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PRALAtrexate

Medically reviewed by Drugs.com. Last updated on May 12, 2020.

Pronunciation

(pral a TREX ate)

Index Terms

  • PDX

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)

Brand Names: U.S.

  • Folotyn

Pharmacologic Category

  • Antineoplastic Agent, Antimetabolite
  • Antineoplastic Agent, Antimetabolite (Antifolate)

Pharmacology

Pralatrexate is an 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).

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%

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)

Off Label Uses

Cutaneous T-cell lymphomas (relapsed or refractory)

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, support the use of pralatrexate for the treatment of relapsed or refractory CTCL [Horwitz 2012].

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

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

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 at 2°C to 8°C (36°F to 46°F). Store in original carton to protect from light until use.

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. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. 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

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

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. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. 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: Avoid coadministration of pralatrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). If coadministration cannot be avoided, closely monitor for increased pralatrexate serum levels or toxicity. Consider therapy modification

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

Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. 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. Management: Avoid coadministration of pralatrexate with probenecid. If coadministration cannot be avoided, closely monitor for increased pralatrexate serum concentrations or possible toxicity with concomitant use of probenecid. Consider therapy modification

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

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. 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. Management: Consider avoiding concomitant use of salicylates and pralatrexate. If coadministered, monitor for increased pralatrexate adverse effects. Salicylate doses used for prophylaxis of cardiovascular events are not likely 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

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. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. 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%)

Dermatologic: Night sweats (11%), pruritus (14%), skin rash (15%)

Endocrine & metabolic: Hypokalemia (15%)

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

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

Hepatic: Increased serum transaminases (13%)

Nervous system: Fatigue (36%)

Neuromuscular & skeletal: Back pain (11%), limb pain (12%)

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

Miscellaneous: Fever (32%)

1% to 10%:

Cardiovascular: Tachycardia (10%)

Endocrine & metabolic: Dehydration

Hematologic & oncologic: Febrile neutropenia

Infection: Sepsis

Neuromuscular & skeletal: Asthenia (10%)

Respiratory: Upper respiratory tract infection (10%)

<1%, postmarketing, and/or case reports: Dermal ulcer, exfoliation of skin, toxic epidermal necrolysis

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Pralatrexate 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, 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 LFT abnormalities have been observed with use. Persistent abnormalities may indicate hepatotoxicity and may require dosage modification or discontinuation. Monitor liver function. If hepatotoxicity occurs, omit dose until recovery and adjust or discontinue pralatrexate based on the severity.

• Mucositis: Pralatrexate may cause mucositis (includes stomatitis or mucosal inflammation of GI 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: Pralatrexate may cause tumor lysis syndrome (TLS). Monitor closely; if TLS develops, treat for associated complications.

Disease-related concerns:

• Renal impairment: Patients with 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 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 LFTs (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. Evaluate pregnancy status prior to use in females of reproductive potential.

Reproductive Considerations

Evaluate pregnancy status prior to use in females of reproductive potential.

Females of reproductive potential should use effective contraception during therapy and for 6 months after the last pralatrexate dose. Males with female partners of reproductive potential should use effective contraception during therapy and for 3 months after the last dose of pralatrexate.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to pralatrexate may cause fetal harm.

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.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Nausea

• Vomiting

• Lack of appetite

• Abdominal pain

• Sore throat

• Back pain

• Constipation

• Diarrhea

• Night sweats

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• 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 an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.