PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionThe pharmacokinetics of pralatrexate administered as single agent at dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes once weekly for weeks in 7-week cycles have been evaluated in 10 patients with PTCL. 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%). Pralatrexate total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with dose (dose range 30-325 mg/m2, including pharmacokinetics data from high-dose solid tumor clinical studies). The pharmacokinetics of pralatrexate did not change significantly over multiple treatment cycles, and no accumulation of pralatrexate was observed. DistributionPralatrexate diastereomers showed steady-state volume of distribution of 105 (S-diastereomer) and 37 (R-diastereomer). In vitro studies indicate that pralatrexate is approximately 67% bound to plasma proteins. EliminationMetabolismIn vitro studies using human hepatocytes, liver microsomes and S9 fractions, and recombinant human CYP450 isozymes showed that pralatrexate is not significantly metabolized by the phase hepatic CYP450 isozymes or phase II hepatic glucuronidases. ExcretionThe mean fraction of unchanged pralatrexate diastereomers excreted in urine following pralatrexate dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes was 31% (S-diastereomer) (CV 47%) and 38% (R-diastereomer) (CV 45%), respectively. In mass balance study conducted in patients with advanced cancer, an average of 39% (CV 28%) of the administered radiolabeled pralatrexate dose was excreted in urine as parent, racemic pralatrexate (fe). An average of 34% (CV 88%) of the administered dose was recovered in feces as total radiation (fe TR) which included both parent pralatrexate and/or any metabolites. An average of 10% (CV 95%) of total dose was exhaled as total radioactivity over 24 hours.. Pharmacokinetics in Specific PopulationsRenal ImpairmentIn patients with cancer without renal impairment, approximately 34% of pralatrexate was excreted unchanged into urine following single dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes. The pharmacokinetics of FOLOTYN was studied in patients with varying degrees of renal impairment. In patients with severe renal impairment (eGFR 15 to <30 mL/min/1.73 m2), the FOLOTYN dose was 15 mg/m2. Patients with normal renal clearance, mild renal impairment, and moderate renal impairment were all dosed with 30 mg/m2. Mean exposures of the pralatrexate S-diastereomer and R-diastereomer were comparable across cohorts. The mean fraction of the administered dose excreted as unchanged diastereomers in urine (fe) decreased with declining renal function. The non-renal clearance and volume of distribution of pralatrexate were unaffected by renal impairment [see Use in Specific Populations (8.7)]. Hepatic ImpairmentPralatrexate has not been studied in patients with hepatic impairment.GenderThere was no significant effect of gender on pharmacokinetics.. Drug InteractionsIn vitro studies indicated that pralatrexate does not induce or inhibit the activity of CYP450 isozymes at concentrations of pralatrexate that can be reasonably expected clinically. In vitro, pralatrexate is substrate for the breast cancer resistance protein (BCRP), MRP2, multidrug resistance-associated protein (MRP3), and organic anion transport protein 1B3 (OATP1B3) transporter systems at concentrations of pralatrexate that can be reasonably expected clinically. Pralatrexate is not substrate of the glycoprotein (P-gp), organic anion transport protein 1B1 (OATP1B1), organic cation transporter (OCT2), organic anion transporter (OAT1), and organic anion transporter (OAT3) transporter systems. In vitro, pralatrexate inhibits MRP2 and MRP3 transporter systems ([I]/IC50 0.1) at concentrations of pralatrexate that can be reasonably expected clinically. MRP3 is transporter that may affect the transport of etoposide and teniposide. In vitro, pralatrexate did not significantly inhibit the P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1, and OATP1B3 transporter systems at concentrations of pralatrexate that can be reasonably expected clinically.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described below and elsewhere in the labeling: oBone Marrow Suppression [see Warnings and Precautions (5.1)]oMucositis [see Warnings and Precautions (5.2)]oDermatologic Reactions [see Warnings and Precautions (5.3)]oTumor Lysis Syndrome [see Warnings and Precautions (5.4)]oHepatic Toxicity [see Warnings and Precautions (5.5)]The most common adverse reactions observed in patients with peripheral T-cell lymphoma (PTCL) treated with FOLOTYN were mucositis, thrombocytopenia, nausea, and fatigue. oBone Marrow Suppression [see Warnings and Precautions (5.1)]. oMucositis [see Warnings and Precautions (5.2)]. oDermatologic Reactions [see Warnings and Precautions (5.3)]. oTumor Lysis Syndrome [see Warnings and Precautions (5.4)]. oHepatic Toxicity [see Warnings and Precautions (5.5)]. Most common adverse reactions (>35%) are mucositis, thrombocytopenia, nausea, and fatigue. Most common serious adverse reactions are pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Allos Therapeutics, Inc at 1-888-ALLOS88 (1-888-255-6788) or www.FOLOTYN.