Pralatrexate Drug Information
Generic name: PRALATREXATE
Folate Analog Metabolic Inhibitor [EPC]
Uses of Pralatrexate
FOLOTYN 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
Dosage & Administration of Pralatrexate
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 FOLOTYN 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 FOLOTYN Dose Modifications for Mucositis a Based National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0) Table 2 FOLOTYN Dosage Modifications for Myelosuppression G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte macrophage colony-stimulating factor Table 3 FOLOTYN Dosage Modifications for All Other Adverse Reactions a Based on NCI CTCAE version 3.0
Preparation and Administration
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. FOLOTYN is a hazardous drug.
Follow applicable special handling and disposal procedures. 1 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. Aseptically withdraw the calculated dose from the appropriate number of vial(s) into a syringe for immediate use.
Do not dilute FOLOTYN. Administer undiluted FOLOTYN intravenously over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection. After withdrawal of dose, discard vial(s) including any unused portion.
| 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 | Continue prior dose | Continue prior dose |
| Grade 2 recurrence | Omit dose | 20 mg/m 2 | 10 mg/m 2 |
| Grade 3 | Omit dose | 20 mg/m 2 | 10 mg/m 2 |
| Grade 4 | Stop therapy | ||
| Blood Count on Day of Treatment | Duration of Toxicity | Action | Recommended Dose Upon Recovery | |
|---|---|---|---|---|
| Patients Without Severe Renal Impairment | Patients with Severe Renal Impairment | |||
| Platelet less than 50,000/mcL | 1 week | Omit dose | Continue prior dose | Continue prior dose |
| 2 weeks | Omit dose | 20 mg/m 2 | 10 mg/m 2 | |
| 3 weeks | Stop therapy | |||
| ANC 500 to 1,000/mcL and no fever | 1 week | Omit dose | Continue prior dose | Continue prior dose |
| ANC 500 to 1,000/mcL with fever or ANC less than 500/mcL | 1 week | Omit dose, give G‑CSF or GM‑CSF | Continue prior dose with G-CSF or GM‑CSF | Continue prior dose with G-CSF or GM‑CSF support |
| 2 weeks or recurrence | Omit dose, give G‑CSF or GM‑CSF | 20 mg/m 2 with G-CSF or GM-CSF | 10 mg/m 2 with G-CSF or GM-CSF | |
| 3 weeks or 2 nd recurrence | Stop therapy | |||
| Toxicity Grade a on Day of Treatment | Action | Recommended Dose upon Recovery to Grade 2 or Lower | |
|---|---|---|---|
| Patients Without Severe Renal Impairment | Patients with Severe Renal Impairment | ||
| Grade 3 | Omit dose | 20 mg/m 2 | 10 mg/m 2 |
| Grade 4 | Stop therapy | ||
Side Effects of Pralatrexate
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 FOLOTYN was evaluated in Study PDX-008. Patients received FOLOTYN 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 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.
Across clinical trials, deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients who received doses ranging from. Twenty-three percent of patients (n = 25) discontinued treatment with FOLOTYN 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.
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of FOLOTYN. 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.
| FOLOTYN N=111 | |||
| All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Any Adverse Event | 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 |
| Hypokalemia | 15 | 4 | 1 |
| Anorexia | 15 | 3 | 0 |
| 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 |
| Leukopenia | 11 | 3 | 4 |
| Back pain | 11 | 3 | 0 |
| Night sweats | 11 | 0 | 0 |
| Asthenia | 10 | 1 | 0 |
| Upper respiratory tract infection | 10 | 1 | 0 |
| Tachycardia | 10 | 0 | 0 |
Warnings & Cautions for Pralatrexate
Myelosuppression FOLOTYN can cause myelosuppression, manifested by thrombocytopenia, neutropenia, and/or anemia. Administer vitamin B 12 and instruct patients to take folic acid to reduce the risk of treatment-related myelosuppression. Monitor complete blood counts and omit and/or reduce the dose based on ANC and platelet count prior to each dose.
