Pralatrexate is a dihydrofolate reductase inhibitor that is indicated for the treatment of adults with relapsed or refractory peripheral T-cell lymphoma. All patients require vitamin B12 and folic acid supplementation starting prior to pralatrexate therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
-If pralatrexate gets on the skin, wash the area immediately with soap and water. If pralatrexate comes in contact with mucous membranes, flush thoroughly with water.
Emetic Risk
-Minimal
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Preparation:
-Withdraw the calculated dose of pralatrexate directly from the vial into a syringe for immediate use; do not dilute.
-Discard any unused portion left in the vial.
Intravenous (IV) Injection:
-Administer pralatrexate as a slow IV push over 3 to 5 minutes via the side port of a free flowing 0.9% Sodium Chloride injection IV line.
Bone marrow suppression may occur with pralatrexate therapy. Thrombocytopenia (all grade, 41%; grade 3, 14%; grade 4, 19%), anemia (all grade, 34%; grade 3, 15%; grade 4, 2%), neutropenia (all grade, 24%; grade 3, 15%; grade 4, 2%), and leukopenia (all grade, 11%; grade 3, 3%; grade 4, 4%) were reported in patients who received pralatrexate for the treatment of peripheral T-cell lymphoma in a single-arm trial (n = 111). Five patients had platelet counts < 10,000/mcL. Febrile neutropenia occurred in > 3% of patients within 30 days of the last pralatrexate dose; additionally, death from febrile neutropenia and pancytopenia has been reported. Monitor complete blood cell counts prior to starting therapy and then weekly. Dose modifications are required for hematologic toxicity. Bone morrow toxicity may be reduced by folic acid and vitamin B12 supplementation.
Mucositis (all grade), defined as stomatitis or mucosal inflammation of the gastrointestinal and/or genitourinary tracts, was reported in 70% of patients who received pralatrexate for the treatment of peripheral T-cell lymphoma in a single-arm trial (n = 111). Additionally, grade 3 and 4 mucositis occurred in 17% and 4% of patients, respectively. Mucositis was reported in pralatrexate-treated patients with end stage renal disease who were undergoing dialysis, suggesting these patients may have increased toxicity. Death from mucositis has been reported. Monitor for mucositis at baseline and then weekly. Dose modifications are necessary in patients who develop grade 2 or higher mucositis. Mucositis may be reduced by folic acid and vitamin B12 supplementation.
Nausea (all grade, 40%; grade 3, 4%), constipation (all grade, 33%), vomiting (all grade, 25%; grade 3, 2%), diarrhea (all grade, 21%; grade 3, 2%), anorexia (all grade, 15%; grade 3, 3%), and abdominal pain (all grade, 12%; grade 3, 4%) were reported in patients who received pralatrexate for the treatment of peripheral T-cell lymphoma in a single-arm trial (n = 111).
Hepatic toxicity may occur with pralatrexate therapy. Elevated hepatic enzymes (all grade), including increased AST and ALT levels, were reported in 13% of patients who received pralatrexate for the treatment of peripheral T-cell lymphoma in a single-arm trial (n = 111). Additionally, grade 3 elevated hepatic enzymes occurred in 5% of patients. Monitor liver function tests prior to the start of the first and fourth dose of every cycle. Patients with signs of hepatic impairment or hepatic disease may require dose modification or discontinuation.
Tumor lysis syndrome (TLS) has been reported with pralatrexate therapy. Monitor patients for TLS; treat promptly if TLS occurs.