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of FOLOTYN was evaluated in 111 PTCL patients in single-arm clinical study in which patients received starting dose of 30 mg/m2 once weekly for weeks in 7-week cycles. The median duration of treatment was 70 days (range 1-540 days). Most Frequent Adverse ReactionsTable summarizes the most frequent adverse reactions, regardless of causality, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, version 3.0). Table Adverse Reactions Occurring in PTCL Patients (Incidence >= 10% of patients) N=111TotalGrade 3Grade 4Preferred TermN%N%N%Any Adverse Event 111 100 48 43 34 31 Mucositisa 78 70 19 17 4 Thrombocytopeniab 45 41 15 14 21 19b Nausea 44 40 4 0 Fatigue 40 36 5 2 Anemia 38 34 17 15 2 Constipation 37 33 0 0 Pyrexia 36 32 1 1 Edema 33 30 1 0 Cough 31 28 1 0 Epistaxis 29 26 0 0 Vomiting 28 25 2 0 Neutropenia 27 24 14 13 7 Diarrhea 23 21 2 0 Dyspnea 21 19 7 0 Anorexia 17 15 3 0 Hypokalemia 17 15 4 1 Rash 17 15 0 0 Pruritus 16 14 2 0 Pharyngolaryngeal pain 15 14 1 0 Liver function test abnormalc 14 13 5 0 Abdominal pain 13 12 4 0 Pain in extremity 13 12 0 0 Back pain 12 11 3 0 Leukopenia 12 11 3 4 Night sweats 12 11 0 0 Asthenia 11 10 1 0 Tachycardia 11 10 0 0 Upper respiratory tract infection 11 10 1 0 cAlanine aminotransferase, aspartate aminotransferase, and transaminases increased Serious Adverse EventsForty-four percent of patients (n 49) experienced serious adverse event while on study or within 30 days after their last dose of FOLOTYN. 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 patient with mucositis and febrile neutropenia was reported in this trial. Deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated on all FOLOTYN trials at doses ranging from 30 to 325 mg/m2. DiscontinuationsTwenty-three percent of patients (n 25) discontinued treatment with FOLOTYN due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment were mucositis (6%, = 7) and thrombocytopenia (5%, = 5). Dose ModificationsThe target dose of FOLOTYN was 30 mg/m2 once weekly for weeks in 7-week cycles. The majority of patients (69%, = 77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered. 6.2 Post Marketing Experience. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Dermatologic ReactionsToxic epidermal necrolysis, sometimes fatal, has been reported during post-marketing use of FOLOTYN. Fatal cases have been reported following the first dose of FOLOTYN, including when reduced dose is given, and have been reported in patients with end-stage renal disease undergoing dialysis [see Warnings and Precautions (5.3), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Pralatrexate is folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase. It is also competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biological molecules the synthesis of which depends on single carbon transfer. 12.3 Pharmacokinetics. AbsorptionThe pharmacokinetics of pralatrexate administered as single agent at dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes once weekly for weeks in 7-week cycles have been evaluated in 10 patients with PTCL. 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%). Pralatrexate total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with dose (dose range 30-325 mg/m2, including pharmacokinetics data from high-dose solid tumor clinical studies). The pharmacokinetics of pralatrexate did not change significantly over multiple treatment cycles, and no accumulation of pralatrexate was observed. DistributionPralatrexate diastereomers showed steady-state volume of distribution of 105 (S-diastereomer) and 37 (R-diastereomer). In vitro studies indicate that pralatrexate is approximately 67% bound to plasma proteins. EliminationMetabolismIn vitro studies using human hepatocytes, liver microsomes and S9 fractions, and recombinant human CYP450 isozymes showed that pralatrexate is not significantly metabolized by the phase hepatic CYP450 isozymes or phase II hepatic glucuronidases. ExcretionThe mean fraction of unchanged pralatrexate diastereomers excreted in urine following pralatrexate dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes was 31% (S-diastereomer) (CV 47%) and 38% (R-diastereomer) (CV 45%), respectively. In mass balance study conducted in patients with advanced cancer, an average of 39% (CV 28%) of the administered radiolabeled pralatrexate dose was excreted in urine as parent, racemic pralatrexate (fe). An average of 34% (CV 88%) of the administered dose was recovered in feces as total radiation (fe TR) which included both parent pralatrexate and/or any metabolites. An average of 10% (CV 95%) of total dose was exhaled as total radioactivity over 24 hours.. Pharmacokinetics in Specific PopulationsRenal ImpairmentIn patients with cancer without renal impairment, approximately 34% of pralatrexate was excreted unchanged into urine following single dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes. The pharmacokinetics of FOLOTYN was studied in patients with varying degrees of renal impairment. In patients with severe renal impairment (eGFR 15 to <30 mL/min/1.73 m2), the FOLOTYN dose was 15 mg/m2. Patients with normal renal clearance, mild renal impairment, and moderate renal impairment were all dosed with 30 mg/m2. Mean exposures of the pralatrexate S-diastereomer and R-diastereomer were comparable across cohorts. The mean fraction of the administered dose excreted as unchanged diastereomers in urine (fe) decreased with declining renal function. The non-renal clearance and volume of distribution of pralatrexate were unaffected by renal impairment [see Use in Specific Populations (8.7)]. Hepatic ImpairmentPralatrexate