Folotyn (Pralatrexate) - Warnings and Precautions

WARNINGS AND PRECAUTIONS

Bone Marrow Suppression

FOLOTYN can suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Dose modifications are based on ANC and platelet count prior to each dose [ see Dosage and Administration (2.5) and Adverse Reactions (6) ].

Mucositis

Treatment with FOLOTYN may cause mucositis. If ≥ Grade 2 mucositis is observed, omit dose and follow guidelines in Section 2.5, Table 1 [ see Dosage and Administration (2.5) ].

5.3 Folic Acid and Vitamin B _{Supplementation}

Patients should be instructed to take folic acid and receive vitamin B₁₂ to potentially reduce treatment-related hematological toxicity and mucositis [ see Dosage and Administration (2.2) ].

Pregnancy Category D

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) ].

Decreased Renal Function

Although FOLOTYN has not been formally tested in patients with renal impairment, caution is advised when administering FOLOTYN to patients with moderate to severe impairment. Monitor patients for renal function and systemic toxicity due to increased drug exposure [ see Clinical Pharmacology (12.3) ].

Elevated Liver Enzymes

Liver function test abnormalities have been observed after FOLOTYN administration. Persistent liver function test abnormalities may be indicators of liver toxicity and require dose modification. Monitor patients for liver function [ see Dosage and Administration (2.5) ].

Dermatologic Reactions

Dermatologic reactions have been reported in clinical studies and post-marketing safety reports in patients treated with FOLOTYN. Dermatologic reactions have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN). These reactions, as well as tumor lysis syndrome, may involve skin and subcutaneous sites of known lymphoma. Skin reactions may be progressive and increase in severity with further treatment. Severe skin reactions have been associated with fatal outcomes. Patients with skin reactions should be monitored closely, and if skin reactions are severe, FOLOTYN should be withheld or discontinued.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D [ see Warnings and Precautions (5.4) ].

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.

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.

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.

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).

No dosage adjustment is required in elderly patients with normal renal function [ see Clinical Pharmacology (12.3) ]

Hepatic Impairment

Formal studies have not been performed with FOLOTYN 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.

Renal Impairment

[ see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3) ].