion nd/or leeding. If you hve fever (temperture ove. F) or severe wekness or tiredness, ll your dotor right wy. Tell your dotor if you hve or hve hd liver or kidney prolems in the pst. Your dose of my hve to e hnged, or my not e right for you.

3 Importnt Sfety Informtion for (pemetrexed for injetion) Wht is the most importnt informtion tht I should know out? n suppress one mrrow funtion, whih my use low lood ell ounts. my not e pproprite for some ptients. If you re llergi to, tell your dotor euse you should not reeive it. If you hve liver or kidney prolems, e sure to tell your dotor. Your dose of my hve to e hnged, or my not e right for you. It is very importnt to tke the following meditions prior to nd during your tretment with to lower your hnes of hrmful side effets: You must tke foli id every dy y mouth eginning 7 dys efore your first dose of. You must keep tking foli id every dy during the time you re eing treted with, nd every dy for dys fter you reeive your lst dose of. Your dotor will give you vitmin B injetions while you re getting tretment with. You will get your first vitmin B injetion one week efore your first dose of, nd then out every 9 weeks during tretment. Your dotor will presrie mediine lled ortiosteroid tht you must tke the dy efore, the dy of, nd the dy fter eh tretment with to redue rsh. You will hve regulr lood tests efore nd during your tretment with. Your dotor my djust your dose of or dely your tretment sed on the results of your lood test nd on your generl ondition. Wht should I tell my dotor efore reeiving? If you think you re pregnnt, re plnning to eome pregnnt, or re nursing, plese tell your helthre tem. my hrm your unorn or nursing y. Your physiin my dvise you to use effetive ontreption (irth ontrol) to prevent pregnny while you re eing treted with. Tell your dotor if you re tking other mediines, inluding presription nd nonpresription mediines, vitmins, nd herl supplements. nd other mediines my ffet eh other, using serious side effets. Espeilly, tell your dotor if you re tking mediines lled nonsteroidl nti-inflmmtory drugs (NSAIDs) for pin or swelling. is pproved y the FDA in omintion with ispltin (nother hemotherpy drug) for the initil tretment of dvned nonsqumous non-smll ell lung ner (NSCLC), speifi type of NSCLC. is pproved y the FDA for the tretment of ptients with dvned nonsqumous non-smll ell lung ner (NSCLC), speifi type of NSCLC, to mintin the effet of initil tretment with hemotherpy nd whose disese hs not worsened. is pproved y the FDA s single gent (used lone) for the tretment of ptients with dvned nonsqumous non-smll ell lung ner (NSCLC), speifi type of NSCLC, fter prior hemotherpy. is not indited for ptients who hve different type of NSCLC lled squmous ell. is tretment for mlignnt pleurl mesotheliom (MPM), whih is ner tht ffets the inside lining of the hest vity. is given with ispltin, nother ntiner mediine (hemotherpy), when surgery is not n option. n suppress one mrrow funtion, whih my use low lood ell ounts.

4 Importnt Sfety Informtion for (pemetrexed for injetion) (ontinued) Wht re the possile side effets of? Most ptients tking will hve side effets. Sometimes it is not lwys possile to tell whether, nother mediine, or the ner itself is using these side effets. Cll your dotor right wy if you hve fever, hills, dirrhe, or mouth sores. These symptoms ould men you hve n infetion, whih my e severe nd ould led to deth. The most ommon side effets of when given lone or in omintion with ispltin re: Stomh upset, inluding nuse, vomiting, dirrhe, or onstiption. You n otin mediines to help ontrol some of these symptoms. Cll your dotor if you get ny of these symptoms. Low lood ell ounts: Low red lood ells. Low red lood ells my mke you feel tired, get tired esily, pper ple, nd eome short of reth. Low white lood ells. Low white lood ells my give you greter hne for infetion. If you hve fever (temperture ove. F) or other signs of infetion, ll your dotor right wy. Low pltelets. Low pltelets give you greter hne for leeding. Your dotor will do lood tests to hek your lood ounts efore nd during tretment with. Tiredness. You my feel tired or wek for few dys fter your tretments. If you hve severe wekness or tiredness, ll your dotor. Redness or sores in your mouth, throt, on your lips, or in the tue tht onnets your throt nd stomh (esophgus). You my get redness or sores in your mouth, throt, on your lips, or in your esophgus (stomtitis, phryngitis, esophgitis) or you my feel pin or hve diffiulty when drinking or swllowing food. These symptoms my hppen few dys fter tretment. Tlk with your dotor if you get ny of these symptoms. Loss of ppetite. You my lose your ppetite nd lose weight during your tretment. Tlk to your dotor if this is prolem for you. Rsh. You my get rsh or ithing during tretment. These retions usully pper etween tretments with nd usully go wy efore the next tretment. Skin retions or rshes tht inlude listering or peeling my e severe nd ould led to deth. Cll your dotor if you hve ny of these symptoms.

5 Importnt Sfety Informtion for (pemetrexed for injetion) (ontinued) Tlk with your dotor, nurse, or phrmist out ny side effet tht others you or tht doesn t go wy. These re not ll the side effets of. For more informtion, sk your dotor, nurse, or phrmist. How is given? is slowly infused (injeted) into vein. The injetion or infusion will lst out minutes. You will usully reeive one every dys ( weeks). For more informtion out ll of the side effets of, plese tlk with your helthre tem, see the Ptient Presriing Informtion nd Presriing Informtion ompnying this doument, visit or ll You re enourged to report negtive side effets of presription drugs to the FDA. Visit or ll --FDA-. PM_CON_ISI_All_7OCT PM97 / Lilly USA, LLC. All rights reserved. is registered trdemrk of Eli Lilly nd Compny.