has not been studied in patients with hepatic impairment.GenderThere was no significant effect of gender on pharmacokinetics.. Drug InteractionsIn vitro studies indicated that pralatrexate does not induce or inhibit the activity of CYP450 isozymes at concentrations of pralatrexate that can be reasonably expected clinically. In vitro, pralatrexate is substrate for the breast cancer resistance protein (BCRP), MRP2, multidrug resistance-associated protein (MRP3), and organic anion transport protein 1B3 (OATP1B3) transporter systems at concentrations of pralatrexate that can be reasonably expected clinically. Pralatrexate is not substrate of the glycoprotein (P-gp), organic anion transport protein 1B1 (OATP1B1), organic cation transporter (OCT2), organic anion transporter (OAT1), and organic anion transporter (OAT3) transporter systems. In vitro, pralatrexate inhibits MRP2 and MRP3 transporter systems ([I]/IC50 0.1) at concentrations of pralatrexate that can be reasonably expected clinically. MRP3 is transporter that may affect the transport of etoposide and teniposide. In vitro, pralatrexate did not significantly inhibit the P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1, and OATP1B3 transporter systems at concentrations of pralatrexate that can be reasonably expected clinically.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Peripheral T-cell Lymphoma (PTCL)The safety and efficacy of FOLOTYN was evaluated in an open-label, single-arm, multi-center, international trial that enrolled 115 patients with relapsed or refractory PTCL. One hundred and eleven patients were treated with FOLOTYN at 30 mg/m2 once weekly by IV push over 3-5 minutes for weeks in 7-week cycles until disease progression or unacceptable toxicity. Of the 111 patients treated, 109 patients were evaluable for efficacy. Evaluable patients had histologically confirmed PTCL by independent central review using the Revised European American Lymphoma (REAL) World Health Organization (WHO) disease classification, and relapsed or refractory disease after at least one prior treatment. The primary efficacy endpoint was overall response rate (complete response, complete response unconfirmed, and partial response) as assessed by International Workshop Criteria (IWC). The key secondary efficacy endpoint was duration of response. Response assessments were scheduled at the end of cycle 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 of treated patients was 59.0 years (range 21-85); 68% were male and 32% were female. Most patients were White (72%) and other racial origins included: Black (13%), Hispanic (8%), Asian (5%), other and unknown (<1% each). Patients had an Eastern Cooperative Oncology Group (ECOG) performance status at study entry of (39%), (44%), or (17%). The median time from initial diagnosis to study entry was 15.6 months (range 0.8 322.3). The median number of prior systemic therapies was (range 1-12). Approximately one-fourth of patients (24%, = 27) did not have evidence of response to any previous therapy. Approximately two-thirds of patients (63%, = 70) did not have evidence of response to their most recent prior therapy before entering the study. In all evaluable patients (n 109) treated with FOLOTYN, the response rate, as determined by independent central review by IWC, was 27% (n 29) (Table 5). Table Response Analysis per Independent Central Review (IWC) Evaluable Patients(N=109)N (%)95% CIMedian Duration of ResponseRange of Duration of ResponseOverall ResponseCR+CRu+PR 29 (27) 19, 36 287 days(9.4 months) 1-503 days CR/CRu (8) PR 20 (18) Responses >= 14 weeksCR+CRu+PR 13 (12) 7, 20 Not Reached 98-503 days CR/CRu (6) PR (6) CR Complete Response, CRu Complete Response unconfirmed, PR Partial Response 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).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oThe recommended dose of FOLOTYN is 30 mg/m2 administered as an intravenous push over to minutes once weekly for weeks in 7-week cycles. (2.1) oFor patients with severe renal impairment (eGFR 15 to 30 mL/min/1.73 m2), the recommended dose of FOLOTYN is 15 mg/m2 (2.1).oPrior to initiating FOLOTYN, supplement patients with vitamin B12 mg intramuscularly every 8-10 weeks and folic acid 1.0-1.25 mg orally on daily basis. (2.1) oDose omissions and/or dose reductions may be needed to manage adverse drug reactions. (2.2) oThe recommended dose of FOLOTYN is 30 mg/m2 administered as an intravenous push over to minutes once weekly for weeks in 7-week cycles. (2.1) oFor patients with severe renal impairment (eGFR 15 to 30 mL/min/1.73 m2), the recommended dose of FOLOTYN is 15 mg/m2 (2.1).. oPrior to initiating FOLOTYN, supplement patients with vitamin B12 mg intramuscularly every 8-10 weeks and folic acid 1.0-1.25 mg orally on daily basis. (2.1) oDose omissions and/or dose reductions may be needed to manage adverse drug reactions. (2.2) 2.1 General Dosing and Administration. Pretreatment Vitamin Supplementation. Folic Acid: Patients should take folic acid 1.0-1.25 mg orally once daily beginning 10 days before the first dose of FOLOTYN. Continue folic acid during the full course of therapy and for 30 days after the last dose of FOLOTYN [see Warnings and Precautions (5.1, 5.2)]. Vitamin B12: Administer vitamin B12 mg intramuscularly within 10 weeks prior to the first dose of FOLOTYN and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with FOLOTYN [see Warnings and Precautions (5.1, 5.2)]. Dosing and AdministrationThe recommended dose of FOLOTYN is 30 mg/m2 administered as an intravenous push over 3-5 minutes via the side port of free-flowing 0.9% Sodium Chloride Injection, intravenous line once weekly for weeks in 7-week cycles until progressive disease or unacceptable toxicity. The calculated dose of FOLOTYN should be aseptically withdrawn into syringe for immediate use. Do not dilute FOLOTYN. For patients with severe renal impairment (eGFR 15 to 30 mL/min/1.73 m2), the recommended dose of FOLOTYN is 15 mg/m2.FOLOTYN is clear, yellow solution. 