Testosterone Gels Receive Boxed Warnings and REMS

By William T. Koustas & Carrie S. Martin –

On May 7, 2009, FDA announced that it is requiring both approved testosterone gel products to include boxed warnings on their labels and to implement a REMS.  The two products are indicated for testosterone replacement therapy in men that either have a deficiency or absence of endogenous testosterone.  The products may be applied to the patient’s skin, including upper arms, shoulders, or abdomen.  The current product labels instruct users to wash their hands after using the products as well as covering the treated areas.  

According to the FDA’s announcement, as of December 1, 2008, FDA was aware of eight cases of children developing serious side effects after inadvertent exposure to these products and has since received additional reports of secondary exposure.  The children exposed range in age from nine months to five years.  Children in these cases experienced “inappropriate enlargement of the genitalia, premature development of pubic hair, advanced bone age, increased libido and aggressive behavior.”  In most cases, the symptoms subsided when the children were no longer exposed to the products, but some children did not completely recover and required invasive diagnostic procedures. One child was hospitalized after a delay in recognizing that exposure to testosterone gel was the likely cause of the symptoms.

In response, FDA has used its powers under sections 505(o)(4) and 505-1 of the Food, Drug, and Cosmetic Act (“FDC Act”) to mandate several labeling changes, including a boxed warning, and a REMS in the form of a medication guide.  FDA letters to the manufacturers of the testosterone gels note that they consider adverse event reports and peer-reviewed biomedical literature of children inadvertently affected by the drugs to be “new safety information” under the Food and Drug Administration Amendments Act (“FDAAA”), thus providing the basis necessary for the Agency to require these changes.  The focus of the labeling changes is a boxed warning that highlights the risks of virilization in children and women exposed to the products, warns that children and women should avoid contact with the areas on men using the products and a warning that patients should adhere to the instructions for use that come with the products.  FDA is also requiring testosterone gel manufacturers to submit a proposed REMS consisting of a medication guide in an attempt to mitigate risk of secondary exposure to women and children.

It is interesting to note, however, that the medication guide is intended to mitigate a risk that is not a risk to the patient using testosterone gels, but a risk to other persons not intended to use the product.  Under section 505-1 of the FDC Act, FDA can require a REMS post-approval if the Agency becomes aware of new safety information and determines that the REMS is necessary to ensure that the benefits of the drug outweigh its risks.  Although this language does not explicitly prohibit a REMS that is designed to protect a third-party, one might argue that the law intended that the benefits of the drug outweigh its risks to the patient.  Setting aside REMS for teratogens where the risk is to the fetus, this is the first product to receive a REMS exclusively for a non-patient related risk.  The proposed class-wide opioid REMS also includes measures to protect non-patients from certain risks, but it includes measures to protect patients as well.