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Acute and Chronic (Late Occurring) Adverse Events, Adverse Events That Disappear (Bendectin), and Diethylstilbesterol
Adverse events (AEs) seen shortly after starting or stopping drugs are common and relatively easy to recognize (though if it were that easy, there would be little need for this book). There is usually a high index of suspicion, a close temporal relationship, and often biologic and pharmacologic plausibility.
This is not the case for AEs that occur weeks, months, or even years after stopping the drug (“long latency period”). There may be no medical record available, the patient’s memory of using the product may be hazy, the index of suspicion is low or nonexistent, and there may be no logical, biologic, or pharmacologic reason for this AE to be associated with the drug. Examples are common in long-latency diseases or behaviors. Examples include cigarette smoking and cancer of the lung many years later, asbestos inhalation producing pleural mesotheliomas decades after exposure ended, or the classic example of vaginal cancer in the offspring of women taking diethylstilbestrol (DES). If one considers alcohol a drug, then its effects on the liver, brain, and other organs also may not be seen for many years.
It is now increasingly recognized that drug therapy as well as other therapies (radiation therapy, neutraceuticals, OTCs, etc.) can produce late AEs. Usually, it takes an insightful clinician or a good epidemiologic study to show that a particular drug caused (or is associated with) a particular AE years later. Such a finding is often first met with disbelief and even ridicule. However, public health and good science demand that all contingencies be kept in mind and examined when appropriate.
Finally, to keep us humble, an example of what looked like a clear and related AE and that turned out not to be such is presented (Bendectin).
From empirical observations, the latency period from starting or stopping of a drug to the onset of the AE is variable. AEs can be seen immediately after starting a drug, shortly thereafter, or even after weeks or months of taking the drug with no problems. AEs can also be seen long after stopping the drug. Examples that follow are of AEs seen long after starting or stopping a drug.
Bendectin: A False Alert
Market Removal
Bendectin was a fixed combination of three active ingredients used for treating nausea and vomiting during pregnancy:
- Doxylamine, an H1 antihistamine that acts as an antinausea and antivomiting agent
- Pyridoxine, vitamin B6
- Dicycloverine, removed from the product shortly before market withdrawal of Bendectin
This product was incorrectly suspected of causing congenital abnormalities. Several case-control studies were performed, and their results formed the basis for the exoneration of this product. It had been on the market for about 27 years and was taken by some 33 million pregnant women in the United States, representing 20–40% of all pregnant women. It was voluntarily withdrawn from the U.S. market and never returned even after its exoneration. It was sold under the name of Debendoxin other countries (Fleming BMJ 1981;283:99; CSM/MCA, Curr Problems Pharmacovigilance 1981;6; Lancet 1984;2:205; BMJ 1985;271:918).
Return to the Market in Canada and Europe
A laboratory was authorized to sell a product containing doxylamine and pyridoxine under the name of Diclectin. To reduce the remaining suspicions held by obstetricians, it was specified in the product labeling that the therapeutic category for which this combination was approved was “anti-nausea agent for the nausea and vomiting of pregnancy.” A group of Canadian experts published a statement on August 11, 1989, affirming that this fixed association was safe. The British authorities had also expressed the same opinion. The Canadian government had thus maintained a marketing authorization for this product for a Canadian manufacturer (CSM/MCA, Curr Problems Pharmacovigilance 1981;6; Lancet 1984;2:205; Medico-Legal Committee Opinion, J Soc Obstet Gynaecol Can 1995;17:162; Koren, Can J Clin Pharmacol 1995;2:38). An epidemiologic study in 2003 compared the rate of birth defects in the United States in the years 1970 to 1992 and found no change in the rate of birth defects after the cessation of Bendectin in the 1980–1984 period (Bendectin and birth defects II: Ecological analyses, Kutcher JS, Engle A, Firth J, Lamm SH, Birth Defects Res A: Clin Mol Teratol 67[2]:88–97).
There is an enormous literature on Bendectin, and it is maintained by some workers that this is the most-studied drug in pregnancy ever. There are several books and hundreds of references available.
Adriamycin
Examples of drugs producing late AEs include Adriamycin (doxorubicin HCl), which may produce cardiac problems years after therapy has ended.
Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure may occur either during therapy or months to years after termination of therapy. The probability of developing impaired myocardial function based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of doxorubicin, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at 450 mg/m2 and 6 to 20% at 500 mg/m2.* The risk of developing congestive heart failure (CHF) increases rapidly with increasing total cumulative doses of doxorubicin in excess of 450 mg/m2. This toxicity may occur at lower cumulative doses in patients with prior mediastinal irradiation or on concurrent cyclophosphamide therapy or with pre-existing heart disease (Package Insert for Adriamycin, Pharmacia, 2005).
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