injection dose based on adverse reactions. ( 2.3 , 2.4 , 5.6 ) embryo-fetal toxicity : can cause fetal harm. advise patients of the potential risk to a fetus and to use an effective method of contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 myelosuppression pralatrexate injection can cause myelosuppression, manifested by thrombocytopenia, neutropenia, and/or anemia. administer vitamin b 12 and instruct patients to take folic acid to reduce the risk of treatment-related myelosuppression [see dosage and administration ( 2.1 )]. monitor complete blood counts and omit and/or reduce the dose based on anc and platelet count prior to each dose [see dosage and administration ( 2.4 )] . 5.2 mucositis pralatrexate injection can cause mucositis [see adverse reactions ( 6.1 )] . administer vitamin b 12 and instruct patients to take folic acid to reduce the risk of mucositis [see dosage and administration ( 2.1 )]. monitor for mucositis weekly and omit and/or reduce the dose for grade 2 or higher mucositis [see dosage and administration ( 2.4 )]. 5.3 dermatologic reactions pralatrexate injection can cause severe dermatologic reactions, which may result in death. these dermatologic reactions have been reported in clinical studies (2.1% of 663 patients) and post marketing experience, and have included skin exfoliation, ulceration, and toxic epidermal necrolysis (ten) [see adverse reactions ( 6.1 , 6.2 )] . they may be progressive and increase in severity with further treatment and may involve skin and subcutaneous sites of known lymphoma. monitor closely for dermatologic reactions. withhold or discontinue pralatrexate injection based on severity [see dosage and administration ( 2.4 )]. 5.4 tumor lysis syndrome pralatrexate injection can cause tumor lysis syndrome (tls). monitor patients who are at increased risk of tls and treat promptly. 5.5 hepatic toxicity pralatrexate injection can cause hepatic toxicity and liver function test abnormalities [see adverse reactions ( 6.1 )] . persistent liver function test abnormalities may be indicators of hepatic toxicity and require dose modification or discontinuation. monitor liver function tests. omit dose until recovery, adjust or discontinue therapy based on the severity of the hepatic toxicity [see dosage and administration ( 2.4 )]. 5.6 risk of increased toxicity with renal impairment patients with severe renal impairment (egfr 15 to < 30 ml/min/1.73 m 2 based on mdrd) may be at greater risk for increased exposure and adverse reactions. reduce pralatrexate injection dosage in patients with severe renal impairment [see dosage and administration ( 2.3 )] . serious adverse reactions, including ten and mucositis, were reported in patients with end stage renal disease (esrd) undergoing dialysis who were administered pralatrexate injection. avoid pralatrexate injection in patients with esrd with or without dialysis. if the potential benefit of administration justifies the potential risk, monitor renal function and reduce the pralatrexate injection dose based on adverse reactions [see dosage and administration ( 2.3 )] . 5.7 embryo-fetal toxicity based on findings in animals and its mechanism of action, pralatrexate injection can cause fetal harm when administered to a pregnant woman. pralatrexate injection was embryotoxic and fetotoxic in rats and rabbits. advise pregnant women of the potential risk to a fetus. advise females of reproductive potential to use effective contraception during treatment with pralatrexate injection and for 6 months after the last dose. advise males with female partners of reproductive potential to use effective contraception during treatment with pralatrexate injection and for 3 months after the last dose [see use in specific populations ( 8.1 , 8.3 )] .

