Pralatrexate

Risk Summary

Based on findings from animal studies and its mechanism of action, pralatrexate can cause fetal harm when administered to a pregnant woman. There are insufficient data on pralatrexate use in pregnant women to evaluate for a drug-associated risk. Pralatrexate 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/m² 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/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, intravenous 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.

Risk Summary

There is no data on the presence of pralatrexate in human milk or its effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with pralatrexate and for 1 week after the last dose.

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.

• Myelosuppression
• Mucositis
• Dermatologic Reactions
• Tumor Lysis Syndrome
• Hepatic Toxicity

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 was evaluated in Study PDX-008. Patients received pralatrexate 30 mg/m² 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. 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/m² to 325 mg/m².

Twenty-three percent of patients (n=25) discontinued treatment with pralatrexate 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.

The following table summarizes the adverse reactions in Study PDX-008.

Adverse Reactions in (≥10%) in Patients Who Received Pralatrexate 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.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of pralatrexate. 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.