Folotyn

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 ].

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 ].

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.

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)].

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.

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.

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.

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.

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.

Pediatric Use

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

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)].

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)].

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)].

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)].

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)].

Tumor Lysis Syndrome

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

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)].

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)].

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)].