Hexalen Information
Hexalen (Altretamine)
Hexalen (Altretamine) Description
Hexalen (Altretamine) capsules, is a synthetic cytotoxic antineoplastic s-triazine derivative. Hexalen (Altretamine) capsules contain 50 mg of altretamine for oral administration. Inert ingredients include lactose, anhydrous and calcium stearate. Altretamine, known chemically as ,,',',”,”-hexamethyl-1,3,5-triazine-2,4,6-triamine, has the following structural formula:
Its empirical formula is C9H18N6 with a molecular weight of 210.28. Altretamine is a white crystalline powder, melting at 172°± 1°C. Altretamine is practically insoluble in water but is increasingly soluble at pH 3 and below.
Hexalen (Altretamine) Clinical Pharmacology
The precise mechanism by which Hexalen (Altretamine) capsules exerts its cytotoxic effect is unknown, although a number of theoretical possibilities have been studied. Structurally, Hexalen (Altretamine) capsules resembles the alkylating agent triethylenemelamine, yet tests for alkylating activity of Hexalen (Altretamine) capsules and its metabolites have been negative. Hexalen (Altretamine) capsules has been demonstrated to be efficacious for certain ovarian tumors resistant to classical alkylating agents. Metabolism of altretamine is a requirement for cytotoxicity. Synthetic monohydroxymethylmelamines, and products of altretamine metabolism, and , can form covalent adducts with tissue macromolecules including DNA, but the relevance of these reactions to antitumor activity is unknown.
Hexalen (Altretamine) capsules is well-absorbed following oral administration in humans, but undergoes rapid and extensive demethylation in the liver, producing variation in altretamine plasma levels. The principal metabolites are pentamethylmelamine and tetramethylmelamine.
Pharmacokinetic studies were performed in a limited number of patients and should be considered preliminary. After oral administration of Hexalen (Altretamine) capsules to 11 patients with advanced ovarian cancer in doses of 120-300 mg/m, peak plasma levels (as measured by gas-chromatographic assay) were reached between 0.5 and 3 hours, varying from 0.2 to 20.8 mg/l. Half-life of the β-phase of elimination ranged from 4.7 to 10.2 hours. Altretamine and metabolites show binding to plasma proteins. The free fractions of altretamine, pentamethylmelamine and tetramethylmelamine are 6%, 25% and 50%, respectively.
Following oral administration of C-ring-labeled altretamine (4 mg/kg), urinary recovery of radioactivity was 61% at 24 hours and 90% at 72 hours. Human urinary metabolites were Ndemethylated homologues of altretamine with <1% unmetabolized altretamine excreted at 24 hours.
After intraperitoneal administration of C-ring-labeled altretamine to mice, tissue distribution was rapid in all organs, reaching a maximum at 30 minutes. The excretory organs (liver and kidney) and the small intestine showed high concentrations of radioactivity, whereas relatively low concentrations were found in other organs, including the brain.
There have been no formal pharmacokinetic studies in patients with compromised hepatic and/or renal function, though Hexalen (Altretamine) capsules has been administered both concurrently and following nephrotoxic drugs such as cisplatin.
Hexalen (Altretamine) capsules has been administered in 4 divided doses, with meals and at bedtime, though there is no pharmacokinetic data on this schedule nor information from formal interaction studies about the effect of food on its bioavailability or pharmacokinetics.
In two studies in patients with persistent or recurrent ovarian cancer following first-line treatment with cisplatin and/or alkylating agent-based combinations, Hexalen (Altretamine) capsules was administered as a single agent for 14 or 21 days of a 28 day cycle. In the 51 patients with measurable or evaluable disease, there were 6 clinical complete responses, 1 pathologic complete response, and 2 partial responses for an overall response rate of 18%. The duration of these responses ranged from 2 months in a patient with a palpable pelvic mass to 36 months in a patient who achieved a pathologic complete response. In some patients, tumor regression was associated with improvement in symptoms and performance status.
Hexalen (Altretamine) Indications And Usage
Hexalen (Altretamine) capsules is indicated for use as a single agent in the palliative treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based combination.
Hexalen (Altretamine) Contraindications
Hexalen (Altretamine) capsules is contraindicated in patients who have shown hypersensitivity to it. Hexalen (Altretamine) capsules should not be employed in patients with preexisting severe bone marrow depression or severe neurologic toxicity. Hexalen (Altretamine) capsules has been administered safely, however, to patients heavily pretreated with cisplatin and/or alkylating agents, including patients with preexisting cisplatin neuropathies. Careful monitoring of neurologic function in these patients is essential.
