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PRALATREXATE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pralatrexate, an antineoplastic folate analog, is a dihydrofolate reductase inhibitor. Additionally, it is a competitive inhibitor for polyglutamylation via the folylpolyglutamyl synthetase enzyme.

Specific Substances

    1) (2S)-2-[[4-[(1RS)-1-[(2,4-diaminopteridin-6-yl)methyl]methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid
    2) CAS 146464-95-1
    1.2.1) MOLECULAR FORMULA
    1) C23-H23-N7-O5 (Prod Info FOLOTYN(TM) solution for IV injection, 2009)

Available Forms Sources

    A) FORMS
    1) Pralatrexate is available in the United States as sterile, single-use vials containing pralatrexate at a concentration of 20 mg/mL (20 mg of pralatrexate in 1 mL of solution; 40 mg of pralatrexate in 2 mL of solution) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    B) USES
    1) Pralatrexate is used to treat patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Pralatrexate is used to treat patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
    B) PHARMACOLOGY: Pralatrexate, an antineoplastic folate analog, is a dihydrofolate reductase inhibitor. Additionally, it is a competitive inhibitor for polyglutamylation via the folylpolyglutamyl synthetase enzyme.
    C) TOXICOLOGY: After an overdose, the effects of decreased DNA synthesis and cell death may be noticed primarily in organ systems with rapidly dividing cells (eg, bone marrow, gastrointestinal tract).
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Mucositis, thrombocytopenia, nausea, and fatigue. The following adverse effects have also been reported: Edema, tachycardia, pruritus, rash, fever, night sweats, hypokalemia, vomiting, diarrhea, constipation, anorexia, abdominal pain, anemia, neutropenia, leukopenia, pancytopenia, back pain, asthenia, cough, epistaxis, dyspnea, pharyngolaryngeal pain, upper respiratory tract infection, and fever.
    2) DRUG INTERACTIONS: Probenecid, trimethoprim/sulfamethoxazole, and nonsteroidal antiinflammatory agents may reduce pralatrexate elimination and increase the risk of toxicity.
    F) WITH POISONING/EXPOSURE
    1) TOXICITY: There are no reports of toxicity following acute overdose. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses, particularly myelosuppression, nausea, vomiting and mucositis.
    0.2.20) REPRODUCTIVE
    A) Pralatrexate is classified by the manufacturer as FDA pregnancy category D. There are no adequate and well-controlled studies of pralatrexate use during pregnancy; however, pralatrexate may cause fetal harm when used during pregnancy. In animal studies, pralatrexate use resulted in increased resorption, post implantation loss, and a decreased number of live fetuses.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for pralatrexate in humans.

