Folotyn

FOLOTYN is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

This indication is approved under accelerated approval based on overall response rate

• Supplement patients with vitamin B₁₂ mg intramuscularly every 8-10 weeks starting 10 weeks before the first dose and folic acid 1 to 1.25 mg orally once daily starting 10 days before the first dose. (
  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]

  .

  Vitamin B₁₂

  
  
  Administer vitamin B₁₂1 mg intramuscularly within 10 weeks prior to the first dose of FOLOTYN and every 8-10 weeks thereafter. Subsequent vitamin B₁₂injections may be given the same day as treatment with FOLOTYN

  [ see Warnings and Precautions]

  .
  )
• The recommended dosage of FOLOTYN is 30 mg/m² intravenously over 3 to 5 minutes once weekly for 6 weeks in 7-week cycles. (
  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]

  .

  Vitamin B₁₂

  
  
  Administer vitamin B₁₂1 mg intramuscularly within 10 weeks prior to the first dose of FOLOTYN and every 8-10 weeks thereafter. Subsequent vitamin B₁₂injections may be given the same day as treatment with FOLOTYN

  [ see Warnings and Precautions]

  .
  )
• For patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m²), reduce the FOLOTYN dose to 15 mg/m² (
  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]

  .

  Vitamin B₁₂

  
  
  Administer vitamin B₁₂1 mg intramuscularly within 10 weeks prior to the first dose of FOLOTYN and every 8-10 weeks thereafter. Subsequent vitamin B₁₂injections may be given the same day as treatment with FOLOTYN

  [ see Warnings and Precautions]

  .
  ).

Injection: 40 mg/2 mL (20 mg/mL) and 20 mg/mL clear yellow sterile solution in single-dose vial

• Lactation
  : Advise not to breastfeed. (
  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.
  )

• Myelosuppression
  : Monitor complete blood counts and omit and/or reduce dose based on ANC and platelet count. (
  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.

  Recommended Dosage Modifications

  
  
  Do not administer FOLOTYN until:

  • Mucositis Grade 1 or less.
  • Platelet of 100,000/mcL or greater for first dose and 50,000/mcL or greater for all subsequent doses.
  • Absolute neutrophil count (ANC) of 1,000/mcL or greater.

  Dosage modifications for adverse reactions are provided in Tables 1, 2, and 3.

  Table 1 FOLOTYN Dose Modifications for Mucositis

  Mucositis Gradeaon Day of Treatment	Action	Recommended Dose upon Recovery to Grade 0 or 1
  		Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Grade 2	Omit dose	Continue prior dose	Continue prior dose
  Grade 2 recurrence	Omit dose	20 mg/m2	10 mg/m2
  Grade 3	Omit dose	20 mg/m2	10 mg/m2
  Grade 4	Stop therapy

  ^aBased National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0)

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Table 2 FOLOTYN Dosage Modifications for Myelosuppression

  Blood Count on Day of Treatment	Duration of Toxicity	Action	Recommended Dose Upon Recovery
  			Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Platelet less than 50,000/mcL	1 week	Omit dose	Continue prior dose	Continue prior dose
  	2 weeks	Omit dose	20 mg/m2	10 mg/m2
  	3 weeks	Stop therapy
  ANC 500 to 1,000/mcL and no fever	1 week	Omit dose	Continue prior dose	Continue prior dose
  ANC 500 to 1,000/mcL with fever or ANC less than 500/mcL	1 week	Omit dose, give G‑CSF or GM‑CSF	Continue prior dose with G-CSF or GM‑CSF	Continue prior dose with G-CSF or GM‑CSF support
  	2 weeks or recurrence	Omit dose, give G‑CSF or GM‑CSF	20 mg/m2with G-CSF or GM-CSF	10 mg/m2with G-CSF or GM-CSF
  	3 weeks or 2ndrecurrence	Stop therapy

  G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte macrophage colony-stimulating factor

  
  
  
  
  
  