Severe dermatologic reactions, some cases fatal, including skin exfoliation, skin ulcer, and toxic epidermal necrolysis (TEN), have been reported with pralatrexate use in clinical studies (n = 14/663; 2.1%) and in postmarketing surveillance. These reactions may be progressive, may increase in severity with further treatment, and may involve skin and subcutaneous sites of known lymphoma. Additionally, TEN was reported in pralatrexate-treated patients with end stage renal disease who were undergoing dialysis, suggesting these patients may have increased toxicity. Rash (unspecified) (all grade, 15%) and pruritus (all grade, 14%; grade 3, 2%) were reported in patients who received pralatrexate for the treatment of peripheral T-cell lymphoma in a single-arm trial (n = 111). Monitor patients with dermatologic toxicity closely; withhold or discontinue pralatrexate therapy in patients who develop severe toxicity.
Fatigue (all grade, 36%; grade 3, 5%; grade 4, 2%) and asthenia (all grade, 10%; grade 3, 1%) were reported in patients who received pralatrexate for the treatment of peripheral T-cell lymphoma in a single-arm trial (n = 111).
Edema (all grade, 30%; grade 3, 1%) and sinus tachycardia (all grade, 10%) occurred in patients who received pralatrexate for the treatment of peripheral T-cell lymphoma in a single-arm trial (n = 111). Cardiac arrest, specifically cardiopulmonary arrest, that resulted in death was reported in a patient who had mucositis and febrile neutropenia.
Epistaxis (all grade, 26%) and pharyngolaryngeal pain (all grade, 14%; grade 3, 1%) were reported in patients who received pralatrexate for the treatment of peripheral T-cell lymphoma in a single-arm trial (n = 111).
Cough (all grade, 28%; grade 3, 1%), dyspnea (all grade, 19%; grade 3, 7%), and upper respiratory tract infection (all grade, 10%; grade 3, 1%) were reported in patients who received pralatrexate for the treatment of peripheral T-cell lymphoma in a single-arm trial (n = 111). Sepsis was reported in > 3% of patients within 30 days of the last pralatrexate dose; death due to sepsis was reported.
Extremity pain (all grade, 12%) and back pain (all grade, 11%; grade 3, 3%) were reported in patients who received pralatrexate for the treatment of peripheral T-cell lymphoma in a single-arm trial (n = 111).
Hypokalemia (all grade) was reported in 15% of patients who received pralatrexate for the treatment of peripheral T-cell lymphoma in a single-arm trial (n = 111); additionally, grade 3 and 4 hypokalemia occurred in 4% and 1% of patients, respectively. Dehydration occurred in > 3% of patients within 30 days of the last pralatrexate dose.
Night sweats (all grade) were reported in 11% of patients who received pralatrexate for the treatment of peripheral T-cell lymphoma in a single-arm trial (n = 111).
Hematologic toxicity (e.g., thrombocytopenia, neutropenia, and anemia) has been reported with pralatrexate therapy. Monitor complete blood cell counts prior to starting therapy and then weekly during therapy. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop severe myelosuppression. Do not give a pralatrexate dose until the absolute neutrophil count is 1,000 cells/mcL or greater AND the platelet count is 100,000 cells/mcL or greater for the first dose or 50,000 cells/mcL or greater for subsequent doses. To reduce the risk of treatment-related myelosuppression, all patients require vitamin B12 and folic acid supplementation starting prior to and continuing during pralatrexate therapy.
An initial dosage adjustment is recommended in patients with severe renal impairment (estimated glomerular filtration rate (eGFR), 15 to 29 mL/min/1.73 m2); these patients may be at greater risk for pralatrexate toxicity. Avoid pralatrexate use in patients with end-stage renal disease (ESRD; eGFR less than 15 mL/min/1.73 m2) with or without dialysis; serious toxicity including (e.g., TEN and mucositis) has been reported in patients with ESRD undergoing dialysis. If the potential benefit of therapy justifies the potential risk in these patients, monitor renal function and reduce the pralatrexate dose based on adverse reactions. In all patients, evaluate renal function (e.g., serum creatinine level)/BUN) prior to the first and fourth dose of every cycle. Therapy interruption, dose reduction, or discontinuation may be necessary in patients with severe renal impairment.