Mucositis FOLOTYN can cause mucositis
Monitor for mucositis weekly and omit and/or reduce the dose for grade 2 or higher mucositis.
Dermatologic Reactions FOLOTYN can cause severe dermatologic reactions, which may result in death. These dermatologic reactions have been reported in clinical studies (2.1% of 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 closely for dermatologic reactions. Withhold or discontinue FOLOTYN based on severity.
Tumor Lysis Syndrome FOLOTYN can cause tumor lysis syndrome (TLS). Monitor patients who are at increased risk of TLS and treat promptly.
Hepatic Toxicity 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.
Risk of Increased Toxicity with Renal Impairment Patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m 2 based on MDRD) may be at greater risk for increased exposure and adverse reactions. Reduce FOLOTYN dosage in patients with severe renal impairment. Serious adverse reactions, including TEN and mucositis, were reported in patients with end stage renal disease (ESRD) undergoing dialysis who were administered FOLOTYN.
Avoid FOLOTYN in patients with ESRD with or without dialysis. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the FOLOTYN dose based on adverse reactions.
Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, FOLOTYN can cause fetal harm when administered to a pregnant woman. FOLOTYN was embryotoxic and fetotoxic in rats and rabbits. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with FOLOTYN and for 6 months after the last dose.
Drug Interactions with Pralatrexate
Effects of Other Drugs on FOLOTYN Coadministration of FOLOTYN with probenecid increased pralatrexate plasma concentrations, 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.
Pregnancy Safety for Pralatrexate
Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, FOLOTYN can cause fetal harm when administered to a pregnant woman. There are insufficient data on FOLOTYN use in pregnant women to evaluate for a drug- associated risk. FOLOTYN 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. 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.
This toxicity manifested as early and total resorptions, post-implantation loss, and a decrease in the total number of live fetuses.
Pediatric Use of Pralatrexate
Pediatric Use The safety and effectiveness of FOLOTYN in pediatric patients have not been established.
Overdosage Information for Pralatrexate
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 healthcare provider. Based on FOLOTYN's mechanism of action, consider the prompt administration of leucovorin.
Clinical Studies of Pralatrexate
The efficacy of FOLOTYN was evaluated in Study PDX-008, an open-label, single-arm, multi-center, international trial that enrolled patients with relapsed or refractory PTCL. 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 major efficacy outcome measure was overall response rate (complete response, complete response unconfirmed, and partial response) as assessed by International Workshop Criteria (IWC). An additional efficacy outcome measure 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. Patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of The median time from initial diagnosis to study entry was 1.3 years (range 24 days to 26.8 years).
The median number of prior systemic therapies was 3 (range 1 to 12). Approximately 24% of patients (n = 27) did not have evidence of response to any previous therapy. Approximately 63% of patients (n = 70) did not have evidence of response to their most recent prior therapy before entering the study.
Efficacy results are provided in Table 5. Table 5 Efficacy Results for Study PDX-008 per Independent Central Review (IWC) 6 Fourteen patients went off treatment in cycle 1; 2 patients were unevaluable for response by IWC due to insufficient materials provided to central review. CR = Complete Response, CRu = Complete Response unconfirmed, PR = Partial Response The initial response assessment was scheduled at the end of cycle 1.
Of the responders, 66% responded within cycle 1. The median time to first response was 45 days (range 37-349 days).
| Evaluable Patients (N=109) | ||||
| N (%) | 95% CI | Median Duration of Response | Range of Duration of Response | |
| Overall Response | ||||
| CR+CRu+PR | 29 (27) | 19, 36 | 287 days (9.4 months) | 1-503 days |
| CR/CRu | 9 (8) | |||
| PR | 20 (18) | |||
| Responses ≥ 14 weeks | ||||
| CR+CRu+PR | 13 (12) | 7, 20 | Not Reached | 98-503 days |
| CR/CRu | 7 (6) | |||
| PR | 6 (6) | |||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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