  
  
  
  
  
  
  

  Table 3 FOLOTYN Dosage Modifications for All Other Adverse Reactions

  Toxicity Gradeaon Day of Treatment	Action	Recommended Dose upon Recovery to Grade 2 or Lower
  		Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Grade 3	Omit dose	20 mg/m2	10 mg/m2
  Grade 4	Stop therapy

  ^aBased on NCI CTCAE version 3.0
  ,
  5.1 Myelosuppression

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

  Administer vitamin B₁₂and 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
  : Monitor at least weekly. Omit and/or reduce dose for grade 2 or higher mucositis. (
  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.

  Recommended Dosage Modifications

  
  
  Do not administer FOLOTYN until:

  • Mucositis Grade 1 or less.
  • Platelet of 100,000/mcL or greater for first dose and 50,000/mcL or greater for all subsequent doses.
  • Absolute neutrophil count (ANC) of 1,000/mcL or greater.

  Dosage modifications for adverse reactions are provided in Tables 1, 2, and 3.

  Table 1 FOLOTYN Dose Modifications for Mucositis

  Mucositis Gradeaon Day of Treatment	Action	Recommended Dose upon Recovery to Grade 0 or 1
  		Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Grade 2	Omit dose	Continue prior dose	Continue prior dose
  Grade 2 recurrence	Omit dose	20 mg/m2	10 mg/m2
  Grade 3	Omit dose	20 mg/m2	10 mg/m2
  Grade 4	Stop therapy

  ^aBased National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0)

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Table 2 FOLOTYN Dosage Modifications for Myelosuppression

  Blood Count on Day of Treatment	Duration of Toxicity	Action	Recommended Dose Upon Recovery
  			Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Platelet less than 50,000/mcL	1 week	Omit dose	Continue prior dose	Continue prior dose
  	2 weeks	Omit dose	20 mg/m2	10 mg/m2
  	3 weeks	Stop therapy
  ANC 500 to 1,000/mcL and no fever	1 week	Omit dose	Continue prior dose	Continue prior dose
  ANC 500 to 1,000/mcL with fever or ANC less than 500/mcL	1 week	Omit dose, give G‑CSF or GM‑CSF	Continue prior dose with G-CSF or GM‑CSF	Continue prior dose with G-CSF or GM‑CSF support
  	2 weeks or recurrence	Omit dose, give G‑CSF or GM‑CSF	20 mg/m2with G-CSF or GM-CSF	10 mg/m2with G-CSF or GM-CSF
  	3 weeks or 2ndrecurrence	Stop therapy

  G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte macrophage colony-stimulating factor

  
  
  
  
  
  
  
  
  
  
  
  
  

  Table 3 FOLOTYN Dosage Modifications for All Other Adverse Reactions

  Toxicity Gradeaon Day of Treatment	Action	Recommended Dose upon Recovery to Grade 2 or Lower
  		Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Grade 3	Omit dose	20 mg/m2	10 mg/m2
  Grade 4	Stop therapy

  ^aBased on NCI CTCAE version 3.0
  ,
  5.2 Mucositis

  FOLOTYN can cause mucositis

  [ see Adverse Reactions (6.1)]

  .

  Administer vitamin B₁₂and 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
  : Reactions, including fatal reactions, occurred and may be progressive and increase in severity with further treatment. Monitor closely and withhold or discontinue FOLOTYN based on severity. (
  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.

  Recommended Dosage Modifications

  
  
  Do not administer FOLOTYN until:

  • Mucositis Grade 1 or less.
  • Platelet of 100,000/mcL or greater for first dose and 50,000/mcL or greater for all subsequent doses.
  • Absolute neutrophil count (ANC) of 1,000/mcL or greater.

  Dosage modifications for adverse reactions are provided in Tables 1, 2, and 3.

