Folotyn

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Bone Marrow Suppression [see Warnings and Precautions ( 5.1 )] • Mucositis [see Warnings and Precautions ( 5.2 )] • Dermatologic Reactions [see Warnings and Precautions ( 5.3 )] • Tumor Lysis Syndrome [see Warnings and Precautions ( 5.4 )] • Hepatic 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. 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 a 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 a single-arm clinical study in which patients received a starting dose of 30 mg/m 2 once weekly for 6 weeks in 7-week cycles. The median duration of treatment was 70 days (range 1-540 days). Most Frequent Adverse Reactions Table 4 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 4 Adverse Reactions Occurring in PTCL Patients (Incidence ≥ 10% of patients) N=111 Total Grade 3 Grade 4 Preferred Term N % N % N % Any Adverse Event 111 100 48 43 34 31 Mucositis a 78 70 19 17 4 4 Thrombocytopenia b 45 41 15 14 21 19 b Nausea 44 40 4 4 0 0 Fatigue 40 36 5 5 2 2 Anemia 38 34 17 15 2 2 Constipation 37 33 0 0 0 0 Pyrexia 36 32 1 1 1 1 Edema 33 30 1 1 0 0 Cough 31 28 1 1 0 0 Epistaxis 29 26 0 0 0 0 Vomiting 28 25 2 2 0 0 Neutropenia 27 24 14 13 8 7 Diarrhea 23 21 2 2 0 0 Dyspnea 21 19 8 7 0 0 Anorexia 17 15 3 3 0 0 Hypokalemia 17 15 4 4 1 1 Rash 17 15 0 0 0 0 Pruritus 16 14 2 2 0 0 Pharyngolaryngeal pain 15 14 1 1 0 0 Liver function test abnormal c 14 13 6 5 0 0 Abdominal pain 13 12 4 4 0 0 Pain in extremity 13 12 0 0 0 0 Back pain 12 11 3 3 0 0 Leukopenia 12 11 3 3 4 4 Night sweats 12 11 0 0 0 0 Asthenia 11 10 1 1 0 0 Tachycardia 11 10 0 0 0 0 Upper respiratory tract infection 11 10 1 1 0 0 c Alanine aminotransferase, aspartate aminotransferase, and transaminases increased Serious Adverse Events Forty-four percent of patients (n = 49) experienced a 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 a 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/m 2 . Discontinuations Twenty-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%, n = 7) and thrombocytopenia (5%, n = 5). Dose Modifications The target dose of FOLOTYN was 30 mg/m 2 once weekly for 6 weeks in 7-week cycles. The majority of patients (69%, n = 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 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, sometimes fatal, has been reported during post-marketing use of FOLOTYN. Fatal cases have been reported following the first dose of FOLOTYN, including when a 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 ) ].

4 CONTRAINDICATIONS None • None. ( 4 )

11 DESCRIPTION FOLOTYN (pralatrexate injection) contains pralatrexate, which is an antineoplastic folate analog. Pralatrexate has the chemical name (2 S )-2-[[4-[(1 RS )-1-[(2, 4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid. The structural formula is as follows: Pralatrexate is a 1:1 racemic mixture of S - and R - diastereomers at the C10 position (indicated with *). The molecular formula is C 23 H 23 N 7 O 5 and the molecular weight is 477.48 g/mol. Pralatrexate is an off-white to yellow solid. It is soluble in aqueous solutions at pH 6.5 or higher. Pralatrexate is practically insoluble in chloroform and ethanol. The pKa values are 3.25, 4.76, and 6.17. FOLOTYN is supplied as a preservative-free, sterile, isotonic, non-pyrogenic clear yellow aqueous parenteral solution contained in a single-dose clear glass vial (Type I) for intravenous administration. Each 1 mL of solution contains 20 mg of pralatrexate, sufficient sodium chloride to achieve an isotonic (280-300 mOsm) solution, and sufficient sodium hydroxide, and hydrochloric acid if needed, to adjust and maintain the pH at 7.5-8.5. FOLOTYN is supplied as either 20 mg (1 mL) or 40 mg (2 mL) single-dose vials at a concentration of 20 mg/mL. Structural Formula

