This information is not for clinical use. These highlights do not include all the information needed to use Folotyn safely and effectively. Before taking Folotyn please consult with your doctor. See full prescribing information for Folotyn.

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)

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Dosage And Administration

Table 1 FOLOTYN Dose Modifications for Mucositis
a Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0)
Mucositis Gradea 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/m2 10 mg/m2
Grade 3 Omit dose 20 mg/m2 10 mg/m2
Grade 4 Stop therapy

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)

Contraindications

None •None. (4)

Warning and Cautions

•Thrombocytopenia, neutropenia, and anemia: Monitor blood counts and omit and/or reduce dose for hematologic toxicities. (2.2, 5.1) •Mucositis: Monitor at least weekly. If ≥ Grade 2 mucositis is observed, omit and/or reduce dose. (2.2, 5.2) •Dermatologic 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) •Tumor lysis syndrome: Anticipate, monitor, and treat promptly. (5.4) •Hepatic toxicity: Monitor for toxicity. For liver function test abnormalities Grade 3 or greater, omit until recovery then reduce dose or discontinue therapy as required. (2.2, 5.5) •Risk 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) •Embryo-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 2 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 a 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)].

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/m2 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 % aStomatitis or mucosal inflammation of the gastrointestinal and genitourinary tracts. bFive patients with platelets < 10,000/mcL cAlanine aminotransferase, aspartate aminotransferase, and transaminases increased Any Adverse Event 111 100 48 43 34 31 Mucositisa 78 70 19 17 4 4 Thrombocytopeniab 45 41 15 14 21 19b 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 abnormalc 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 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/m2. 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/m2 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)].

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)

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 m2) (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/m2/day or about 1.2% of the clinical dose on a mg/m2 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/m2/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 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)].