Pralatrexate

## Pretreatment Vitamin Supplementation
- Folic Acid: Patients should take folic acid 1.0-1.25 mg orally once daily beginning 10 days before the first dose of Pralatrexate. Continue folic acid during the full course of therapy and for 30 days after the last dose of Pralatrexate.
- Vitamin B12: Administer vitamin B12 1 mg intramuscularly within 10 weeks prior to the first dose of Pralatrexate and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with Pralatrexate.

## Dosing and Administration
- The recommended dose of Pralatrexate is 30 mg/m2 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 The calculated dose of Pralatrexate should be aseptically withdrawn into a syringe for immediate use. Do not dilute Pralatrexate.
- Pralatrexate 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.

# Monitoring and Dose Modifications
- Management of severe or intolerable adverse reactions may require dose omission, reduction, or discontinuation of Pralatrexate therapy.

## Monitoring
- Monitor complete blood cell counts and severity of mucositis at baseline and weekly. Perform serum chemistry tests, including renal function and hepatic function, prior to the start of the first and fourth dose of each cycle.

## Dose Modification Recommendations
Prior to administering any dose of Pralatrexate:
- 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.

# Special Handling Precautions
- Pralatrexate 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 Pralatrexate comes in contact with the skin, immediately and thoroughly wash with soap and water. If Pralatrexate comes in contact with mucous membranes, flush thoroughly with water.
- Several published guidelines for handling and disposal of anticancer agents are available:
- Pralatrexate vials should be refrigerated at 2-8C (36-46F) until use.
- Pralatrexate vials should be stored in original carton to protect from light until use.
- Pralatrexate 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 Pralatrexate 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.
- Pralatrexate 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 B12 and instruct patients to take folic acid to reduce the risk of treatment-related hematological toxicity.

## Mucositis
- Pralatrexate 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 B12 and instruct patients to take folic acid to reduce the risk of mucositis.

## Dermatologic Reactions
- Pralatrexate can cause severe dermatologic reactions, which may result in death. These dermatologic reactions have been reported in clinical studies (14/663 patients ) 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 Pralatrexate.

## Tumor Lysis Syndrome
- Pralatrexate can cause tumor lysis syndrome (TLS). Monitor patients who are at increased risk of TLS and treat promptly.

## Hepatic Toxicity
- Pralatrexate 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.

## Risk of Increased Toxicity in the Presence of Impaired Renal Function
- 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 Pralatrexate therapy. Avoid Pralatrexate use in patients with end stage renal disease including those undergoing dialysis unless the potential benefit justifies the potential risk.

## Embryo-Fetal Toxicity
- Pralatrexate can cause fetal harm when administered to a pregnant woman. Pralatrexate 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.
- 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 Pralatrexate 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 Pralatrexate 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 cyc

## 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).

## Serious Adverse Events
- Forty-four percent of patients (n = 49) experienced a serious adverse event while on study or within 30 days after their last dose of Pralatrexate  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 Pralatrexate trials at doses ranging from 30 to 325 mg/m2.

## Discontinuations
- Twenty-three percent of patients (n = 25) discontinued treatment with Pralatrexate 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 Pralatrexate 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.

## Dermatologic Reactions
- Toxic epidermal necrolysis, sometimes fatal, has been reported during post-marketing use of Pralatrexate  Fatal cases have been reported following the first dose of Pralatrexate  including when a reduced dose is given, and have been reported in patients with end-stage renal disease undergoing dialysis.
- When administering Pralatrexate 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.
- The risk for toxicity may be greater when administering Pralatrexate 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 Pralatrexate in patients with end stage renal disease undergoing dialysis unless the potential benefit justifies the potential risk.
The molecular formula is C23H23N7O5 and the molecular weight is 477.48 g/mol.
- 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  = 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.

## 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
- 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 intravenous push over 3-5 minutes was 31% (S-diastereomer) (CV = 47%) and 38% (R-diastereomer) (CV = 45%), respectively.

## 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.

## Impairment of Fertility
- No fertility studies have been performed.
- The safety and efficacy of Pralatrexate 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 patients were treated with Pralatrexate at 30 mg/m2 once weekly by IV push over 3-5 minutes 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 first 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 59.0 years (range 21-85); 68% were male and 32% were female. Most patients were White (72%) and other racial origins included: 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 one-fourth of patients (24%, n = 27) did not have evidence of response to any previous therapy. Approximately two-thirds 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 Pralatrexate, the response rate, as determined by independent central review by IWC, was 27% (n = 29) (TABLE 5).
- 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)