Laboratory Monitoring

    A) Monitor vital signs, serial CBC with differential, serum electrolytes, renal function, and liver enzymes.
    B) Obtain a chest radiograph in patients with respiratory symptoms.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Administer intravenous fluids and antiemetics. Intravenous hydration to maintain adequate urine output. Administer colony-stimulating factor to patients with severe neutropenia at risk for neutropenic sepsis.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) In addition to the above, administer intravenous leucovorin as soon as possible. Administer colony stimulating factor to patients who develop severe neutorpenia.
    C) INTRATHECAL OVERDOSE
    1) No clinical reports are available; the following information is derived from experience with methotrexate. Keep the patient upright and perform cerebrospinal fluid drainage. CSF exchange and ventriculolumbar perfusion should also be considered. Administration of corticosteroids (dexamethasone 4 mg IV every 6 hours for 4 doses) and leucovorin (100 mg IV every 6 hours for 4 doses) also may help. DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY.
    D) DECONTAMINATION
    1) Decontamination is not necessary; pralatrexate is administered intravenously.
    E) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may rarely be required in patients with severe CNS and cardiac toxicity.
    F) ANTIDOTE
    1) No clinical reports are available; the following information is derived from experience with methotrexate. LEUCOVORIN: Leucovorin calcium should be given as soon as possible (ideally within the first hour). In most cases, leucovorin 100 mg/m(2) IV infused over 15 to 30 minutes every 3 to 6 hours for several days is sufficient. NEVER administer leucovorin intrathecally. THYMIDINE: Thymidine can ameliorate cellular toxicity from methotrexate and is given at a dose of 8 g/m(2)/day via continuous infusion.
    G) ENHANCED ELIMINATION
    1) No clinical reports are available; the following information is derived from experience with methotrexate. High flux hemodialysis can clear methotrexate in patients with renal failure, but it has not been used after overdose. . Pralatrexate is approximately 67% protein bound in blood and has a steady-state Vd of 37 L (R-diastereomer) and 105 L (S-diastereomer); hemodialysis may be of some benefit early after a large overdose.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management, as leucovorin rescue is most effective when given early. All exposures should be evaluated in a health care facility.
    2) OBSERVATION CRITERIA: All patients should be sent to a healthcare facility for observation. If patients are asymptomatic for 6 hours, they may be sent home provided close follow up can be arranged. Since toxic effects may be delayed, patients should return to a healthcare provider for serial monitoring.
    3) ADMISSION CRITERIA: Any symptomatic patients should be admitted to the hospital, and depending on the severity of their symptoms, either to the floor or ICU. Criteria for discharge should be improvement in laboratory analyses and resolution of symptoms.
    4) CONSULT CRITERIA: Toxicologists should be consulted on symptomatic cases, as well as potentially oncologists, rheumatologists or other physicians who are familiar with giving the drug and its adverse side effects.
    I) PITFALLS
    1) Leucovorin therapy is most effective if given early. It is frequently administered in standard high-dose methotrexate chemotherapy immediately after methotrexate infusion.
    J) PHARMACOKINETICS
    1) In vitro, pralatrexate was 67% protein bound in blood. The S-diastereomer and R-diastereomer had a steady state Vd of 105 L and 37 L, respectively. Following a single 30 mg/m(2) dose administered to patients as an IV push over 3 to 5 minutes, approximately 31% of S-diastereomer and 38% of R-diastereomer were excreted in urine unchanged. The terminal elimination half-life of pralatrexate was 12 to 18 hours.
    K) TOXICOKINETICS
    1) In overdose, the pharmacokinetics may be prolonged, and associated toxicity (renal failure, hepatotoxicity) may delay metabolism and elimination of pralatrexate from the body.
    L) PREDISPOSING CONDITIONS
    1) Dosing should be adjusted for renal and hepatic impairments. Contraindications to its use include those with pre-existing bone marrow suppression, alcoholic liver disease, AIDS, pre-existing blood dyscrasias, and pregnancy. The elderly and patients with renal insufficiency are at increased risk of toxicity.
    M) DIFFERENTIAL DIAGNOSIS
    1) The differential diagnosis for pralatrexate toxicity includes other chemotherapeutic agents that might have similar systemic and antimetabolic effects.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: 30 mg/m(2) administered as an IV push over 3 to 5 minutes once weekly for 6 weeks in 7-week cycles. PEDIATRIC: The safety and effectiveness of pralatrexate have not been established in pediatric patients.