2 DOSAGE AND ADMINISTRATION • The recommended dose of FOLOTYN is 30 mg/m 2 administered as an intravenous push over 3 to 5 minutes once weekly for 6 weeks in 7-week cycles. ( 2.1 ) • For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m 2 ), the recommended dose of FOLOTYN is 15 mg/m 2 ( 2.1 ). • Prior to initiating FOLOTYN, supplement patients with vitamin B 12 1 mg intramuscularly every 8-10 weeks and folic acid 1.0-1.25 mg orally on a daily basis. ( 2.1 ) • Dose 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 B 12 : Administer vitamin B 12 1 mg intramuscularly within 10 weeks prior to the first dose of FOLOTYN and every 8-10 weeks thereafter. Subsequent vitamin B 12 injections may be given the same day as treatment with FOLOTYN [ see Warnings and Precautions ( 5.1 , 5.2 ) ]. Dosing and Administration The recommended dose of FOLOTYN is 30 mg/m 2 administered as an intravenous push over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection, intravenous line once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity. The calculated dose of FOLOTYN should be aseptically withdrawn into a syringe for immediate use. Do not dilute FOLOTYN. For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m 2 ), the recommended dose of FOLOTYN is 15 mg/m 2 . FOLOTYN is a 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. 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. Dose Modification Recommendations Prior to administering any dose of FOLOTYN: • Mucositis should be ≤ Grade 1. • Platelet count should be ≥ 100,000/mcL for first dose and ≥ 50,000/mcL for all subsequent doses. • Absolute 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 a 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 m 2 ), the recommended starting dose of FOLOTYN is 15 mg/m 2 with dose modification to 10 mg/m 2 for the toxicities specified in Tables 1 , 2 , and 3 . Table 1 FOLOTYN Dose Modifications for Mucositis Mucositis Grade a on Day of Treatment Action Dose upon Recovery to ≤ Grade 1 Dose Upon Recovery in 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 a Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0) Table 2 FOLOTYN Dose Modifications for Hematologic Toxicities Blood Count on Day of Treatment Duration of Toxicity Action Dose upon Restart Dose Upon Recovery in Patients with Severe Renal Impairment Platelet < 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 500-1,000/mcL and no fever 1 week Omit dose Continue prior dose Continue prior dose ANC 500-1,000/mcL with fever or ANC < 500/mcL 1 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 2 weeks or recurrence Omit dose, give G‑CSF or GM‑CSF support 20 mg/m 2 with G-CSF or GM-CSF support 10 mg/m 2 with G-CSF or GM-CSF support 3 weeks or 2 nd recurrence Stop therapy G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte macrophage colony-stimulating factor Table 3 FOLOTYN Dose Modifications for All Other Treatment-related Toxicities Toxicity Grade a on Day of Treatment Action Dose upon Recovery to ≤ Grade 2 Dose Upon Recovery in Patients with Severe Renal Impairment Grade 3 Omit dose 20 mg/m 2 10 mg/m 2 Grade 4 Stop therapy a Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0) 2.3 Special Handling Precautions FOLOTYN is a 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 available 1-4 . • FOLOTYN vials should be refrigerated at 2-8°C (36-46°F) until use. • FOLOTYN vials should be stored in original carton to protect from light until use. • FOLOTYN vials contain no preservatives and are intended for single use only. After withdrawal of dose, discard vial including any unused portion. • Unopened 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.

1 INDICATIONS AND USAGE FOLOTYN is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on overall response rate. Clinical benefit such as improvement in progression-free survival or overall survival has not been demonstrated. FOLOTYN is a folate analog metabolic inhibitor indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on overall response rate. Clinical benefit such as improvement in progression-free survival or overall survival has not been demonstrated. ( 1 )

10 OVERDOSAGE No specific information is available on the treatment of overdosage of FOLOTYN. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. Based on FOLOTYN's mechanism of action, consider the prompt administration of leucovorin.