Hepatic toxicity (e.g., elevated hepatic enzymes) has been reported with pralatrexate therapy; use with caution in patients with hepatic disease. Evaluate hepatic function (e.g., liver function tests) prior to the first and fourth dose of every cycle. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop severe hepatotoxicity.
Oral ulceration/mucositis has been reported with pralatrexate therapy. Monitor for symptoms of mucositis weekly during therapy. Therapy interruption, dos e reduction, or discontinuation may be necessary in patients who develop grade 2 or higher mucositis. To reduce the risk of treatment-related mucositis, all patients require vitamin B12 and folic acid supplementation starting prior to and continuing during pralatrexate therapy.
Tumor lysis syndrome (TLS) may occur in patients who receive pralatrexate therapy. Monitor patients who are at increased risk of TLS (e.g., high tumor burden) closely for signs and symptoms of TLS and treat TLS promptly.
Serious rash (e.g., skin exfoliation, ulceration, and toxic epidermal necrolysis) has been reported with pralatrexate therapy; the rash progress and increase in severity if treatment is continued. Some rashes may involve skin and subcutaneous sites of known lymphoma. Monitor patients for dermatologic reactions. Therapy interruption or discontinuation may be necessary in patients who develop a dermatologic reaction.
Monitor geriatric patients more closely for pralatrexate-related toxicity; these patients may be at increased risk for developing adverse reactions.
Pralatrexate may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid pregnancy during pralatrexate therapy. Patients should be apprised of the potential hazard to the fetus if this drug is used during pregnancy. Pralatrexate was embryotoxic and fetotoxic in rats and rabbits at doses of 0.36 mg/m2 (approximately 1.2% of the clinical dose on a mg/m2 basis). This toxicity manifested as early, late, and total resorptions, post implantation loss and a decrease in the total number of live fetuses.
Counsel patients about the contraception requirements during pralatrexate treatment. Females of reproductive potential should receive pregnancy testing prior to starting pralatrexate. These patients should avoid pregnancy and use effective contraception during and for at least 6 months after the final pralatrexate dose. Women who become pregnant while receiving pralatrexate should be apprised of the potential hazard to the fetus. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use effective contraception during and for 3 months after the final pralatrexate dose.
It is not known if pralatrexate is secreted in human milk or if it has effects on the breast-fed child or on milk production. Due to the risk of serious adverse reactions in nursing children, women should discontinue breast-feeding during pralatrexate therapy and for 1 week after the last dose.
For the treatment of peripheral T-cell lymphoma (PTCL):
NOTE: Pralatrexate has been designated an orphan drug by the FDA for the treatment of T-cell lymphoma.
-for the treatment of relapsed or refractory PTCL:
Intravenous dosage:
Adults: 30 mg/m2 IV once weekly for 6 weeks; repeat cycles every 7 weeks until disease progression. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop severe toxicity. Ten days prior to the first dose of pralatrexate, start folic acid 1 to 1.25 mg PO daily; continue folic acid during treatment and for 30 days after the last pralatrexate dose. Within 10 weeks prior to the first dose of pralatrexate, give vitamin B12 1,000 mcg intramuscularly once and repeat the dose every 8 to 10 weeks during therapy. Subsequent vitamin B12 injections may be given the same day as pralatrexate. The overall response rate was 29% (complete response rate, 11%) in 109 evaluable patients with peripheral T-cell lymphoma who progressed after 1 or more prior therapies (median 3 prior therapies; range, 1 to 13 therapies) in a multinational, single-arm, phase 2 trial (the PROPEL trial). The median duration of response was 10.1 months in this study. Four patients who achieved a response received a subsequent transplant (2 autologous; 2 allogeneic). Additionally, the median progression-free survival and overall survival times were 3.5 and 14.5 months, respectively.
Therapeutic Drug Monitoring:
Dosage Guidelines for Treatment-Related Toxicity
Thrombocytopenia
Platelet count less than 50,000 cells/mcL:
Lasting 1 week: Omit dose and resume pralatrexate at the previous dose when the platelet count is 50,000 cells/mcL or greater.