6 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not inlude ll the informtion needed to use sfely nd effetively. See full presriing informtion for. (pemetrexed for injetion), for Intrvenous Use Initil U.S. Approvl: RECENT MAJOR CHANGES Dosge nd Administrtion, Premedition Regimen nd Conurrent Meditions (.) / Wrnings nd Preutions, Requirement for Premedition nd Conomitnt Medition to Redue Toxiity (.) / Wrnings nd Preutions, Required Lortory Monitoring (.) / INDICATIONS AND USAGE is folte nlog metoli inhiitor indited for: Lolly Advned or Metstti Nonsqumous Non-Smll Cell Lung Cner: Initil tretment in omintion with ispltin. (.) Mintenne tretment of ptients whose disese hs not progressed fter four yles of pltinum-sed first-line hemotherpy. (.) After prior hemotherpy s single-gent. (.) Mesotheliom: in omintion with ispltin. (.) Limittions of Use: is not indited for the tretment of ptients with squmous ell non-smll ell lung ner. (.) DOSAGE AND ADMINISTRATION Comintion use in Non-Smll Cell Lung Cner nd Mesotheliom: Reommended dose of is mg/m i.v. on Dy of eh -dy yle in omintion with ispltin 7 mg/m i.v. eginning minutes fter dministrtion. (.) Single-Agent use in Non-Smll Cell Lung Cner: Reommended dose of is mg/m i.v. on Dy of eh -dy yle. (.) Prior to inititing, initite supplementtion with orl foli id nd intrmusulr vitmin B. Continue foli id nd vitmin B supplementtion throughout tretment. Administer ortiosteroids the dy efore, the dy of, nd the dy fter dministrtion. (.) Dose Redutions: Dose redutions or disontinution my e needed sed on toxiities from the preeding yle of therpy. (.) DOSAGE FORMS AND STRENGTHS mg vil for injetion () mg vil for injetion () CONTRAINDICATIONS History of severe hypersensitivity retion to pemetrexed. () WARNINGS AND PRECAUTIONS Premedition regimen: Prior to tretment with, initite supplementtion with orl foli id nd intrmusulr vitmin B to redue the severity of hemtologi nd gstrointestinl toxiity of. (.) Bone mrrow suppression: Redue doses for susequent yles sed on hemtologi nd nonhemtologi toxiities. (.) Renl funtion: Do not dminister when CrCl < ml/min. (.,.) NSAIDs with renl insuffiieny: Use ution in ptients with mild to moderte renl insuffiieny (CrCl -79 ml/min). (.) L monitoring: Do not initite yle unless ANC ells/mm, pltelets, ells/mm, nd CrCl ml/min. (.) Pregnny: Fetl hrm n our when dministered to pregnnt womn. Women should e dvised to use effetive ontreption mesures to prevent pregnny during tretment with. (.) ADVERSE REACTIONS The most ommon dverse retions (inidene %) with single-gent use re ftigue, nuse, nd norexi. Additionl ommon dverse retions when used in omintion with ispltin inlude vomiting, neutropeni, leukopeni, nemi, stomtitis/phryngitis, thromoytopeni, nd onstiption. (.) To report SUSPECTED ADVERSE REACTIONS, ontt Eli Lilly nd Compny t --LillyRx (---979) or FDA t --FDA- or DRUG INTERACTIONS NSAIDs: Use ution with NSAIDs. (7.) Nephrotoxi drugs: Conomitnt use of these drugs nd/or sustnes whih re tuulrly sereted my result in delyed lerne. (7.) See 7 for PATIENT COUNSELING INFORMATION nd FDA-pproved ptient leling. Revised: 9/ FULL PRESCRIBING INFORMATION: CONTENTS* INDICATIONS AND USAGE. Nonsqumous Non-Smll Cell Lung Cner Comintion with Cispltin. Nonsqumous Non-Smll Cell Lung Cner Mintenne. Nonsqumous Non-Smll Cell Lung Cner After Prior Chemotherpy. Mesotheliom. Limittions of Use DOSAGE AND ADMINISTRATION. Comintion Use with Cispltin for Nonsqumous Non-Smll Cell Lung Cner or Mlignnt Pleurl Mesotheliom. Single-Agent Use s Mintenne Following First-Line Therpy, or s Seond- Line Therpy. Premedition Regimen nd Conurrent Meditions. Lortory Monitoring nd Dose Redution/Disontinution Reommendtions. Preprtion nd Administrtion Preutions. Preprtion for Intrvenous Infusion Administrtion DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS. Requirement for Premedition nd Conomitnt Medition to Redue Toxiity. Bone Mrrow Suppression. Deresed Renl Funtion. Use with Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) with Mild to Moderte Renl Insuffiieny. Required Lortory Monitoring. Pregnny Ctegory D ADVERSE REACTIONS. Clinil Trils Experiene. Postmrketing Experiene 7 DRUG INTERACTIONS 7. Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) 7. Nephrotoxi Drugs USE IN SPECIFIC POPULATIONS. Pregnny. Nursing Mothers. Peditri Use. Geritri Use. Ptients with Hepti Impirment.7 Ptients with Renl Impirment. Gender.9 Re OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY. Mehnism of Ation. Phrmodynmis. Phrmokinetis NONCLINICAL TOXICOLOGY. Crinogenesis, Mutgenesis, Impirment of Fertility CLINICAL STUDIES. Non-Smll Cell Lung Cner (NSCLC) Comintion with Cispltin. Non-Smll Cell Lung Cner Mintenne. Non-Smll Cell Lung Cner After Prior Chemotherpy. Mlignnt Pleurl Mesotheliom REFERENCES HOW SUPPLIED/STORAGE AND HANDLING. How Supplied. Storge nd Hndling 7 PATIENT COUNSELING INFORMATION *Setions or susetions omitted from the full presriing informtion re not listed. (pemetrexed for injetion), for Intrvenous Use PV 97 AMP (pemetrexed for injetion), for Intrvenous Use PV 97 AMP PI PV97AMP W/ PPI PXAMP PRINTER VERSION OF

