Pralatrexate

Pronunciation: PRAL-a-TREX-ate
Class: Folic acid antagonist

Trade Names

Folotyn
- Injection, solution 20 mg/mL

Pharmacology

Disrupts folate-dependent metabolic processes essential for cell replication.

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Pharmacokinetics

Distribution

Vd is approximately 105 L (S-diastereomer) and 37 L (R-diastereomer). Protein binding is approximately 67%.

Metabolism

Not appreciably metabolized.

Elimination

Total systemic Cl is 417 mL/min (S-diastereomer) and 191 mL/min (R-diastereomer). Terminal elimination half-life is 12 to 18 h. Excreted in urine (31% as S-diastereomer and 38% as R-diastereomer).

Special Populations

Renal Function Impairment

Cl decreases with decreasing CrCl.

Hepatic Function Impairment

Studies have not been conducted.

Elderly

Age-related decline in renal function may lead to reduction in Cl and increase in plasma exposure.

Gender

Pharmacokinetics not affected by gender.

Indications and Usage

Treatment of patients with relapsed or refractory peripheral T-cell lymphoma.

Contraindications

None well documented.

Dosage and Administration

Adults

IV 30 mg/m ² once weekly for 6 wk in 7-wk cycles until progressive disease or unacceptable toxicity.

Dosage Adjustment
Mucositis Adults

IV If grade 2 mucositis on day of treatment, omit the dose; once recovery to grade 1 or less occurs, continue prior dose. If grade 2 recurrence or grade 3 mucositis, omit the dose; once recovery to grade 1 or less occurs, administer a dose of 20 mg/m ² . If grade 4 mucositis on day of treatment occurs, stop therapy.

Hematologic toxicity Platelets Adults

IV If platelet count is less than 50,000/mcL on day of treatment and the duration of toxicity is 1 wk, omit the dose. Upon restart, may continue prior dose. If duration of toxicity is 2 wk, omit the dose and upon restart administer 20 mg/m ² . If duration of toxicity is 3 wk then stop therapy.

Absolute neutrophil count Adults

IV If the absolute neutrophil count (ANC) is 500 to 1,000/mcL with no fever on day of treatment and the duration of toxicity is 1 wk, omit the dose and continue with prior dose upon restart. If the ANC is 500 to 1,000/mcL with fever or if the ANC is less than 500/mcL on the day of treatment and the duration of toxicity is 1 wk, omit the dose and give granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) support. Continue the prior dose upon restart with G-CSF or GM-CSF support. If the duration of toxicity is 2 wk or if recurrence, omit the dose and give G-CSF or GM-CSF support; upon dose restart, give 20 mg/m ² with G-CSF or GM-CSF support. If the duration of toxicity is 3 wk or if a second recurrence occurs, stop therapy.

Other treatment-related toxicities Adults

IV If grade 3 toxicity on day of treatment, omit the dose; once recovery to grade 2 or less occurs, restart dose at 20 mg/m ² . If grade 4 toxicity on day of treatment occurs, stop therapy.

Concomitant therapy

Low-dose folic acid (1 to 1.25 mg) daily. Initiate during the 10 days preceding the first dose of pralatrexate, and continue dosing during the full course of therapy and for 30 days after the last dose. One IM vitamin B ₁₂ injection must be given no more than 10 wk prior to the first dose of pralatrexate and every 8 to 10 wk thereafter. Subsequent vitamin B ₁₂ injections may be given the same day as pralatrexate.

General Advice

• Administer as an IV push over 3 to 5 min via the side port of a free-flowing sodium chloride 0.9% injection IV line.
• The calculated dose of pralatrexate should be aseptically withdrawn into a syringe for immediate use. Do not dilute pralatrexate.
• Follow institutional procedures for handling, administering, and disposing of anticancer drugs.
• For single use only; discard unused portions of vial. Do not save any unused portions for future use.
• If pralatrexate solution comes into contact with the skin, wash the skin immediately and thoroughly with soap and water. If pralatrexate comes into contact with mucous membranes, flush thoroughly with water.
• Prior to administering any dose, mucositis should be grade 1 or less, platelet count 100,000/mcL or more for the first dose and 50,000/mcL for all subsequent doses, and ANC 1,000/mcL or more.