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. 2.2 Monitoring and Dose Modifications. Management of severe or intolerable adverse reactions may require dose omission, reduction, or discontinuation of FOLOTYN therapy. MonitoringMonitor 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. Dose Modification RecommendationsPrior to administering any dose of FOLOTYN: oMucositis should be <= Grade 1. oPlatelet count should be >= 100,000/mcL for first dose and >= 50,000/mcL for all subsequent doses. oAbsolute neutrophil count (ANC) should be >= 1,000/mcL. Doses may be omitted or reduced based on patient tolerance. Omitted doses will not be made up at the end of the cycle; once dose reduction occurs for toxicity, do not re-escalate. For dose modifications and omissions, use the guidelines in Tables 1, 2, and 3. For patients with severe renal impairment (eGFR 15 to 30 mL/min/1.73 m2), the recommended starting dose of FOLOTYN is 15 mg/m2 with dose modification to 10 mg/m2 for the toxicities specified in Tables 1, 2, and 3.Table FOLOTYN Dose Modifications for Mucositis Mucositis Gradea on Day of Treatment ActionDose upon Recovery to <= Grade 1Dose Upon Recovery in Patients with Severe Renal ImpairmentGrade Omit dose Continue prior dose Continue prior dose Grade recurrence Omit dose 20 mg/m2 10 mg/m2 Grade Omit dose 20 mg/m2 10 mg/m2 Grade Stop therapy Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0) Table FOLOTYN Dose Modifications for Hematologic Toxicities Blood Count on Day of Treatment Duration of ToxicityActionDose upon RestartDose Upon Recovery in Patients with Severe Renal ImpairmentPlatelet 50,000/mcL week Omit dose Continue prior dose Continue prior dose weeks Omit dose 20 mg/m2 10 mg/m2 weeks Stop therapy ANC 500-1,000/mcL and no fever week Omit dose Continue prior dose Continue prior dose ANC 500-1,000/mcL with feveror ANC 500/mcL week Omit dose, give G-CSF or GM-CSF support Continue prior dose with G-CSF or GM-CSF support Continue prior dose with G-CSF or GM-CSF support weeks or recurrence Omit dose, give G-CSF or GM-CSF support 20 mg/m2 with G-CSF or GM-CSF support 10 mg/m2 with G-CSF or GM-CSF support weeks or 2nd recurrence Stop therapy G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte macrophage colony-stimulating factor Table FOLOTYN Dose Modifications for All Other Treatment-related Toxicities Toxicity Grade on Day of Treatment ActionDose upon Recovery to <= Grade Dose Upon Recovery in Patients with Severe Renal ImpairmentGrade Omit dose 20 mg/m2 10 mg/m2 Grade Stop therapy Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0) oMucositis should be <= Grade 1. oPlatelet count should be >= 100,000/mcL for first dose and >= 50,000/mcL for all subsequent doses. oAbsolute neutrophil count (ANC) should be >= 1,000/mcL. 2.3 Special Handling Precautions. FOLOTYN is cytotoxic anticancer agent. Caution should be exercised in handling, preparing, and administering of the solution. The use of gloves and other protective clothing is recommended. If FOLOTYN comes in contact with the skin, immediately and thoroughly wash with soap and water. If FOLOTYN comes in contact with mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available1-4. oFOLOTYN vials should be refrigerated at 2-8C (36-46F) until use. oFOLOTYN vials should be stored in original carton to protect from light until use. oFOLOTYN vials contain no preservatives and are intended for single use only. After withdrawal of dose, discard vial including any unused portion. oUnopened vial(s) of FOLOTYN are stable if stored in the original carton at room temperature for 72 hours. Any vials left at room temperature for greater than 72 hours should be discarded. oFOLOTYN vials should be refrigerated at 2-8C (36-46F) until use. oFOLOTYN vials should be stored in original carton to protect from light until use. oFOLOTYN vials contain no preservatives and are intended for single use only. After withdrawal of dose, discard vial including any unused portion. oUnopened vial(s) of FOLOTYN are stable if stored in the original carton at room temperature for 72 hours. Any vials left at room temperature for greater than 72 hours should be discarded.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved labeling (Patient Information). Patients should be instructed to read the Patient Information carefully. 17.1 Need for Folic Acid and Vitamin B12. Advise patients treated with FOLOTYN to take folic acid and vitamin B12 as prophylactic measure to reduce the risk of possible side effects [see Dosage and Administration (2.1)]. 17.2 Low Blood Cell Counts. Inform patients of the risk of low blood cell counts and to immediately contact their physician should any signs of infection develop, including fever. Inform patients to contact their physician if bleeding or symptoms of anemia occur. 