Folotyn

Folotyn

Manufacturer:

Mundipharma

Distributor:

DKSH
Full Prescribing Info
Contents
Pralatrexate.
Description
Folotyn (pralatrexate injection) contains pralatrexate, which is an antineoplastic folate analog. Pralatrexate has the chemical name (2S)-2-[[4-[(1RS)-1-[(2, 4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid.
Pralatrexate is a 1:1 racemic mixture of S- and R- diastereomers at the C10 position.
The molecular formula is C23H23N7O5 and the molecular weight is 477.48 g/mol.
Pralatrexate is an off-white to yellow solid. It is soluble in aqueous solutions at pH 6.5 or higher. Pralatrexate is practically insoluble in chloroform and ethanol. The pKa values are 3.25, 4.76 and 6.17.
Folotyn is supplied as a preservative-free, sterile, isotonic, non-pyrogenic clear yellow aqueous parenteral solution contained in a single-use clear glass vial (type I) for intravenous administration. Each 1 mL of solution contains 20 mg of pralatrexate, sufficient sodium chloride to achieve an isotonic (280-300 mOsm) solution and sufficient sodium hydroxide and hydrochloric acid if needed, to adjust and maintain the pH at 7.5-8.5. Folotyn is supplied as either 20 mg (1 mL) or 40 mg (2 mL) single-use vials at a concentration of 20 mg/mL.
Action
Pharmacology: Pharmacodynamics: 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.
Clinical Studies: Peripheral T-Cell Lymphoma (PTCL): The safety and efficacy of Folotyn was evaluated in an open-label, single-arm, multi-center, international trial that enrolled 115 patients with relapsed or refractory PTCL. One hundred and eleven (111) patients were treated with Folotyn at 30 mg/m2 once weekly by IV push over 3-5 min for 6 weeks in 7-week cycles until disease progression or unacceptable toxicity. Of the 111 patients treated, 109 patients were evaluable for efficacy. Evaluable patients had histologically confirmed PTCL by independent central review using the revised European-American lymphoma (REAL) World Health Organization (WHO) disease classification and relapsed or refractory disease after at least one prior treatment.
The primary efficacy endpoint was overall response rate (complete response, complete response unconfirmed and partial response) as assessed by international workshop criteria (IWC). The key secondary efficacy endpoint was duration of response. Response assessments were scheduled at the end of cycle 1 and then every other cycle (every 14 weeks). Duration of response was measured from the 1st day of documented response to disease progression or death. Response and disease progression were evaluated by independent central review using the IWC.
The median age of treated patients was 59 years (range 21-85); 68% were male and 32% were female. Most patients were White (72%) and other racial origins including: Black (13%), Hispanic (8%), Asian (5%), other and unknown (<1% each). Patients had an Eastern cooperative oncology group (ECOG) performance status at study entry of 0 (39%), 1 (44%) or 2 (17%). The median time from initial diagnosis to study entry was 15.6 months (range 0.8-322.3).
The median number of prior systemic therapies was 3 (range 1-12). Approximately ¼ of patients (24%, n=27) did not have evidence of response to any previous therapy. Approximately 2/3 of patients (63%, n=70) did not have evidence of response to their most recent prior therapy before entering the study.
In all evaluable patients (n=109) treated with Folotyn, the response rate, as determined by independent central review by IWC, was 27% (n=29). (See Table1.)

