2.1 Important Dosing Information

Pretreatment Vitamin Supplementation

Folic Acid
Instruct patients to take folic acid 1 to 1.25 mg orally once daily beginning 10 days before the first dose of FOLOTYN. Continue folic acid during treatment with FOLOTYN and for 30 days after the last dose [see Warnings and Precautions (5.1, 5.2)].

Vitamin B12
Administer vitamin B12 1 mg intramuscularly within 10 weeks prior to the first dose of FOLOTYN and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with FOLOTYN [see Warnings and Precautions (5.1, 5.2)].

2.2 Recommended Dosage

The recommended dosage of FOLOTYN is 30 mg/m2 intravenously over 3-5 minutes once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity.

2.3 Dosage Modifications for Renal Impairment and End Stage Renal Disease

• Severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2 by MDRD): Reduce the FOLOTYN dose to 15 mg/m2 [see Use in Specific Populations (8.6)].
• End stage renal disease (ESRD: eGFR less than 15 mL/min/1.73 m2 by MDRD) with or without dialysis: Avoid administration. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the FOLOTYN dose based on adverse reactions [see Warnings and Precautions (5.6), Use in Specific Populations (8.6)].

2.4 Monitoring and Dosage Modifications for Adverse Reactions

Monitoring
Monitor complete blood cell counts and severity of mucositis at baseline and weekly. Perform serum chemistry tests, including renal and hepatic function, prior to the start of the first and fourth dose of each cycle.

2.5 Preparation and Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use any vials exhibiting particulate matter or discoloration.

FOLOTYN is a hazardous drug. Follow applicable special handling and disposal procedures.1 If FOLOTYN comes in contact with the skin, immediately and thoroughly wash with soap and water. If FOLOTYN
comes in contact with mucous membranes, flush thoroughly with water.

Aseptically withdraw the calculated dose from the appropriate number of vial(s) into a syringe for immediate use. Do not dilute FOLOTYN.

Administer undiluted FOLOTYN intravenously over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection.

After withdrawal of dose, discard vial(s) including any unused portion.

5.1 Myelosuppression

FOLOTYN can cause myelosuppression, manifested by thrombocytopenia, neutropenia, and/or anemia.

Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of treatment-related myelosuppression [see Dosage and Administration (2.1)].

Monitor complete blood counts and omit and/or reduce the dose based on ANC and platelet count prior to each dose [see Dosage and Administration (2.4)].

5.2 Mucositis

FOLOTYN can cause mucositis [see Adverse Reactions (6.1)].

Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of mucositis [see Dosage and Administration (2.1)].

Monitor for mucositis weekly and omit and/or reduce the dose for grade 2 or higher mucositis [see Dosage and Administration (2.4)].

5.3 Dermatologic Reactions

FOLOTYN 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) [see Adverse Reactions (6.1, 6.2)]. 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 FOLOTYN based on severity [see Dosage and Administration (2.4)].

5.4 Tumor Lysis Syndrome

FOLOTYN can cause tumor lysis syndrome (TLS). Monitor patients who are at increased risk of TLS and treat promptly.

5.5 Hepatic Toxicity

FOLOTYN can cause hepatic toxicity and liver function test abnormalities [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.4)].

5.6 Risk of Increased Toxicity with Renal Impairment

Patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2 based on MDRD) may be at greater risk for increased exposure and adverse reactions. Reduce FOLOTYN dosage in patients with severe renal impairment [see Dosage and Administration (2.3)].

Serious adverse reactions, including TEN and mucositis, were reported in patients with end stage renal disease (ESRD) undergoing dialysis who were administered FOLOTYN. Avoid FOLOTYN in patients with ESRD with or without dialysis. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the FOLOTYN dose based on adverse reactions [see Dosage and Administration (2.3)].

5.7 Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, FOLOTYN can cause fetal harm when administered to a pregnant woman. FOLOTYN 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 FOLOTYN and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with FOLOTYN and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6.1 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 FOLOTYN was evaluated in Study PDX-008 [see Clinical Studies (14)]. Patients received FOLOTYN 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 FOLOTYN. 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 FOLOTYN 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval 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.

Dermatologic Reactions: Toxic epidermal necrolysis.

7.1 Effects of Other Drugs on FOLOTYN

Coadministration of FOLOTYN with probenecid increased pralatrexate plasma concentrations [see Clinical Pharmacology (12.3)], 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.

