2 ML pralatrexate 20 MG/ML Injection

INDICATIONS AND USAGE Pralatrexate injection is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on overall response rate [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Pralatrexate injection is a dihydrofolate reductase inhibitor indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 )

DOSAGE AND ADMINISTRATION Supplement patients with vitamin B 12 mg intramuscularly every 8-10 weeks starting 10 weeks before the first dose and folic acid 1 to 1.25 mg orally once daily starting 10 days before the first dose. ( 2.1 ) The recommended dosage of Pralatrexate injection is 30 mg/m 2 intravenously over 3 to 5 minutes once weekly for 6 weeks in 7-week cycles. ( 2.1 ) For patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m 2 ), reduce the Pralatrexate injection dose to 15 mg/m 2 ( 2.1 ). 2.1 Important Dosing Information Pretreatment Vitamin Supplementation Folic Acid Instruct patients to take folic acid 1 to 1.25 mg orally once daily beginning 10 days before the first dose of Pralatrexate injection. Continue folic acid during treatment with Pralatrexate injection and for 30 days after the last dose [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 Pralatrexate injection and every 8-10 weeks thereafter. Subsequent vitamin B 12 injections may be given the same day as treatment with Pralatrexate injection [see Warnings and Precautions ( 5.1 , 5.2 )]. 2.2 Recommended Dosage The recommended dosage of Pralatrexate injection is 30 mg/m 2 intravenously over 3-5 minutes once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity. 2.3 Dosage Modifications for Renal Impairment and End Stage Renal Disease Severe renal impairment (eGFR 15 to 29 mL/min/1.73 m 2 by MDRD): Reduce the Pralatrexate injection dose to 15 mg/m 2 [see Use in Specific Populations ( 8.6 )] . End stage renal disease (ESRD: eGFR less than 15 mL/min/1.73 m 2 by MDRD) with or without dialysis: Avoid administration. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the Pralatrexate injection dose based on adverse reactions [see Warnings and Precautions ( 5.6 ), Use in Specific Populations ( 8.6 )] . 2.4 Monitoring and Dosage Modifications for Adverse Reactions Monitoring Monitor complete blood cell counts and severity of mucositis at baseline and weekly. Perform serum chemistry tests, including renal and hepatic function, prior to the start of the first and fourth dose of each cycle. Recommended Dosage Modifications Do not administer Pralatrexate injection until: Mucositis Grade 1 or less. Platelet of 100,000/mcL or greater for first dose and 50,000/mcL or greater for all subsequent doses. Absolute neutrophil count (ANC) of 1,000/mcL or greater. Dosage modifications for adverse reactions are provided in Tables 1 , 2 , and 3 . Table 1 Pralatrexate Injection Dosage Modifications for Mucositis a Based National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0) Mucositis Grade a on Day of Treatment Action Recommended Dose upon Recovery to Grade 0 or 1 Patients Without Severe Renal Impairment Patients with Severe Renal Impairment Grade 2 Omit dose Continue prior dose Continue prior dose Grade 2 recurrence Omit dose 20 mg/m 2 10 mg/m 2 Grade 3 Omit dose 20 mg/m 2 10 mg/m 2 Grade 4 Stop therapy Table 2 Pralatrexate Injection Dosage Modifications for Myelosuppression G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte macrophage colony-stimulating factor Blood Count on Day of Treatment Duration of Toxicity Action Recommended Dose Upon Recovery Patients Without Severe Renal Impairment Patients with Severe Renal Impairment Platelet less than 50,000/mcL 1 week Omit dose Continue prior dose Continue prior dose 2 weeks Omit dose 20 mg/m 2 10 mg/m 2 3 weeks Stop therapy ANC 500 to 1,000/mcL and no fever 1 week Omit dose Continue prior dose Continue prior dose ANC 500 to 1,000/mcL with fever or ANC less than 500/mcL 1 week Omit dose, give G-CSF or GM-CSF Continue prior dose with G-CSF or GM-CSF Continue prior dose with G-CSF or GM-CSF 2 weeks or recurrence Omit dose, give G-CSF or GM-CSF 20 mg/m 2 with G-CSF or GM-CSF 10 mg/m 2 with G-CSF or GM-CSF 3 weeks or 2 nd recurrence Stop therapy Table 3 Pralatrexate Injection Dosage Modifications for All Other Adverse Reactions a Based on NCI CTCAE version 3.0 Toxicity Grade a on Day of Treatment Action Recommended Dose upon Recovery to Grade 2 or Lower Patients Without Severe Renal Impairment Patients with Severe Renal Impairment Grade 3 Omit dose 20 mg/m 2 10 mg/m 2 Grade 4 Stop therapy 2.5 Preparation and Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use any vials exhibiting particulate matter or discoloration. Pralatrexate injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 If Pralatrexate injection comes in contact with the skin, immediately and thoroughly wash with soap and water. If Pralatrexate injection comes in contact with mucous membranes, flush thoroughly with water. Aseptically withdraw the calculated dose from the appropriate number of vial(s) into a syringe for immediate use. Do not dilute Pralatrexate injection. Administer undiluted Pralatrexate injection intravenously over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection. After withdrawal of dose, discard vial(s) including any unused portion.