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The initial response assessment was scheduled at the end of cycle 1. Of the responders, 66% responded within cycle 1. The median time to 1st response was 45 days (range 37-349 days).
Pharmacokinetics: Absorption: The pharmacokinetics of pralatrexate administered as a single agent at a dose of 30 mg/m2 administered as an intravenous (IV) push over 3-5 min once weekly for 6 weeks in 7-week cycles have been evaluated in 10 patients with PTCL. The total systemic clearance of pralatrexate diastereomers was 417 mL/min (S-diastereomer) and 191 mL/min (R-diastereomer). The terminal elimination half-life (t½) of pralatrexate was 12-18 hrs [coefficient of variance (CV)=62-120%]. Pralatrexate total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with dose (dose range 30-325 mg/m2, including pharmacokinetics data from high-dose solid tumor clinical studies). The pharmacokinetics of pralatrexate did not change significantly over multiple treatment cycles and no accumulation of pralatrexate was observed.
Distribution: Pralatrexate diastereomers showed a steady-state volume of distribution of 105 L (S-diastereomer) and 37 L (R-diastereomer). In vitro studies indicate that pralatrexate is approximately 67% bound to plasma proteins. In in vitro transporter studies, pralatrexate was a low to moderate substrate for BCRP, OATP1B1, MRP2 and MRP3, and a substrate for OATP1B3. Pralatrexate was not a significant substrate for P-gp, OCT2, OAT1 and OAT3. Pralatrexate did not significantly inhibit P-gp, BCRP, OCT2, OAT1, OAT3 and OATP1B3. Pralatrexate was a weak inhibitor of OATP1B1 (35% inhibition at 100 micrometer) and MRP2 (IC50=43.5 micrometer) and a potent inhibitor of MRP3 (IC50 <0.3 micrometer).
Metabolism: In vitro studies using human hepatocytes, liver microsomes and S9 fractions and recombinant human CYP450 isozymes showed that pralatrexate is not significantly metabolized by the phase I hepatic CYP450 isozymes or phase II hepatic glucuronidases. In vitro studies indicated that pralatrexate has low potential to induce or inhibit the activity of CYP450 isozymes.
Excretion: A mass balance study has not been performed. The mean fraction of unchanged pralatrexate diastereomers excreted in urine following a pralatrexate dose of 30 mg/m2 administered as an IV push over 3-5 min was 31% (S-diastereomer) (CV=47%) and 38% (R-diastereomer) (CV=45%), respectively.
Patients with Renal Impairment: Approximately 34% of pralatrexate was excreted unchanged into urine following a single dose of 30 mg/m2 administered as an IV push over 3-5 min. In a population pharmacokinetic analysis drug clearance decreased with decreasing creatinine clearance (see Precautions).
Patients with Hepatic Impairment: Pralatrexate has not been studied in patients with hepatic impairment.
Effects of Age and Gender: Due to the contribution of renal excretion to overall clearance of pralatrexate, age-related decline in renal function may lead to a reduction in clearance and a commensurate increase in plasma exposure. There was no significant effect of gender on pharmacokinetics.
Toxicology: 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. However, in the in vitro chromosomal aberration test, inhibition of mitosis resulted at concentrations far below what is encountered in vivo in clinical use. Based on the pharmacology of pralatrexate and experience with other folate analogs, an increased risk for genotoxicity from pralatrexate treatment cannot be excluded.
Impairment of Fertility: No fertility studies have been performed.
Indications/Uses
Treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on overall response rate with the view to induce responses sufficient to allow patients to be eligible for stem cell transplant. Clinical benefit eg, improvement in progression-free survival or overall survival has not been demonstrated.
In the pivotal open-label, single-arm, phase II study, recruited patients were pretreated with a median of 3 prior systemic therapies.
Dosage/Direction for Use
Peripheral T-cell Lymphoma: Recommended Dose: 30 mg/m2 intravenous (IV) push over 3-5 min via the side port of a free-flowing 0.9% sodium chloride injection IV line once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity.
Vitamin Supplementation: Patients should take low-dose (1-1.25 mg) oral folic acid on a daily basis. Folic acid should be initiated during the 10-day period preceding the 1st 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 >10 weeks prior to the 1st dose of Folotyn and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with Folotyn (see Precautions).
Monitoring and Dose Modifications: Management of severe or intolerable adverse reactions may require dose omission, reduction or interruption of Folotyn therapy.
Monitoring: 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 1st and 4th dose of a given cycle.
Dose Modification Recommendations: Prior to administering any dose of: Mucositis should be ≤Grade 1. Platelet count should be ≥100,000/microliter for 1st dose and ≥50,000/microliter for all subsequent doses. Absolute neutrophil count (ANC) should be ≥1000/microliter.
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 2, 3 and 4. (See Tables 2, 3 and 4.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