7 FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE. Nonsqumous Non-Smll Cell Lung Cner Comintion with Cispltin is indited in omintion with ispltin therpy for the initil tretment of ptients with lolly dvned or metstti nonsqumous non-smll ell lung ner.. Nonsqumous Non-Smll Cell Lung Cner Mintenne is indited for the mintenne tretment of ptients with lolly dvned or metstti nonsqumous non-smll ell lung ner whose disese hs not progressed fter four yles of pltinum-sed first-line hemotherpy.. Nonsqumous Non-Smll Cell Lung Cner After Prior Chemotherpy is indited s single-gent for the tretment of ptients with lolly dvned or metstti nonsqumous non-smll ell lung ner fter prior hemotherpy.. Mesotheliom in omintion with ispltin is indited for the tretment of ptients with mlignnt pleurl mesotheliom whose disese is unresetle or who re otherwise not ndidtes for urtive surgery.. Limittions of Use is not indited for the tretment of ptients with squmous ell non-smll ell lung ner. [see Clinil Studies (.,.,.)] DOSAGE AND ADMINISTRATION. Comintion Use with Cispltin for Nonsqumous Non-Smll Cell Lung Cner or Mlignnt Pleurl Mesotheliom The reommended dose of is mg/m dministered s n intrvenous infusion over minutes on Dy of eh -dy yle. The reommended dose of ispltin is 7 mg/m infused over hours eginning pproximtely minutes fter the end of dministrtion. See ispltin pkge insert for more informtion.. Single-Agent Use s Mintenne Following First-Line Therpy, or s Seond-Line Therpy The reommended dose of is mg/m dministered s n intrvenous infusion over minutes on Dy of eh -dy yle.. Premedition Regimen nd Conurrent Meditions Vitmin Supplementtion Instrut ptients to initite foli id mg to mg orlly one dily eginning 7 dys efore the first dose of. Continue foli id during the full ourse of therpy nd for dys fter the lst dose of [see Wrnings nd Preutions (.)]. Administer vitmin B mg intrmusulrly week prior to the first dose of nd every yles therefter. Susequent vitmin B injetions my e given the sme dy s tretment with [see Wrnings nd Preutions (.)]. Cortiosteroids Administer dexmethsone mg y mouth twie dily the dy efore, the dy of, nd the dy fter dministrtion [see Wrnings nd Preutions (.)].. Lortory Monitoring nd Dose Redution/Disontinution Reommendtions Monitoring Complete lood ell ounts, inluding pltelet ounts, should e performed on ll ptients reeiving. Ptients should e monitored for ndir nd reovery, whih were tested in the linil study efore eh dose nd on dys nd of eh yle. Ptients should not egin new yle of tretment unless the ANC is ells/mm, the pltelet ount is, ells/mm, nd retinine lerne is ml/min. Periodi hemistry tests should e performed to evlute renl nd hepti funtion [see Wrnings nd Preutions (.)]. Dose Redution Reommendtions Dose djustments t the strt of susequent yle should e sed on ndir hemtologi ounts or mximum nonhemtologi toxiity from the preeding yle of therpy. Tretment my e delyed to llow suffiient time for reovery. Upon reovery, ptients should e retreted using the guidelines in Tles -, whih re suitle for using s single-gent or in omintion with ispltin. Ndir ANC </mm nd ndir pltelets,/mm. Ndir pltelets <,/mm without leeding regrdless of ndir ANC. Ndir pltelets <,/mm with leeding, regrdless of ndir ANC. Tle : Dose Redution for (single-gent or in omintion) nd Cispltin Hemtologi Toxiities 7% of previous dose (pemetrexed nd ispltin). 7% of previous dose (pemetrexed nd ispltin). % of previous dose (pemetrexed nd ispltin). These riteri meet the CTC version. (NCI 99) definition of CTC Grde leeding. If ptients develop nonhemtologi toxiities (exluding neurotoxiity) Grde, tretment should e withheld until resolution to less thn or equl to the ptient s pre-therpy vlue. Tretment should e resumed ording to guidelines in Tle. Tle : Dose Redution for (single-gent or in omintion) nd Cispltin Nonhemtologi Toxiities, Dose of (mg/m ) Dose of Cispltin (mg/m ) Any Grde or toxiities exept muositis 7% of previous dose 7% of previous dose Any dirrhe requiring hospitliztion (irrespetive of Grde) or Grde or dirrhe 7% of previous dose 7% of previous dose Grde or muositis % of previous dose % of previous dose NCI Common Toxiity Criteri (CTC). Exluding neurotoxiity (see Tle ). In the event of neurotoxiity, the reommended dose djustments for nd ispltin re desried in Tle. Ptients should disontinue therpy if Grde or neurotoxiity is experiened. Tle : Dose Redution for (single-gent or in omintion) nd Cispltin Neurotoxiity (pemetrexed for injetion), for Intrvenous Use PV 97 AMP (pemetrexed for injetion), for Intrvenous Use PV 97 AMP CTC Grde Dose of (mg/m ) Dose of Cispltin (mg/m ) - % of previous dose % of previous dose % of previous dose % of previous dose Disontinution Reommendtion therpy should e disontinued if ptient experienes ny hemtologi or nonhemtologi Grde or toxiity fter dose redutions or immeditely if Grde or neurotoxiity is oserved. Renlly Impired Ptients In linil studies, ptients with retinine lerne ml/min required no dose djustments other thn those reommended for ll ptients. Insuffiient numers of ptients with retinine lerne elow ml/min hve een treted to mke dosge reommendtions for this group of ptients [see Clinil Phrmology (.)]