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warnings and cautions
5 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 )] .
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [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 )] Most common adverse reactions (>35%) are mucositis, thrombocytopenia, nausea, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 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. Peripheral T-cell Lymphoma The safety of Pralatrexate injection was evaluated in Study PDX-008 [see Clinical Studies ( 14 )]. Patients received Pralatrexate injection 30 mg/m 2 once weekly for 6 weeks in 7-week cycles. The median duration of treatment was 70 days (range: 1 day to 1.5 years). The majority of patients (69%, n = 77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered. Forty-four percent of patients (n = 49) experienced a serious adverse event while on study or within 30 days after their last dose of Pralatrexate injection. The most common serious adverse events (> 3%), regardless of causality, were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. One death from cardiopulmonary arrest in a patient with mucositis and febrile neutropenia was reported in this trial. Across clinical trials, deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients who received doses ranging from 30 mg/m 2 to 325 mg/m 2 . Twenty-three percent of patients (n = 25) discontinued treatment with Pralatrexate injection due to adverse reactions. The most frequent adverse reactions reported as the reason for discontinuation of treatment were mucositis (6%) and thrombocytopenia (5%). The most common adverse reactions (> 35%) were mucositis, thrombocytopenia, nausea, and fatigue. Table 4 summarizes the adverse reactions in Study PDX-008. Table 4 Adverse Reactions in (≥ 10%) in Patients Who Received Pralatrexate Injection in Study PDX-008 a Mucositis includes stomatitis or mucosal inflammation of the gastrointestinal and genitourinary tracts. b Five patients with platelets < 10,000/mcL. c Liver function test abnormal includes increased ALT, increased AST, and increased transaminases Pralatrexate Injection N=111 All Grades (%) Grade 3 (%) Grade 4 (%) Any Adverse Reaction 100 43 31 Mucositis a 70 17 4 Thrombocytopenia b 41 14 19 b Nausea 40 4 0 Fatigue 36 5 2 Anemia 34 15 2 Constipation 33 0 0 Pyrexia 32 1 1 Edema 30 1 0 Cough 28 1 0 Epistaxis 26 0 0 Vomiting 25 2 0 Neutropenia 24 13 7 Diarrhea 21 2 0 Dyspnea 19 7 0 Anorexia 15 3 0 Hypokalemia 15 4 1 Rash 15 0 0 Pruritus 14 2 0 Pharyngolaryngeal pain 14 1 0 Liver function test abnormal c 13 5 0 Abdominal pain 12 4 0 Pain in extremity 12 0 0 Back pain 11 3 0 Leukopenia 11 3 4 Night sweats 11 0 0 Asthenia 10 1 0 Upper respiratory tract infection 10 1 0 Tachycardia 10 0 0 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Pralatrexate injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic Reactions: Toxic epidermal necrolysis.