Nutritional Considerations

• 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).

  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 Investigation 10(1): 1-9, 1992
  2. AMA Council on Scientific Affairs. Guidelines for Handling Parenteral Antineoplastics. Journal of the American Medical Association 1985;253:1590-1591.
  3. National Study Commission on Cytotoxic Exposure. Recommendations for Handling Cytotoxic Agents, 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.
  4. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Medical Journal of Australia 1983;1:426-428.
  5. Jones RB, Frank R, Mass T. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. --A Cancer Journal for Clinicians 1983;33:258-263.
  6. American Society of Hospital Pharmacists. ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J of Hosp Pharm_ 1990;47:1033-1049.
  7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work Practice Guidelines). Am J of Health Syst Pharm. 1996;53:1669-1685.

• Concurrent administration of HEXALEN and antidepressants of the MAO inhibitor class may cause severe orthostatic hypotension. Cimetidine, an inhibitor of microsomal drug metabolism, increased altretamine's half-life and toxicity in a rat model.

  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 Investigation 10(1): 1-9, 1992.

• 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).

  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 Investigation 10(1): 1-9, 1992.

• 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).

  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 Investigation 10(1): 1-9, 1992.

• Pharmacokinetic studies were performed in a limited number of patients and should be considered preliminary. After oral administration of HEXALEN to 11 patients with advanced ovarian cancer in doses of 120-300 mg/m 2 , peak plasma levels (as measured by gas-chromatographic assay) were reached between 0.5 and 3 hours, varying from 0.2 to 20.8 mg/l. Half-life of the (beta)-phase of elimination ranged from 4.7 to 10.2 hours. Altretamine and metabolites show binding to plasma proteins. The free fractions of altretamine, pentamethylmelamine and tetramethylmelamine are 6%, 25% and 50%, respectively.

  1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.

• The carcinogenic potential of HEXALEN has not been studied in animals, but drugs with similar mechanisms of action have been shown to be carcinogenic. HEXALEN was weakly mutagenic when tested in strain TA100 of Salmonella typhimurium . HEXALEN administered to female rats 14 days prior to breeding through the gestation period had no adverse effect on fertility, but decreased postnatal survival at 120 mg/m 2 /day and was embryocidal at 240 m/m 2 /day. Administration of 120 mg/m 2 /day HEXALEN 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 HEXALEN at 450 mg/m 2 /day for 10 days had decreased spermatogenesis, atrophy of testes, seminal vesicles and ventral prostate.

  1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.

• HEXALEN may be administered either for 14 or 21 consecutive days in a 28 day cycle at a dose of 260 mg/m 2 /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 HEXALEN bioavailability or pharmacokinetics has not been evaluated.

  1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.

• HEXALEN should be temporarily discontinued (for 14 days or longer) and subsequently restarted at 200 mg/m 2 /day for any of the following situations

  1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.

• HEXALEN 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).

  1. Recommendations for the Safe Handling of Cytotoxic Drugs. NIH Publication 92-2621. NIH: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Service, 1992. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health.

• HEXALEN should be temporarily discontinued (for 14 days or longer) and subsequently restarted at 200 mg/m 2 /day for any of the following situations: 1. Gastrointestinal intolerance unresponsive to symptomatic measures; 2. White blood count <2000/mm 3 or granulocyte count <1000/mm 3 ; 3. Platelet count <75,000/mm 3 ; 4. Progressive neurotoxicity.

  1. Recommendations for the Safe Handling of Cytotoxic Drugs. NIH Publication 92-2621. NIH: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Service, 1992. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health.

• If neurologic symptoms fail to stabilize on the reduced dose schedule, HEXALEN should be discontinued indefinitely. Procedures to proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published (2-8). There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate

  1. Recommendations for the Safe Handling of Cytotoxic Drugs. NIH Publication 92-2621. NIH: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Service, 1992. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health.