. Therefore, should not e dministered to ptients whose retinine lerne is < ml/min using the stndrd Cokroft nd Gult formul (elow) or GFR mesured y T99m-DTPA serum lerne method: [ - Age in yers] Atul Body Weight (kg) Mles: = ml/min 7 Serum Cretinine (mg/dl) Femles: Estimted retinine lerne for mles. Cution should e exerised when dministering onurrently with NSAIDs to ptients whose retinine lerne is < ml/min [see Drug Intertions (7.)].. Preprtion nd Administrtion Preutions As with other potentilly toxi ntiner gents, re should e exerised in the hndling nd preprtion of infusion solutions of. The use of gloves is reommended. If solution of ontts the skin, wsh the skin immeditely nd thoroughly with sop nd wter. If ontts the muous memrnes, flush thoroughly with wter. Severl pulished guidelines for hndling nd disposl of ntiner gents re ville [see Referenes ()]. is not vesint. There is no speifi ntidote for extrvstion of. To dte, there hve een few reported ses of extrvstion, whih were not ssessed s serious y the investigtor. extrvstion should e mnged with lol stndrd prtie for extrvstion s with other non-vesints.. Preprtion for Intrvenous Infusion Administrtion. Use septi tehnique during the reonstitution nd further dilution of for intrvenous infusion dministrtion.. Clulte the dose of nd determine the numer of vils needed. Vils ontin either mg or mg of. The vils ontin n exess of to filitte delivery of lel mount.. Reonstitute eh -mg vil with. ml of.9% Sodium Chloride Injetion (preservtive free). Reonstitute eh -mg vil with ml of.9% Sodium Chloride Injetion (preservtive free). Reonstitution of either size vil gives solution ontining mg/ml. Gently swirl eh vil until the powder is ompletely dissolved. The resulting solution is ler nd rnges in olor from olorless to yellow or green-yellow without dversely ffeting produt qulity. The ph of the reonstituted solution is etween. nd 7.. FURTHER DILUTION IS REQUIRED.. Prenterl drug produts should e inspeted visully for prtiulte mtter nd disolortion prior to dministrtion, whenever solution nd ontiner permit. If prtiulte mtter is oserved, do not dminister.. An pproprite quntity of the reonstituted solution must e further diluted into solution of.9% Sodium Chloride Injetion (preservtive free), so tht the totl volume of solution is ml. is dministered s n intrvenous infusion over minutes.. Chemil nd physil stility of reonstituted nd infusion solutions of were demonstrted for up to hours following initil reonstitution, when stored refrigerted. When prepred s direted, reonstitution nd infusion solutions of ontin no ntimiroil preservtives. Disrd ny unused portion. Reonstitution nd further dilution prior to intrvenous infusion is only reommended with.9% Sodium Chloride Injetion (preservtive free). is physilly inomptile with diluents ontining lium, inluding Ltted Ringer s Injetion, USP nd Ringer s Injetion, USP nd therefore these should not e used. Codministrtion of with other drugs nd diluents hs not een studied, nd therefore is not reommended. is omptile with stndrd polyvinyl hloride (PVC) dministrtion sets nd intrvenous solution gs. DOSAGE FORMS AND STRENGTHS, pemetrexed for injetion, is white to either light-yellow or green-yellow lyophilized powder ville in sterile single-use vils ontining mg or mg pemetrexed. CONTRAINDICATIONS is ontrindited in ptients who hve history of severe hypersensitivity retion to pemetrexed. WARNINGS AND PRECAUTIONS. Requirement for Premedition nd Conomitnt Medition to Redue Toxiity Vitmin Supplementtion Prior to tretment with, initite supplementtion with orl foli id nd intrmusulr vitmin B to redue the severity of hemtologi nd gstrointestinl toxiity of [see Dosge nd Administrtion (.)]. Do not sustitute orl vitmin B for intrmusulr vitmin B. In linil studies, the inidene of the following Grde - toxiities were higher in ptients with mesotheliom who were never supplemented s ompred to ptients who were fully supplemented with foli id nd vitmin B prior to nd throughout tretment: neutropeni [% versus %], thromoytopeni [9% versus %], ferile neutropeni [9% versus.%], nd infetion with neutropeni [% versus. ]. Cortiosteroids Administer dexmethsone the dy efore, the dy of, nd the dy fter dministrtion [see Dosge nd Administrtion (.)].. Bone Mrrow Suppression n suppress one mrrow funtion, s mnifested y neutropeni, thromoytopeni, nd nemi (or pnytopeni) [see Adverse Retions (.)]; myelosuppression is usully the dose-limiting toxiity. Dose redutions for susequent yles re sed on ndir ANC, pltelet ount, nd mximum nonhemtologi toxiity seen in the previous yle [see Dosge nd Administrtion (.)].. Deresed Renl Funtion is primrily eliminted unhnged y renl exretion. No dosge djustment is needed in ptients with retinine lerne ml/min. Insuffiient numers of ptients hve een studied with retinine lerne < ml/min to give dose reommendtion. Therefore, should not e dministered to ptients whose retinine lerne is < ml/min [see Dosge nd Administrtion (.)]. PI PV97AMP W/ PPI PXAMP PRINTER VERSION OF

8 One ptient with severe renl impirment (retinine lerne 9 ml/min) who did not reeive foli id nd vitmin B died of drug-relted toxiity following dministrtion of lone.. Use with Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) with Mild to Moderte Renl Insuffiieny Cution should e used when dministering NSAIDs onurrently with to ptients with mild to moderte renl insuffiieny (retinine lerne from to 79 ml/min) [see Drug Intertions (7.)].. Required Lortory Monitoring Otin omplete lood ount nd renl funtion tests t the eginning of eh yle nd s needed. Do not initite yle of tretment unless the ANC is ells/mm, the pltelet ount is, ells/mm, nd retinine lerne is ml/min [see Dosge nd Administrtion (.)].. Pregnny Ctegory D Bsed on its mehnism of tion, n use fetl hrm when dministered to pregnnt womn. Pemetrexed dministered intrperitonelly to mie during orgnogenesis ws emryotoxi, fetotoxi nd tertogeni in mie t greter thn /rd the reommended humn dose. If is used during pregnny, or if the ptient eomes pregnnt while tking this drug, the ptient should e pprised of the potentil hzrd to the fetus. Women of hildering potentil should e dvised to void eoming pregnnt. Women should e dvised to use effetive ontreptive mesures to prevent pregnny during tretment with [see Use in Speifi Popultions (.)]