Clinical Effects

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), asthenia (any grade) occurred in 10% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    B) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), fatigue (any grade) occurred in 36% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), mucositis (including stomatitis or mucosal inflammation of the gastrointestinal and genitourinary tracts) occurred in 70% (any grade) of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    b) In all pralatrexate trials, deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated with pralatrexate (dose range, 30 to 325 mg/m(2)) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), nausea (any grade) occurred in 40% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), constipation occurred in 33% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    D) VOMITING
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), vomiting (any grade) occurred in 25% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    E) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), diarrhea (any grade) occurred in 21% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    F) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), anorexia (any grade) occurred in 15% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    G) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), abdominal pain (any grade) occurred in 12% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), elevated liver enzymes (ALT, AST, and transaminases) occurred in 13% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), thrombocytopenia occurred in 41% (any grade) of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), anemia occurred in 34% (any grade) of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    C) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), neutropenia occurred in 24% (any grade) of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    b) In all pralatrexate trials, deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated with pralatrexate (dose range, 30 to 325 mg/m(2)) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    D) PANCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) In all pralatrexate trials, deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated with pralatrexate (dose range, 30 to 325 mg/m(2)) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    E) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), leukopenia (any grade) occurred in 11% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), rash occurred in 15% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    B) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), pruritus (any grade) occurred in 14% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    C) NIGHT SWEATS
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), night sweats occurred in 11% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), back pain (any grade) occurred in 11% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    B) PAIN
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), pain in an extremity occurred in 12% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Pralatrexate is classified by the manufacturer as FDA pregnancy category D. There are no adequate and well-controlled studies of pralatrexate use during pregnancy; however, pralatrexate may cause fetal harm when used during pregnancy. In animal studies, pralatrexate use resulted in increased resorption, post implantation loss, and a decreased number of live fetuses.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies of pralatrexate use during pregnancy; however, pralatrexate may cause fetal harm when used during pregnancy (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies of pralatrexate use during pregnancy; however, pralatrexate may cause fetal harm when used during pregnancy (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    B) PREGNANCY CATEGORY
    1) Pralatrexate is classified by the manufacturer as FDA pregnancy category D (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    C) ANIMAL STUDIES
    1) RATS: In female rats, dose-dependent embryo-fetal toxicities, including increased resorption and post implantation loss, were reported at pralatrexate doses of 0.06 mg/kg/day (0.36 mg/m(2)/day or approximately 1.2% dose on a mg/m(2) basis) administered during gestation days 7 through 20 (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    2) RABBITS: In female rabbits, pralatrexate doses 0.03 mg/kg/day or greater administered during gestation days 8 through 21 resulted in increased resorption, post implantation loss, and a decreased number of live fetuses (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known if pralatrexate is excreted into human breast milk, and there is insufficient clinical experience with pralatrexate to confirm its safety in breastfeeding. Because of the potential for serious adverse reactions in the nursing infant, a decision should be made whether to discontinue nursing or to discontinue the drug. The importance of the drug to the mother should be taken into consideration (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) There have been no reports on fertility outcomes with the use of pralatrexate (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Summary Of Exposure

    A) USES: Pralatrexate is used to treat patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
    B) PHARMACOLOGY: Pralatrexate, an antineoplastic folate analog, is a dihydrofolate reductase inhibitor. Additionally, it is a competitive inhibitor for polyglutamylation via the folylpolyglutamyl synthetase enzyme.
    C) TOXICOLOGY: After an overdose, the effects of decreased DNA synthesis and cell death may be noticed primarily in organ systems with rapidly dividing cells (eg, bone marrow, gastrointestinal tract).
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Mucositis, thrombocytopenia, nausea, and fatigue. The following adverse effects have also been reported: Edema, tachycardia, pruritus, rash, fever, night sweats, hypokalemia, vomiting, diarrhea, constipation, anorexia, abdominal pain, anemia, neutropenia, leukopenia, pancytopenia, back pain, asthenia, cough, epistaxis, dyspnea, pharyngolaryngeal pain, upper respiratory tract infection, and fever.
    2) DRUG INTERACTIONS: Probenecid, trimethoprim/sulfamethoxazole, and nonsteroidal antiinflammatory agents may reduce pralatrexate elimination and increase the risk of toxicity.
    F) WITH POISONING/EXPOSURE
    1) TOXICITY: There are no reports of toxicity following acute overdose. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses, particularly myelosuppression, nausea, vomiting and mucositis.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER: In a single-arm clinical trial (n=111), pyrexia (any grade) occurred in 32% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Heent