Storage/Stability

Store vials refrigerated between 36° and 46°F. Unopened vials are stable if stored in the original carton at room temperature for 72 h. Discard any vials left at room temperature for more than 72 h.

Drug Interactions

NSAIDs (eg, ibuprofen), trimethoprim/sulfamethoxazole

Coadministration may result in delayed Cl of pralatrexate. Observe the clinical response of the patient and adjust the pralatrexate dose as needed.

Palifermin

Coadministration within the same 24-h time period may increase the severity and duration of oral mucositis. Do not administer palifermin 24 h before, during, or 24 h after administration of pralatrexate.

Probenecid

Coadministration of increasing doses of probenecid resulted in delayed Cl of pralatrexate and increased plasma levels. Observe the clinical response of the patient and adjust the pralatrexate dose as needed.

Adverse Reactions

Cardiovascular

Tachycardia (10%).

CNS

Fatigue (36%); asthenia (10%).

Dermatologic

Rash (15%); pruritus (14%); TEN (postmarketing).

GI

Nausea (40%); constipation (33%); vomiting (25%); diarrhea (21%); anorexia (15%); abdominal pain (12%).

Hematologic

Thrombocytopenia (41%); anemia (34%); neutropenia (24%); leukopenia (11%); febrile neutropenia (more than 3%).

Hepatic

LFTs abnormal (13%).

Metabolic

Edema (30%); hypokalemia (15%); dehydration (more than 3%).

Musculoskeletal

Pain in extremity (12%); back pain (11%).

Respiratory

Cough (28%); epistaxis (26%); dyspnea (19%); pharyngolaryngeal pain (14%); upper respiratory tract infection (10%).

Miscellaneous

Mucositis (70%); pyrexia (32%); night sweats (11%); sepsis (more than 3%).

Precautions

Monitor Monitor CBC and severity of mucositis weekly. Perform serum chemistry tests, including renal and hepatic function, prior to the start of the first and fourth dose of a given cycle. Monitor patients for systemic toxicity caused by increased drug exposure. Monitor for signs of tumor lysis syndrome. Closely monitor patients with dermatologic reactions.

Pregnancy

Category D . Can cause fetal harm; avoid use during pregnancy.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Use with caution because of the increased likelihood of decreased renal function.

Renal Function

Use with caution in patients with moderate to severe renal impairment.

Hepatic Function

Formal studies in patients with hepatic impairment have not been conducted.

Bone marrow suppression

Suppression of bone marrow function, manifested by neutropenia, thrombocytopenia, and anemia, may occur.

Dermatologic reactions

Severe dermatologic reactions (eg, skin exfoliation, ulceration, TEN) can occur and may result in death. If these occur, withhold or discontinue pralatrexate.

Hepatic effects

LFT abnormalities have been observed during treatment.

Mucositis

May occur. If at least grade 2 mucositis is observed, modify dose.

Tumor lysis syndrome

Has been reported in patients with lymphoma.

Vitamin supplementation

Ensure that folic acid and vitamin B ₁₂ are taken to reduce treatment-related hematologic toxicity and mucositis.

Overdosage

Symptoms

None well documented.

Patient Information

• Advise patients, families, or caregivers that medication will be prepared and administered by a health care provider in a health care setting.
• Review dosing schedule with patients, families, or caregivers.
• Instruct patients to carefully follow orders for folic acid and vitamin B ₁₂ supplementation to reduce adverse effects.
• Inform patients of the signs and symptoms of mucositis. Instruct patients on ways to reduce the risk of its development and/or ways to maintain nutrition and control discomfort from mucositis if it occurs.
• Advise patients, families, or caregivers to immediately report any of the following to the patient's health care provider: bleeding or unusual bruising; fever, chills, or other signs of infection; pain, redness, or swelling at injection site; paleness.
• Instruct patients to immediately notify their health care provider if any skin reaction occurs (eg, skin exfoliation, ulceration).
• Advise patients, families, or caregivers to report any of the following to the patient's health care provider: persistent nausea, vomiting, diarrhea, or appetite loss; persistent or worsening general body weakness or fatigue; sores in mouth; any other bothersome symptom or feeling.
• Caution women of childbearing potential to avoid becoming pregnant during therapy.

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