. ADVERSE REACTIONS. Clinil Trils Experiene Beuse linil trils re onduted under widely vrying onditions, dverse retions rtes nnot e diretly ompred to rtes in other linil trils nd my not reflet the rtes oserved in linil prtie. In linil trils, the most ommon dverse retions (inidene %) during therpy with s single-gent were ftigue, nuse, nd norexi. Additionl ommon dverse retions (inidene %) during therpy with when used in omintion with ispltin inluded vomiting, neutropeni, leukopeni, nemi, stomtitis/phryngitis, thromoytopeni, nd onstiption. Non-Smll Cell Lung Cner (NSCLC) in Comintion with Cispltin Tle provides the frequeny nd severity of dverse retions tht hve een reported in >% of 9 ptients with NSCLC who were rndomized to study nd reeived plus ispltin nd ptients with NSCLC who were rndomized to study nd reeived gemitine plus ispltin. All ptients reeived study therpy s initil tretment for lolly dvned or metstti NSCLC nd ptients in oth tretment groups were fully supplemented with foli id nd vitmin B. Retion Tle : Adverse Retions in Fully Supplemented Ptients Reeiving plus Cispltin in NSCLC /ispltin (N=9) All Grdes Grde - Gemitine/ispltin (N=) All Grdes Grde - All Adverse Retions Lortory Hemtologi Anemi Neutropeni Leukopeni Thromoytopeni 9 Renl Cretinine elevtion 7 Clinil Constitutionl Symptoms Ftigue 7 Gstrointestinl Nuse Vomiting Anorexi Constiption Stomtitis/Phryngitis Dirrhe Dyspepsi/Herturn Neurology Neuropthy-sensory Tste disturne Dermtology/Skin Alopei Rsh/Desqumtion For the purpose of this tle ut off of % ws used for inlusion of ll events where the reporter onsidered possile reltionship to. Refer to NCI CTC Criteri version. for eh Grde of toxiity. Aording to NCI CTC Criteri version., this dverse event term should only e reported s Grde or. No linilly relevnt differenes in dverse retions were seen in ptients sed on histology. In ddition to the lower inidene of hemtologi toxiity on the nd ispltin rm, use of trnsfusions (RBC nd pltelet) nd hemtopoieti growth ftors ws lower in the nd ispltin rm ompred to the gemitine nd ispltin rm. The following dditionl dverse retions were oserved in ptients with non-smll ell lung ner rndomly ssigned to reeive plus ispltin. Inidene % to % Body s Whole ferile neutropeni, infetion, pyrexi Generl Disorders dehydrtion Metolism nd Nutrition inresed AST, inresed ALT Renl retinine lerne derese, renl filure Speil Senses onjuntivitis 7 Inidene Less thn % Crdiovsulr rrhythmi Generl Disorders hest pin Metolism nd Nutrition inresed GGT Neurology motor neuropthy Non-Smll Cell Lung Cner (NSCLC) Mintenne Mintenne Following Non- Contining, Pltinum-Bsed Indution Therpy Tle provides the frequeny nd severity of dverse retions reported in >% of the ptients with NSCLC who reeived mintenne nd the ptients with NSCLC who reeived pleo following pltinum-sed indution therpy. All ptients reeived study therpy immeditely following yles of pltinum-sed tretment for lolly dvned or metstti NSCLC. Ptients in oth study rms were fully supplemented with foli id nd vitmin B. Tle : Adverse Retions in Ptients Reeiving versus Pleo in NSCLC Following Pltinum-Bsed Indution Therpy Retion All Grdes (N=) Grde - All Grdes Pleo (N=) Grde - All Adverse Retions 7 Lortory Hemtologi Anemi Neutropeni Leukopeni Hepti Inresed ALT Inresed AST Clinil Constitutionl Symptoms Ftigue Gstrointestinl Nuse Anorexi Vomiting Muositis/stomtitis Dirrhe Infetion Neurology Neuropthy-sensory 9 Dermtology/Skin Rsh/Desqumtion For the purpose of this tle ut off of % ws used for inlusion of ll events where the reporter onsidered possile reltionship to. Refer to NCI CTCAE Criteri version. for eh Grde of toxiity. No linilly relevnt differenes in Grde / dverse retions were seen in ptients sed on ge, gender, ethni origin, or histology exept higher inidene of Grde / ftigue for Cusin ptients ompred to non-cusin ptients (.% versus.%). Sfety ws ssessed y exposure for ptients who reeived t lest one dose of (N=). The inidene of dverse retions ws evluted for ptients who reeived yles of, nd ompred to ptients who reeived > yles of. Inreses in dverse retions (ll grdes) were oserved with longer exposure; however no linilly relevnt differenes in Grde / dverse retions were seen. Consistent with the higher inidene of nemi (ll grdes) on the rm, use of trnsfusions (minly RBC) nd erythropoiesis stimulting gents (ESAs; erythropoietin nd drepoetin) were higher in the rm ompred to the pleo rm (trnsfusions 9.% versus.%, ESAs.9% versus.%). The following dditionl dverse retions were oserved in ptients with non-smll ell lung ner who reeived. Inidene % to % Dermtology/Skin lopei, pruritis/ithing Gstrointestinl onstiption Generl Disorders edem, fever (in the sene of neutropeni) Hemtologi thromoytopeni Renl deresed retinine lerne, inresed retinine, deresed glomerulr filtrtion rte Speil Senses oulr surfe disese (inluding onjuntivitis), inresed lrimtion Inidene Less thn % Crdiovsulr suprventriulr rrhythmi Dermtology/Skin erythem multiforme Generl Disorders ferile neutropeni, llergi retion/hypersensitivity Neurology motor neuropthy Renl renl filure Continution of s Mintenne Following Plus Pltinum Indution Therpy Tle provides the frequeny nd severity of dverse retions reported in >% of the ptients with non-squmous NSCLC who reeived t lest one yle of mintenne (n=) or pleo (n=7) on the ontinution mintenne tril. The medin of mintenne yles dministered to ptients reeiving one or more doses of mintenne therpy ws on oth the pemetrexed nd pleo rms. Dose redutions for dverse events ourred in.% of ptients in the rm nd.% in the pleo rm. Dose delys for dverse events ourred in % of ptients in the rm nd % in the pleo rm. Ptients in oth study rms were supplemented with foli id nd vitmin B. (pemetrexed for injetion), for Intrvenous Use PV 97 AMP (pemetrexed for injetion), for Intrvenous Use PV 97 AMP PI PV97AMP W/ PPI PXAMP PRINTER VERSION OF

