DrugindexOnline^{2nd edition}

Pronouncation: (ahl-TRETT-uh-meen)
Class: Alkylating agent, Ethylenimines, Methylmelamines

Trade Names:
Hexalen
- Gelatin capsules 50 mg

Mechanism of Action

Pharmacology

The precise mechanism by which altretamine exerts its cytotoxic effect is unknown. Synthetic monohydroxymethylmelamines and products of altretamine metabolism in vitro and in vivo can form covalent adducts with tissue macromolecules including DNA, but the relevance of these reactions to antitumor activity is unknown.

Pharmacokinetics

Absorption

Well absorbed; T _max of 0.5 to 3 h; C _max is 0.2 to 20.8 mg/L.

Distribution

Does bind to plasma proteins.

Metabolism

Metabolism occurs in the liver with rapid and extensive demethylation to 2 metabolites.

Elimination

T _½ of the beta-phase is 4.7 to 10.2 h. 90% is excreted in the urine at 72 h. Less than 1% of unmetabolized altretamine is excreted at 24 h.

Indications and Usage

Palliative therapy of refractory ovarian cancer.

Contraindications

Hypersensitivity to altretamine; pre-existing severe bone marrow depression or severe neurologic toxicity. Careful monitoring of neurologic function in these patients is essential.

Dosage and Administration

Refractory Ovarian Cancer
Adults

PO 260 mg/m ² /day for 14 or 21 days in a 28-day cycle, given in 4 divided doses (round dose to the nearest 50 mg) after meals and at bedtime (usual dose, 400 mg/day). Discontinue therapy for at least 14 days and resume at 200 mg/m ² /day in any of the following situations: treatment-resistant GI adverse effects; WBC less than 2,000/mm ³ ; granulocyte count less than 1,000/mm ³ ; platelet count less than 75,000/mm ³ ; progressive neurotoxicity. Discontinue permanently if neurologic symptoms persist after dose reduction.

Storage/Stability

Store capsules at controlled room temperature in a tightly closed container.

Drug Interactions

Cimetidine

May increase altretamine's half-life and toxicity.

CYP-450 enzymes

Altretamine elimination may be altered by agents that inhibit or induce CYP-450 enzymes.

Tricyclic antidepressants or MAOIs

Coadministration of altretamine with these drugs may cause orthostatic hypotension.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Reversible peripheral neuropathy; ataxia; depression; vertigo; agitation; confusion; hallucinations.

Dermatologic

Rash; pruritus.

GI

Moderate potential for nausea and vomiting.

Hematologic

Bone marrow suppression; nadir at 3 to 4 wk with intermittent therapy (for 14 to 21 days in a cycle) and at 6 to 8 wk with continuous administration.

Precautions

Warnings Neurotoxicity Altretamine causes mild to moderate neurotoxicity. Peripheral neuropathy and CNS symptoms (eg, mood disorders, disorders of consciousness, ataxia, dizziness, vertigo) have occurred. These are more likely to occur in patients receiving continuous high-dose daily altretamine. Neurologic toxicity appears to be reversible when therapy is discontinued. Perform neurologic exams regularly during therapy. Hematologic Altretamine causes mild to moderate dose-related myelosuppression. Perform peripheral blood counts at baseline; prior to each course, at least monthly and when clinically indicated.

Monitor CBC Ensure that CBC and differential are determined at baseline, prior to each course, and as indicated during therapy. Neurologic examination Ensure that a neurologic examination is performed at baseline, prior to each course, and as indicated during therapy.

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Carcinogenesis

Drugs with similar mechanisms of actions are carcinogenic.

Nausea and vomiting

With continuous high-dose daily altretamine, nausea and vomiting of gradual onset occur frequently.

Patient Information

• Review dosing schedule with patient (ie, 14 or 21 consecutive days in a 28-day cycle).
• Advise patient to take prescribed dose 4 times a day, after meals, and at bedtime.
• Advise patient that if a dose is missed, take it as soon as possible, but if close to the next dose, do not double the dose to catch up and take the next dose as scheduled.
• Advise patient to immediately report any of the following to their health care provider: fever, chills or other signs of infection; sore throat; persistent nausea, vomiting or appetite loss; unusual bruising or bleeding, skin rash; abnormal skin sensations; mood changes; feeling of a whirling motion; incoordination.
• Advise patient that drug may cause dizziness and to use caution while driving or performing other tasks requiring mental alertness.