Action And Clinical Pharmacology: Altretamine, better known in the scientific literature as hexamethylmelamine (HMM), is a synthetic cytotoxic antineoplastic s-triazine derivative. While altretamine bears structural similarity to, and cross-reactivity with, triethylenemelamine (TEM), a classical alkylating agent, evidence demonstrating altretamine to be an alkylating agent is not conclusive. Altretamine does not consistently demonstrate cross-resistance with classical alkylating agents used in rodent tumors or in human cancer treatment, but its clinical antitumor spectrum resembles that of an alkylating agent. Additionally, altretamine has been demonstrated to be efficacious for tumors resistant to classical alkylating agents.
The mechanism of action of altretamine is not completely understood. There are no mechanistic studies to suggest antifolate or antimetabolite properties of the molecule, and the parent drug is chemically very stable. Metabolism, specifically N-demethylation, has been shown to be necessary for the antitumor activity of altretamine. It has been proposed that altretamine N-demethylation may produce reactive intermediates which covalently bind to tissue macromolecules, including DNA.
Pharmacokinetics: Radiolabelled studies indicate that altretamine is rapidly absorbed and almost completely absorbed orally: the maximum plasma level of radioactivity is obtained within 1 to 4 hours and the elimination half-life is about 13 hours. Once absorbed, altretamine is extensively metabolized by N-demethylation via hepatic microsomal enzymes, producing variation in altretamine plasma levels.
In man, about 61% of the administered dose is recovered in the urine within 24 hours. In contrast, elimination in the feces is negligible.
Indications And Clinical Uses: As palliative therapy in ovarian carcinoma as follows: First-line therapy in combination with other established antineoplastic agents: Impressive response rates and median survival times have been reported in advanced ovarian cancer studies of Hexalen in combination with other known chemotherapeutic agents including cyclophosphamide, doxorubicin, cisplatin, 5-fluorouracil and methotrexate.
Second-line combination or single-agent therapy in patients who have not responded or who have relapsed on other chemotherapeutic regimens.
Results from Northwestern University Medical School, Hershey Medical Center, and Norwegian Radium Hospital demonstrate the efficacy of altretamine as second-line therapy after failure of first-line, platinum-based combination chemotherapy.
Contra-Indications: In individuals with known hypersensitivity to the drug.
It is also contraindicated in patients with severe myeloid suppression (leukopenia, thrombocytopenia, anemia).
Therapy with altretamine should be deferred for at least 3 weeks after prior alkylating agent therapy.
Manufacturers’ Warnings In Clinical States: Altretamine is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs (see Precautions). Toxicity to altretamine is dose-related and cumulative. Blood counts should be monitored weekly and neurological examinations performed regularly.
When used as indicated, the physician must carefully weigh the therapeutic benefit versus risk of toxicity which may occur.
Altretamine should be given cautiously to individuals with pre-existing renal and hepatic impairment.
If altretamine is used in combination with other cytotoxic agents, the toxic effects may be potentiated.
Pregnancy: The safe use of altretamine in pregnant women has not been established. It should not be used in pregnancy, particularly in early pregnancy, unless in the judgement of the physician, the potential benefits outweigh the possible risks.
Lactation: It is not known whether altretamine or its metabolites are excreted in human milk. Nursing should be discontinued in patients receiving altretamine.
Precautions: Altretamine should be administered by physicians experienced in the use of antineoplastic agents.
The toxicities seen with altretamine have been gastrointestinal (nausea and vomiting), hematologic (leukopenia and mild anemia) and, occasionally, neurologic (ataxia, depression and peripheral neuropathy). Since toxicity to altretamine is not only dose-related, but also dose-cumulative, peripheral blood counts should be monitored weekly and neurological examinations performed regularly. Antiemetics may be of help in reducing gastric upset.
Altretamine should be given cautiously to patients with the following: leukopenia, thrombocytopenia and/or anemia; tumor infiltration of bone marrow; previous radiation therapy or treatment with cytotoxic agents.
Adverse Reactions: Gastrointestinal: With continuous high-dose daily altretamine, nausea and vomiting of gradual onset occur frequently. Although in most instances these symptoms are controllable with antiemetics, at times the severity requires altretamine dose reduction or, rarely, discontinuation of altretamine therapy. In some instances, a tolerance to these symptoms develops after several weeks of therapy. The incidence and severity of nausea and vomiting are reduced with moderate-dose administration of altretamine. In 2 clinical studies of single-agent altretamine utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued altretamine due to severe nausea and vomiting.
Neurotoxicity: Peripheral neuropathy and CNS symptoms (mood disorders, disorders of consciousness, ataxia, dizziness, vertigo) have been reported. They are more likely to occur in patients receiving continuous, high-dose daily altretamine than moderate-dose altretamine administered on an intermittent schedule. Neurologic toxicity has been reported to be reversible when therapy is discontinued. Data from a randomized trial of altretamine and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response duration suggesting that pryridoxine should not be administered with altretamine and/or cisplatin.
Data in Table V are based on the experience of 76 patients with ovarian cancer previously treated with a cisplatin-based combination regimen who received single-agent altretamine. In 1 study, altretamine (260 mg/mday) was administered for 14 days of a 28-day cycle. In another study, altretamine (6 to 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 1 014 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 (6 to 12 mg/kg/day). In general, adverse reaction experiences were similar in the 2 trials described above.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Accidental overdosage with altretamine would be expected to intensify the severity of hematopoietic depression, gastrointestinal and neurological symptomatology. In the event of overdosage, general supportive measures should be instituted to sustain the patient through any period of toxicity that might occur.
Dosage And Administration: Chemotherapy with altretamine, as with other drugs used in cancer chemotherapy, is potentially hazardous. It is therefore recommended that it be administered by physicians aware of the associated risks.
The usual daily dose of altretamine as a single agent is 260 mg/m(6 to 8 mg/kg) administered orally in 3 or 4 divided doses in 14- to 21-day cycles. A 7- to 14-day off-drug period between cycles is recommended.
When employed in combination with other antineoplastic agents, the daily dose of altretamine may be appropriately reduced to 150 mg/m(4 to 6 mg/kg) given in 3 or 4 divided doses in 7- to 14-day cycles. A 14- to 21-day off-drug period between cycles is recommended.
If intolerable side effects occur, a dose reduction or a temporary discontinuation of the drug should be considered.
Concomitant antiemetics have been useful in the control of severe nausea and vomiting.
Availability And Storage: Each clear, hard gelatin capsule, imprinted with the following inscription: USB001 HEXALEN 50 mg, contains: altretamine 50 mg. Nonmedicinal ingredients: calcium stearate and lactose, anhydrous; capsule shell: gelatin, silicon dioxide and sodium lauryl sulfate. Bottles of 100. Store at controlled room temperature (15 to 30°C).
HEXALEN® Lilly Altretamine Antineoplastic Agent