    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) EPISTAXIS: In a single-arm clinical trial (n=111), epistaxis occurred in 26% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) THROAT PAIN: In a single-arm clinical trial (n=111), pharyngolaryngeal pain (any grade) occurred in 14% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) EDEMA
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), edema (any grade) occurred in 30% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    B) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), tachycardia occurred in 10% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for pralatrexate in humans.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential for pralatrexate in humans (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Genotoxicity

    A) Pralatrexate was not mutagenic in the Ames test, the mouse micronucleus assay, or the Chinese hamster ovary cell chromosome aberration assay (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), cough (any grade) occurred in 28% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), dyspnea (any grade) occurred in 19% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).
    C) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) In a single-arm clinical trial (n=111), upper respiratory tract infection (any grade) occurred in 10% of patients treated with pralatrexate monotherapy for peripheral T-cell lymphoma at a starting dose of 30 mg/m(2) once weekly for 6 weeks in 7-week cycles (median treatment duration, 70 days; range 1 to 540 days) (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, serial CBC with differential, serum electrolytes, renal function, and liver enzymes.
    B) Obtain a chest radiograph in patients with respiratory symptoms.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Monitor serial CBC with differential.
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, renal function, and liver enzymes.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor for signs and symptoms of infection or bleeding during neutropenic and thrombocytopenic phases.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Any symptomatic patients should be admitted to the hospital, and depending on the severity of their symptoms, either to the floor or ICU. Criteria for discharge should be improvement in laboratory analyses and resolution of symptoms.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management, as leucovorin rescue is most effective when given early. All exposures should be evaluated in a health care facility.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Toxicologists should be consulted on symptomatic cases, as well as potentially oncologists, rheumatologists or other physicians who are familiar with giving the drug and its adverse side effects.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) All patients should be sent to a healthcare facility for observation. If patients are asymptomatic for 6 hours, they may be sent home. Since toxic effects may be delayed, patients should return to a healthcare provider for any symptoms.

