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European countries. The finasteride example illustrates how functional relatedness can signal concern, as discussed below.

Initial Review: Considering the Nature of the Evidence

The cardiac events reported to FDA were placed in perspective by reviewing whether a pattern of cardiac events existed in clinical trials or published case reports. There was no consistent pattern of serious adverse events reported, and they were largely nonserious or their relevance to saw palmetto was unconvincing. The concern level from the original signal was thus lower and would be unlikely to prompt an integrative evaluation according to the Framework process.

If saw palmetto’s drug status and possible mechanistic similarity to the regulated drug finasteride was the original signal, the initial review may have prompted an integrative evaluation. Investigation of this signal would have revealed in vitro evidence and animal evidence suggesting antiandrogenic effects, such as 5-α-reductase inhibition. Male human reproductive developmental anomalies are a feature of the congenital deficiency of 5-α-reductase, and the prescription 5-α-reductase inhibitor, finasteride, has been found to cause similar anomalies in male rats. Consequently, labeling of finasteride notes that it is contraindicated in women and children. In summary, the information about saw palmetto’s similarity to finasteride and similar drugs should raise concern, consistent with the following guiding principle (see “Constituents Functionally Related to Known Classes of Toxic Compounds” in Chapter 6): “When data (i.e., in vitro or animal data) suggest that a dietary supplement constituent targets a receptor, enzyme, or other biological target in a manner similar to a compound known to be toxic, concern is warranted, especially if the dietary supplement constituent is known to reach the biological target in a relevant concentration.”

Finally, the high prevalence of saw palmetto use is a modifying factor, suggesting an evaluation of the safety of this dietary supplement ingredient might be of value even if initial review did not result in higher concern if resources are available for such a proactive integrative evaluation. Benign prostatic hyperplasia is a very common condition among older men, and the prevalence of saw palmetto use among individuals with this disease is relatively high, suggesting that if saw palmetto were unsafe, the public health impact might be substantial. On the other hand, available evidence does not suggest this dietary supplement ingredient is frequently used in women or male children, the individuals to which the concerns apply.



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