Folotyn (pralatrexate)

Overdose

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, consider the prompt administration of leucovorin.

Contraindications

None

Undesirable effects

The following serious adverse reactions are described below and elsewhere in the labeling:

• Bone Marrow Suppression
• Mucositis
• Dermatologic Reactions
• Tumor Lysis Syndrome
• Hepatic Toxicity

The most common adverse reactions observed in patients with peripheral T-cell lymphoma (PTCL) treated with FOLOTYN were mucositis, thrombocytopenia, nausea, and fatigue.

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 4 summarizes the most frequent adverse reactions, regardless of causality, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, version 3.0).

Table 4 : Adverse Reactions Occurring in PTCL Patients (Incidence ≥ 10% of patients )

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. Deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated on all FOLOTYN trials at doses ranging from 30 to 325 mg/m².

Twenty-three percent 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).

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.

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.

Toxic epidermal necrolysis, sometimes fatal, has been reported during post-marketing use of FOLOTYN. Fatal cases have been reported following the first dose of FOLOTYN, including when a reduced dose is given, and have been reported in patients with end-stage renal disease undergoing dialysis.

Therapeutic indications

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.

Pharmacokinetic properties

The pharmacokinetics of pralatrexate administered as a single agent at a dose of 30 mg/m² administered as an intravenous push over 3-5 minutes 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 of pralatrexate was 12-18 hours (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.

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.

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.

Excretion

The mean fraction of unchanged pralatrexate diastereomers excreted in urine following a pralatrexate dose of 30 mg/m² administered as an intravenous push over 35 minutes was 31% (Sdiastereomer) (CV = 47%) and 38% (R-diastereomer) (CV = 45%), respectively. In a mass balance study conducted in patients with advanced cancer, an average of 39% (CV = 28%) of the administered radiolabeled pralatrexate dose was excreted in urine as parent, racemic pralatrexate (fe). An average of 34% (CV = 88%) of the administered dose was recovered in feces as total radiation (feTR) which included both parent pralatrexate and/or any metabolites. An average of 10% (CV = 95%) of total dose was exhaled as total radioactivity over 24 hours.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

FOLOTYN can cause bone marrow suppression, manifested by thrombocytopenia, neutropenia, and/or anemia. Monitor complete blood counts and omit and/or reduce the dose based on ANC and platelet count prior to each dose as outlined in Section 2.2 Table 2. Administer vitamin B and instruct patients to take folic acid to reduce the risk of treatment-related hematological toxicity.

FOLOTYN can cause mucositis. Monitor for mucositis weekly and if ≥ Grade 2 mucositis is observed, omit and/or reduce the dose as outlined in Section 2.2 Table 1. Administer vitamin B and instruct patients to take folic acid to reduce the risk of mucositis.

FOLOTYN can cause 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). They may be progressive and increase in severity with further treatment, and may involve skin and subcutaneous sites of known lymphoma. Monitor patients with dermatologic reactions closely, and if severe, withhold or discontinue FOLOTYN.

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

FOLOTYN can cause hepatic toxicity and liver function test abnormalities. 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.

Patients with moderate to severe renal function impairment may be at greater risk for increased exposure and toxicity. Monitor patients for renal function and systemic toxicity and adjust dosing accordingly.

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.

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 FDA-approved labeling (PATIENT INFORMATION).

Patients should be instructed to read the Patient Information carefully.

Advise patients treated with FOLOTYN to take folic acid and vitamin B as a prophylactic measure to reduce the risk of possible side effects.

Inform patients of the risk of low blood cell counts and to immediately contact their physician should any signs of infection develop, including fever. Inform patients to contact their physician if bleeding orsymptoms of anemia occur.

Inform patients of the signs and symptoms of mucositis. Instruct patients on ways to reduce the risk of its development, and on ways to maintain nutrition and control discomfort from mucositis if it occurs.

Advise patients about the risks for and the signs and symptoms of dermatologic reactions. Instructpatients to immediately notify their physician if any skin reactions occur.

Inform patients about the risk of and the signs and symptoms of tumor lysis syndrome. Patients should be instructed to notify their physician if they experience these symptoms.

Patients should be instructed to inform their physician if they are taking any concomitant medications including prescription drugs (such as trimethoprim/sulfamethoxazole) and nonprescription drugs (such as nonsteroidal anti-inflammatory drugs).

Patients should be instructed to tell their physician if they are pregnant or plan to become pregnant due to the risk of fetal harm. Patients should be instructed to tell their physician if they are nursing.

Carcinogenicity studies have not been performed with pralatrexate.

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.

No fertility studies have been performed.

Pregnancy Category D

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 through 20. Treatment with pralatrexate caused a dosedependent 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 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. 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.

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.

Pediatric patients were not included in clinical studies with FOLOTYN. The safety and effectiveness of FOLOTYN in pediatric patients have not been established.

In the PTCL efficacy study, 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 exposure related toxicity.

The safety, efficacy and pharmacokinetics of FOLOTYN have not been evaluated 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.

For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m²), the recommended dose of FOLOTYN is 15 mg/m². For patients with mild to moderate renal impairment, dose reduction is not necessary.

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.

Dosage (Posology) and method of administration

Folic Acid: Patients should take folic acid 1.0-1.25 mg orally once daily beginning 10 days before the first dose of FOLOTYN. Continue folic acid during the full course of therapy and for 30 days after the last dose of FOLOTYN.

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.

The recommended dose of FOLOTYN is 30 mg/m administered as an intravenous push over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection, intravenous line once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity. The calculated dose of FOLOTYN should be aseptically withdrawn into a syringe for immediate use. Do not dilute FOLOTYN.

For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m²), the recommended dose of FOLOTYN is 15 mg/m².

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.

Management of severe or intolerable adverse reactions may require dose omission, reduction, or discontinuation of FOLOTYN therapy.

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.

Sections or subsections omitted from the full prescribing information are not listed.

Prior to administering any dose of FOLOTYN:

• Mucositis should be ≤ Grade 1.
• Platelet count should be ≥ 100,000/mcL for first dose and ≥ 50,000/mcL for all subsequent doses.
• Absolute neutrophil count (ANC) should be ≥ 1,000/mcL.

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.

For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m²), the recommended starting dose of FOLOTYN is 15 mg/m² with dose modification to 10 mg/m² for the toxicities specified in Tables 1, 2, and 3.

Table 1 : FOLOTYN Dose Modifications for Mucositis

Table 2 : FOLOTYN Dose Modifications for Hematologic Toxicities

Table 3 : FOLOTYN Dose Modifications for All Other Treatment-related Toxicities

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 available1-4.

• 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 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.