Pralatrexate
FDA Drug Information • Also known as: Folotyn, Pralatrexate
- Brand Names
- Folotyn, Pralatrexate
- Drug Class
- Folate Analog Metabolic Inhibitor [EPC]
- Route
- INTRAVENOUS
- Dosage Form
- INJECTION
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION Pralatrexate is a dihydrofolate reductase inhibitor. Pralatrexate has the chemical name (2 S )-2[[4-[(1 RS )-1-[(2, 4-diaminopteridin-6-yl)methyl]but-3- ynyl]benzoyl]amino]pentanedioic acid. The molecular formula is C 23 H 23 N 7 O 5 and the molecular weight is 477.48 g/mol. Pralatrexate is a 1:1 racemic mixture of S- and R- diastereomers at the C10 position (indicated with *). The structural formula is as follows: 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. Pralatrexate Injection is supplied as a preservative-free, sterile, isotonic, non-pyrogenic clear yellow aqueous solution contained in a clear glass single-dose vial (Type I) for intravenous use. 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. Pralatrexate Injection is supplied as either 20 mg (1 mL) or 40 mg (2 mL) single-dose vials at a concentration of 20 mg/mL. Structural Formula
What Is Pralatrexate Used For?
1 INDICATIONS AND USAGE Pralatrexate injection 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 [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Pralatrexate injection is a dihydrofolate reductase inhibitor 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Supplement patients with vitamin B 12 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 ) The recommended dosage of Pralatrexate injection is 30 mg/m 2 intravenously over 3 to 5 minutes once weekly for 6 weeks in 7-week cycles. ( 2.1 ) For patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m 2 ), reduce the Pralatrexate injection dose to 15 mg/m 2 ( 2.1 ). 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 Pralatrexate injection. Continue folic acid during treatment with Pralatrexate injection and for 30 days after the last dose [see Warnings and Precautions ( 5.1 , 5.2 )]. Vitamin B 12 Administer vitamin B 12 1 mg intramuscularly within 10 weeks prior to the first dose of Pralatrexate injection and every 8-10 weeks thereafter. Subsequent vitamin B 12 injections may be given the same day as treatment with Pralatrexate injection [see Warnings and Precautions ( 5.1 , 5.2 )]. 2.2 Recommended Dosage The recommended dosage of Pralatrexate injection is 30 mg/m 2 intravenously over 3-5 minutes once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity. 2.3 Dosage Modifications for Renal Impairment and End Stage Renal Disease Severe renal impairment (eGFR 15 to 29 mL/min/1.73 m 2 by MDRD): Reduce the Pralatrexate injection dose to 15 mg/m 2 [see Use in Specific Populations ( 8.6 )] . End stage renal disease (ESRD: eGFR less than 15 mL/min/1.73 m 2 by MDRD) with or without dialysis: Avoid administration. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the Pralatrexate injection 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 Pralatrexate injection 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 Pralatrexate Injection Dosage Modifications for Mucositis a Based National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0) Mucositis Grade a on 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...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions ( 5.1 )] Mucositis [see Warnings and Precautions ( 5.2 )] Dermatologic Reactions [see Warnings and Precautions ( 5.3 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.4 )] Hepatic Toxicity [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (>35%) are mucositis, thrombocytopenia, nausea, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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. Peripheral T-cell Lymphoma The safety of Pralatrexate injection was evaluated in Study PDX-008 [see Clinical Studies ( 14 )]. Patients received Pralatrexate injection 30 mg/m 2 once weekly for 6 weeks in 7-week cycles. The median duration of treatment was 70 days (range: 1 day to 1.5 years). The majority of patients (69%, n = 77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered. 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 injection. 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. Across clinical trials, deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients who received doses ranging from 30 mg/m 2 to 325 mg/m 2 . Twenty-three percent of patients (n = 25) discontinued treatment with Pralatrexate injection due to adverse reactions. The most frequent adverse reactions reported as the reason for discontinuation of treatment were mucositis (6%) and thrombocytopenia (5%). The most common adverse reactions (> 35%) were mucositis, thrombocytopenia, nausea, and fatigue. Table 4 summarizes the adverse reactions in Study PDX-008. Table 4 Adverse Reactions in (≥ 10%) in Patients Who Received Pralatrexate Injection in Study PDX-008 a Mucositis includes stomatitis or mucosal inflammation of the gastrointestinal and genitourinary tracts. b Five patients with platelets < 10,000/mcL. c Liver function test abnormal includes increased ALT, increased AST, and increased transaminases Pralatrexate Injection N=111 All Grades (%) Grade 3 (%) Grade 4 (%) Any Adverse Reaction 100 43 31 Mucositis a 70 17 4 Thrombocytopenia b 41 14 19 b Nausea 40 4 0 Fatigue 36 5 2 Anemia 34 15 2 Constipation 33 0 0 Pyrexia 32 1 1 Edema 30 1 0 Cough 28 1 0 Epistaxis 26 0 0 Vomiting 25 2 0 Neutropenia 24 13 7 Diarrhea 21 2 0 Dyspnea 19 7 0 Anorexia 15 3 0 Hypokalemia 15 4 1 Rash 15 0 0 Pruritus 14 2 0 Pharyngolaryngeal pain 14 1 0 Liver function test abnormal c 13 5 0 Abdominal pain 12 4 0 Pain in extremity 12 0 0 Back pain 11 3 0 Leukopenia 11 3 4 Night sweats 11 0 0 Asthenia 10 1 0 Upper respiratory tract infection 10 1 0 Tachycardia 10 0 0 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Pralatrexate injection. 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. Dermatologic Reactions: Toxic epidermal necrolysis.
Drug Interactions
7 DRUG INTERACTIONS Avoid coadministration with probenecid or nonsteroidal anti-inflammatory drugs. If coadministration is unavoidable, monitor for increased risk of adverse reactions. ( 7.1 ) 7.1 Effects of Other Drugs on Pralatrexate Injection Coadministration of Pralatrexate injection with probenecid increased pralatrexate plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions. Avoid coadministration with probenecid or nonsteroidal anti-inflammatory drugs. If coadministration is unavoidable, monitor for increased risk of adverse reactions.
Contraindications
4 CONTRAINDICATIONS None None. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )], Pralatrexate injection can cause fetal harm when administered to a pregnant woman. There are insufficient data on Pralatrexate injection use in pregnant women to evaluate for a drug- associated risk. Pralatrexate injection 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/m 2 basis. 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/m 2 /day or about 1.2% of the clinical dose on a mg/m 2 basis) 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 dosedependent increase in post-implantation loss. In rabbits, intravenous doses of 0.03 mg/kg/day (0.36 mg/m 2 /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.
Overdosage
10 OVERDOSAGE No specific information is available on the treatment of overdosage of Pralatrexate injection. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating healthcare provider. Based on Pralatrexate injection's mechanism of action, consider the prompt administration of leucovorin.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Pralatrexate Injection is available in single-dose 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: Product Code Unit of Sale Strength 550101 NDC 65219-550-01 20 mg/1 mL 552102 NDC 65219-552-02 40 mg/2 mL Store refrigerated at 2-8°C (36-46°F) [ see USP Controlled Cold Temperature] in original carton to protect from light. Pralatrexate Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.