WARNINGS AND PRECAUTIONS Myelosuppression : Monitor complete blood counts and omit and/or reduce dose based on ANC and platelet count. ( 2.4 , 5.1 ) Mucositis :Monitor at least weekly. Omit and/or reduce dose for grade 2 or higher mucositis. ( 2.4 , 5.2 ) Dermatologic reactions : Reactions, including fatal reactions, occurred and may be progressive and increase in severity with further treatment. Monitor closely and withhold or discontinue Pralatrexate injection based on severity. ( 2.4 , 5.3 ) Tumor lysis syndrome : Monitor patients who are increased risk and treat promptly. ( 5.4 ) Hepatic toxicity : Monitor for liver function tests. Omit until recovery, adjust or discontinue therapy based on severity. ( 2.4 , 5.5 ) Risk of increased toxicity with renal impairment : Avoid Pralatrexate injection in patients with end stage renal disease with or without dialysis. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the Pralatrexate injection dose based on adverse reactions. ( 2.3 , 2.4 , 5.6 ) Embryo-fetal toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use an effective method of contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 Myelosuppression Pralatrexate injection can cause myelosuppression, manifested by thrombocytopenia, neutropenia, and/or anemia. Administer vitamin B 12 and instruct patients to take folic acid to reduce the risk of treatment-related myelosuppression [see Dosage and Administration ( 2.1 )]. Monitor complete blood counts and omit and/or reduce the dose based on ANC and platelet count prior to each dose [see Dosage and Administration ( 2.4 )] . 5.2 Mucositis Pralatrexate injection can cause mucositis [see Adverse Reactions ( 6.1 )] . Administer vitamin B 12 and instruct patients to take folic acid to reduce the risk of mucositis [see Dosage and Administration ( 2.1 )]. Monitor for mucositis weekly and omit and/or reduce the dose for grade 2 or higher mucositis [see Dosage and Administration ( 2.4 )]. 5.3 Dermatologic Reactions Pralatrexate injection can cause severe dermatologic reactions, which may result in death. These dermatologic reactions have been reported in clinical studies (2.1% of 663 patients) and post marketing experience, and have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN) [see Adverse Reactions ( 6.1 , 6.2 )] . They may be progressive and increase in severity with further treatment and may involve skin and subcutaneous sites of known lymphoma. Monitor closely for dermatologic reactions. Withhold or discontinue Pralatrexate injection based on severity [see Dosage and Administration ( 2.4 )]. 5.4 Tumor Lysis Syndrome Pralatrexate injection can cause tumor lysis syndrome (TLS). Monitor patients who are at increased risk of TLS and treat promptly. 5.5 Hepatic Toxicity Pralatrexate injection can cause hepatic toxicity and liver function test abnormalities [see Adverse Reactions ( 6.1 )] . Persistent liver function test abnormalities may be indicators of hepatic toxicity and require dose modification or discontinuation. Monitor liver function tests. Omit dose until recovery, adjust or discontinue therapy based on the severity of the hepatic toxicity [see Dosage and Administration ( 2.4 )]. 5.6 Risk of Increased Toxicity with Renal Impairment Patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m 2 based on MDRD) may be at greater risk for increased exposure and adverse reactions. Reduce Pralatrexate injection dosage in patients with severe renal impairment [see Dosage and Administration ( 2.3 )] . Serious adverse reactions, including TEN and mucositis, were reported in patients with end stage renal disease (ESRD) undergoing dialysis who were administered Pralatrexate injection. Avoid Pralatrexate injection in patients with ESRD with or without dialysis. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the Pralatrexate injection dose based on adverse reactions [see Dosage and Administration ( 2.3 )] . 5.7 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, Pralatrexate injection can cause fetal harm when administered to a pregnant woman. Pralatrexate injection was embryotoxic and fetotoxic in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Pralatrexate injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Pralatrexate injection and for 3 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

CONTRAINDICATIONS None None. ( 4 )

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.