tion and every 8-10 weeks thereafter. subsequent vitamin b 12 injections may be given the same day as treatment with pralatrexate injection [see warnings and precautions ( 5.1 , 5.2 )]. 2.2 recommended dosage the recommended dosage of pralatrexate injection is 30 mg/m 2 intravenously over 3-5 minutes once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity. 2.3 dosage modifications for renal impairment and end stage renal disease severe renal impairment (egfr 15 to 29 ml/min/1.73 m 2 by mdrd): reduce the pralatrexate injection dose to 15 mg/m 2 [see use in specific populations ( 8.6 )] . end stage renal disease (esrd: egfr less than 15 ml/min/1.73 m 2 by mdrd) with or without dialysis: avoid administration. if the potential benefit of administration justifies the potential risk, monitor renal function and reduce the pralatrexate injection dose based on adverse reactions [see warnings and precautions ( 5.6 ), use in specific populations ( 8.6 )] . 2.4 monitoring and dosage modifications for adverse reactions monitoring monitor complete blood cell counts and severity of mucositis at baseline and weekly. perform serum chemistry tests, including renal and hepatic function, prior to the start of the first and fourth dose of each cycle. recommended dosage modifications do not administer pralatrexate injection until: mucositis grade 1 or less. platelet of 100,000/mcl or greater for first dose and 50,000/mcl or greater for all subsequent doses. absolute neutrophil count (anc) of 1,000/mcl or greater. dosage modifications for adverse reactions are provided in tables 1 , 2 , and 3 . table 1 pralatrexate injection dosage modifications for mucositis a based national cancer institute common terminology criteria for adverse events (nci ctcae version 3.0) mucositis grade a on day of treatment action recommended dose upon recovery to grade 0 or 1 patients without severe renal impairment patients with severe renal impairment grade 2 omit dose continue prior dose continue prior dose grade 2 recurrence omit dose 20 mg/m 2 10 mg/m 2 grade 3 omit dose 20 mg/m 2 10 mg/m 2 grade 4 stop therapy table 2 pralatrexate injection dosage modifications for myelosuppression g-csf=granulocyte colony-stimulating factor; gm-csf=granulocyte macrophage colony-stimulating factor blood count on day of treatment duration of toxicity action recommended dose upon recovery patients without severe renal impairment patients with severe renal impairment platelet less than 50,000/mcl 1 week omit dose continue prior dose continue prior dose 2 weeks omit dose 20 mg/m 2 10 mg/m 2 3 weeks stop therapy anc 500 to 1,000/mcl and no fever 1 week omit dose continue prior dose continue prior dose anc 500 to 1,000/mcl with fever or anc less than 500/mcl 1 week omit dose, give g-csf or gm-csf continue prior dose with g-csf or gm-csf continue prior dose with g-csf or gm-csf 2 weeks or recurrence omit dose, give g-csf or gm-csf 20 mg/m 2 with g-csf or gm-csf 10 mg/m 2 with g-csf or gm-csf 3 weeks or 2 nd recurrence stop therapy table 3 pralatrexate injection dosage modifications for all other adverse reactions a based on nci ctcae version 3.0 toxicity grade a on day of treatment action recommended dose upon recovery to grade 2 or lower patients without severe renal impairment patients with severe renal impairment grade 3 omit dose 20 mg/m 2 10 mg/m 2 grade 4 stop therapy 2.5 preparation and administration parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. do not use any vials exhibiting particulate matter or discoloration. pralatrexate injection is a hazardous drug. follow applicable special handling and disposal procedures. 1 if pralatrexate injection comes in contact with the skin, immediately and thoroughly wash with soap and water. if pralatrexate injection comes in contact with mucous membranes, flush thoroughly with water. aseptically withdraw the calculated dose from the appropriate number of vial(s) into a syringe for immediate use. do not dilute pralatrexate injection. administer undiluted pralatrexate injection intravenously over 3-5 minutes via the side port of a free-flowing 0.9% sodium chloride injection. after withdrawal of dose, discard vial(s) including any unused portion.

