Гексален

Гексален (altretamine) ® (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.

Гексален® (altretamine) capsules is administered orally. Doses are calculated on the basis of body surface area.

Гексален® (altretamine) capsules may be administered either for 14 or 21 consecutive days in a 28 day cycle at a dose of 260 mg/m²/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 Гексален® (altretamine) capsules bioavailability or pharmacokinetics has not been evaluated.

Гексален® (altretamine) capsules should be temporarily discontinued (for 14 days or longer) and subsequently restarted at 200 mg/m²/day for any of the following situations:

1. Gastrointestinal intolerance unresponsive to symptomatic measures;
2. White blood count <2000/mm³or granulocyte count <1000/mm³;
3. Platelet count <75,000/mm³;
4. Progressive neurotoxicity.

If neurologic symptoms fail to stabilize on the reduced dose schedule, Гексален® (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.

Гексален® (altretamine) capsules is contraindicated in patients who have shown hypersensitivity to it. Гексален® (altretamine) capsules should not be employed in patients with preexisting severe bone marrow depression or severe neurologic toxicity. Гексален® (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.

WARNINGS

See BOXED WARNINGS.

Concurrent administration of Гексален® (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 Гексален® (altretamine) capsules and MAO inhibitors.

Гексален® (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 Гексален® (altretamine) capsules adjusted as clinically indicated (see DOSAGE AND ADMINISTRATION).

Pregnancy: Category D

Гексален® (altretamine) capsules has been shown to be embryotoxic and teratogenic in rats and rabbits when given at doses 2 and 10 times the human dose. Гексален® (altretamine) capsules may cause fetal damage when administered to a pregnant woman. If Гексален® (altretamine) 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.

PRECAUTIONS

General

Neurologic examination should be performed regularly (see ADVERSE REACTIONS).

Laboratory Tests

Peripheral blood counts should be monitored at least monthly, prior to the initiation of each course of Гексален® (altretamine) capsules, and as clinically indicated (see ADVERSE REACTIONS).

Carcinogenesis, Mutagenesis and Impairment of Fertility

The carcinogenic potential of Гексален® (altretamine) capsules has not been studied in animals, but drugs with similar mechanisms of action have been shown to be carcinogenic. Гексален® (altretamine) capsules was weakly mutagenic when tested in strain TA100 of Salmonella typhimurium. Гексален® (altretamine) capsules administered to female rats 14 days prior to breeding through the gestation period had no adverse effect on fertility, but decreased post-natal survival at 120 mg/m²/day and was embryocidal at 240 mg/m²/day. Administration of 120 mg/m²/day Гексален® (altretamine) capsules to male rats for 60 days prior to mating resulted in testicular atrophy, reduced fertility and a possible dominant lethal mutagenic effect. Male rats treated with Гексален® (altretamine) capsules at 450 mg/m²/day for 10 days had decreased spermatogenesis, atrophy of testes, seminal vesicles and ventral prostate.

Pregnancy

Pregnancy Category D: see WARNINGS section.

Nursing Mothers

It is not known whether altretamine is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to Гексален® (altretamine) capsules treatment of the mother, it is recommended that breast feeding be discontinued if the mother is treated with Гексален® (altretamine) capsules.

Pediatric Use

The safety and effectiveness of Гексален® (altretamine) capsules in children have not been established.

REFERENCES

1.Wiernik PH, et al. Hexamethylmelamine and Low or Moderate Dose Cisplatin With or Without Pyridoxine for Treatment of Advanced Ovarian Carcinoma: A Study of the Eastern Cooperative Oncology Group. Cancer Invest. 1992; 10(1): 1-9.

Gastrointestinal

With continuous high-dose daily Гексален® (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 Гексален® (altretamine) capsules dose reduction or, rarely, discontinuation of Гексален® (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 Гексален® (altretamine) capsules. In 2 clinical studies of single-agent Гексален® (altretamine) capsules utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued Гексален® (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 Гексален (altretamine) ® (altretamine) capsules than moderate-dose Гексален® (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 Гексален® (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 Гексален® (altretamine) capsules and/or cisplatin (1).

Hematologic

Гексален® (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 Гексален® (altretamine) capsules. In one study, Гексален® (altretamine) capsules, 260 mg/m²/day, was administered for 14 days of a 28 day cycle. In another study, Гексален® (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 Гексален® (altretamine) 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.

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.