Thalidomide Pharmion (Pharmion)
50 mg capsules
Approved indication: erythema nodosum leprosum, multiple myeloma
Australian Medicines Handbook section 14
Thalidomide was originally marketed as a sedative, but was withdrawn in 1961 because of its association with birth defects. The drug was still made available for research purposes, and by chance it was found to be effective in erythema nodosum leprosum. This prompted further research into thalidomide's effects on inflammation and the immune system. Despite this research, the mechanism of action remains unclear and our knowledge of thalidomide's pharmacokinetics is incomplete.
Patients with leprosy may develop painful papules on the limbs. In more severe cases this erythema nodosum leprosum can be more widespread and make the patient systemically ill. Studies in the 1960s found that 66-75% of patients would respond to a seven-day course of thalidomide. Although thalidomide is effective for the cutaneous manifestations of erythema nodosum leprosum, it has no known action on Mycobacterium leprae.
The birth defects associated with thalidomide may have been related to its inhibition of angiogenesis. As neovascularisation occurs in the bone marrow of patients with multiple myeloma, thalidomide has been tried after other treatments have failed. A study of 84 patients with refractory multiple myeloma found that 32% responded to a course of thalidomide (median duration of treatment 80 days).1Despite this response rate, the hypothesis of thalidomide acting by inhibiting angiogenesis was not supported. There was no significant difference in the microvascular density of the bone marrow between patients who responded and those who did not.
Patient responses in studies of multiple myeloma are primarily judged by changes in the concentrations of paraprotein. It is not certain how these responses correlate with survival. The median event-free survival for the 84 patients was three months. After a year 58% of the patients were still alive.1An Australian study, which had an overall response rate of 28%, found that the median overall survival was 14.6 months. Increasing age may be associated with a poorer outcome.2
The optimum dose for thalidomide in refractory multiple myeloma is not yet clear. Many patients in the clinical trials were not able to increase their dose according to the maximum planned in the study design.1,2 Higher doses are associated with an increased frequency of adverse effects.
Some of the adverse effects of thalidomide, such as sedation, are predictable. Before the drug was withdrawn in the 1960s there had been reports associating it with peripheral neuropathy, which may be irreversible. In the Australian study 29% of patients developed a degree of motor neuropathy and 47% developed some sensory neuropathy.2Patients need regular checks to detect early signs of neuropathy. The white blood cell count also needs regular monitoring as thalidomide may cause neutropenia. Fatigue and constipation are the most frequent adverse effects of thalidomide.
Women of childbearing age who are prescribed thalidomide must not have intercourse or should use two types of contraception. As it is unknown if thalidomide is present in the semen of male patients they must use barrier contraception, even if they have had a vasectomy. As even a single dose may cause birth defects prescription of thalidomide will be tightly controlled. Only specialists and pharmacists registered with the Pharmion Risk Management Program will be allowed to prescribe and dispense thalidomide. Patients will need to give written informed consent before treatment.
- Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341:1565-71.
- Mileshkin L, Biagi JJ, Mitchell P, Underhill C, Grigg A, Bell R, et al. Multi center phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age. Blood 2003;102:69-77.