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Altretamine

Class: Antineoplastic Agents
Chemical Name: N,N,N′,N′,N″,N″-Hexamethyl-1,3,5-triazine-2,4,6-triamine
Molecular Formula: C9H18N6
CAS Number: 645-05-6
Brands: Hexalen

Medically reviewed by Drugs.com on May 24, 2021. Written by ASHP.

Warning

    Experience of Supervising Clinician
  • Use only under the supervision of a clinician experienced in therapy with antineoplastic agents.

    Dose-Related Toxicities
  • Monitor peripheral blood counts at least monthly, prior to initiation of each course of therapy, and as clinically indicated.

  • Risk of neurotoxicity. Perform neurologic examinations regularly during therapy.

Introduction

Antineoplastic agent; s-triazine derivative.

Uses for Altretamine

Ovarian Cancer

Used as a single agent for palliative treatment of ovarian cancer that has persisted or recurred following first-line treatment with combination therapy containing cisplatin and/or an alkylating agent.

Considered an alternative drug for salvage therapy for platinum-resistant ovarian cancer.

Has been used as consolidation therapy in women with complete clinical remission following surgical debulking and first-line chemotherapy (typically platinum and paclitaxel) for stage III ovarian epithelial cancer; however, no further investigation conducted to date.

Altretamine Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.

Administration

Oral Administration

Administer orally.

Manufacturer recommends that total daily dosage be divided into 4 doses (e.g., dose after each meal and a dose at bedtime); however, no pharmacokinetic data to support this dosage schedule.

Food may decrease rate and extent of absorption of altretamine.

Dosage

Calculate dosage according to body surface area.

Adults

Ovarian Cancer
Palliative Treatment of Persistent or Recurrent Disease
Oral

260 mg/m2 daily in 4 divided doses for either 14 or 21 consecutive days in a 28-day cycle.

Dosage Modification for Toxicity
GI Toxicity
Oral

For GI intolerance unresponsive to management of symptoms, interrupt therapy for ≥14 days. Upon resolution of GI toxicity, reinitiate at a reduced dosage of 200 mg/m2 daily.

Neurologic Toxicity
Oral

For progressive neurotoxicity, interrupt therapy for ≥14 days. Upon resolution of neurologic toxicity, reinitiate at a reduced dosage of 200 mg/m2 daily. If neurologic manifestations persist at reduced dosage, discontinue indefinitely.

Hematologic Toxicity
Oral

For patients experiencing myelosuppression (e.g., WBC count <2000/mm3, granulocyte count <1000/mm3, or platelet count <75,000/mm3), interrupt therapy for ≥14 days. Upon resolution of hematologic toxicity, reinitiate at a reduced dosage of 200 mg/m2 daily.

Special Populations

No special population dosage recommendations at this time.

Cautions for Altretamine

Contraindications

  • Known hypersensitivity to altretamine.

  • Preexisting severe bone marrow depression. (See Hematologic Effects under Cautions.)

  • Preexisting severe neurologic toxicity. (See Nervous System Effects under Cautions.)

Warnings/Precautions

Warnings

Nervous System Effects

Risk of dose-related neurotoxicity, manifested as peripheral neuropathy and CNS manifestations (e.g., mood disorders, disorders of consciousness, ataxia, dizziness, vertigo). Neurotoxicity may be reversible upon discontinuance of the drug.

Perform neurologic examinations prior to the initiation of each course and regularly during therapy. If manifestations of neurotoxicity occur, discontinue therapy; dosage modification may be required. (See Dosage Modification for Toxicity under Dosage and Administration.)

Careful monitoring of neurologic function required during therapy in patients who have received previous treatment with cisplatin and/or alkylating agents, particularly in patients with preexisting cisplatin-induced neuropathies.

Hematologic Effects

Risk of mild to moderate dose-related myelosuppression, including leukopenia, anemia, and thrombocytopenia. Perform peripheral blood cell counts at least monthly, prior to the initiation of each course of therapy, and as clinically indicated; dosage modification may be required. (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxic and teratogenic effects demonstrated in animals. Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Major Toxicities

GI Effects

Risk of dose-related nausea and vomiting; reported frequently with continuous high-dose therapy. If required, administer antiemetic therapy; dose reduction or, rarely, discontinuance of therapy may be required for severe symptoms. (See Dosage Modification for Toxicity under Dosage and Administration.) Tolerance to GI symptoms may develop after several weeks of therapy.

General Precautions

Carcinogenic Effects

Acute myeloid leukemia reported in one patient.

Studies not performed to evaluate carcinogenic potential; drugs with similar mechanisms of action have been shown to be carcinogenic.

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known if distributed into milk. Discontinue nursing because of potential risk to nursing infant.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Safety and efficacy in geriatric patients not studied.

Common Adverse Effects

Nausea, vomiting, peripheral sensory neuropathy, leukopenia, thrombocytopenia, anemia, increased serum alkaline phosphatase, increased serum creatinine/BUN.

Interactions for Altretamine

Specific Drugs

Drug

Interaction

Comments

Cimetidine

Potentially increased half-life and toxicity of altretamine

MAO inhibitors (antidepressants)

Potentially severe orthostatic hypotension

Usually resolves upon discontinuance of the antidepressant

Pyridoxine

Reduced neurotoxicity but shortened response duration in patients receiving altretamine and cisplatin

Concomitant administration not recommended

Altretamine Pharmacokinetics

Absorption

Bioavailability

Readily absorbed from GI tract, with peak plasma concentrations attained within 0.5–3 hours.

Food

Food may delay and decrease extent of absorption.

Distribution

Extent

Distributed into tissues with a high lipid component (e.g., omentum and subcutaneous tissue).

Concentrations in primary tumor similar to plasma concentrations; concentrations higher in metastases than in primary tumor.

Not known if distributed into milk.

Plasma Protein Binding

Altretamine: 94%.

Pentamethylmelamine and tetramethylmelamine: 75% and 50%, respectively.

Elimination

Metabolism

Rapidly and extensively metabolized in the GI tract and liver; oxidative N-demethylation occurs to form active hydroxymethyl derivatives, principally pentamethylmelamine and tetramethylmelamine.

Metabolism and activation also may occur in tumor cells or other extrahepatic sites.

Elimination Route

Excreted in urine, mostly as metabolites.

Half-life

Biphasic; terminal half-life is about 5–10 hours.

Special Populations

Effect of hepatic and/or renal impairment on elimination not established.

Ascites does not appear to alter pharmacokinetics.

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).

Actions

  • Exact mechanism of action not known.

  • Structurally similar to triethylenemelamine (an alkylating agent); however, no evidence from in vitro tests of alkylating activity.

  • Efficacy established for certain ovarian tumors resistant to classic alkylating agents.

  • Must be metabolized to exert cytotoxic effect. Hydroxymethyl derivatives are metabolized to release formaldehyde, which may contribute to cytotoxic activity.

  • Metabolites and synthetic monohydroxymethylmelamines form covalent adducts with tissue macromolecules (e.g., DNA); relevance to antitumor activity not known.

Advice to Patients

  • Risk of nausea, vomiting, myelosuppression, and neurotoxicity.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Altretamine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

50 mg

Hexalen

MGI Pharma

AHFS DI Essentials™. © Copyright 2022, Selected Revisions June 1, 2009. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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