not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Dermatologic Reactions
Toxic epidermal necrolysis, sometimes fatal, has been reported during post-marketing use of Folotyn. Fatal cases have been reported following the first dose of Folotyn, including when a reduced dose is given, and have been reported in patients with end-stage renal disease undergoing dialysis [see Warnings and Precautions (5.3), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].
Drug Interactions
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 (an inhibitor of multiple transporter systems including the multidrug resistance-associated protein 2 (MRP2) efflux transporter) 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 [see Clinical Pharmacology (12.3)].
When administering Folotyn to patients receiving probenecid or other drugs that may affect relevant transporter systems (eg, NSAIDs), monitor patients closely for signs of systemic toxicity due to increased drug exposure.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.7)]
Embryo-Fetal Toxicity
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). Due to the contribution of renal excretion to overall clearance of pralatrexate (approximately 34%), age-related decline in renal function may lead to a reduction in clearance and a commensurate increase in plasma exposure. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreas |
