When potent teratogens are irreplaceable drugs: Lessons of thalidomide and isotretinoin

The large number of female patients who could derive benefit from thalidomide and isotretinoin therapy necessitates the establishment of programs that ensure that effective contraception be combined with drug therapy. The success of the Pregnancy Prevention Program for isotretinoin may serve as a precedent from which the pharmaceutical companies marketing thalidomide in the future may construct a similar package to ensure the proper education of physicians and patients regarding potential teratogenic sequelae. Successful development of an assay to quantify serum levels of isotretinoin, etretinate and their metabolites in females (66) may serve as an example for those re-introducing thalidomide. Similar to the interanimal differences found in animal models, considerable interindividual pharmacokinetic variability occurs between patients, so the time required for drug elimination from the body may have serious implications if a patient conceives before complete removal of the teratogen or its metabolite(s) has occurred. The most effective way to ensure that in utero exposure will not occur is through the appropriate education of female patients, their use of a reliable form of birth control and possibly by monitoring serum concentrations of teratogens during and after cessation of therapy. If such steps are implemented, thalidomide and isotretinoin may become therapeutic options for many females. Some pharmaceuticals that are also potent teratogens are clinically beneficial to the nonpregnant patient. Experience with thalidomide led regulators to believe that the acknowledgement of an agent's teratogenicity would prevent fetal disasters; however, clinical experience with isotretinoin clearly demonstrates that merely labelling a compound as teratogenic is far from enough. Education about the need for effective contraception during therapy with a known teratogen must be a mandatory component of patient education and compliance. Use of assays that quantify serum concentrations of the teratogenic drug and its metabolite(s) will help determine the length of time that a woman needs to wait before knowing that no teratogen remains in her system, ie, length of time before conception can take place after therapy. Future drugs deemed clinically irreplaceable may also be teratogenic. New strategies for dispensing such drugs need to be developed and tested. With the advancements and lessons learned from experience with thalidomide and isotretinoin, there is little reason why women of reproductive age need be excluded from the benefits of therapeutic agents that may be teratogenic.