Inactive pharmaceutical ingredients : implications for pregnancy.

dministration of pharmaceutical agents to pregnant women is a concern, because of safety issues to both mother and fetus. However, all medication formulations contain many other inactive ingredients in addition to the active drug. In contrast to the extensive research on the safety of active pharmaceutical ingredients in pregnant patients, the fetal safety of the inactive ingredients has been largely ignored. This is likely due to the fact that the inactive ingredients are considered to be in “small amounts” and are believed to be “inert”. However, this is often not the case. Most pharmaceutical preparations will typically contain 5 to 10 times more inactive ingredients in terms of weight versus the actual active ingredients. Therefore, most tablets, for example, are mainly made up of inactive ingredients. It is common for a medicine to have a dozen or so inactive ingredients within its formulation acting as lubricants, fillers, binders, disintegrating agents, stabilizers or silica flow conditioners. Also, there are numerous oral liquid or syrup drugs that contain 15-20% of ethanol, the most widespread human teratogen. For instance, a patient taking 2 teaspoons of Choledyl elixir 4 times daily will absorb 8g of alcohol. This is equal to the amount of ethanol in one bottle of beer. The Kaletra (oral solution of lopinavir /ritonavir) contains a surprising 42.4% of ethanol (Table 1). As this review highlights, many chemicals that are commonly used as inactive ingredients in drugs have adverse effects on reproductions. These inactive ingredients have been described in variety of models, and most often the NoObserved-Adverse-Effect-Level (NOAEL) in humans has not yet been established. Given these examples, a manufacturer should employ a great deal of prudence while formulating drugs that contain ethanol or other unstudied alcohols destined to be consumed by pregnant women. Hence, it seems logical that rather than risking fetal safety, the use of such compounds as inactive ingredients should be restricted or banned. We propose that to study the safety of medications in pregnancy, one should apply the principles of teratology not only to the active ingredients, but also to the ingredients termed in-active. The basic principles of evaluating teratogenic potential have been articulated by scores of different authors and include the following: 1. Biological plausibility for teratogenic potential, including mechanism of action, periods of greatest sensitivity, and genetic susceptibility. 2. Analysis of dose-response relationships and pharmacokinetics in an animal model and in humans. 3. Analysis and interpretation of human epidemiologic studies. 4. The examination of the relationship between the secular trend of birth defects and the population exposure to drugs.