s evaluated in study pdx-008 [see clinical studies ( 14 )]. patients received pralatrexate injection 30 mg/m 2 once weekly for 6 weeks in 7-week cycles. the median duration of treatment was 70 days (range: 1 day to 1.5 years). the majority of patients (69%, n = 77) remained at the target dose for the duration of treatment. overall, 85% of scheduled doses were administered. forty-four percent of patients (n = 49) experienced a serious adverse event while on study or within 30 days after their last dose of pralatrexate injection. the most common serious adverse events (> 3%), regardless of causality, were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. one death from cardiopulmonary arrest in a patient with mucositis and febrile neutropenia was reported in this trial. across clinical trials, deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients who received doses ranging from 30 mg/m 2 to 325 mg/m 2 . twenty-three percent of patients (n = 25) discontinued treatment with pralatrexate injection due to adverse reactions. the most frequent adverse reactions reported as the reason for discontinuation of treatment were mucositis (6%) and thrombocytopenia (5%). the most common adverse reactions (> 35%) were mucositis, thrombocytopenia, nausea, and fatigue. table 4 summarizes the adverse reactions in study pdx-008. table 4 adverse reactions in (≥ 10%) in patients who received pralatrexate injection in study pdx-008 a mucositis includes stomatitis or mucosal inflammation of the gastrointestinal and genitourinary tracts. b five patients with platelets < 10,000/mcl. c liver function test abnormal includes increased alt, increased ast, and increased transaminases pralatrexate injection n=111 all grades (%) grade 3 (%) grade 4 (%) any adverse reaction 100 43 31 mucositis a 70 17 4 thrombocytopenia b 41 14 19 b nausea 40 4 0 fatigue 36 5 2 anemia 34 15 2 constipation 33 0 0 pyrexia 32 1 1 edema 30 1 0 cough 28 1 0 epistaxis 26 0 0 vomiting 25 2 0 neutropenia 24 13 7 diarrhea 21 2 0 dyspnea 19 7 0 anorexia 15 3 0 hypokalemia 15 4 1 rash 15 0 0 pruritus 14 2 0 pharyngolaryngeal pain 14 1 0 liver function test abnormal c 13 5 0 abdominal pain 12 4 0 pain in extremity 12 0 0 back pain 11 3 0 leukopenia 11 3 4 night sweats 11 0 0 asthenia 10 1 0 upper respiratory tract infection 10 1 0 tachycardia 10 0 0 6.2 postmarketing experience the following adverse reactions have been identified during postapproval use of pralatrexate injection. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. dermatologic reactions: toxic epidermal necrolysis.

15-20%, respectively. data animal data pralatrexate was embryotoxic and fetotoxic in rats at intravenous doses of 0.06 mg/kg/day (0.36 mg/m 2 /day or about 1.2% of the clinical dose on a mg/m 2 basis) given on gestation days 7 through 20. treatment with pralatrexate caused a dose-dependent decrease in fetal viability manifested as an increase in late, early, and total resorptions. there was also a dosedependent increase in post-implantation loss. in rabbits, intravenous doses of 0.03 mg/kg/day (0.36 mg/m 2 /day) or greater given on gestation days 8 through 21 also caused abortion and fetal lethality. this toxicity manifested as early and total resorptions, post-implantation loss, and a decrease in the total number of live fetuses. 8.2 lactation risk summary there is no data on the presence of pralatrexate in human milk or its effects on the breastfed child or milk production. because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with pralatrexate injection and for 1 week after the last dose. 8.3 females and males of reproductive potential pralatrexate injection can cause fetal harm when administered to a pregnant woman [see use in specific populations ( 8.1 ) ] . pregnancy testing verify pregnancy status in females of reproductive potential prior to initiation of pralatrexate injection. contraception females advise females of reproductive potential to use effective contraception during treatment with pralatrexate injection and for 6 months following the last dose. males advise males with female partners of reproductive potential to use effective contraception during treatment with pralatrexate injection and for 3 months following the last dose. 8.4 pediatric use the safety and effectiveness of pralatrexate injection in pediatric patients have not been established. 8.5 geriatric use in the study pdx-008, 36% of patients (n = 40) were 65 years of age and over. no overall differences in efficacy and safety were observed in patients based on age (< 65 years compared with ≥ 65 years). due to the contribution of renal excretion to overall clearance of pralatrexate (approximately 34%), age-related decline in renal function may lead to a reduction in clearance and a commensurate increase in plasma exposure. in general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. since elderly patients may be at higher risk, monitor more closely. omit dose and subsequently adjust or discontinue therapy for adverse reactions [see dosage and administration ( 2.4 )]. 8.6 renal impairment no dosage modification is recommended for patients with mild or moderate renal impairment (egfr 30 to 59 ml/min/1.73 m 2 based on mdrd). for patients with severe renal impairment (egfr 15 to 29 ml/min/1.73 m 2 ), reduce the recommended dose of pralatrexate injection [see dosage and administration ( 2.3 )] . serious adverse drug reactions, including ten and mucositis, have been reported in patients with esrd undergoing dialysis. avoid the use of pralatrexate injection in patients with esrd with or without dialysis. if the potential benefit of administration justifies the potential risk, monitor renal function and reduce the pralatrexate injection dose based on adverse reactions [see dosage and administration ( 2.3 ), warnings and precautions ( 5.6 )].