17.3 Mucositis. Inform patients of the signs and symptoms of mucositis. Instruct patients on ways to reduce the risk of its development, and on ways to maintain nutrition and control discomfort from mucositis if it occurs. 17.4 Fatal Dermatologic Reactions. Advise patients about the risks for and the signs and symptoms of dermatologic reactions. Instruct patients to immediately notify their physician if any skin reactions occur [see Warnings and Precautions (5.3)]. 17.5 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 physician if they experience these symptoms [see Warnings and Precautions (5.4)]. 17.6 Concomitant Medications. Patients should be instructed to inform their physician if they are taking any concomitant medications including prescription drugs (such as trimethoprim/sulfamethoxazole) and nonprescription drugs (such as nonsteroidal anti-inflammatory drugs) [see Drug Interactions (7)]. 17.7 Pregnancy/Nursing. Patients should be instructed to tell their physician if they are pregnant or plan to become pregnant due to the risk of fetal harm. Patients should be instructed to tell their physician if they are nursing. Manufactured for: Spectrum Pharmaceuticals, Inc. and its wholly-owned subsidiary Allos Therapeutics, Inc.Westminster, CO 800211-888-ALLOS88 (1-888-255-6788) FOLOTYN, ALLOS, and the mobius triangle symbol are all registered trademarks of Allos Therapeutics, Inc.U.S. Patents: 6,028,071, 7,622,470 and 8,299,078Rev. November 2016(C) 2016 Spectrum Pharmaceuticals, Inc. and its wholly-owned subsidiary Allos Therapeutics, Inc. All rights reserved. mobius triangle symbol.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationFOLOTYN(R)(FOH-loh-tin)(pralatrexate injection)Read the Patient Information that comes with FOLOTYN before you start treatment and each time you get treated with FOLOTYN. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about FOLOTYN. What is FOLOTYNFOLOTYN is prescription anti-cancer (chemotherapy) medicine. FOLOTYN is used to treat people with type of cancer called Peripheral T-cell Lymphoma (PTCL) that does not go away, gets worse, or comes back after use of another cancer treatment. What should tell my doctor before receiving FOLOTYN Before you receive FOLOTYN, tell your doctor if you:ohave liver problems. ohave kidney problems. ohave any other medical conditions. oare pregnant or plan to become pregnant. FOLOTYN can harm your unborn baby. Talk to your doctor about the best way to prevent pregnancy while taking FOLOTYN. Tell your doctor right away if you become pregnant while taking FOLOTYN. oare breast-feeding or plan to breast-feed. It is not known if FOLOTYN passes into breast milk. You and your doctor should decide if you will take FOLOTYN or breast-feed. You should not do both. Talk to your doctor about the best way to feed your baby while you are being treated with FOLOTYN. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how FOLOTYN works, and FOLOTYN may affect how other medicines work. Especially tell your doctor if you take:osulfamethoxazole trimethoprim (Bactrim(R), Septra(R), Septra DS, Sulfatrim Pediatric, Sulfamethoprim, Sulfamethoprim-DS) onon-steroidal anti-inflammatory drugs (NSAIDs) oprobenecid (Probalan, Col-Probenecid) Ask your doctor or pharmacist if you are not sure if your medicine is listed above. Know the medicines you take. Keep list of them and show it to your doctor or pharmacist each time you start new medicine. How will receive FOLOTYNoFOLOTYN will be given to you as directed by your doctor, as an intravenous (IV) injection into your vein over to minutes. oFOLOTYN is usually given in cycles, one time each week for weeks, with no treatment on the 7th week. Treatment with FOLOTYN may be continued as long as it is helpful to you. To lower your chances of harmful side effects, it is important that you take folic acid and vitamin B12 during your treatment with FOLOTYN. Your doctor will give you specific instructions for vitamin supplementation. oYou will take folic acid by mouth for 10 days before your first dose of FOLOTYN. Do not take more or less folic acid than your doctor tells you to take. Continue taking folic acid every day until your doctor tells you to stop. oYour doctor will give you vitamin B12 injection into your muscle (intramuscular) before your first dose of FOLOTYN and about every to 10 weeks during treatment with FOLOTYN. You should have regular blood tests before and during your treatment with FOLOTYN. Your doctor may change your dose of FOLOTYN or delay treatment based on the results of your blood tests and on your general condition.What are the possible side effects of FOLOTYN FOLOTYN may cause serious side effects, including:oLow Blood Cell Counts: FOLOTYN can affect your bone marrow and cause you to have low blood cell counts. Your doctor will do blood tests as needed to check your blood cell counts. oLow Platelet Count (thrombocytopenia): Tell your doctor right away if you have any unusual bleeding, such as nosebleeds, or bruising under your skin. oLow White Blood Cell Count (neutropenia): low white blood cell count can cause you to get infections, which may be serious. Serious illness or death can happen if an infection is not treated right away when white blood cell counts are very low. Tell your doctor right away if you have any of the following signs or symptoms of an infection:ofever ochills ocough oshortness of breath opain or burning on urination oLow Red Blood Cell Count (anemia): Tell your doctor if you have any of these symptoms of