Hexalen (Altretamine) Warnings
See .
Concurrent administration of Hexalen (Altretamine) capsules and antidepressants of the monoamine oxidase (MAO) inhibitor class may cause severe orthostatic hypotension. Four patients, all over 60 years of age, were reported to have experienced symptomatic hypotension after 4 to 7 days of concomitant therapy with Hexalen (Altretamine) capsules and MAO inhibitors.
Hexalen (Altretamine) capsules causes mild to moderate myelosuppression and neurotoxicity. Blood counts and a neurologic examination should be performed prior to the initiation of each course of therapy and the dose of Hexalen (Altretamine) capsules adjusted as clinically indicated (see ).
Hexalen (Altretamine) Precautions
Concurrent administration of Hexalen (Altretamine) capsules and antidepressants of the MAO inhibitor class may cause severe orthostatic hypotension (see section). Cimetidine, an inhibitor of microsomal drug metabolism, increased altretamine's half-life and toxicity in a rat model.
Data from a randomized trial of Hexalen (Altretamine) capsules and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response duration suggesting that pyridoxine should not be administered with Hexalen (Altretamine) capsules and/or cisplatin (1).
Hexalen (Altretamine) Adverse Reactions
Hexalen (Altretamine) capsules causes mild to moderate dose-related myelosuppression. Leukopenia below 3000 WBC/mm occurred in <15% of patients on a variety of intermittent or continuous dose regimens. Less than 1% had leukopenia below 1000 WBC/mm. Thrombocytopenia below 50,000 platelets/mm was seen in <10% of patients. When given in doses of 8-12 mg/kg/day over a 21 day course, nadirs of leukocyte and platelet counts were reached by 3-4 weeks, and normal counts were regained by 6 weeks. With continuous administration at doses of 6-8 mg/kg/day, nadirs are reached in 6-8 weeks (median).
Data in the following table are based on the experience of 76 patients with ovarian cancer previously treated with a cisplatin-based combination regimen who received single-agent Hexalen (Altretamine) capsules. In one study, Hexalen (Altretamine) capsules, 260 mg/m/day, was administered for 14 days of a 28 day cycle. In another study, Hexalen (Altretamine) capsules, 6-8 mg/kg/day, was administered for 21 days of a 28 day cycle.
Additional adverse reaction information is available from 13 single-agent altretamine studies (total of 1014 patients) conducted under the auspices of the National Cancer Institute. The treated patients had a variety of tumors and many were heavily pretreated with other chemotherapies; most of these trials utilized high, continuous daily doses of altretamine (612 mg/kg/day). In general, adverse reaction experiences were similar in the two trials described above. Additional toxicities, not reported in the above table, included hepatic toxicity, skin rash, pruritus and alopecia, each occurring in <1% of patients.
Hexalen (Altretamine) Overdosage
No case of acute overdosage in humans has been described. The oral LD50 dose in rats was 1050 mg/kg and 437 mg/kg in mice.
Hexalen (Altretamine) Dosage And Administration
Hexalen (Altretamine) capsules is administered orally. Doses are calculated on the basis of body surface area.
Hexalen (Altretamine) capsules may be administered either for 14 or 21 consecutive days in a 28 day cycle at a dose of 260 mg/m/day. The total daily dose should be given as 4 divided oral doses after meals and at bedtime. There is no pharmacokinetic information supporting this dosing regimen and the effect of food on Hexalen (Altretamine) capsules bioavailability or pharmacokinetics has not been evaluated.
Hexalen (Altretamine) capsules should be temporarily discontinued (for 14 days or longer) and subsequently restarted at 200 mg/m/day for any of the following situations:
If neurologic symptoms fail to stabilize on the reduced dose schedule, Hexalen (Altretamine) capsules should be discontinued indefinitely.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published (2-9). There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Hexalen (Altretamine) How Supplied
Hexalen (Altretamine) capsules is available in 50 mg clear, hard gelatin capsules imprinted with the following inscription:
Store up to 25ºC (77ºF); excursions permitted to 15° to 30°C (59° to 86°F).
Hexalen (Altretamine) References
Hexalen (Altretamine) capsules is a registered trademark of MGI PHARMA, INC.
Manufactured by:
An aaiPharma Company 1726 North 23 St. Wilmington, North Carolina 28405
Manufactured for:
For Medical Inquiries call: 1-800-562-5580
Revision Date November, 2003 HEXUS PO5
