pralatrexate


pralatrexate

Folotyn

Pharmacologic class: Folic acid antagonist

Therapeutic class: Antineoplastic

Pregnancy risk category D

Action

Competitively inhibits dihydrofolate reductase and is a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase, resulting in depletion of thymidine and other biological molecules, the synthesis of which depends on single carbon transfer

Availability

Solution for injection: 20 mg/1 ml, 40 mg/2 ml in single-use vials

Indications and dosages

➣ Relapsed or refractory peripheral T-cell lymphoma

Adults: 30 mg/m2 by I.V. push over 3 to 5 minutes weekly for 6 weeks in 7-week cycles until disease progression or unacceptable toxicity occurs. Give with supplemental oral folic acid and I.M. vitamin B12.

Dosage adjustment

• Mucositis

• Hematologic toxicities

• Liver function test abnormalities of Grade 3 or greater

Contraindications

None

Precautions

Use cautiously in:

• moderate to severe renal impairment, liver function test abnormalities

• thrombocytopenia, neutropenia, anemia, mucositis, dermatologic reactions, tumor lysis syndrome

• pregnant or breastfeeding patients (avoid use)

• children (safety and efficacy not established).

Administration

• Be aware that drug should be administered under supervision of qualified physician experienced in the use of antineoplastics, with appropriate management of complications and adequate diagnostic and treatment facilities readily available.

• Obtain serum chemistry tests, including renal and hepatic function, before start of first and fourth dose of a given cycle.

• Before administering, be aware that mucositis should be Grade 1 or less, platelet count should be 100,000/mm3 or more for first dose and 50,000/mm3 or more for all subsequent doses, and absolute neutrophil count (ANC) should be 1,000/mm3 or more.

• Don't dilute drug.

• Administer by I.V. push over 3 to 5 minutes through side port of a free-flowing 0.9% Sodium Chloride Injection I.V. line once weekly for 6 weeks in 7-week cycles (6 weeks on drug and 1 week off each cycle) until progressive disease or unacceptable toxicity occurs.

• Be aware that patient should take low-dose (1.0 to 1.25 mg) oral folic acid daily, initiated during 10-day period preceding first pralatrexate dose, with dosing continued during full course of therapy and for 30 days after last pralatrexate dose. In addition, patient should receive vitamin B12 (1 mg) I.M. no more than 10 weeks before first pralatrexate dose and every 8 to 10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as pralatrexate treatment.

• Omit or modify doses for hematologic toxicities, Grade 2 or greater mucositis, severe dermatologic reactions, or liver function test abnormalities of Grade 3 or greater. Omitted doses must not be made up at end of cycle, and once a dosage has been reduced for toxicity, it must not be reescalated.

Adverse reactions

CNS: fatigue, asthenia

CV: tachycardia

EENT: epistaxis, pharyngolaryngeal pain

GI: nausea, vomiting, diarrhea, constipation, abdominal pain, anorexia, stomatitis, mucositis of GI tract

GU: mucositis of GU tract

Hematologic: anemia, neutropenia, leukopenia, thrombocytopenia, febrile neutropenia

Hepatic: liver function test abnormalities

Metabolic: hypokalemia

Musculoskeletal: extremity pain, back pain

Respiratory: dyspnea, cough, upper respiratory tract infection

Skin: rash, pruritus

Other: pyrexia, dehydration, edema, night sweats, sepsis, tumor lysis syndrome

Interactions

Drug-drug. Probenecid, other drugs that may affect relevant transporter systems (such as NSAIDs): delayed pralatrexate clearance resulting in increased pralatrexate exposure with subsequent increased risk of systemic toxicity

Drug-diagnostic tests. ALT, AST, transaminases: increased levels

Platelets, potassium: decreased levels

Patient monitoring

• Monitor CBC with differential and severity of mucositis weekly.

• Continue to monitor serum chemistry tests, including renal and hepatic function.

See Continue to closely monitor patient for tumor lysis syndrome (irregular heartbeat, shortness of breath, high potassium level, high uric acid level, impaired mental ability, kidney failure), and dermatologic reactions.

Patient teaching

• Inform patient about the need to take folic acid and vitamin B12 during treatment.

See Instruct patient to immediately report signs and symptoms of infection (including fever), skin reactions, mucositis, tumor lysis syndrome (irregular heartbeat, shortness of breath, impaired mental ability, urinary problems), yellowing of skin or eyes, dark urine, or right upper abdominal pain or discomfort.

