PRALAtrexate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Folotyn: 20 mg/mL (1 mL); 40 mg/2 mL (2 mL)

Pharmacology

Mechanism of Action

Antifolate analog; inhibits DNA, RNA, and protein synthesis by selectively entering cells expressing reduced folate carrier (RFC-1), is polyglutamylated by folylpolyglutamate synthetase (FPGS) and then competes for the DHFR-folate binding site to inhibit dihydrofolate reductase (DHFR)

Pharmacokinetics/Pharmacodynamics

Distribution

S-diastereomer: 105 L; R-diastereomer: 37 L

Metabolism

Not significantly metabolized by phase I hepatic isoenzymes or phase II glucuronidases.

Excretion

Urine (~34% as unchanged drug; parent drug [racemic pralatrexate]: ~39%); Feces (34%); Respiratory (10% [exhaled])

Half-Life Elimination

12 to 18 hours

Protein Binding

~67%

Use in Specific Populations

Special Populations: Renal Function Impairment

The mean fractions of a dose excreted as unchanged drug in the urine decreases with declining renal function.

Use: Labeled Indications

Peripheral T-cell lymphoma: Treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL)

Use: Off Label

Cutaneous T-cell lymphomas (relapsed or refractory)b

Data from an open-label, dose-finding study in patients with histologically confirmed cutaneous T-cell lymphomas (CTCL) with disease progression after at least 1 prior systemic therapy, including patients with mycosis fungoides and Sezary syndrome, supports the use of pralatrexate for the treatment of relapsed or refractory CTCL Horwitz 2012. Additional trials may be necessary to further define the role of pralatrexate in the treatment of this condition.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to pralatrexate or any component of the formulation

Dosage and Administration

Dosing: Adult

Note: Initiate vitamin supplements before initial pralatrexate dose: Folic acid 1 to 1.25 mg/day orally beginning 10 days prior to initial pralatrexate dose; continue during treatment and for 30 days after last pralatrexate dose; vitamin B₁₂ 1,000 mcg IM within 10 weeks prior to initial pralatrexate dose and every 8 to 10 weeks thereafter (after first dose, subsequent B₁₂ doses may be administered on the same day as pralatrexate).

Prior to administering any dose, mucositis should be ≤ grade 1 and absolute neutrophil count (ANC) should be ≥1,000/mm³; platelets should be ≥100,000/mm³ for the first dose and ≥50,000/mm³ for subsequent doses

Peripheral T-cell lymphoma (PTCL), relapsed or refractory: IV: 30 mg/m² once weekly for 6 weeks of a 7-week treatment cycle; continue until disease progression or unacceptable toxicity (O’Connor 2011)

Cutaneous T-cell lymphoma, relapsed or refractory (off-label use): IV: 15 mg/m² once weekly for 3 weeks of a 4-week treatment cycle (Horwitz 2012)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Severe or intolerable adverse events may require dose omission, reduction or interruption. Do not make up omitted doses at the end of a cycle; do not re-escalate dose after a reduction due to toxicity.

Hematologic toxicity:

Platelets:

<50,000/mm³ (for 1-week duration): Omit dose; continue at previous dose if platelets recover within 1 week

<50,000/mm³ (for 2-week duration): Omit dose; decrease to 20 mg/m² (10 mg/m² in patients with eGFR 15 to <30 mL/minute/1.73 m²) if platelets recover within 2 weeks

<50,000/mm³ (for 3-week duration): Discontinue treatment.

ANC:

500 to 1,000/mm³ without fever (for 1-week duration): Omit dose; continue at previous dose if ANC recovers within 1 week

500 to 1,000/mm³ with fever or ANC <500/mm³ (for 1-week duration): Omit dose, give filgrastim or sargramostim support; continue at previous dose (with growth factor support) if ANC recovers within 1 week

500 to 1,000/mm³ with fever or ANC <500/mm³ (recurrent or for 2-week duration): Omit dose and give filgrastim or sargramostim support; decrease to 20 mg/m² (10 mg/m² in patients with eGFR 15 to <30 mL/minute/1.73 m²) with growth factor support if ANC recovers within 2 weeks

500 to 1,000/mm³ with fever or ANC <500/mm³ (second recurrence or for 3 week duration): Discontinue treatment.

Nonhematologic toxicity: Mucositis (on day of treatment):

Grade 2: Omit dose; continue at previous dose when recovers to ≤ grade 1

Grade 3 or recurrent grade 2: Omit dose and decrease to 20 mg/m² (10 mg/m² in patients with eGFR 15 to <30 mL/minute/1.73 m²) when recovers to ≤grade 1

Grade 4: Discontinue treatment.

Nonhematologic toxicity (other than mucositis):

Grade 3: Omit dose; decrease to 20 mg/m² (10 mg/m² in patients with eGFR 15 to <30 mL/minute/1.73 m²) when recovers to ≤ grade 2

Grade 4: Discontinue treatment.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Withdraw into syringe for administration; do not dilute (manufacturer recommends immediate use after placing in syringe). Discard unused portion in the vial.

Administration

IV: Administer IV push (undiluted) over 3 to 5 minutes into the line of a free-flowing normal saline IV

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F). Store in original carton to protect from light until use. Unopened vials (stored in the original carton) are stable for up to 72 hours at room temperature (discard after 72 hours).

