Dose Modifications

The target dose of FOLOTYN was 30 mg/m once weekly for 6 weeks in 7-week cycles. The majority of patients (69%, n = 77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered.

Toxic epidermal necrolysis has been identified during post approval use of FOLOTYN. 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 [see Warnings and Precautions (5.3)].

In vitro studies indicate that pralatrexate is not a substrate, inhibitor, or inducer of CYP450 isoenzymes and has low potential for drug-drug interactions at CYP450 isoenzymes [see Clinical Pharmacology (12.3)]. No formal clinical assessments of pharmacokinetic drug-drug interactions between FOLOTYN and other drugs have been conducted. The effect of co-administration of the uricosuric drug probenecid on pralatrexate pharmacokinetics was investigated in a Phase 1 clinical study. Co-administration of increasing doses of probenecid resulted in delayed clearance of pralatrexate and a commensurate increase in exposure.

Due to the contribution of renal excretion (approximately 34%) to the overall clearance of pralatrexate, concomitant administration of drugs that are subject to substantial renal clearance (eg, NSAIDs, trimethoprim/sulfamethoxazole) may result in delayed clearance of pralatrexate.

Pregnancy Category D [see Warnings and Precautions (5.6)].

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/m/day or about 1.2% of the clinical dose on a mg/m 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/m/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.

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 patients were not included in clinical studies with FOLOTYN. The safety and effectiveness of FOLOTYN in pediatric patients have not been established.

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)]

Formal studies have not been performed wit