7 DRUG INTERACTIONS No formal clinical assessments of pharmacokinetic drug-drug interactions between FOLOTYN and other drugs have been conducted. The effect of co-administration of the uricosuric drug probenecid (an inhibitor of multiple transporter systems including the multidrug resistance-associated protein 2 (MRP2) efflux transporter) on pralatrexate pharmacokinetics was investigated in a Phase 1 clinical study. Co-administration of increasing doses of probenecid resulted in delayed clearance of pralatrexate and a commensurate increase in exposure [ see Clinical Pharmacology ( 12.3 ) ]. When administering FOLOTYN to patients receiving probenecid or other drugs that may affect relevant transporter systems (eg, NSAIDs), monitor patients closely for signs of systemic toxicity due to increased drug exposure. • Co-administration with probenecid or other drugs that may affect relevant transporter systems (eg, NSAIDs) requires close monitoring for signs of systemic toxicity. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pralatrexate is a folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase. It is also a 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 Absorption The pharmacokinetics of pralatrexate administered as a single agent at a dose of 30 mg/m 2 administered as an intravenous push over 3-5 minutes once weekly for 6 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 (C max ) increased proportionally with dose (dose range 30-325 mg/m 2 , 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. Distribution Pralatrexate diastereomers showed a steady-state volume of distribution of 105 L ( S- diastereomer) and 37 L ( R -diastereomer). In vitro studies indicate that pralatrexate is approximately 67% bound to plasma proteins. Elimination Metabolism In 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 I hepatic CYP450 isozymes or phase II hepatic glucuronidases. Excretion The mean fraction of unchanged pralatrexate diastereomers excreted in urine following a pralatrexate dose of 30 mg/m 2 administered as an intravenous push over 3‑5 minutes was 31% ( S ‑diastereomer) (CV = 47%) and 38% ( R -diastereomer) (CV = 45%), respectively. In a 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 (f e ). An average of 34% (CV = 88%) of the administered dose was recovered in feces as total radiation (f e 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 Populations Renal Impairment In patients with cancer without renal impairment, approximately 34% of pralatrexate was excreted unchanged into urine following a single dose of 30 mg/m 2 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 m 2 ), the FOLOTYN dose was 15 mg/m 2 . Patients with normal renal clearance, mild renal impairment, and moderate renal impairment were all dosed with 30 mg/m 2 . 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 (f e ) 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 Impairment Pralatrexate has not been studied in patients with hepatic impairment. Gender There was no significant effect of gender on pharmacokinetics. Drug Interactions In 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 a substrate for the breast cancer resistance protein (BCRP), MRP2, multidrug resistance-associated protein 3 (MRP3), and organic anion transport protein 1B3 (OATP1B3) transporter systems at concentrations of pralatrexate that can be reasonably expected clinically. Pralatrexate is not a substrate of the P glycoprotein (P-gp), organic anion transport protein 1B1 (OATP1B1), organic cation transporter 2 (OCT2), organic anion transporter 1 (OAT1), and organic anion transporter 3 (OAT3) transporter systems. In vitro , pralatrexate inhibits MRP2 and MRP3 transporter systems ([I]/IC 50 > 0.1) at concentrations of pralatrexate that can be reasonably expected clinically. MRP3 is a 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.

12.1 Mechanism of Action Pralatrexate is a folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase. It is also a 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 Absorption The pharmacokinetics of pralatrexate administered as a single agent at a dose of 30 mg/m 2 administered as an intravenous push over 3-5 minutes once weekly for 6 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 (C max ) increased proportionally with dose (dose range 30-325 mg/m 2 , 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. Distribution Pralatrexate diastereomers showed a steady-state volume of distribution of 105 L ( S- diastereomer) and 37 L ( R -diastereomer). In vitro studies indicate that pralatrexate is approximately 67% bound to plasma proteins. Elimination Metabolism In 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 I hepatic CYP450 isozymes or phase II hepatic glucuronidases. Excretion The mean fraction of unchanged pralatrexate diastereomers excreted in urine following a pralatrexate dose of 30 mg/m 2 administered as an intravenous push over 3‑5 minutes was 31% ( S ‑diastereomer) (CV = 47%) and 38% ( R -diastereomer) (CV = 45%), respectively. In a 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 (f e ). An average of 34% (CV = 88%) of the administered dose was recovered in feces as total radiation (f e 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 Populations Renal Impairment In patients with cancer without renal impairment, approximately 34% of pralatrexate was excreted unchanged into urine following a single dose of 30 mg/m 2 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 m 2 ), the FOLOTYN dose was 15 mg/m 2 . Patients with normal renal clearance, mild renal impairment, and moderate renal impairment were all dosed with 30 mg/m 2 . 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 (f e ) 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 Impairment Pralatrexate has not been studied in patients with hepatic impairment. Gender There was no significant effect of gender on pharmacokinetics. Drug Interactions In 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 a substrate for the breast cancer resistance protein (BCRP), MRP2, multidrug resistance-associated protein 3 (MRP3), and organic anion transport protein 1B3 (OATP1B3) transporter systems at concentrations of pralatrexate that can be reasonably expected clinically. Pralatrexate is not a substrate of the P glycoprotein (P-gp), organic anion transport protein 1B1 (OATP1B1), organic cation transporter 2 (OCT2), organic anion transporter 1 (OAT1), and organic anion transporter 3 (OAT3) transporter systems. In vitro , pralatrexate inhibits MRP2 and MRP3 transporter systems ([I]/IC 50 > 0.1) at concentrations of pralatrexate that can be reasonably expected clinically. MRP3 is a 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.