  Table 1 FOLOTYN Dose Modifications for Mucositis

  Mucositis Gradeaon Day of Treatment	Action	Recommended Dose upon Recovery to Grade 0 or 1
  		Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Grade 2	Omit dose	Continue prior dose	Continue prior dose
  Grade 2 recurrence	Omit dose	20 mg/m2	10 mg/m2
  Grade 3	Omit dose	20 mg/m2	10 mg/m2
  Grade 4	Stop therapy

  ^aBased National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0)

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Table 2 FOLOTYN Dosage Modifications for Myelosuppression

  Blood Count on Day of Treatment	Duration of Toxicity	Action	Recommended Dose Upon Recovery
  			Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Platelet less than 50,000/mcL	1 week	Omit dose	Continue prior dose	Continue prior dose
  	2 weeks	Omit dose	20 mg/m2	10 mg/m2
  	3 weeks	Stop therapy
  ANC 500 to 1,000/mcL and no fever	1 week	Omit dose	Continue prior dose	Continue prior dose
  ANC 500 to 1,000/mcL with fever or ANC less than 500/mcL	1 week	Omit dose, give G‑CSF or GM‑CSF	Continue prior dose with G-CSF or GM‑CSF	Continue prior dose with G-CSF or GM‑CSF support
  	2 weeks or recurrence	Omit dose, give G‑CSF or GM‑CSF	20 mg/m2with G-CSF or GM-CSF	10 mg/m2with G-CSF or GM-CSF
  	3 weeks or 2ndrecurrence	Stop therapy

  G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte macrophage colony-stimulating factor

  
  
  
  
  
  
  
  
  
  
  
  
  

  Table 3 FOLOTYN Dosage Modifications for All Other Adverse Reactions

  Toxicity Gradeaon Day of Treatment	Action	Recommended Dose upon Recovery to Grade 2 or Lower
  		Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Grade 3	Omit dose	20 mg/m2	10 mg/m2
  Grade 4	Stop therapy

  ^aBased on NCI CTCAE version 3.0
  ,
  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)]

  .
  )
• Tumor lysis syndrome
  : Monitor patients who are increased risk and treat promptly. (
  5.4 Tumor Lysis Syndrome

  FOLOTYN can cause tumor lysis syndrome (TLS). Monitor patients who are at increased risk of TLS and treat promptly.
  )
• Hepatic toxicity
  : Monitor for liver function tests. Omit until recovery, adjust or discontinue therapy based on severity. (
  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.

  Recommended Dosage Modifications

  
  
  Do not administer FOLOTYN until:

  • Mucositis Grade 1 or less.
  • Platelet of 100,000/mcL or greater for first dose and 50,000/mcL or greater for all subsequent doses.
  • Absolute neutrophil count (ANC) of 1,000/mcL or greater.

  Dosage modifications for adverse reactions are provided in Tables 1, 2, and 3.

  Table 1 FOLOTYN Dose Modifications for Mucositis

  Mucositis Gradeaon Day of Treatment	Action	Recommended Dose upon Recovery to Grade 0 or 1
  		Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Grade 2	Omit dose	Continue prior dose	Continue prior dose
  Grade 2 recurrence	Omit dose	20 mg/m2	10 mg/m2
  Grade 3	Omit dose	20 mg/m2	10 mg/m2
  Grade 4	Stop therapy

  ^aBased National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0)

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Table 2 FOLOTYN Dosage Modifications for Myelosuppression

  Blood Count on Day of Treatment	Duration of Toxicity	Action	Recommended Dose Upon Recovery
  			Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Platelet less than 50,000/mcL	1 week	Omit dose	Continue prior dose	Continue prior dose
  	2 weeks	Omit dose	20 mg/m2	10 mg/m2
  	3 weeks	Stop therapy
  ANC 500 to 1,000/mcL and no fever	1 week	Omit dose	Continue prior dose	Continue prior dose
  ANC 500 to 1,000/mcL with fever or ANC less than 500/mcL	1 week	Omit dose, give G‑CSF or GM‑CSF	Continue prior dose with G-CSF or GM‑CSF	Continue prior dose with G-CSF or GM‑CSF support
  	2 weeks or recurrence	Omit dose, give G‑CSF or GM‑CSF	20 mg/m2with G-CSF or GM-CSF	10 mg/m2with G-CSF or GM-CSF
  	3 weeks or 2ndrecurrence	Stop therapy