otoxic in rats at intravenous doses of 0.06 mg/kg/day (0.36 mg/m 2 /day or about 1.2% of the clinical dose on a mg/m 2 basis) given on gestation days 7 through 20. treatment with pralatrexate caused a dose-dependent decrease in fetal viability manifested as an increase in late, early, and total resorptions. there was also a dosedependent increase in post-implantation loss. in rabbits, intravenous doses of 0.03 mg/kg/day (0.36 mg/m 2 /day) or greater given on gestation days 8 through 21 also caused abortion and fetal lethality. this toxicity manifested as early and total resorptions, post-implantation loss, and a decrease in the total number of live fetuses.

y-state volume of distribution of pralatrexate s- and r-diastereomers is 105 l and 37 l, respectively. protein binding of pralatrexate is approximately 67% in vitro. elimination the total systemic clearance of pralatrexate diastereomers was 417 ml/min ( s -diastereomer) and 191 ml/min ( r -diastereomer). the terminal elimination half-life of pralatrexate was 12-18 hours (coefficient of variance [cv] = 62-120%). metabolism pralatrexate is not significantly metabolized by cyp450 isozymes or glucuronidases in vitro. excretion following a single dose of pralatrexate injection 30 mg/m 2 , approximately 34% of the pralatrexate dose was excreted unchanged into urine. following a radiolabeled pralatrexate dose, 39% (cv = 28%) of the dose was recovered in urine as unchanged pralatrexate and 34% (cv = 88%) in feces as unchanged pralatrexate and/or any metabolites. 10% (cv = 95%) of the dose was exhaled over 24 hours. specific populations no clinically meaningful effect on the pharmacokinetics of pralatrexate was observed based on sex. the effect of hepatic impairment on the pharmacokinetics of pralatrexate has not been studied. patients with renal impairment following administration of a single dose of pralatrexate injection, mean exposures of the pralatrexate s-diastereomer and r-diastereomer were comparable in patients with mild to moderate (egfr 30 to 59 ml/min/1.73 m 2 based on mdrd) renal impairment as compared with severe (egfr 15 to 29 ml/min/1.73 m 2 ) renal impairment. the mean fraction of the administered dose excreted as unchanged diastereomers in urine (f e ) decreased with declining renal function [see use in specific populations ( 8.6 )] . drug interaction studies clinical studies coadministration of probenecid (an inhibitor of multidrug resistance-associated protein 2 [mrp2] in vitro) resulted in delayed clearance of pralatrexate. in vitro studies cytochrome p450 (cyp) enzymes : pralatrexate does not induce or inhibit cyp enzymes. transporter systems : pralatrexate is a substrate for bcrp, mrp2, mrp3, and oatp1b3, but is not a substrate of p-gp, oatp1b1, oct2, oat1, or oat3. pralatrexate inhibits mrp2 and mrp3, but does not inhibit p-gp, bcrp, oct2, oat1, oat3, oatp1b1, or oatp1b3. mrp3 is a transporter that may affect the transport of etoposide and teniposide.