20230605

25

3 DOSAGE FORMS AND STRENGTHS FOLOTYN is available as a clear yellow solution in sterile, single-dose vials containing pralatrexate at a concentration of 20 mg/mL in the following presentations: 20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL) 40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL) • Sterile, single-dose vials containing pralatrexate at a concentration of 20 mg/mL in the following presentations: - 20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL) ( 3 ) - 40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL) ( 3 )

Folotyn pralatrexate PRALATREXATE PRALATREXATE SODIUM CHLORIDE SODIUM HYDROXIDE HYDROCHLORIC ACID WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies have not been performed with pralatrexate. Mutagenesis Pralatrexate did not cause mutations in the Ames test or the Chinese hamster ovary cell chromosome aberration assay. Nevertheless, these tests do not reliably predict genotoxicity for this class of compounds. Pralatrexate did not cause mutations in the mouse micronucleus assay. Impairment of Fertility No fertility studies have been performed.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies have not been performed with pralatrexate. Mutagenesis Pralatrexate did not cause mutations in the Ames test or the Chinese hamster ovary cell chromosome aberration assay. Nevertheless, these tests do not reliably predict genotoxicity for this class of compounds. Pralatrexate did not cause mutations in the mouse micronucleus assay. Impairment of Fertility No fertility studies have been performed.

NDA022468

Folotyn

pralatrexate

48818-001

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE CARTON - FOLOTYN 20 mg/1 mL Vial NDC 48818-001-01 FOLOTYN ® (pralatrexate injection) 20 mg/mL For intravenous use Rx only 1 mL Folotyn 20 mg/mL Carton

Dosage and Administration ( 2.1 , 2.2 ) 05/2016

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 B 12 as a 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 80021 1-888-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 8,299,078 Rev. November 2016 © 2016 Spectrum Pharmaceuticals, Inc. and its wholly-owned subsidiary Allos Therapeutics, Inc. All rights reserved. mobius triangle symbol

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/m 2 once weekly by IV push over 3-5 minutes for 6 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 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 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 0 (39%), 1 (44%), or 2 (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 3 (range 1-12). Approximately one-fourth of patients (24%, n = 27) did not have evidence of response to any previous therapy. Approximately two-thirds of patients (63%, n = 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 5 Response Analysis per Independent Central Review (IWC) 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) 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).

15 REFERENCES 1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/o tm/otm_vi/otm_vi_2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193. 4. Polovich, M., White, J. M., & Kelleher, L. O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

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 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 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 ) ].

8.3 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, a 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.

8.1 Pregnancy Pregnancy Category D [ see Warnings and Precautions ( 5.7 ) ] Embryo-Fetal Toxicity FOLOTYN can cause fetal harm when administered to a pregnant woman. Pralatrexate was embryotoxic and fetotoxic in rats at IV 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 dose-dependent increase in post-implantation loss. In rabbits, IV 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. 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 USE IN SPECIFIC POPULATIONS • Women should be advised against breastfeeding while being treated with FOLOTYN. ( 8.3 ) • Dose is reduced for patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m 2 ) ( 2.1 , 8.7 ) 8.1 Pregnancy Pregnancy Category D [ see Warnings and Precautions ( 5.7 ) ] Embryo-Fetal Toxicity FOLOTYN can cause fetal harm when administered to a pregnant woman. Pralatrexate was embryotoxic and fetotoxic in rats at IV 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 dose-dependent increase in post-implantation loss. In rabbits, IV 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. 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, a 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 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 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 m 2 ), the recommended dose of FOLOTYN is 15 mg/m 2 . 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 ) ].

16 HOW SUPPLIED/STORAGE AND HANDLING FOLOTYN is available in single-dose clear glass vials containing pralatrexate at a concentration of 20 mg/mL as a preservative-free, sterile, clear yellow solution individually packaged for intravenous use in the following presentations: NDC 48818-001-01: 20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL) NDC 48818-001-02: 40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL) Vials must be stored refrigerated at 2-8°C (36-46°F) ( see USP Controlled Cold Temperature) in original carton to protect from light. Handle and dispose of FOLOTYN according to guidelines issued for cytotoxic drugs, including the use of gloves and other protective clothing to prevent skin contact [ see References ( 15 ) ]. Each vial of FOLOTYN is intended for single use only. Any unused drug remaining after injection must be discarded.