  G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte macrophage colony-stimulating factor

  
  
  
  
  
  
  
  
  
  
  
  
  

  Table 3 FOLOTYN Dosage Modifications for All Other Adverse Reactions

  Toxicity Gradeaon Day of Treatment	Action	Recommended Dose upon Recovery to Grade 2 or Lower
  		Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Grade 3	Omit dose	20 mg/m2	10 mg/m2
  Grade 4	Stop therapy

  ^aBased on NCI CTCAE version 3.0
  ,
  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)]

  .
  )
• Risk of increased toxicity with renal impairment
  : Avoid FOLOTYN in patients with end stage renal disease 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. (
  2.3 Dosage Modifications for Renal Impairment and End Stage Renal Disease

  • Severe renal impairment (eGFR 15 to 29 mL/min/1.73 m²by 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 m²by 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.

  Recommended Dosage Modifications

  
  
  Do not administer FOLOTYN until:

  • Mucositis Grade 1 or less.
  • Platelet of 100,000/mcL or greater for first dose and 50,000/mcL or greater for all subsequent doses.
  • Absolute neutrophil count (ANC) of 1,000/mcL or greater.

  Dosage modifications for adverse reactions are provided in Tables 1, 2, and 3.

  Table 1 FOLOTYN Dose Modifications for Mucositis

  Mucositis Gradeaon Day of Treatment	Action	Recommended Dose upon Recovery to Grade 0 or 1
  		Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Grade 2	Omit dose	Continue prior dose	Continue prior dose
  Grade 2 recurrence	Omit dose	20 mg/m2	10 mg/m2
  Grade 3	Omit dose	20 mg/m2	10 mg/m2
  Grade 4	Stop therapy

  ^aBased National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0)

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Table 2 FOLOTYN Dosage Modifications for Myelosuppression

  Blood Count on Day of Treatment	Duration of Toxicity	Action	Recommended Dose Upon Recovery
  			Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Platelet less than 50,000/mcL	1 week	Omit dose	Continue prior dose	Continue prior dose
  	2 weeks	Omit dose	20 mg/m2	10 mg/m2
  	3 weeks	Stop therapy
  ANC 500 to 1,000/mcL and no fever	1 week	Omit dose	Continue prior dose	Continue prior dose
  ANC 500 to 1,000/mcL with fever or ANC less than 500/mcL	1 week	Omit dose, give G‑CSF or GM‑CSF	Continue prior dose with G-CSF or GM‑CSF	Continue prior dose with G-CSF or GM‑CSF support
  	2 weeks or recurrence	Omit dose, give G‑CSF or GM‑CSF	20 mg/m2with G-CSF or GM-CSF	10 mg/m2with G-CSF or GM-CSF
  	3 weeks or 2ndrecurrence	Stop therapy

  G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte macrophage colony-stimulating factor

  
  
  
  
  
  
  
  
  
  
  
  
  

  Table 3 FOLOTYN Dosage Modifications for All Other Adverse Reactions

  Toxicity Gradeaon Day of Treatment	Action	Recommended Dose upon Recovery to Grade 2 or Lower
  		Patients Without Severe Renal Impairment	Patients with Severe Renal Impairment
  Grade 3	Omit dose	20 mg/m2	10 mg/m2
  Grade 4	Stop therapy

  ^aBased on NCI CTCAE version 3.0
  ,
  5.6 Risk of Increased Toxicity with Renal Impairment

  Patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m²based 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
  : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use an effective method of contraception. (
  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)]

  .
  ,
  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/m²basis. 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/m²basis) 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.
  ,
  8.3 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.
  )