anemia during treatment with FOLOTYN:ofeeling weak, tired, or you get tired easily oyou look pale oyou feel short of breath oRedness and sores of the mucous membrane lining of the mouth, lips, throat, digestive tract, and genitals (mucositis). Discomfort or pain due to mucositis may happen as early as few days after treatment with FOLOTYN. Your doctor should tell you about ways to reduce your risk of getting mucositis, and how to maintain nutrition and control the discomfort from mucositis. oSevere skin reactions. Severe skin reactions may happen after treatment with FOLOTYN, especially if you have lymphoma in or under your skin. If your skin reactions are severe, they may lead to serious illness or death. Tell your doctor right away if you have any of the following skin reactions:orash opeeling and loss of skin osores oblisters oTumor Lysis Syndrome (TLS). FOLOTYN can cause the fast breakdown of certain types of cancer cells. This can lead to TLS. Your doctor may do blood tests to check you for TLS and treat you for TLS if needed. oHarm to an unborn baby. Females should avoid becoming pregnant while being treated with FOLOTYN. Talk to your doctor about how to avoid pregnancy while taking FOLOTYN. oFever. Fever is often one of the most common and earliest signs of infection. Follow your doctors instructions about how often to take your temperature, especially during the days after treatment with FOLOTYN. If you have fever, tell your doctor or nurse right away. oLoss of too much fluid from the body (dehydration). If you feel tired and weak this could be sign of dehydration. Follow your doctors instructions for what to do to help prevent or treat dehydration. oShortness of breath. Tell your doctor if this is problem for you. Common side effects of FOLOTYN include: onausea ovomiting otiredness oconstipation oswelling ocough onosebleed odiarrhea Tell your doctor about any side effect that bothers you or that does not go away. These are not all the possible side effects of FOLOTYN. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You can report side effects to FDA at 1-800-FDA-1088. General information about FOLOTYNMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. This patient information leaflet summarizes the most important information about FOLOTYN. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about FOLOTYN that is written for health professionals. For more information, go to www.FOLOTYN.com or call 1-888-255-6788. What are the ingredients in FOLOTYNActive ingredient: pralatrexate Inactive ingredients: sodium chloride, sodium hydroxide, and hydrochloric acid What is PTCLPTCL is rare type of non-Hodgkins lymphoma, cancer of the lymphatic system. It happens when type of T-cell (a kind of white blood cell) grows too much. PTCL may be found in different parts of the body, such as the lymph nodes, skin, bone marrow, liver, or spleen. Spectrum Pharmaceuticals, Inc. and its wholly-owned subsidiary Allos Therapeutics, Inc.Westminster, CO 80021 Issued: May 2010Revised: November 2016 FOLOTYN, ALLOS, the mobius triangle symbol, and the flower symbol are all registered trademarks of Allos Therapeutics, Inc.(C) 2016 Spectrum Pharmaceuticals, Inc. and its wholly-owned subsidiary Allos Therapeutics, Inc. All rights reserved. ohave liver problems. ohave kidney problems. ohave any other medical conditions. oare pregnant or plan to become pregnant. FOLOTYN can harm your unborn baby. Talk to your doctor about the best way to prevent pregnancy while taking FOLOTYN. Tell your doctor right away if you become pregnant while taking FOLOTYN. oare breast-feeding or plan to breast-feed. It is not known if FOLOTYN passes into breast milk. You and your doctor should decide if you will take FOLOTYN or breast-feed. You should not do both. Talk to your doctor about the best way to feed your baby while you are being treated with FOLOTYN. osulfamethoxazole trimethoprim (Bactrim(R), Septra(R), Septra DS, Sulfatrim Pediatric, Sulfamethoprim, Sulfamethoprim-DS) onon-steroidal anti-inflammatory drugs (NSAIDs) oprobenecid (Probalan, Col-Probenecid) oFOLOTYN will be given to you as directed by your doctor, as an intravenous (IV) injection into your vein over to minutes. oFOLOTYN is usually given in cycles, one time each week for weeks, with no treatment on the 7th week. Treatment with FOLOTYN may be continued as long as it is helpful to you. oYou will take folic acid by mouth for 10 days before your first dose of FOLOTYN. Do not take more or less folic acid than your doctor tells you to take. Continue taking folic acid every day until your doctor tells you to stop. oYour doctor will give you vitamin B12 injection into your muscle (intramuscular) before your first dose of FOLOTYN and about every to 10 weeks during treatment with FOLOTYN. oLow Blood Cell Counts: FOLOTYN can affect your bone marrow and cause you to have low blood cell counts. Your doctor will do blood tests as needed to check your blood cell counts. oLow Platelet Count (thrombocytopenia): Tell your doctor right away if you have any unusual bleeding, such as nosebleeds, or bruising under your skin. oLow White Blood Cell Count (neutropenia): low white blood cell count can cause you to get infections, which may be serious. Serious illness or death can happen if an infection is not treated right away when white blood cell counts are very low. Tell your doctor right away if you have any of the following signs or symptoms of an infection:. ofever