9 Tle : Seleted Adverse Retions Ourring in % of Ptients Reeiving in Nonsqumous NSCLC Following Plus Cispltin Indution Therpy Adverse Retion Orgn (N=) Pleo (N=7) System nd Term All Grdes Grde - All Grdes Grdes - All Adverse Retions 7. Lortory Hemtologi Anemi Neutropeni 9 Clinil Constitutionl Symptoms Ftigue.. Gstrointestinl Nuse Vomiting Muositis/stomtitis Generl Disorders Edem. Adverse retions of ny severity (ll grdes) ourring more frequently ( %) or Grde - dverse retions ourring more frequently ( %) in -treted ptients ompred to those reeiving pleo. NCI CTCAE Criteri version. Administrtion of RBC (% versus.%) nd pltelet (.% versus.%) trnsfusions, erythropoiesis stimulting gents (% versus 7%), nd grnuloyte olony stimulting ftors (% versus ) were higher in the rm ompred to the pleo rm. The following dditionl Grde or dverse retions were oserved more frequently in the rm. Inidene % to % Blood/Bone Mrrow thromoytopeni Generl Disorders ferile neutropeni Inidene Less thn % Crdiovsulr ventriulr thyrdi, synope Generl Disorders pin Gstrointestinl gstrointestinl ostrution Neurologi depression Renl renl filure Vsulr pulmonry emolism Non-Smll Cell Lung Cner (NSCLC) After Prior Chemotherpy Tle 7 provides the frequeny nd severity of dverse retions tht hve een reported in >% of ptients rndomly ssigned to reeive single-gent with foli id nd vitmin B supplementtion nd 7 ptients rndomly ssigned to reeive single-gent doetxel. All ptients were dignosed with lolly dvned or metstti NSCLC nd reeived prior hemotherpy. Tle 7: Adverse Retions in Fully Supplemented Ptients Reeiving versus Doetxel in NSCLC Retion Lortory Hemtologi Anemi Leukopeni Neutropeni Thromoytopeni Hepti Inresed ALT Inresed AST Clinil Gstrointestinl Nuse Anorexi Vomiting Stomtitis/Phryngitis Dirrhe Constiption Constitutionl Symptoms Ftigue Fever Dermtology/Skin Rsh/Desqumtion Pruritis Alopei All Grdes (N=)..9.. Grdes All Grdes 7 7 Doetxel (N=7). Grdes - For the purpose of this tle ut off of % ws used for inlusion of ll events where the reporter onsidered possile reltionship to. Refer to NCI CTC Criteri for l vlues for eh Grde of toxiity (version.). Aording to NCI CTC Criteri version., this dverse event term should only e reported s Grde or. No linilly relevnt differenes in dverse retions were seen in ptients sed on histology. Clinilly relevnt dverse retions ourring in <% of ptients tht reeived tretment ut >% of ptients tht reeived doetxel inlude CTC Grde / ferile neutropeni (.9%,.7% doetxel). The following dditionl dverse retions were oserved in ptients with non-smll ell lung ner rndomly ssigned to reeive. 7 Inidene % to % Body s Whole dominl pin, llergi retion/hypersensitivity, ferile neutropeni, infetion Dermtology/Skin erythem multiforme Neurology motor neuropthy, sensory neuropthy Renl inresed retinine Inidene Less thn % Crdiovsulr suprventriulr rrhythmis Mlignnt Pleurl Mesotheliom (MPM) Tle provides the frequeny nd severity of dverse retions tht hve een reported in >% of ptients with mesotheliom who were rndomly ssigned to reeive ispltin nd nd ptients with mesotheliom rndomly ssigned to reeive single-gent ispltin. In oth tretment rms, these hemonive ptients were fully supplemented with foli id nd vitmin B. Tle : Adverse Retions in Fully Supplemented Ptients Reeiving plus Cispltin in MPM (pemetrexed for injetion), for Intrvenous Use PV 97 AMP (pemetrexed for injetion), for Intrvenous Use PV 97 AMP Retion Lortory Hemtologi Neutropeni Leukopeni Anemi Thromoytopeni Renl Cretinine elevtion Cretinine lerne deresed /ispltin (N=) All Grdes Grde - All Grdes 7 9 Cispltin (N=) Grde - Clinil Eye Disorder Conjuntivitis Gstrointestinl Nuse Vomiting Stomtitis/Phryngitis Anorexi Dirrhe Constiption Dyspepsi 7 7 Constitutionl Symptoms Ftigue 9 Metolism nd Nutrition Dehydrtion 7 Neurology Neuropthy-sensory Tste Disturne Dermtology/Skin Rsh Alopei 77 7 For the purpose of this tle ut off of % ws used for inlusion of ll events where the reporter onsidered possile reltionship to. Refer to NCI CTC Criteri version. for eh Grde of toxiity exept the term retinine lerne deresed whih is derived from the CTC term renl/genitourinry-other. Aording to NCI CTC Criteri version., this dverse event term should only e reported s Grde or. The following dditionl dverse retions were oserved in ptients with mlignnt pleurl mesotheliom rndomly ssigned to reeive plus ispltin. Inidene % to % Body s Whole ferile neutropeni, infetion, pyrexi Dermtology/Skin urtiri Generl Disorders hest pin Metolism nd Nutrition inresed AST, inresed ALT, inresed GGT Renl renl filure Inidene Less thn % Crdiovsulr rrhythmi Neurology motor neuropthy Effets of Vitmin Supplementtions on Toxiity Tle 9 ompres the inidene (perentge of ptients) of CTC Grde / toxiities in ptients who reeived vitmin supplementtion with dily foli id nd vitmin B from the time of enrollment in the study (fully supplemented) with the inidene in ptients who never reeived vitmin supplementtion (never supplemented) during the study in the plus ispltin rm. Tle 9: Seleted Grde / Adverse Events Compring Fully Supplemented versus Never Supplemented Ptients in the plus Cispltin rm (% inidene) Fully Supplemented Never Supplemented Adverse Event (%) Ptients (N=) Ptients (N=) Neutropeni/grnuloytopeni Thromoytopeni 9 Vomiting Ferile neutropeni 9 Infetion with Grde / neutropeni Dirrhe 9 Refer to NCI CTC riteri for l nd non-lortory vlues for eh grde of toxiity (Version.). PI PV97AMP W/ PPI PXAMP PRINTER VERSION OF