Lasting 2 weeks: Omit dose and resume pralatrexate at 20 mg/m2 when the platelet count is 50,000 cells/mcL or greater.
Lasting 3 weeks: Discontinue pralatrexate therapy.
Neutropenia
Absolute neutrophil count (ANC) of 500 to 1,000 cells/mcL without fever:
Lasting 1 week: Omit dose and resume pralatrexate at previous dose when the ANC is 1,000 cells/mcL or greater.
ANC less than 500 cells/mcL OR ANC of 500 to 1,000 cells/mcL with fever:
Lasting 1 week: Omit dose, give growth-factor (G-CSF or GM-CSF) support, and resume pralatrexate at the previous dose with growth-factor support when the ANC is 1,000 cells/mcL or greater and fever resolves.
Lasting 2 weeks or recurrence: Omit dose, growth-factor support, and resume pralatrexate at 20 mg/m2 with growth-factor support when the ANC is 1,000 cells/mcL or greater and fever resolves.
Lasting 3 weeks or second recurrence: Discontinue pralatrexate therapy.
Mucositis
Grade 2 toxicity: Omit dose and resume pralatrexate at previous dose when the toxicity resolves to grade 1 or less.
Grade 2 toxicity recurrence or grade 3 toxicity: Omit dose and resume pralatrexate at 20 mg/m2 when the toxicity resolves to grade 1 or less.
Grade 4 toxicity: Discontinue pralatrexate therapy.
Other Non-Hematologic Toxicity
Grade 3 toxicity: Omit dose and resume pralatrexate at 20 mg/m2 when the toxicity resolves to grade 2 or less.
Grade 4 toxicity: Discontinue pralatrexate therapy.
Maximum Dosage Limits:
-Adults
30 mg/m2 IV once weekly.
-Geriatric
30 mg/m2 IV once weekly.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in patients with baseline hepatic impairment are not available; it appears that no initial dosage adjustments are needed.
Patients with Renal Impairment Dosing
Mild or moderate renal impairment (estimated glomerular filtration rate (eGFR), 30 to 59 mL/min/1.73 m2): No initial dose adjustment.
Severe renal impairment (eGFR of 15 to 29 mL/min/1.73 m2): Reduce initial dose to 15 mg/m2. If a dose adjustment is necessary due to treatment-related toxicity, resume therapy at a dose of 10 mg/m2.
End stage renal disease (eGFR less than 15 mL/min/1.73 m2) with or without dialysis: Avoid use if possible. If the potential benefit of therapy justifies the potential risk, monitor renal function and reduce the pralatrexate dose based on adverse reactions.
Dosage Guidelines for Treatment-Related Toxicity in Patients with Severe Renal Impairment
Thrombocytopenia
Platelet count less than 50,000 cells/mcL:
Lasting 1 week: Omit dose and resume pralatrexate at the previous dose when the platelet count is 50,000 cells/mcL or greater.
Lasting 2 weeks: Omit dose and resume pralatrexate at 10 mg/m2 when the platelet count is 50,000 cells/mcL or greater.
Lasting 3 weeks: Discontinue pralatrexate therapy.
Neutropenia
Absolute neutrophil count (ANC) of 500 to 1,000 cells/mcL without fever:
Lasting 1 week: Omit dose and resume pralatrexate at previous dose when the ANC is 1,000 cells/mcL or greater.
ANC less than 500 cells/mcL OR ANC of 500 to 1,000 cells/mcL with fever:
Lasting 1 week: Omit dose, give growth-factor (G-CSF or GM-CSF) support, and resume pralatrexate at the previous dose with growth-factor support when the ANC is 1,000 cells/mcL or greater and fever resolves.