following a single dose of pralatrexate injection 30 mg/m 2 , approximately 34% of the pralatrexate dose was excreted unchanged into urine. following a radiolabeled pralatrexate dose, 39% (cv = 28%) of the dose was recovered in urine as unchanged pralatrexate and 34% (cv = 88%) in feces as unchanged pralatrexate and/or any metabolites. 10% (cv = 95%) of the dose was exhaled over 24 hours. specific populations no clinically meaningful effect on the pharmacokinetics of pralatrexate was observed based on sex. the effect of hepatic impairment on the pharmacokinetics of pralatrexate has not been studied. patients with renal impairment following administration of a single dose of pralatrexate injection, mean exposures of the pralatrexate s-diastereomer and r-diastereomer were comparable in patients with mild to moderate (egfr 30 to 59 ml/min/1.73 m 2 based on mdrd) renal impairment as compared with severe (egfr 15 to 29 ml/min/1.73 m 2 ) renal impairment. the mean fraction of the administered dose excreted as unchanged diastereomers in urine (f e ) decreased with declining renal function [see use in specific populations ( 8.6 )] . drug interaction studies clinical studies coadministration of probenecid (an inhibitor of multidrug resistance-associated protein 2 [mrp2] in vitro) resulted in delayed clearance of pralatrexate. in vitro studies cytochrome p450 (cyp) enzymes : pralatrexate does not induce or inhibit cyp enzymes. transporter systems : pralatrexate is a substrate for bcrp, mrp2, mrp3, and oatp1b3, but is not a substrate of p-gp, oatp1b1, oct2, oat1, or oat3. pralatrexate inhibits mrp2 and mrp3, but does not inhibit p-gp, bcrp, oct2, oat1, oat3, oatp1b1, or oatp1b3. mrp3 is a transporter that may affect the transport of etoposide and teniposide.

esponse assessments were scheduled at the end of cycle 1 and then every other cycle (every 14 weeks). duration of response was measured from the first day of documented response to disease progression or death. response and disease progression were evaluated by independent central review using the iwc. the median age was 59 years (range: 21 to 85); 68% were male; 72% were white, 13% were black, 8% were hispanic and 5% were asian. patients had a baseline eastern cooperative oncology group (ecog) performance status of 0 (39%), 1 (44%), or 2 (17%). the median time from initial diagnosis to study entry was 1.3 years (range 24 days to 26.8 years). the median number of prior systemic therapies was 3 (range 1 to 12). approximately 24% of patients (n = 27) did not have evidence of response to any previous therapy. approximately 63% of patients (n = 70) did not have evidence of response to their most recent prior therapy before entering the study. efficacy results are provided in table 5 . table 5 efficacy results for study pdx-008 per independent central review (iwc) fourteen patients went off treatment in cycle 1; 2 patients were unevaluable for response by iwc due to insufficient materials provided to central review. cr = complete response, cru = complete response unconfirmed, pr = partial response evaluable patients (n=109) n (%) 95% ci median duration of response range of duration of response overall response cr+cru+pr 29 (27) 19, 36 287 days (9.4 months) 1-503 days cr/cru 9 (8) pr 20 (18) responses ≥ 14 weeks cr+cru+pr 13 (12) 7, 20 not reached 98-503 days cr/cru 7 (6) pr 6 (6) the initial response assessment was scheduled at the end of cycle 1. of the responders, 66% responded within cycle 1. the median time to first response was 45 days (range 37-349 days).

reactions. instruct patients to immediately notify their healthcare provider if any skin reactions occur [see warnings and precautions ( 5.3 )]. tumor lysis syndrome inform patients about the risk of and the signs and symptoms of tumor lysis syndrome. patients should be instructed to notify their healthcare provider if they experience these symptoms [see warnings and precautions ( 5.4 )]. concomitant medications patients should be instructed to inform their healthcare provider if they are taking any concomitant medications including prescription drugs (such as trimethoprim/sulfamethoxazole and probenecid) and nonprescription drugs (such as nonsteroidal anti-inflammatory drugs) [see drug interactions ( 7.1 )]. embryo-fetal toxicity advise pregnant women and females of reproductive potential of the potential risk to a fetus. advise females or reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see warnings and precautions ( 5.7 ) and use in specific populations ( 8.1 )] . advise females patients of reproductive potential to use effective contraception during treatment with pralatrexate injection and for 6 months after the final dose [see use in specific populations ( 8.3 )] . advise males with female partners of reproductive potential to use effective contraception during treatment with pralatrexate injection and for at least 3 months after the final dose [see use in specific populations ( 8.3 )] lactation advise females women not to breastfeed during treatment with pralatrexate injection and for 1 week after the final dose [see use in specific populations ( 8.2 )] . manufactured for: lake zurich, il 60047 www.fresenius-kabi.com/us made in germany 451756 fresenius kabi logo