• Instruct patient to tell prescriber about all drugs he's taking, including nonprescription drugs, because some drugs have potential for serious drug interactions.

• Advise female patient of childbearing age to avoid pregnancy and breastfeeding during therapy.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs and tests mentioned above.

PRALAtrexate

(pra-le-trex-ate) pralatrexate,

Folotyn

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: folic acid analogues
Pregnancy Category: D

Indications

Treatment relapsed/refractory peripheral T-cell lymphoma.

Action

Interferes with folic acid metabolism by acting as a folate analogue metabolic inhibitor that competitively inhibits dihydrofolate reductase; also acts as a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. Result is inhibition of DNA synthesis.

Therapeutic effects

Death of rapidly replication cells, particularly malignant ones.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.Distribution: .Metabolism and Excretion: Some metabolism by the liver; 34% excreted unchanged in urine.Half-life: 12–18 hr.

Time/action profile (effects on blood counts)

ROUTEONSETPEAKDURATION
IV45 days†unknownunknown
†median time to first response

Contraindications/Precautions

Contraindicated in: End-stage renal disease (↑ risk of toxicity) Obstetric: Avoid use during pregnancy; Lactation: Breastfeeding should be avoided.Use Cautiously in: Moderate to severe renal impairment (↑ risk of toxicity); Geriatric: Consider age-related ↓ in renal function; Obstetric: Patients with childbearing potential; Pediatric: Safety and effectiveness not established.

Adverse Reactions/Side Effects

Central nervous system

  • fatigue (most frequent)

Ear, Eye, Nose, Throat

  • epistaxis
  • pharyngolaryngeal pain

Respiratory

  • dyspnea (most frequent)
  • cough

Cardiovascular

  • edema
  • tachycardia

Gastrointestinal

  • mucositis (most frequent)
  • nausea (most frequent)
  • abdominal pain
  • anorexia
  • constipation
  • diarrhea
  • vomiting
  • ↑ liver enzymes

Dermatologic

  • toxic epidermal necrolysis (life-threatening)
  • exfoliation
  • pruritus
  • rash
  • ulceration

Fluid and Electrolyte

  • dehydration (most frequent)
  • hypokalemia

Hematologic

  • neutropenia
  • thrombocytopenia
  • anemia

Musculoskeletal

  • back pain
  • extremity pain

Miscellaneous

  • sepsis
  • fever (most frequent)
  • night sweats
  • tumor lysis syndrome

Interactions

Drug-Drug interaction

Probenecid, NSAIDs, and trimethoprim/sulfamethoxazole may ↓ clearance and ↑ blood levels and the risk of toxicity.

Route/Dosage

Intravenous (Adults) 30 mg/m2 once weekly for 6 wk in 7-wk cycles until disease progresses or unacceptable toxicity occurs (supplemental intramuscular vitamin B12 1 mg every 8-10 wk and folic acid 1.0-1.25 mg orally on a daily basis is required); if adverse reactions occur, dose may be ↓ to 20 mg/m2 .