Lasting 2 weeks or recurrence: Omit dose, growth-factor support, and resume pralatrexate at 10 mg/m2 with growth-factor support when the ANC is 1,000 cells/mcL or greater and fever resolves.
Lasting 3 weeks or second recurrence: Discontinue pralatrexate therapy.
Mucositis
Grade 2 toxicity: Omit dose and resume pralatrexate at previous dose when the toxicity resolves to grade 1 or less.
Grade 2 toxicity recurrence or grade 3 toxicity: Omit dose and resume pralatrexate at 10 mg/m2 when the toxicity resolves to grade 1 or less.
Grade 4 toxicity: Discontinue pralatrexate therapy.
Other Non-Hematologic Toxicity
Grade 3 toxicity: Omit dose and resume pralatrexate at 10 mg/m2 when the toxicity resolves to grade 2 or less.
Grade 4 toxicity: Discontinue pralatrexate therapy.
*non-FDA-approved indication
Acetaminophen; Ibuprofen: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Alteplase: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
Amlodipine; Celecoxib: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Bupivacaine; Meloxicam: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Celecoxib: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Celecoxib; Tramadol: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Chikungunya Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Diclofenac: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Diclofenac; Misoprostol: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Diflunisal: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Diphenhydramine; Ibuprofen: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Diphenhydramine; Naproxen: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Etodolac: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Fenoprofen: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Flurbiprofen: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Glucarpidase: (Moderate) Potential exogenous substrates of glucarpidase include reduced folates and folate antimetabolites. Thus, administration of pralatrexate with glucarpidase may be inadvisable because reduced concentrations of pralatrexate may occur.
Hydrocodone; Ibuprofen: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Ibuprofen: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Ibuprofen; Famotidine: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Ibuprofen; Oxycodone: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Ibuprofen; Pseudoephedrine: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Indomethacin: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Ketoprofen: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Ketorolac: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Meclofenamate Sodium: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Mefenamic Acid: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Meloxicam: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Nabumetone: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Naproxen: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Naproxen; Esomeprazole: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Naproxen; Pseudoephedrine: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Nonsteroidal antiinflammatory drugs: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Oxaprozin: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Piroxicam: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Probenecid: (Major) Coadministration of increasing doses of probenecid, a uricosuric drug, and pralatrexate resulted in a delayed clearance of pralatrexate and a commensurate increase in systemic exposure of pralatrexate.
Probenecid; Colchicine: (Major) Coadministration of increasing doses of probenecid, a uricosuric drug, and pralatrexate resulted in a delayed clearance of pralatrexate and a commensurate increase in systemic exposure of pralatrexate.
Reteplase, r-PA: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
Ropeginterferon alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Sapropterin: (Moderate) Significant increases in serum phenylalanine concentrations have been noted after methotrexate infusions of 58 g/m2 to 46 patients with an unknown PKU status. Increased concentrations occurred at the end of the infusion in 95% of methotrexate cycles, but large inter-individual variations in the concentrations existed. Individual predispositions may exist, as maximal phenylalanine concentrations were of the same magnitude in a given patient. Phenylalanine concentrations returned to baseline concentrations 24 hours after the end of the methotrexate infusion. Methotrexate has been shown to decrease endogenous tetrahydrobiopterin (BH4) concentrations by inhibiting the enzyme dihydropteridine reductase; a similar reaction could be expected in patients receiving sapropterin. Dihydropteridine reductase recycles quinonoid dihydropterin (q-BH2) back to the active cofactor BH4. Reduction of BH4 could make management of hyperphenylalaninemia more difficult. Drugs that inhibit folate metabolism should be used with caution in patients taking sapropterin.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as sulfamethoxazole; trimethoprim, SMX-TMP, may result in delayed clearance of pralatrexate.