8.1 Pregnancy

Risk Summary
Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], FOLOTYN can cause fetal harm when administered to a pregnant woman. There are insufficient data on FOLOTYN use in pregnant women to evaluate for a drug- associated risk. FOLOTYN 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.

8.2 Lactation

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 FOLOTYN and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

FOLOTYN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiation of FOLOTYN.

Contraception

Females
Advise females of reproductive potential to use effective contraception during treatment with FOLOTYN and for 6 months following the last dose.

Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with FOLOTYN and for 3 months following the last dose.

8.4 Pediatric Use

The safety and effectiveness of FOLOTYN in pediatric patients have not been established.

8.5 Geriatric Use

In the Study PDX-008, 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 decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Since elderly patients may be at higher risk, monitor more closely. Omit dose and subsequently adjust or discontinue therapy for adverse reactions [see Dosage and Administration (2.4)].

8.6 Renal Impairment

No dosage modification is recommended for patients with mild or moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2 based on MDRD). For patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), reduce the recommended dose of FOLOTYN [see Dosage and Administration (2.3)].

Serious adverse drug reactions, including TEN and mucositis, have been reported in patients with ESRD undergoing dialysis. Avoid the use of FOLOTYN in patients with ESRD with or without dialysis. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the FOLOTYN dose based on adverse reactions [see Dosage and Administration (2.3), Warnings and Precautions (5.6)].

12.1 Mechanism of Action

Pralatrexate is a folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase. It is also a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biological molecules the synthesis of which depends on single carbon transfer.

12.2 Pharmacodynamics

Pralatrexate exposure-response relationship and the time course of pharmacodynamics responses are unknown.

12.3 Pharmacokinetics

Pralatrexate is a racemic mixture of S- and R-diastereomers. The pharmacokinetics of pralatrexate at the recommended dosage of 30 mg/m2 once weekly have been evaluated in 10 patients with PTCL. Pralatrexate total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally over a dose range 30 to 325 mg/m2 (10.8 times the approved recommended dosage). No accumulation of pralatrexate was observed.

Distribution
Steady-state volume of distribution of pralatrexate S- and R-diastereomers is 105 L and 37 L, respectively. Protein binding of pralatrexate is approximately 67% in vitro.

Elimination
The total systemic clearance of pralatrexate diastereomers was 417 mL/min (S-diastereomer) and 191 mL/min (R-diastereomer). The terminal elimination half-life of pralatrexate was 12-18 hours (coefficient of variance [CV] = 62-120%).

Metabolism
Pralatrexate is not significantly metabolized by CYP450 isozymes or glucuronidases in vitro.

Excretion
Following a single dose of FOLOTYN 30 mg/m2, approximately 34% of the pralatrexate dose was excreted unchanged into urine. Following a radiolabeled pralatrexate dose, 39% (CV = 28%) of the dose was recovered in urine as unchanged pralatrexate and 34% (CV = 88%) in feces as unchanged pralatrexate and/or any metabolites. 10% (CV = 95%) of the dose was exhaled over 24 hours.

Specific Populations
No clinically meaningful effect on the pharmacokinetics of pralatrexate was observed based on sex. The effect of hepatic impairment on the pharmacokinetics of pralatrexate has not been studied.

Patients with Renal Impairment
Following administration of a single dose of FOLOTYN, mean exposures of the pralatrexate S-diastereomer and R- diastereomer were comparable in patients with mild to moderate (eGFR 30 to 59 mL/min/1.73 m2 based on MDRD) renal impairment as compared with severe (eGFR 15 to 29 mL/min/1.73 m2) renal impairment. The mean fraction of the administered dose excreted as unchanged diastereomers in urine (fe) decreased with declining renal function [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies
Coadministration of probenecid (an inhibitor of multidrug resistance-associated protein 2 [MRP2] in vitro) resulted in delayed clearance of pralatrexate.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Pralatrexate does not induce or inhibit CYP enzymes.

Transporter Systems: Pralatrexate is a substrate for BCRP, MRP2, MRP3, and OATP1B3, but is not a substrate of P-gp, OATP1B1, OCT2, OAT1, or OAT3.

Pralatrexate inhibits MRP2 and MRP3, but does not inhibit P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1, or OATP1B3. MRP3 is a transporter that may affect the transport of etoposide and teniposide.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.