Availability

Solution for injection: 20 mg/mL

Nursing implications

Nursing assessment

  • Monitor BP, pulse, respiratory rate, and temperature frequently during administration. Report significant changes.
  • Monitor for bone marrow depression. Assess for bleeding (bleeding gums, bruising, petechiae, guaiac stools, urine, and emesis) and avoid IM injections and taking rectal temperatures if platelet count is low. Apply pressure to venipuncture sites for 10 min. Assess for signs of infection during neutropenia. Anemia may occur. Monitor for increased fatigue, dyspnea, and orthostatic hypotension.
  • Assess oral mucosa prior to and wkly for development of mucositis. Increased dosing interval and/or decreased dosing is recommended if lesions are painful or interfere with nutrition. Mucositis must be ≤Grade 1 for administration of pralatrexate. If Grade 2, omit dose and continue prior dose when mucositis recovers to ≤Grade 1. If Grade 2 recurs, omit dose and decrease next pralatrexate dose to 20 mg/m2 when mucositis recovers to ≤Grade 1.If Grade 3, omit dose and decrease next pralatrexate dose to 20 mg/m2 when mucositis recovers to ≤Grade 1. If Grade 4, stop therapy.
  • Assess for rash periodically during therapy. May cause toxic epidermal necrolysis. Discontinue therapy if severe or if accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
  • Monitor for tumor lysis syndrome (malignant disease progression, high WBC counts, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcamia and/or dehydration); treat symptomatically.
  • Lab Test Considerations: Monitor CBC and differential prior to and wkly during therapy. May cause thrombocytopenia, neutropenia, and anemia. Platelet count should be ≥100,000 cells/mm3 for first dose and ≥50,000 cells/mm3 for all subsequent doses. If platelet count <50,000 cells/mm3, for 1 wk, omit dose and continue prior dose upon restart. If platelet count <50,000 cells/mm3, for 2 wks, omit dose and decrease pralatrexate dose to 20 mg/m2upon restart. If platelet count <50,000 cells/mm3, for 3 wks, stop therapy.
    • Absolute neutrophil count (ANC) should be ≥1,000 cells/mm3prior to administering each dose of pralatrexate. If ANC 500–1,000 cells/mm3 and no fever for 1 wk, omit dose and continue prior dose upon restart. If ANC 500–1,000 cells/mm3 with fever or ANC <500 cells/mm3 for 1 wk , omit dose, give filgrastim or sargramostim and continue prior dose with filgrastim or sargramostim upon restart. If ANC 500–1,000 cells/mm3 with fever or ANC <500 cells/mm3 for 2 wks or recurrence, omit dose, give filgrastim or sargramostim and decrease pralatrexate dose to 20 mg/m2 with filgrastim or sargramostim upon restart. If ANC 500–1,000 cells/mm3 with fever or ANC <500 cells/mm3 for 3 wks or 2nd recurrence, stop therapy.
    • For all other treatment-related toxicities: if Grade 3, omit dose and upon recovery to Grade 2, decrease dose to 20 mg/m2. If Grade 4, stop therapy.
    • Monitor serum chemistry, including liver and renal function prior to the first and fourth doses of each cycle during therapy.

Potential Nursing Diagnoses

Risk for infection (Adverse Reactions)

Implementation

  • Do not confuse pralatrexate with pemetrexed.
  • Patients should take oral folic acid 1.0–1.25 mg daily starting 10 days prior to first dose of pralatrexate, through full course of therapy, and for 30 days after completion of therapy. Patients should also receive vitamin B12 1 mg IM no more than 10 wks prior to first dose of pralatrexate and every 8–10 wks during therapy; may be given on same day as pralatrexate.
  • Intravenous Administration
  • high alert: Fatalities have occurred with incorrect administration of chemotherapeutic agents. Before administering, clarify all ambiguous orders; double check single, daily, and course-of-therapy dose limits; have second practitioner independently double check original order, calculations and infusion pump settings. Clarify orders that do not include generic and brand names.
  • Solution should be prepared in a biologic cabinet. Wear gloves, gown, and mask while handling medication. Discard IV equipment in specially designated containers (see ).
  • Withdraw calculated dose into syringe for immediate use. Do not dilute. Solution is clear yellow; do not administer solutions that are discolored or contain particulate matter. For single use only; discard unused portion. Stable if stored in original carton for 72 hrs at room temperature; protect from light.
  • Rate: Administer as an IV push over 3–5 minutes via side port of a free-flowing 0.9% NaCl injection.

Patient/Family Teaching

  • Advise patient to read the Patient Information that comes with medication prior to each dose.
  • Instruct patient to notify health care professional promptly if rash, fever; sore throat; signs of infection; bleeding gums; bruising; petechiae; blood in stools, urine, or emesis; increased fatigue; weakness; dyspnea; or orthostatic hypotension occurs. Caution patient to avoid crowds and persons with known infections. Instruct patient to use soft toothbrush and electric razor and to avoid falls. Caution patient not to drink alcoholic beverages or take medication containing aspirin or NSAIDs, because these may precipitate gastric bleeding.
  • Instruct patient to inspect oral mucosa for erythema and ulceration. If ulceration occurs, advise patient to use sponge brush, rinse mouth with water after eating and drinking, and confer with health care professional if mouth pain interferes with eating. Pain may require treatment with opioid analgesics.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
  • Advise patient that this medication may have teratogenic effects. Contraception should be used during therapy. Advise patient to notify health care professional if pregnancy is planned or suspected or is breastfeeding.
  • Emphasize the need for periodic lab tests to monitor for side effects.

Evaluation/Desired Outcomes

  • Decreased T-cell count in patients with T-cell lymphoma.