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.
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.
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 hrs. Any vials left at room temperature for >72 hrs should be discarded.
Overdosage
No specific information is available on the treatment of overdosage of Folotyn. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. Based on Folotyn's mechanism of action, the prompt administration of leucovorin should be considered.
Contraindications
None.
Special Precautions
Bone Marrow Suppression: Folotyn can suppress bone marrow function, manifested by thrombocytopenia, neutropenia and anemia. Dose modifications are based on absolute neutrophil count (ANC) and platelet count prior to each dose (see Dosage & Administration and Adverse Reactions).
Mucositis: Treatment with Folotyn may cause mucositis. If ≥grade 2 mucositis is observed, omit dose and follow guidelines in Table 2 (see Dosage & Administration).
Dermatologic Reactions: Folotyn has been associated with severe dermatologic reactions, which may result in death. These dermatologic reactions have been reported in clinical studies [14/663 patients (2.1%)] and post-marketing experience, and have included skin exfoliation, ulceration and toxic epidermal necrolysis (TEN). These reactions may be progressive and increase in severity with further treatment and may involve skin and subcutaneous sites of known lymphoma. Patients with dermatologic reactions should be monitored closely and if severe, Folotyn should be withheld or discontinued.
Tumor Lysis Syndrome: Tumor lysis syndrome has been reported in patients with lymphoma receiving Folotyn. Patients receiving Folotyn should be monitored closely and treated for complications.
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 & Administration).
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. No data are available to safely guide the use of Folotyn in patients with end stage renal disease undergoing dialysis and therefore, its use in these patients is not recommended. (See Pharmacology: Pharmacokinetics under Actions.)
Serious adverse drug reactions including toxic epidermal necrolysis and mucositis were reported in patients with end stage renal disease (ESRD) undergoing dialysis who were administered Folotyn therapy. Avoid Folotyn use in patients with end stage renal disease including those undergoing dialysis unless the potential benefit justifies the potential risk.
Elevated Liver Enzymes: Folotyn can cause hepatic toxicity and liver function test abnormalities. Persistent liver function test abnormalities may be indicators of liver toxicity and require dose modification. Monitor patients for liver function. Omit dose until recovery, adjust or discontinue therapy based on the severity of the hepatic toxicity (see Dosage & Administration).
Hepatic Impairment: Formal studies have not been performed with Folotyn in patients with hepatic impairment. Patients with the following laboratory values were excluded from the pralatrexate lymphoma clinical trials: Total bilirubin >1.5 mg/dL; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN) and AST or ALT >5 x ULN if documented hepatic involvement with lymphoma. Treatment with Folotyn can cause hepatic toxicity and liver function test abnormalities.
Renal Impairment: The safety, efficacy and pharmacokinetics of Folotyn have not been evaluated in patients with renal impairment. The risk for toxicity may be greater when administering Folotyn to patients with moderate-to-severe impairment due to the contribution of renal excretion (approximately 34%) to the overall clearance of pralatrexate. Serious adverse drug reactions, including TEN and mucositis have been reported in patients with ESRD undergoing dialysis. Monitor patients for renal function and for systemic toxicity due to increased drug exposure and adjust dosing accordingly. Avoid the use of Folotyn in patients with end stage renal disease undergoing dialysis unless the potential benefit justifies the potential risk.
Use in pregnancy: 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.
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 7-20. 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 8-21 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.
Use in lactation: 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.
Use in children: Pediatric patients were not included in clinical studies with Folotyn. The safety and effectiveness of Folotyn in pediatric patients have not been established.
Use in elderly: In the PTCL efficacy study, 36% of patients (n=40) were ≥65 years. 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 exposure related toxicity.
Use In Pregnancy & Lactation
Use in pregnancy: 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. 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 7-20. 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 8-21 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.
Use in lactation: It is not known whether pralatrexateis 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.
Adverse Reactions
The most common adverse reactions observed in patients with peripheral T-cell lymphoma (PTCL) treated with Folotyn were mucositis, thrombocytopenia, nausea and fatigue.
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.
The safety of Folotyn was evaluated in 111 PTCL patients in a single-arm clinical study in which patients received a starting dose of 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The median duration of treatment was 70 days (range 1-540 days).
Most Frequent Adverse Reactions: Table 5 summarizes the most frequent adverse reactions, regardless of causality, using the national cancer institute-common terminology criteria for adverse events (NCI CTCAE, version 3). (See Table 5.)

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Serious Adverse Events: Forty-four percent (44%) 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. Deaths from mucositis, febrile neutropenia, sepsis and pancytopenia occurred in 1.2% of patients treated on all Folotyn trials at doses ranging from 30-325 mg/m2.
Discontinuations: Twenty-three percent (23%) of patients (n=25) discontinued treatment with Folotyn due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment were mucositis (6%, n=7) and thrombocytopenia (5%, n=5).
Dose Modifications: The target dose of Folotyn was 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The majority of patients (69%, n=77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered.
Post-Marketing Experience: Toxic epidermal necrolysis, sometimes fatal, has been identified during post-marketing use of Folotyn. Fatal cases have been reported following the 1st dose of Folotyn, including when a reduced dose is given and have been reported in patients with end-stage renal disease undergoing dialysis. 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 (see Precautions).
Drug Interactions
In vitro studies indicated that pralatrexate is not a substrate, inhibitor or inducer of CYP450 isoenzymes and has low potential for drug-drug interactions at CYP450 isoenzymes (see Pharmacology: Pharmacokinetics under Actions). In vitro transporter studies indicated that pralatrexate is not a significant substrate for P-gp, OCT2, OAT1 and OAT3, is a low to moderate substrate for BCRP, OATP1B1, MRP2 and MRP3, and is a substrate for OATP1B3. Pralatrexate does not significantly inhibit P-gp, BCRP, OCT2, OAT1 and OAT3, and OATP1B3, is a weak inhibitor of OATP1B1 and MRP2, and is a potent inhibitor of MRP3 (see Pharmacology under Actions). MRP3 is a liver transporter implicated in the transport of etoposide, teniposide and methotrexate.
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 Pharmacology: Pharmacokinetics under Actions). 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.
Due to the contribution of renal excretion (approximately 34%) to the overall clearance of pralatrexate, concomitant administration of drugs that are subject to substantial renal clearance (eg, NSAIDs, trimethoprim/sulfamethotrexate) may result in delayed clearance of pralatrexate.
Caution For Usage
Instructions for Disposal, Use and Handling: 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.
Each vial of Folotyn is intended for single use only. Any unused drug remaining after injection must be discarded.
Storage
Store at 2-8°C (36-46°F). Protect from light.
Shelf-Life: 4 years.
ATC Classification
L01BA05 - pralatrexate ; Belongs to the class of antimetabolites, folic acid analogues. Used in the treatment of cancer.
Presentation/Packing
Soln for inj 20 mg/mL (preservative-free, sterile, clear yellow soln) x 1 mL, 2 mL.
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