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Gastrointestinal

With continuous high-dose daily HEXALEN® (altretamine) capsules, 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® (altretamine) capsules dose reduction or, rarely, discontinuation of HEXALEN® (altretamine) capsules 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® (altretamine) capsules. In 2 clinical studies of single-agent HEXALEN® (altretamine) capsules utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued HEXALEN® (altretamine) capsules 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) ® (altretamine) capsules than moderate-dose HEXALEN® (altretamine) capsules administered on an intermittent schedule. Neurologic toxicity has been reported to be reversible when therapy is discontinued. 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).

Hematologic

HEXALEN® (altretamine) capsules causes mild to moderate dose-related myelosuppression. Leukopenia below 3000 WBC/mm³occurred 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/mm³was 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/m²/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.

ADVERSE EXPERIENCES IN 76 PREVIOUSLY TREATED OVARIAN CANCER PATIENTS RECEIVING SINGLE-AGENT HEXALEN® (altretamine) CAPSULES

Adverse Experiences %Patients
Gastrointestinal
Nausea and Vomiting 33  
  Mild to Moderate   32
  Severe   1
Increased Alkaline Phosphatase 9  
Neurologic
Peripheral Sensory Neuropathy 31  
  Mild   22
  Moderate to Servere   9
Anorexia and Fatigue 1  
Seizures 1  
Hematologic
Leukopenia 5  
  WBC 2000-2999/mm³   4
  WBC<2000/mm³   1
Thrombocytopenia 9  
  Platelets 75,000-99,000/mm³   6
  Platelets <75,000mm³   3
Anemia 33  
  Mild   20
  Moderate to Severe   13
Renal
Serum Cretinine 1.6-3.75mg/dl 7  
BUN 9  
  25-40mg%   5
  41-60mg%   3
  >60mg%   1

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.