FDA label 375d59e0-7396-406d-abb5-618741131f67

WARNINGS 1. HEXALEN ® capsules should only be given under the supervision of a physician experienced in the use of antineoplastic agents. 2. Peripheral blood counts should be monitored at least monthly, prior to the initiation of each course of HEXALEN ® capsules, and as clinically indicated (see Adverse Reactions ). 3. Because of the possibility of HEXALEN ® capsules-related neurotoxicity, neurologic examination should be performed regularly during HEXALEN ® capsules administration (see Adverse Reactions ).

WARNINGS See boxed Warnings . Concurrent administration of HEXALEN ® 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 ® capsules and MAO inhibitors. HEXALEN ® 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 ® capsules adjusted as clinically indicated (see Dosage and Administration ). Pregnancy: Category D HEXALEN ® capsules has been shown to be embryotoxic and teratogenic in rats and rabbits when given at doses 2 and 10 times the human dose. HEXALEN ® capsules may cause fetal damage when administered to a pregnant woman. If HEXALEN ® capsules is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

ADVERSE REACTIONS Gastrointestinal With continuous high-dose daily HEXALEN ® 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 ® capsules dose reduction or, rarely, discontinuation of HEXALEN ® 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 ® capsules. In 2 clinical studies of single-agent HEXALEN ® capsules utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued HEXALEN ® 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) capsules than moderate-dose HEXALEN ® 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 ® 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 ® capsules and/or cisplatin (1). Hematologic HEXALEN ® capsules causes mild to moderate dose-related myelosuppression. Leukopenia below 3000 WBC/mm 3 occurred in <15% of patients on a variety of intermittent or continuous dose regimens. Less than 1% had leukopenia below 1000 WBC/mm 3 . Thrombocytopenia below 50,000 platelets/mm 3 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 ® capsules. In one study, HEXALEN ® capsules, 260 mg/m 2 /day, was administered for 14 days of a 28 day cycle. In another study, HEXALEN ® 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 ® CAPSULES 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. ADVERSE EXPERIENCES IN 76 PREVIOUSLY TREATED OVARIAN CANCER PATIENTS RECEIVING SINGLE-AGENT HEXALEN® CAPSULES