exate injection and for 6 months after the last dose. talk to your healthcare provider about the best birth control methods you can use during this time. tell your healthcare provider if you become pregnant or think you maybe pregnant during treatment with pralatrexate injection. males with female partners who are able to become pregnant should use effective birth control during treatment with pralatrexate injection and for 3 months after the last dose of pralatrexate injection. are breastfeeding or plan to breastfeed. it is not known if pralatrexate injection passes into your breast milk. do not breastfeed during treatment with pralatrexate injection and for 1 week after the last dose. talk to your healthcare provider about the best way to feed your baby during treatment with pralatrexate injection. tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. some medicines may affect how pralatrexate injection works. especially tell your healthcare provider if you take: sulfamethoxazole trimethoprim non-steroidal anti-inflammatory (nsaids) medicines probenecid know the medicines you take. keep a list of them and show it to your healthcare provider or pharmacist each time you start a new medicine. how will i receive pralatrexate injection? pralatrexate injection will be given to you by your healthcare provider as an intravenous (iv) injection into your vein over 3 to 5 minutes. pralatrexate injection is usually given in cycles, one time each week for 6 weeks, with no treatment on the 7th week. your healthcare provider will treat you with folic acid and vitamin b12 before and during your treatment with pralatrexate injection to help reduce the risk of possible side effects. you will take folic acid by mouth for 10 days before your first dose of pralatrexate injection. continue taking folic acid during treatment with pralatrexate injection and for 30 days after the last dose. your healthcare provider will give you a vitamin b12 injection into your muscle (intramuscular). you will get your first vitamin b12 injection 10 weeks before your first dose of pralatrexate injection and every 8 to 10 weeks during treatment with pralatrexate injection. your healthcare provider will do blood tests before and during treatment with pralatrexate injection. your healthcare provider may stop treatment, delay treatment, or change your dose of pralatrexate injection based on results of your blood tests and if you have certain side effects. what are the possible side effects of pralatrexate injection? pralatrexate injection may cause serious side effects, including: low blood cell counts: your healthcare provider will do blood tests to check your blood cell counts before and during treatment with pralatrexate injection. tell your healthcare provider right away if you develop any signs of infection, fever, bleeding or tiredness during treatment with pralatrexate injection. redness and sores of the mucous membrane lining of the mouth, lips,throat, digestive tract, and genitals (mucositis). mucositis is common with pralatrexate injection and can be severe. tell your healthcare provider if you develop redness or painful sores in your mouth or throat, or have trouble speaking, eating or drinking. your healthcare provider will tell you about ways to reduce your risk of getting mucositis, and how to maintain nutrition and help control the discomfort from mucositis. severe skin reactions. pralatrexate injection can cause severe skin reactions that may lead to death. in people with lymphoma, severe skin reactions may happen on and under your skin. tell your healthcare provider right away if you develop any of the following skin reactions: rash peeling and loss of skin sores blisters tumor lysis syndrome (tls). tls is caused by the fast breakdown of certain types of cancer cells. your healthcare provider may do blood tests to check you for tls and treat you if needed. liver problems. your healthcare provider will monitor you for liver problems during treatment with pralatrexate injection. increased risk of serious reactions in people with kidney problems. people with severe kidney problems may have a greater risk for increased serious reactions during treatment with pralatrexate injection. the most common side effects of pralatrexate injection include: low platelet blood counts, nausea, and tiredness. these are not all of the possible side effects of pralatrexate injection. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. general information about the safe and effective use of pralatrexate injection. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. this patient information leaflet summarizes the most important information about pralatrexate injection. if you would like more information, talk with your healthcare provider. you can ask your healthcare provider or pharmacist for information about pralatrexate injection that is written for health professionals. what are the ingredients in pralatrexate injection? active ingredient: pralatrexate inactive ingredients: sodium chloride, sodium hydroxide, and hydrochloric acid. manufactured for: lake zurich, il 60047 www.fresenius-kabi.com/us made in germany 451757 fresenius kabi logo