Pralatrexate Drug Information
Generic name: PRALATREXATE
Folate Analog Metabolic Inhibitor [EPC]
Uses of Pralatrexate
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 . 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).
Dosage & Administration of Pralatrexate
| Grade 2 | Omit dose |
|---|---|
| Grade 2 recurrence | Omit dose |
| Grade 3 | Omit dose |
| Grade 4 | Stop therapy |
Side Effects of Pralatrexate
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. 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
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.
Warnings & Cautions for Pralatrexate
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. Monitor complete blood counts and omit and/or reduce the dose based on ANC and platelet count prior to each dose .
Mucositis Pralatrexate injection can cause mucositis . Administer vitamin B 12 and
instruct patients to take folic acid to reduce the risk of mucositis. Monitor for mucositis weekly and omit and/or reduce the dose for grade 2 or higher mucositis.
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) . 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.
Tumor Lysis Syndrome Pralatrexate injection can cause tumor lysis syndrome (TLS).
Monitor patients who are at increased risk of TLS and treat promptly.
Hepatic Toxicity Pralatrexate injection 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.
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 . 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 .
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 .
Drug Interactions with Pralatrexate
Effects of Other Drugs on Pralatrexate Injection Coadministration of Pralatrexate injection with
probenecid increased pralatrexate plasma concentrations , which may increase the risk of adverse reactions. Avoid coadministration with probenecid or nonsteroidal anti-inflammatory drugs. If coadministration is unavoidable, monitor for increased risk of adverse reactions.
Pregnancy Safety for Pralatrexate
Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, Pralatrexate injection can cause fetal harm when administered to a pregnant woman. There are insufficient data on Pralatrexate injection use in pregnant women to evaluate for a drug- associated risk. Pralatrexate injection was embryotoxic and fetotoxic in rats and rabbits when administered during organogenesis at doses about 1.2% (0.012 times) of the clinical dose on a mg/m 2 basis.
Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Pralatrexate was embryotoxic and fetotoxic in rats at intravenous 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 dosedependent increase in post-implantation loss.
In rabbits, intravenous 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.
Pediatric Use of Pralatrexate
Pediatric Use The safety and effectiveness of Pralatrexate injection in pediatric patients have not been established.
Overdosage Information for Pralatrexate
No specific information is available on the treatment of overdosage of Pralatrexate injection. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating healthcare provider. Based on Pralatrexate injection's mechanism of action, consider the prompt administration of leucovorin.
Clinical Studies of Pralatrexate
The efficacy of Pralatrexate injection was evaluated in Study PDX-008, an open-label, single-arm, multi-center, international trial that enrolled patients with relapsed or refractory PTCL. One hundred and eleven patients received Pralatrexate injection 30 mg/m 2 intravenously over 3 to 5 minutes once weekly by 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 major efficacy outcome measure was overall response rate (complete response, complete response unconfirmed, and partial response) as assessed by International Workshop Criteria (IWC). An additional efficacy outcome measure 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 was 59 years (range: 21 to 85); 68% were male; 72% were White, 13% were Black, 8% were Hispanic and 5% were Asian.
Patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (39%), 1 (44%), or 2 (17%). The median time from initial diagnosis to study entry was 1.3 years (range 24 days to 26.8 years). The median number of prior systemic therapies was 3 (range 1 to 12). Approximately 24% of patients (n = 27) did not have evidence of response to any previous therapy. Approximately 63% of patients (n = 70) did not have evidence of response to their most recent prior therapy before entering the study. Efficacy results are provided in Table 5. Table 5 Efficacy Results for Study PDX-008 per Independent Central Review (IWC) Fourteen patients went off treatment in cycle 1; 2 patients were unevaluable for response by IWC due to insufficient materials provided to central review.
CR = Complete Response, CRu = Complete Response unconfirmed, PR = Partial Response Evaluable Patients (N=109) N (%) 95% CI Median Duration of Response Range of Duration of Response Overall Response CR+CRu+PR 29 19, 36 287 days (9.4 months) 1-503 days CR/CRu 9 PR 20 Responses ≥ 14 weeks CR+CRu+PR 13 7, 20 Not Reached 98-503 days CR/CRu 7 PR 6 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).
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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