pralatrexate (Rx)

>10%

Inflammatory disease of mucous membrane, Any grade (70% )

Thrombocytopenia, Any grade (41% )

Nausea (40% )

Fatigue (36% )

Anemia, Any grade (34% )

Constipation (33% )

Pancytopenia, Thrombocytopenia, Grade 3/4 (33% )

Edema (30% )

Cough (28% )

Neutropenia, Any grade (24% )

Inflammatory disease of mucous membrane, Grade 3/4 (21% )

Neutropenia, Grade 3/4 (20% )

Dyspnea (19% )

Anemia (17% )

1-10%

Febrile neutropenia (>3% )

Sepsis (>3% )

Postmarketing Reports

Skin exfoliation, ulceration, and toxic epidermal necrolysis

Contraindications

Hypersensitivity

Cautions

Treatment can cause mucositis; administer vitamin B12 and instruct patients to take folic acid to reduce risk of mucositis; monitor for mucositis weekly and omit and/or reduce dose for grade 2 or higher mucositis

Treatment interruption or dose reduction to 20 mg/sq.meter may be required with severe mucositis, thrombocytopenia, or elevated liver function tests

Caution with moderate-to-severe renal impairment (higher risk for toxicity); monitor for systemic toxicity and adjust dose accordingly

Reports of severe dermatologic reactions including skin exfoliation, ulceration, and toxic epidermal necrolysis; reactions 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 treatment)

Treatment can cause tumor lysis syndrome (TLS); monitor patients who are at increased risk of TLS and treat promptly

Avoid breastfeeding

Probenecid decreases renal elimination of pralatrexate

Myelosuppression

• Therapy can cause myelosuppression, manifested by thrombocytopenia, neutropenia, and/or anemia
• Administer vitamin B12 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

Hepatotoxicity

• 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

Renal Impairment

• Patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m² based on MDRD) may be at greater risk for increased exposure and adverse reactions; reduce dosage in patients with severe renal impairment
• Serious adverse reactions, including TEN and mucositis, reported in patients receiving therapy with end-stage renal disease (ESRD) undergoing dialysis; avoid therapy in patients with ESRD with or without dialysis; If the potential benefit of administration justifies the potential risk, monitor renal function and reduce dose based on adverse reactions

Pregnancy

Based on findings from animal studies and mechanism of action therapy can cause fetal harm when administered to a pregnant woman; there are insufficient data on use in pregnant women to evaluate for a drug-associated risk; drug was embryotoxic and fetotoxic in rats and rabbits when administered during organogenesis at doses about 1.2% (0.012 times) of clinical dose on a mg/m² basis; advise pregnant women of potential risk to a fetus

Therapy can cause fetal harm when administered to a pregnant woman; verify pregnancy status in females of reproductive potential prior to initiation of therapy

Contraception

• Females: Advise females of reproductive potential to use effective contraception during treatment and for 6 months following last dose
• Males: Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months following last dose

Lactation

There is no data on presence in human milk or effects on breastfed child or milk production; because of potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment and for 1 week after last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Folate inhibitor

Pharmacokinetics

Clearance: 417 mL/min (S-diastereomer); 191 mL/min (R-diastereomer)

Half-life: 12-18 hr

Vd: 105 L (S-diastereomer); 37 L (R-diastereomer)

Protein Bound: 67%

Metabolism: Not significantly metabolized by CYP450 or hepatic glucuronidases

Excretion: (urine) 34% unchanged

IV Preparation

Do not dilute

Contains no preservatives

Clear, yellow solution; inspect for discoloration/particulate matter

IV Administration

Infuse IV over 3-5 minute via side port of free-flowing 0.9% NaCl IV line

Dose omissions and/or dose reductions may be needed to manage adverse drug reactions

Pretreatment vitamin supplementation

• Folic acid: Initiate 1-1.25 mg PO qDay 10 days before first pralatrexate dose; continue daily folic acid during entire treatment course and for 30 days after last pralatrexate dose
• Vitamin B12: 1 mg IM within 10 weeks before first pralatrexate dose and q8-10 wk thereafter

Extravasation Management

Terminate injection or infusion immediately & aspirate back as much as possible

Apply warm pack for 15-20 min QID & elevate

Storage

Store intact vials under refrigeration at 2-8°C

Store in original carton to protect from light

Intact, unopened vials stable at room temperature for 72 hr if protected from light (discard after 72 hr)