Monitoring

    A) Monitor vital signs, serial CBC with differential, serum electrolytes, renal function, and liver enzymes.
    B) Obtain a chest radiograph in patients with respiratory symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Decontamination is not necessary; pralatrexate is administered intravenously.
    6.5.2) PREVENTION OF ABSORPTION
    A) Decontamination is not necessary; pralatrexate is administered intravenously.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Pralatrexate is administered intravenously; refer to parenteral section for information on specific treatment.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    B) DISPOSAL GUIDELINES
    1) LABELING: Cytotoxic waste should be regarded as HAZARDOUS or TOXIC waste. It must be handled differently from other trash and should be clearly labeled "HAZARDOUS CHEMICAL WASTE - DISPOSE OF PROPERLY" (Anon, 1990).
    2) CONTAINER: Cytotoxic waste may be placed in a leakproof, puncture resistant container which is then placed in disposable wire-tie or sealable 4-mil-thick polyethylene or 2-mil-thick propylethylene bags. These bags should be colored so as to be easily distinguishable from other trash bags, and labeled with a "Cytotoxic Hazard" label (Jeffrey LP, Anderson RW & Fortner CL et al, 1984; Anon, 1986).
    3) SPILL PROCEDURE: Spills should be cleaned up immediately by a person trained in such procedures and wearing appropriate protective clothing (commercial spill kits are available) (Anon, 1990). The area of the spill should be marked so that while cleanup is occurring someone in the area is not accidentally contaminated. Broken glass should be carefully removed possibly by using a scoop. A broom or mop is not advised due to the risk of further contamination of the environment.
    4) DISPOSAL: Cytotoxic waste may be disposed of at an EPA permitted hazardous waste incinerator, an EPA permitted hazardous waste burial site, or by a licensed hazardous waste disposal company and in accordance with all applicable state, federal, and local regulations (Anon, 1990; Jeffrey LP, Anderson RW & Fortner CL et al, 1984).
    C) SMALL SPILL DECONTAMINATION
    1) SUMMARY: Small spills (less than 5 milliliters or 5 grams) should be cleaned immediately by personnel wearing double surgical latex gloves, disposable gown, a face shield or splash goggles and a dust/mist respirator mask (Anon, 1986; Chasse & Gaudet, 1992; Peters, 1995).
    a) CLEAN UP PROCEDURE: Liquids should be adsorbed with gauze pads; solids should be wiped up with wet absorbent gauze (Anon, 1986).
    b) DECONTAMINATION: The spill area should be further decontaminated by THREE washings using a detergent solution (germicidal solutions are not recommended) followed by a rinse of clear water (Anon, 1986).
    c) DISPOSAL: All materials used in the cleanup procedure should be disposed of in the cytotoxic waste bag (Anon, 1986).
    D) LARGE SPILL DECONTAMINATION
    1) SUMMARY: Large spills (greater than 5 milliliters or 5 grams) should be covered immediately with absorbent sheets or spill control pads to reduce the spread. If a powder was spilled use a damp cloth or towel (Anon, 1986).
    a) SECURE AREA: Restrict access to the spill area and take precautions to minimize the generation of aerosols (Anon, 1986).
    b) PERSONNEL PROTECTION: Protective clothing should be worn as with the small spill with the addition of a respirator or breathing apparatus when there is an airborne contamination danger (Anon, 1986).
    c) DECONTAMINATION: The area should be further decontaminated by THREE washings using a detergent solution (germicidal solutions are not recommended) followed by a rinse of clear water (Anon, 1986).
    d) DISPOSAL: All materials used in the cleanup procedure should be disposed of in the cytotoxic waste bag (Anon, 1986).
    E) PERSONNEL PROTECTION
    1) PROTECTIVE CLOTHING: A double layer of disposable surgical latex gloves, protective disposable gowns (non-permeable, made of lint-free, low-permeability fabric with a solid front, long sleeves, and tight-fitting elastic or knit cuffs) with cuff tucked into glove, eye protection (splash goggles), breathing apparatus, in ventilated cabinets when there is airborne contamination danger (Centers for Disease Control and Prevention (CDC), 2012; Anon, 1990a; Anon, 1986).
    2) DECONTAMINATION/CLOTHING: Laundering of non-disposable materials has not been demonstrated to remove cytotoxic contaminants. DISPOSAL: The appropriate procedure for the disposal of these materials should be determined by the institution (or as required by state or local regulation or disposal contractor) (Centers for Disease Control and Prevention (CDC), 2012; Anon, 1990a).

Enhanced Elimination

    A) HEMODIALYSIS
    1) No clinical reports are available; the following information is derived from experience with methotrexate. High flux hemodialysis can clear methotrexate in patients with renal failure, but it has not been used after overdose (Wall et al, 1996). Pralatrexate is approximately 67% protein bound in blood and has a steady-state Vd of 37 L (R-diastereomer) and 105 L (S-diastereomer) (Prod Info FOLOTYN(TM) solution for IV injection, 2009); hemodialysis may be of some benefit if performed soon after a large overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: 30 mg/m(2) administered as an IV push over 3 to 5 minutes once weekly for 6 weeks in 7-week cycles. PEDIATRIC: The safety and effectiveness of pralatrexate have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) 30 mg/m(2) administered as an IV push over 3 to 5 minutes via the side port of a free flowing NS line, once weekly for 6 weeks in 7-week cycles; vitamin supplementation (vitamin B12 and folic acid) should be given prior to first dose (Prod Info FOLOTYN(R) intravenous injection, 2012).
    7.2.2) PEDIATRIC
    A) The safety and effectiveness have not been established in pediatric patients (Prod Info FOLOTYN(R) intravenous injection, 2012).

Maximum Tolerated Exposure

    A) A toxic dose has not been established (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Pralatrexate, an antineoplastic folate analog, is a dihydrofolate reductase inhibitor. Additionally, it is a competitive inhibitor for polyglutamylation via the folylpolyglutamyl synthetase enzyme (Prod Info FOLOTYN(TM) solution for IV injection, 2009).