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of PRALAtrexate. More specifically, NSAIDS may decrease the renal excretion of pralatrexate. Management: Closely monitor for increased pralatrexate serum levels and/or toxicity if used concomitantly with an NSAID. Monitor for decreased pralatrexate serum levels with NSAID discontinuation. Monitor therapy

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Probenecid: May increase the serum concentration of PRALAtrexate. Monitor therapy

Pyrimethamine: May enhance the adverse/toxic effect of PRALAtrexate. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Salicylates: May increase the serum concentration of PRALAtrexate. Salicylate doses used for prophylaxis of cardiovascular events are unlikely to be of concern. Consider therapy modification

Sapropterin: PRALAtrexate may decrease the serum concentration of Sapropterin. Specifically, pralatrexate may decrease tissue concentrations of tetrahydrobiopterin. Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Sulfamethoxazole: May increase the serum concentration of PRALAtrexate. More specifically, sulfamethoxazole may decrease excretion of pralatrexate. Management: Closely monitor for increased pralatrexate serum level and/or possible toxicity with concomitant use of sulfamethoxazole. Monitor for decreased pralatrexate levels with discontinuation of sulfamethoxazole. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Trimethoprim: May increase the serum concentration of PRALAtrexate. More specifically, trimethoprim may decrease excretion of pralatrexate. Management: Closely monitor for increased pralatrexate serum level and/or possible toxicity with concomitant use of trimethoprim. Monitor for decreased pralatrexate levels with discontinuation of trimethoprim. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Edema (30%)

Central nervous system: Fatigue (36%)

Dermatologic: Skin rash (15%), pruritus (14%; grade 3: 2%), night sweats (11%)

Endocrine & metabolic: Hypokalemia (15%)

Gastrointestinal: Mucositis (70%; grade 3: 17%; grade 4: 4%), nausea (40%), constipation (33%), vomiting (25%), diarrhea (21%), anorexia (15%), abdominal pain (12%)

Hematologic & oncologic: Thrombocytopenia (41%; grade 3: 14%; grade 4: 19%), anemia (34%; grade 3: 15%; grade 4: 2%), neutropenia (24%; grade 3: 13%; grade 4: 7%), leukopenia (11%; grade 3: 3%; grade 4: 4%)

Hepatic: Increased serum transaminases (13%; grade 3: 5%)

Infection: Infection

Neuromuscular & skeletal: Limb pain (12%), back pain (11%)

Respiratory: Cough (28%), epistaxis (26%), dyspnea (19%), pharyngolaryngeal pain (14%)

Miscellaneous: Fever (32%)

1% to 10%:

Cardiovascular: Tachycardia (10%)

Endocrine & metabolic: Severe dehydration (>3%)

Hematologic & oncologic: Febrile neutropenia (serious: >3%)

Infection: Sepsis (serious: >3%)

Neuromuscular & skeletal: Weakness (10%)

Respiratory: Upper respiratory tract infection (10%)

<1%, postmarketing, and/or case reports: Dermal ulcer, desquamation, intestinal obstruction, lymphocytopenia, odynophagia, pancytopenia, toxic epidermal necrolysis, tumor lysis syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: May cause thrombocytopenia, neutropenia and anemia; may require dosage modification. Monitor blood counts. Prophylactic folic acid and vitamin B₁₂ supplements are necessary to reduce hematologic toxicity.
• Dermatologic reactions: Severe and potentially fatal dermatologic reactions, including skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN), have been reported. Skin reaction may be progressive; severity may increase with continued treatment; may also involve skin and subcutaneous tissues which are affected by lymphoma. Monitor all dermatologic reactions closely; withhold or discontinue treatment for severe dermatologic reaction.
• Hepatotoxicity: Hepatotoxicity and liver function test abnormalities have been observed with use. Monitor liver function. Persistent abnormalities may indicate hepatotoxicity and may require dosage modification or discontinuation.
• Mucositis: Pralatrexate may cause mucositis (includes stomatitis or mucosal inflammation of gastrointestinal and genitourinary tracts). Monitor weekly; may require dosage modification. Prophylactic folic acid and vitamin B₁₂ supplements are necessary to reduce treatment-related mucositis.
• Tumor lysis syndrome (TLS): Pralatrexate may cause (TLS). Monitor closely; if TLS develops, treat for associated complications.

Disease-related concerns:

• Renal impairment: Patients with moderate to severe renal impairment are at higher risk for increased exposure and toxicity. Monitor renal function and for systemic toxicity due to increased exposure. Dosage adjustment is recommended in patients with severe renal impairment (eGFR 15 to <30 mL/minute/1.73 m²). Unless the potential benefits outweigh potential risks, avoid use in patients with end-stage renal disease (ESRD), including patients undergoing dialysis. Serious adverse reactions, including toxic epidermal necrolysis and mucositis were reported in patients with ESRD undergoing dialysis. Concurrent use with drugs with substantial renal clearance (eg, NSAIDs, sulfamethoxazole/trimethoprim) may result in delayed pralatrexate clearance.

Concurrent drug therapy issues

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

CBC with differential (baseline and weekly), serum chemistries, including renal and liver function tests (prior to the first and fourth doses in each cycle); mucositis severity (baseline and weekly); monitor for signs of tumor lysis syndrome and for dermatologic reactions

Pregnancy

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies. May cause fetal harm if administered to a pregnant woman.

Patient Education

What is this drug used for?

• It is used to treat a type of lymphoma.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Lack of appetite
• Abdominal pain
• Sore throat
• Back pain
• Constipation
• Diarrhea
• Night sweats

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes
• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, fast heartbeat, increased thirst, seizures, severe loss of strength and energy, lack of appetite, unable to pass urine or change in the amount of urine passed, dry mouth, dry eyes, or nausea or vomiting
• Shortness of breath
• Severe or persistent mouth sores or irritation
• Pale skin
• Swelling
• Toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.