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.
1. INDICATIONS AND USAGE
FOLOTYN is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on overall response rate. Clinical benefit such as improvement in progression-free survival or overall survival has not been demonstrated.
2. DOSAGE AND ADMINISTRATION
FOLOTYN should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
2.1 Peripheral T-cell Lymphoma
The recommended dose of FOLOTYN is 30 mg/m2 administered as an intravenous (IV) push over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection, USP IV line once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity.
2.2 Vitamin Supplementation
Patients should take low-dose (1.0-1.25 mg) oral folic acid on a daily basis. Folic acid should be initiated during the 10-day period preceding the first dose of FOLOTYN, and dosing should continue during the full course of therapy and for 30 days after the last dose of FOLOTYN. Patients should also receive a vitamin B12 (1 mg) intramuscular injection no more than 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 (5.3)].
2.3 Preparation and Administration Precautions
FOLOTYN is a cytotoxic anticancer agent. Caution should be exercised in handling, preparing, and administering of the solution. The use of gloves and other protective clothing is recommended. 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.
Several published guidelines for handling and disposal of anticancer agents are available [see References (15)].
2.4 Preparation for Intravenous Push Administration FOLOTYN vials should be refrigerated at 2-8°C (36-46°F) until use. FOLOTYN vials should be stored in original carton to protect from light until use. FOLOTYN is a clear, yellow solution. 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. The calculated dose of FOLOTYN should be aseptically withdrawn into a syringe for immediate use. Do not dilute FOLOTYN. FOLOTYN vials contain no preservatives and are intended for single use only. After withdrawal of dose, discard vial including any unused portion. Unopened vial(s) of FOLOTYN are stable if stored in the original carton at room temperature for 72 hours. Any vials left at room temperature for greater than 72 hours should be discarded. 2.5 Monitoring and Dose Modifications
Management of severe or intolerable adverse reactions may require dose omission, reduction, or interruption of FOLOTYN therapy.
Complete blood cell counts and severity of mucositis should be monitored weekly. Serum chemistry tests, including renal and hepatic function, should be performed prior to the start of the first and fourth dose of a given cycle.
Dose Modification Recommendations
Prior to administering any dose of FOLOTYN: Mucositis should be ≤ Grade 1. Platelet count should be ≥ 100,000/µL for first dose and ≥ 50,000/µL for all subsequent doses. Absolute neutrophil count (ANC) should be ≥ 1,000/µL.
Doses may be omitted or reduced based on patient tolerance. Omitted doses will not be made up at the end of the cycle; once a dose reduction occurs for toxicity, do not re-escalate. For dose modifications and omissions, use the guidelines in Tables 1, 2, and 3.
Table 1 FOLOTYN Dose Modifications for Mucositis
| Mucositis Gradea on Day of Treatment
| Dose upon Recovery to ≤ Grade 1
|Continue prior dose
|Grade 2 recurrence
Table 2 FOLOTYN Dose Modifications for Hematologic Toxicities
| Blood Count on Day of Treatment
| Duration of Toxicity
| Dose upon Restart
|Platelet < 50,000/µL
|Continue prior dose
|ANC 500-1,000/µL and no fever
|Continue prior dose
|ANC 500-1,000/µL with fever
ANC < 500/µL
|Omit dose, give G-CSF or GM-CSF support
|Continue prior dose with G-CSF or GM-CSF support
|2 weeks or recurrence
|Omit dose, give G-CSF or GM-CSF support
|20 mg/m2 with G-CSF or GM-CSF support
|3 weeks or 2nd recurrence
Table 3 FOLOTYN Dose Modifications for All Other Treatment-related Toxicities
| Toxicity Grade a on Day of Treatment
| Dose upon Recovery to ≤ Grade 2
3. DOSAGE FORMS AND STRENGTHS
FOLOTYN is available in sterile, single-use vials containing pralatrexate at a concentration of 20 mg/mL in the following presentations:
20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL)
40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL)
5. WARNINGS AND PRECAUTIONS
5.1 Bone Marrow Suppression
FOLOTYN can suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Dose modifications are based on ANC and platelet count prior to each dose [see Dosage and Administration (2.5) and Adverse Reactions (6)].
Treatment with FOLOTYN may cause mucositis. If ≥ Grade 2 mucositis is observed, omit dose and follow guidelines in Section 2.5, Table 1 [see Dosage and Administration (2.5)].
5.3 Folic Acid and Vitamin B12 Supplementation
Patients should be instructed to take folic acid and receive vitamin B12 to potentially reduce treatment-related hematological toxicity and mucositis [see Dosage and Administration (2.2)].
5.4 Pregnancy Category D
FOLOTYN can cause fetal harm when administered to a pregnant woman. FOLOTYN was embryotoxic and fetotoxic in rats and rabbits. 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 [see Use in Specific Populations (8.1)].
5.5 Decreased Renal Function
Although FOLOTYN has not been formally tested in patients with renal impairment, caution is advised when administering FOLOTYN to patients with moderate to severe impairment. Monitor patients for renal function and systemic toxicity due to increased drug exposure [see Clinical Pharmacology (12.3)].
5.6 Elevated Liver Enzymes
Liver function test abnormalities have been observed after FOLOTYN administration. Persistent liver function test abnormalities may be indicators of liver toxicity and require dose modification. Monitor patients for liver function [see Dosage and Administration (2.5)].
5.7 Dermatologic Reactions
Dermatologic reactions have been reported in clinical studies and post-marketing safety reports in patients treated with FOLOTYN. Dermatologic reactions have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN). These reactions, as well as tumor lysis syndrome, may involve skin and subcutaneous sites of known lymphoma. Skin reactions may be progressive and increase in severity with further treatment. Severe skin reactions have been associated with fatal outcomes. Patients with skin reactions should be monitored closely, and if skin reactions are severe, FOLOTYN should be withheld or discontinued.
HOW SUPPLIED/STORAGE AND HANDLING
FOLOTYN is available in single-use clear glass vials containing pralatrexate at a concentration of 20 mg/mL as a preservative-free, sterile, clear yellow solution individually packaged for intravenous use in the following presentations:
NDC 48818-001-01: 20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL)
NDC 48818-001-02: 40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL)
Vials must be stored refrigerated at 2-8°C (36-46°F) (see USP Controlled Cold Temperature) in original carton to protect from light.
Handle and dispose of FOLOTYN according to guidelines issued for cytotoxic drugs, including the use of gloves and other protective clothing to prevent skin contact [see References (15)].
Each vial of FOLOTYN is intended for single use only. Any unused drug remaining after injection must be discarded
FOLOTYN is a trademark of Allos Therapeutics, Inc.
© 2010 Allos Therapeutics, Inc. All rights reserved.