ochills ocough oshortness of breath opain or burning on urination oLow Red Blood Cell Count (anemia): Tell your doctor if you have any of these symptoms of anemia during treatment with FOLOTYN:ofeeling weak, tired, or you get tired easily oyou look pale oyou feel short of breath ofeeling weak, tired, or you get tired easily oyou look pale oyou feel short of breath oRedness and sores of the mucous membrane lining of the mouth, lips, throat, digestive tract, and genitals (mucositis). Discomfort or pain due to mucositis may happen as early as few days after treatment with FOLOTYN. Your doctor should tell you about ways to reduce your risk of getting mucositis, and how to maintain nutrition and control the discomfort from mucositis. oSevere skin reactions. Severe skin reactions may happen after treatment with FOLOTYN, especially if you have lymphoma in or under your skin. If your skin reactions are severe, they may lead to serious illness or death. Tell your doctor right away if you have any of the following skin reactions:orash opeeling and loss of skin osores oblisters orash opeeling and loss of skin osores oblisters oTumor Lysis Syndrome (TLS). FOLOTYN can cause the fast breakdown of certain types of cancer cells. This can lead to TLS. Your doctor may do blood tests to check you for TLS and treat you for TLS if needed. oHarm to an unborn baby. Females should avoid becoming pregnant while being treated with FOLOTYN. Talk to your doctor about how to avoid pregnancy while taking FOLOTYN. oFever. Fever is often one of the most common and earliest signs of infection. Follow your doctors instructions about how often to take your temperature, especially during the days after treatment with FOLOTYN. If you have fever, tell your doctor or nurse right away. oLoss of too much fluid from the body (dehydration). If you feel tired and weak this could be sign of dehydration. Follow your doctors instructions for what to do to help prevent or treat dehydration. oShortness of breath. Tell your doctor if this is problem for you. onausea ovomiting otiredness oconstipation oswelling ocough onosebleed odiarrhea mobius triangle symbol. flower-symbol.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oWomen should be advised against breastfeeding while being treated with FOLOTYN. (8.3) oDose is reduced for patients with severe renal impairment (eGFR 15 to 30 mL/min/1.73 m2) (2.1, 8.7) oWomen should be advised against breastfeeding while being treated with FOLOTYN. (8.3) oDose is reduced for patients with severe renal impairment (eGFR 15 to 30 mL/min/1.73 m2) (2.1, 8.7) 8.1 Pregnancy. Pregnancy Category [see Warnings and Precautions (5.7)] Embryo-Fetal ToxicityFOLOTYN can cause fetal harm when administered to pregnant woman. Pralatrexate was embryotoxic and fetotoxic in rats at IV doses of 0.06 mg/kg/day (0.36 mg/m2/day or about 1.2% of the clinical dose on mg/m2 basis) given on gestation days through 20. Treatment with pralatrexate caused dose-dependent decrease in fetal viability manifested as an increase in late, early, and total resorptions. There was also dose-dependent increase in post-implantation loss. In rabbits, IV doses of 0.03 mg/kg/day (0.36 mg/m2/day) or greater given on gestation days through 21 also caused abortion and fetal lethality. This toxicity manifested as early and total resorptions, post-implantation loss, and decrease in the total number of live fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 8.3 Nursing Mothers. It is not known whether pralatrexate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from this drug, decision should be made whether to discontinue nursing or to discontinue FOLOTYN, taking into account the importance of FOLOTYN to the mother. 8.4 Pediatric Use. Pediatric patients were not included in clinical studies with FOLOTYN. The safety and effectiveness of FOLOTYN in pediatric patients have not been established. 8.5 Geriatric Use. In the PTCL efficacy study, 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 reduction in clearance and 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 exposure related toxicity [see Dosage and Administration (2.2), Warnings and Precautions (5.5, 5.6), Use in Specific Populations (8.6, 8.7), and Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment. The safety, efficacy and pharmacokinetics of FOLOTYN have not been evaluated in patients with hepatic impairment. Patients with the following laboratory values were excluded from the pralatrexate lymphoma clinical trials: total bilirubin 1.5 mg/dL; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 2.5 upper limit of normal (ULN); and AST or ALT 5 ULN if documented hepatic involvement with lymphoma. Treatment with FOLOTYN can cause hepatic toxicity and liver function test abnormalities [see Dosage and Administration (2.2) and Warnings and Precautions (5.6)]. 