Sulindac: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Sumatriptan; Naproxen: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Tenecteplase: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
Thrombolytic Agents: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
Tolmetin: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
Trimethoprim: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as sulfamethoxazole; trimethoprim, SMX-TMP, may result in delayed clearance of pralatrexate.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Pralatrexate is a folate analogue that is primarily cytotoxic through competitive inhibition of dihydrofolate reductase, an enzyme critical for DNA replication within cells. It is an antifolate structurally similar to methotrexate. Antifolates cross cell membranes predominantly via the reduced folate carrier (RFC), an oncofetoprotein found primarily in tumor cells and fetal cells. Upon entry into the malignant cell, antifolates undergo polyglutamylation by folylpolyglutamate synthetase (FPGS). The polyglutamylated conjugates of antifolates are less susceptible to drug-efflux, have an increased intracellular half-life, and an increased time of biologic activity. Polyglutamylation is both time-dependent and concentration-dependent. Pralatrexate was rationally designed to have an increased affinity for the RFC transport and subsequently increased intracellular drug retention through increased formation of polyglutamylate conjugates. Increasing the intracellular drug retention of pralatrexate makes it a more effective inhibitor of dihydrofolate reductase.
Pralatrexate is administered as an IV push. It was approximately 67% bound to plasma proteins in in vitro studies. The steady-state volume of distribution was 105 liters (L) for the S-diastereomer and 37 L for the R-diastereomer; the total systemic clearance of pralatrexate was 417 mL/min for the S-diastereomer and 191 mL/min for the R-diastereomer; and the terminal elimination half-life was 12 to 18 hours (coefficient of variance (CV), 62% to 120%) in 10 patients with peripheral T-cell lymphoma who received pralatrexate (30 mg/m2 IV once weekly for 6 weeks in 7-week cycles) in a pharmacokinetic study. In vitro pralatrexate is not significantly metabolized by the phase I hepatic CYP450 isozymes or phase II hepatic glucuronidases. Following a pralatrexate dose of 30 mg/m2, the mean fraction of unchanged pralatrexate excreted in urine was 31% (CV, 47%) for the S-diastereomer and 38% (CV, 45%) for the R-diastereomer, respectively. Following the administration of a radiolabeled pralatrexate dose in a mass balance study, 38% (CV, 28%) of the radioactivity was recovered in the urine as the parent drug in patients with advanced cancer. Additionally, 34% of the total dose was recovered in the feces and 10% of the total dose was exhaled total radioactivity over 24 hours.
Affected CYP450 isoenzymes or transporters: none
Based on in vitro studies, pralatrexate is not an inducer or inhibitor of CYP450 isozymes at clinically studied doses. In vitro, pralatrexate is a substrate for the breast cancer resistance protein (BCRP), multidrug resistance-associated proteins -2 and -3 (MRP2 and MRP3), and organic anion transport protein 1B3 (OATP1B3) transporter systems.
-Route-Specific Pharmacokinetics
Intravenous Route
Total systemic exposure (AUC) and the maximum plasma concentration (Cmax) of pralatrexate increased proportionally over a dose range of 30 to 325 mg/m2. No pralatrexate accumulation was observed.
-Special Populations
Renal Impairment
The mean AUC values of pralatrexate were not significantly different in patients with mild or moderate renal impairment (estimated glomerular filtration rate (GFR) of 30 mL/min/1.73 m2 or greater) who received pralatexate 30 mg/m2 IV and in patients with severe renal impairment (estimated GFR of 15 to 29 mL/min/1.73 m2) who received pralatexate 15 mg/m2 IV compared with patients who had normal renal function in a pharmacokinetic study. The mean fraction of the pralatrexate dose excreted as unchanged drug in the urine decreased with decreased renal function; however, the non-renal clearance and volume of distribution were not affected by renal impairment.
Geriatric
Renal excretion contributes to the overall clearance of pralatrexate. Age-related decline in renal function may lead to a reduction in pralatrexate clearance and an increase in plasma exposure.
Gender Differences
Gender had no clinically significant inpact on the pharmacokinetics of pralatrexate.