Trimetrexate

Interrupt therapy if serum creatinine concentration > 2.5 mg/dl and elevation is due to trimetrexate.

Interrupt therapy if transaminase or alkaline phosphatase concentrations > 5 times the upper limit of normal.

Vials containing 25 or 200 mg of trimetrexate powder to be reconstituted with 2 or 16 ml of 5% dextrose or sterile water for inj resulting in a solution containing 12.5 mg/ml of trimetrexate. Reconstituted product should appear as a pale greenish-yellow solution. Do not use if cloudiness or precipitate is observed. Reconstituted solution to be further diluted with 5% dextrose to provide a final trimetrexate concentration of 0.25-2 mg/ml before admin as IV infusion. IV lines should be flushed with at least 10 ml of 5% dextrose between trimetrexate and folinic acid infusions to prevent precipitation.

Incompatible with foscarnet. Mixing with folinic acid or chloride ions results in precipitation.

Severe blood disorders. Hypersensitivity to trimetrexate, methotrexate or folinic acid. Pregnancy, lactation.

Blood disorders; renal or hepatic impairment. Monitor hepatic, renal function and blood counts at least twice a week and adjust trimetrexate and folinic acid dose according to neutrophil and platelet counts. Treatment with zidovudine and other myelosuppressive drugs to be interrupted to allow full doses of trimetrexate to be given. Folinic acid must be used concurrently with trimetrexate therapy and continued for 72 hr after the last dose of trimetrexate to avoid life-threatening toxicity.

Nausea, vomiting, stomatitis, hypersensitivity reactions, increase in LFT, oral and GI mucosal ulceration, renal and hepatic dysfunction.
Potentially Fatal: Anaphylactic reactions, blood dyscrasias such as neutropenia and thrombocytopenia.

IV/Parenteral: D

Symptoms: haematological toxicity. Management: trimetrexate to be stopped and folinic acid to be admin at a dose of 40 mg/m² every 6 hr for 3 days.

Possible interactions with drugs that affect hepatic cytochrome P450 systems. Monitor closely.

Description:
Mechanism of Action: Trimetrexate inhibits the enzyme dihydrofolate reductase and this disrupts the production of DNA and RNA precursors, leading to cell death. At therapeutic doses of trimetrexate, the selective transport of trimetrexate, but not folinic acid, into the Pneumocystis carinii organism allows the folinic acid to protect normal host cells from the cytotoxicity of trimetrexate. It is used as an alternative therapy for treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, who are are unable to tolerate trimethoprim-sulfamethoxazole therapy.
Pharmacokinetics:
Distribution: Protein binding: extensive. Saturable binding with free fraction increasing at plasma concentration >1mcg/ml.
Metabolism: Oxidative O-demethylation followed by conjugation to the sulfate or glucuronide.
Excretion: Mainly via urine, as unchanged drug and metabolites (Some are active metabolites). Terminal elimination half-life: 16-18 hr.

Unconstituted vial: store at 20-25°C (68-77°F); protect from light. Reconstituted vial: store at room temperature (20-25°C) up to 6 hr or under refrigeration at 2-8°C up to 24 hr. Reconstituted solution that is further diluted with 5% dextrose or sterile water: store at 2-8°C under refrigeration or at room temperature (20-25°C) for up to 24 hr; do not freeze.

Antifungals / Cytotoxic Chemotherapy