10 The following dverse events were greter in the fully supplemented group ompred to the never supplemented group: hypertension (%, %), hest pin (%, %), nd thromosis/emolism (%, %). No relevnt effet for sfety due to gender or re ws identified, exept n inresed inidene of rsh in men (%) ompred to women (%). Additionl Experiene Aross Clinil Trils Sepsis, whih in some ses ws ftl, ourred in pproximtely % of ptients. Esophgitis ourred in less thn % of ptients.. Postmrketing Experiene The following dverse retions hve een identified during post-pprovl use of. Beuse these retions re reported voluntrily from popultion of unertin size, it is not lwys possile to relily estimte their frequeny or estlish usl reltionship to drug exposure. These retions ourred with when used s single-gent nd in omintion therpies. Blood nd Lymphti System immune-medited hemolyti nemi Gstrointestinl olitis, pnretitis Generl Disorders nd Administrtion Site Conditions edem Injury, poisoning, nd proedurl omplitions Rdition rell hs een reported in ptients who hve previously reeived rdiotherpy. Respirtory interstitil pneumonitis Skin Bullous onditions, inluding Stevens-Johnson syndrome nd toxi epiderml nerolysis. Some ses were ftl. 7 DRUG INTERACTIONS 7. Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) Although iuprofen ( mg four times dy) n derese the lerne of pemetrexed, it n e dministered with in ptients with norml renl funtion (retinine lerne ml/min). No dose djustment of is needed with onomitnt NSAIDs in ptients with norml renl funtion [see Clinil Phrmology (.)]. Cution should e used when dministering NSAIDs onurrently with to ptients with mild to moderte renl insuffiieny (retinine lerne from to 79 ml/min). NSAIDs with short elimintion hlf-lives (e.g., dilofen, indomethin) should e voided for period of dys efore, the dy of, nd dys following dministrtion of. In the sene of dt regrding potentil intertion etween nd NSAIDs with longer hlf-lives (e.g., meloxim, numetone), ptients tking these NSAIDs should interrupt dosing for t lest dys efore, the dy of, nd dys following dministrtion. If onomitnt dministrtion of NSAIDs is neessry, ptients should e monitored losely for toxiity, espeilly myelosuppression, renl, nd gstrointestinl toxiity. 7. Nephrotoxi Drugs is primrily eliminted unhnged renlly s result of glomerulr filtrtion nd tuulr seretion. Conomitnt dministrtion of nephrotoxi drugs ould result in delyed lerne of. Conomitnt dministrtion of sustnes tht re lso tuulrly sereted (e.g., proeneid) ould potentilly result in delyed lerne of. USE IN SPECIFIC POPULATIONS. Pregnny Tertogeni Effets Pregnny Ctegory D [see Wrnings nd Preutions (.)] Bsed on its mehnism of tion, n use fetl hrm when dministered to pregnnt womn. There re no dequte nd well ontrolled studies of in pregnnt women. Pemetrexed ws emryotoxi, fetotoxi, nd tertogeni in mie. In mie, repeted intrperitonel doses of pemetrexed when given during orgnogenesis used fetl mlformtions (inomplete ossifition of tlus nd skull one; out /rd the reommended intrvenous humn dose on mg/m sis), nd left plte (/rd the reommended intrvenous humn dose on mg/m sis). Emryotoxiity ws hrterized y inresed emryo-fetl deths nd redued litter sizes. If is used during pregnny, or if the ptient eomes pregnnt while tking this drug, the ptient should e pprised of the potentil hzrd to the fetus. Women of hildering potentil should e dvised to use effetive ontreptive mesures to prevent pregnny during the tretment with.. Nursing Mothers It is not known whether or its metolites re exreted in humn milk. Beuse mny drugs re exreted in humn milk, nd euse of the potentil for serious dverse retions in nursing infnts from, deision should e mde to disontinue nursing or disontinue the drug, tking into ount the importne of the drug for the mother.. Peditri Use Effiy of in peditri ptients hs not een demonstrted. ws dministered s n intrvenous infusion over minutes on Dy of dy yle to peditri ptients with reurrent solid tumors in Phse study ( ptients) nd Phse study (7 ptients). All ptients reeived pretretment with vitmin B nd foli id supplementtion nd dexmethsone. The dose esltion in the Phse study determined the mximum tolerted dose ws 9 mg/m nd this dose (or mg/kg for ptients < months old) ws evluted in the Phse study of ptients with relpsed or refrtory osteosrom, Ewing srom/ peripherl PNET, rhdomyosrom, neurolstom, ependymom, medullolstom/suprtentoril PNET, or non-rinstem high grde gliom. No responses were oserved mong the 7 ptients in this Phse tril. The most ommon toxiities reported were hemtologil (leukopeni, neutropeni/grnuloytopeni, nemi, thromoytopeni, nd lymphopeni), liver funtion normlities (inresed ALT/AST), ftigue, nd nuse. The single dose phrmokinetis of dministered in doses rnging from to mg/m were evluted in the Phse tril in ptients ( mles nd 9 femles) ged to yers (verge ge yers). Pemetrexed exposure (AUC nd C mx ) ppered to inrese proportionlly with dose. The verge pemetrexed lerne (. L/h/m ) nd hlf-life (. hours) in peditri ptients were omprle to vlues reported in dults.. Geritri Use is known to e sustntilly exreted y the kidney, nd the risk of dverse retions to this drug my e greter in ptients with impired renl funtion. Renl funtion monitoring is reommended with dministrtion of. No dose redutions other thn those reommended for ll ptients re neessry for ptients yers of ge or older [see Dosge nd Administrtion (.)]