Physicochemical

Physical Characteristics

    A) Off-white to yellow solid; soluble in aqueous solutions at pH 6.5 or higher and insoluble in chloroform and ethanol (Prod Info FOLOTYN(TM) solution for IV injection, 2009)

Molecular Weight

    A) 477.48 g/mol (Prod Info FOLOTYN(TM) solution for IV injection, 2009)

References

General Bibliography

    1) Abelson HT, Fosburg MT, & Beardsley P: Methotrexate-induced renal impairment: clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine. J Clin Oncol 1983; 1:208-216.
    2) Addiego JE, Ridgway D, & Bleyer WA: The acute management of intrathecal methotrexate overdose: pharmacologic rationale and guidelines. J Pediatr 1981; 98(5):825-828.
    3) Anon: ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990; 47:1033-1048.
    4) Anon: ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990a; 47:1033-1049.
    5) Anon: OSHA work-practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm 1986; 43:1193-1204.
    6) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    7) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    8) Centers for Disease Control and Prevention (CDC): NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2012. Centers for Disease Control and Prevention (CDC). Atlanta, GA. 2012. Available from URL: http://www.cdc.gov/niosh/docs/2012-150/pdfs/2012-150.pdf. As accessed 2013-05-14.
    9) Chasse MA & Gaudet S: Safe handling of cytotoxic agents. AARN News Letter 1992; 48:14-15.
    10) Gosselin S & Isbister GK: Re: Treatment of accidental intrathecal methotrexate overdose. J Natl Cancer Inst 2005; 97(8):609-610.
    11) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    12) Howland MA: Antidotes in Depth. In: Goldfrank LR, Flomenbaum N, Hoffman RS, et al, eds. Goldfrank's Toxicologic Emergencies. 8th ed., 8th ed. McGraw-Hill, New York, NY, 2006, pp 826-828.
    13) Jakobson AM, Kreuger A, & Mortimer A: Cerebrospinal fluid exchange after intrathecal methotrexate overdose. A report of two cases. ACTA Paediatr 1992; 81:359-361.
    14) Jardine LF, Ingram LC, & Bleyer WA: Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematolog Oncol 1996; 18:302-304.
    15) Jeffrey LP, Anderson RW & Fortner CL et al: Recommendations for handling cytotoxic agents. National Study Commission on Cytotoxic Exposure (Sept), 1984.
    16) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    17) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    18) Peters BG: Technical considerations in the preparation and dispensing of chemotherapy. Top Hosp Pharm Manage 1995; 14:78-88.
    19) Poplack DG: Massive intrathecal overdose: check the label twice. N Engl J Med 1984; 311:400-402.
    20) Product Information: FOLOTYN(R) intravenous injection, pralatrexate intravenous injection. Allos Therapeutics, Inc. (per manufacturer), Westminster, CO, 2012.
    21) Product Information: FOLOTYN(TM) solution for IV injection, pralatrexate solution for IV injection. Allos Therapeutics, Inc., Westminister, CO, 2009.
    22) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    23) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    24) Spiegel RJ, Cooper PR, & Blum RH: Treatment of massive intrathecal methotrexate overdose by ventriculolumbar perfusion. N Engl J Med 1984; 311:386-388.
    25) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    26) Wall SM, Johansen MJ, & Molony DA: Effective clearance of methotrexate using high-flux hemodialysis membranes (abstract). Am J Kid Dis 1996; 28:846-854.
    27) Widemann BC, Balis FM, Shalabi A, et al: Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Nat Cancer Inst 2004; 96(20):1557-1559.
    28) vandenBongard HJ, Mathjt RA, Boogerd W, et al: Successful rescue with leucovorin and thymidine in a patient with high-dose methotrexate induced acute renal failure. Cancer Chemother Pharmacol 2001; 47(6):537-540.