8.7 Renal Impairment. For patients with severe renal impairment (eGFR 15 to 30 mL/min/1.73 m2), the recommended dose of FOLOTYN is 15 mg/m2. For patients with mild to moderate renal impairment, dose reduction is not necessary. Serious adverse drug reactions, including TEN and mucositis have been reported in patients with ESRD undergoing dialysis. Monitor patients for renal function and for systemic toxicity due to increased drug exposure and adjust dosing accordingly. Avoid the use of FOLOTYN in patients with end stage renal disease undergoing dialysis unless the potential benefit justifies the potential risk [see Dosage and Administration (2.1, 2.2), Warnings and Precautions (5.3, 5.6), Adverse Reactions (6.2), and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oThrombocytopenia, neutropenia, and anemia: Monitor blood counts and omit and/or reduce dose for hematologic toxicities. (2.2, 5.1) oMucositis: Monitor at least weekly. If >= Grade mucositis is observed, omit and/or reduce dose. (2.2, 5.2) oDermatologic reactions: Reactions, including fatal reactions, have occurred and may be progressive and increase in severity with further treatment. Monitor closely, and omit and/or reduce dose or discontinue FOLOTYN. (2.2, 5.3) oTumor lysis syndrome: Anticipate, monitor, and treat promptly. (5.4) oHepatic toxicity: Monitor for toxicity. For liver function test abnormalities Grade or greater, omit until recovery then reduce dose or discontinue therapy as required. (2.2, 5.5) oRisk of increased toxicity with renal impairment: Patients with moderate to severe renal function impairment may be at greater risk for increased exposure and toxicity. Monitor patients for renal function and systemic toxicity and adjust dosing accordingly. Avoid FOLOTYN use in patients with end stage renal disease including those undergoing dialysis unless the potential benefit justifies the potential risk. (2.1, 2.2, 5.6, 6.2) oEmbryo-Fetal toxicity: Women should avoid becoming pregnant while being treated with FOLOTYN. Inform pregnant women of the potential harm to the fetus. (5.7, 8.1) oThrombocytopenia, neutropenia, and anemia: Monitor blood counts and omit and/or reduce dose for hematologic toxicities. (2.2, 5.1) oMucositis: Monitor at least weekly. If >= Grade mucositis is observed, omit and/or reduce dose. (2.2, 5.2) oDermatologic reactions: Reactions, including fatal reactions, have occurred and may be progressive and increase in severity with further treatment. Monitor closely, and omit and/or reduce dose or discontinue FOLOTYN. (2.2, 5.3) oTumor lysis syndrome: Anticipate, monitor, and treat promptly. (5.4) oHepatic toxicity: Monitor for toxicity. For liver function test abnormalities Grade or greater, omit until recovery then reduce dose or discontinue therapy as required. (2.2, 5.5) oRisk of increased toxicity with renal impairment: Patients with moderate to severe renal function impairment may be at greater risk for increased exposure and toxicity. Monitor patients for renal function and systemic toxicity and adjust dosing accordingly. Avoid FOLOTYN use in patients with end stage renal disease including those undergoing dialysis unless the potential benefit justifies the potential risk. (2.1, 2.2, 5.6, 6.2) oEmbryo-Fetal toxicity: Women should avoid becoming pregnant while being treated with FOLOTYN. Inform pregnant women of the potential harm to the fetus. (5.7, 8.1) 5.1 Bone Marrow Suppression. FOLOTYN can cause bone marrow suppression, manifested by thrombocytopenia, neutropenia, and/or anemia. Monitor complete blood counts and omit and/or reduce the dose based on ANC and platelet count prior to each dose as outlined in Section 2.2 Table 2. Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of treatment-related hematological toxicity [see Dosage and Administration (2.1, 2.2) and Adverse Reactions (6.1)]. 5.2 Mucositis. FOLOTYN can cause mucositis. Monitor for mucositis weekly and if >= Grade mucositis is observed, omit and/or reduce the dose as outlined in Section 2.2 Table 1. Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of mucositis [see Dosage and Administration (2.1, 2.2 and Adverse Reactions (6.1)]. 5.3 Dermatologic Reactions. FOLOTYN can cause severe dermatologic reactions, which may result in death. These dermatologic reactions have been reported in clinical studies (14/663 patients [2.1%]) and post marketing experience, and have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN). They may be progressive and increase in severity with further treatment, and may involve skin and subcutaneous sites of known lymphoma. Monitor patients with dermatologic reactions closely, and if severe, withhold or discontinue FOLOTYN [see Adverse Reactions (6.2) and Use in Specific Populations (8.7)]. 5.4 Tumor Lysis Syndrome. FOLOTYN can cause tumor lysis syndrome (TLS). Monitor patients who are at increased risk of TLS and treat promptly. 5.5 Hepatic Toxicity. FOLOTYN can cause hepatic toxicity and liver function test abnormalities. 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 (2.2) and Use in Specific Populations (8.6)]. 5.6 Risk of Increased Toxicity in the Presence of Impaired Renal Function. Patients with moderate to severe renal function impairment may be at greater risk for increased exposure and toxicity. Monitor patients for renal function and systemic toxicity and adjust dosing accordingly. Serious adverse drug reactions including toxic epidermal necrolysis and mucositis were reported in patients with end stage renal disease (ESRD) undergoing dialysis who were administered FOLOTYN therapy. Avoid FOLOTYN use in patients with end stage renal disease including those undergoing dialysis unless the potential benefit justifies the potential risk [see Dosage and Administration (2.2), Adverse Reactions (6.2), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]. 5.7 Embryo-Fetal Toxicity. FOLOTYN can cause fetal harm when administered to pregnant woman. FOLOTYN was embryotoxic and fetotoxic in rats and rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].