. Of,9 ptients (.% ) studied ross the five linil trils [see Clinil Studies (.,.,., nd.)], the effet of on survivl ws similr in ptients < ompred to yers of ge. There were no differenes in sfety with the exeption of the following Grde - dverse retions, whih were noted in t lest one of the five trils to e greter in ptients yers of ge nd older s ompred to younger ptients: nemi, ftigue, thromoytopeni, hypertension, nd neutropeni.. Ptients with Hepti Impirment There ws no effet of elevted AST, ALT, or totl iliruin on the phrmokinetis of pemetrexed. However, no forml studies hve een onduted to exmine the phrmokinetis of pemetrexed in ptients with hepti impirment [see Clinil Phrmology (.)]..7 Ptients with Renl Impirment is known to e primrily exreted y the kidneys. Deresed renl funtion will result in redued lerne nd greter exposure (AUC) to ompred with ptients with norml renl funtion [see Dosge nd Administrtion (.) nd Clinil Phrmology (.)]. Cispltin odministrtion with hs not een studied in ptients with moderte renl impirment.. Gender Of,9 ptients (Mle 7.%) studied ross the five registrtion studies for inditions [see Clinil Studies (.,.,., nd.)], the effet of on survivl ws similr in femle nd mle ptients..9 Re Of,9 ptients (Cusin 7.%) studied ross the five registrtion studies for inditions [see Clinil Studies (.,.,., nd.)], the effet of on survivl ws similr in the Cusin nd non-cusin ptients. OVERDOSAGE There hve een few ses of overdose. Reported toxiities inluded neutropeni, nemi, thromoytopeni, muositis, nd rsh. Antiipted omplitions of overdose inlude one mrrow suppression s mnifested y neutropeni, thromoytopeni, nd nemi. In ddition, infetion with or without fever, dirrhe, nd muositis my e seen. If n overdose ours, generl supportive mesures should e instituted s deemed neessry y the treting physiin. In linil trils, leuovorin ws permitted for CTC Grde leukopeni lsting dys, CTC Grde neutropeni lsting dys, nd immeditely for CTC Grde thromoytopeni, leeding ssoited with Grde thromoytopeni, or Grde or muositis. The following intrvenous doses nd shedules of leuovorin were reommended for intrvenous use: mg/m, intrvenously one, followed y leuovorin, mg/m, intrvenously every hours for dys. The ility of to e dilyzed is unknown. DESCRIPTION Pemetrexed disodium hepthydrte hs the hemil nme L-Glutmi id, N-[-[-(-mino-, 7-dihydro--oxo-H-pyrrolo[,-d]pyrimidin--yl)ethyl]enzoyl]-, disodium slt, hepthydrte. It is white to lmost-white solid with moleulr formul of C H 9 N N O 7H O nd moleulr weight of The struturl formul is s follows: is supplied s sterile lyophilized powder for intrvenous infusion ville in single-dose vils. The produt is white to either light yellow or green-yellow lyophilized solid. Eh -mg or -mg vil of ontins pemetrexed disodium equivlent to mg pemetrexed nd mg mnnitol or mg pemetrexed nd mg mnnitol, respetively. Hydrohlori id nd/or sodium hydroxide my hve een dded to djust ph. CLINICAL PHARMACOLOGY. Mehnism of Ation, pemetrexed for injetion, is folte nlog metoli inhiitor tht exerts its tion y disrupting folte-dependent metoli proesses essentil for ell replition. In vitro studies hve shown tht pemetrexed inhiits thymidylte synthse (TS), dihydrofolte redutse (DHFR), nd glyinmide rionuleotide formyltrnsferse (GARFT), whih re folte-dependent enzymes involved in the de novo iosynthesis of thymidine nd purine nuleotides. Pemetrexed is tken into ells y memrne rriers suh s the redued folte rrier nd memrne folte inding protein trnsport systems. One in the ell, pemetrexed is onverted to polyglutmte forms y the enzyme folylpolyglutmte synthetse. The polyglutmte forms re retined in ells nd re inhiitors of TS nd GARFT. Polyglutmtion is time- nd onentrtion-dependent proess tht ours in tumor ells nd, is thought to our to lesser extent, in norml tissues. Polyglutmted metolites re thought to hve n inresed intrellulr hlf-life resulting in prolonged drug tion in mlignnt ells.. Phrmodynmis Prelinil studies hve shown tht pemetrexed inhiits the in vitro growth of mesotheliom ell lines (MSTO-H, NCI-H). Studies with the MSTO-H mesotheliom ell line showed synergisti effets when pemetrexed ws omined onurrently with ispltin. Asolute neutrophil ounts (ANC) following single-gent dministrtion of to ptients not reeiving foli id nd vitmin B supplementtion were hrterized using popultion phrmodynmi nlyses. Severity of hemtologi toxiity, s mesured y the depth of the ANC ndir, orreltes with the systemi exposure, or re under the urve (AUC) of pemetrexed. It ws lso oserved tht lower ANC ndirs ourred in ptients with elevted seline ystthionine or homoysteine onentrtions. The levels of these sustnes n e redued y foli id nd vitmin B supplementtion. There is no umultive effet of pemetrexed exposure on ANC ndir over multiple tretment yles. Time to ANC ndir with pemetrexed systemi exposure (AUC), vried etween to 9. dys over rnge of exposures from. to. mg hr/ml. Return to seline ANC ourred. to 7. dys fter the ndir over the sme rnge of exposures.. Phrmokinetis Asorption The phrmokinetis of dministered s single-gent in doses rnging from. to mg/m infused over -minute period hve een evluted in ner ptients with vriety of solid tumors. Pemetrexed totl systemi exposure (AUC) nd mximum plsm onentrtion (C mx ) inrese proportionlly with dose. The phrmokinetis of pemetrexed do not hnge over multiple tretment yles. (pemetrexed for injetion), for Intrvenous Use PV 97 AMP (pemetrexed for injetion), for Intrvenous Use PV 97 AMP PI PV97AMP W/ PPI PXAMP PRINTER VERSION OF