Gastrointestinal
With continuous high-dose daily HEXALEN, nausea and vomiting of gradual onset occur frequently. Although in most instances these symptoms are controllable with anti-emetics, at times the severity requires HEXALEN dose reduction or, rarely, discontinuation of HEXALEN therapy. In some instances, a tolerance of these symptoms develops after several weeks of therapy. The incidence and severity of nausea and vomiting are reduced with moderate-dose administration of HEXALEN. In 2 clinical studies of single-agent HEXALEN utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued HEXALEN due to severe nausea and vomiting.

Neurotoxicity
Peripheral neuropathy and central nervous system 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 HEXALEN (altretamine) than moderate-dose HEXALEN administered on an intermittent schedule. Neurologic toxicity has been reported to be reversible when therapy is discontinued. Data from a randomized trial of HEXALEN 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 and/or cisplatin (1).

Hematologic
HEXALEN causes mild to moderate dose-related myelosuppression. Leukopenia below 3000 WBC/mm³ occurred in <15% of patients on a variety of intermittent or continuous dose regimens. Less than 1% had leukopenia below 1000 WBC/mm³. Thrombocytopenia below 50,000 platelets/mm³ 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. In one study, HEXALEN, 260 mg/m²/day, was administered for 14 days of a 28 day cycle. In another study, HEXALEN, 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 (6-12 mg/kg/day). In general, adverse reaction experiences were similar in the two trails described above. Additional toxicities, not reported in the above table, included hepatic toxicity, skin rash, pruritus and alopecia, each occurring in <1% of patients.

Concurrent administration of HEXALEN and antidepressants of the MAO inhibitor class may cause severe orthostatic hypotension (see WARNINGS 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 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 and/or cisplatin.¹

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