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U.S. Department of Health and Human Services

Drugs

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Science Background - Safety of Phenylpropanolamine

November 6, 2000

This summary is to provide additional information to health care professionals in conjunction with the Food and Drug Administration (FDA) public health advisory concerning the risk of hemorrhagic stroke associated with phenylpropanolamine hydrochloride. FDA is taking steps to remove phenylpropanolamine from all drug products and has requested that all drug companies discontinue marketing products containing phenylpropanolamine.

HISTORY

Phenylpropanolamine has been marketed for many years. During the early 1970's, FDA initiated a scientific review of OTC drug products to determine the safety and effectiveness of products marketed in the United States. That review included phenylpropanolamine. In 1976, one expert panel recommended that phenylpropanolamine be generally recognized as safe and effective as a nasal decongestant, and in 1982 another expert panel recommended that phenylpropanolamine be generally recognized as safe and effective for weight control. FDA did not finalize a safe and effective status for phenylpropanolamine because of concerns about occasional reports of hemorrhagic stroke associated with using this drug.

STUDY

Because of continued reports of hemorrhagic stroke potentially associated with phenylpronalamine, FDA asked the pharmaceutical industry to conduct a study that evaluated the risk of hemorrhagic stroke from taking phenylpropanolamine. The drug was allowed to be marketed while this study was being done based on the previous recommendations of the expert panels. The results of that study (entitled "Phenylpropanolamine & Risk of Hemorrhagic Stroke: Final Report of the Hemorrhagic Stroke Project") were provided to FDA earlier this year. (http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3647b1_tab19.doc)

The study was a case-control study of men and women 18 to 49 years old who were hospitalized with a subarachnoid or intracerebral hemorrhage. Case subjects selected had no prior history of stroke and were able to participate in an interview within 30 days of their event. For each case subject, two control subjects (no stroke) were identified (matched based on age, gender, and race).

The final study comprised 702 case subjects and 1,376 control subjects. Age matching occurred for 1,367 controls (99%) and ethnicity matching occurred for 1,321 controls (96%). Subjects were classified as exposed to phenylpropanolamine if they reported use of this drug within 3 days of the stroke event for case subjects, or a corresponding date for control subjects. Reported exposures were verified by the study investigators.

The study reported an association between phenylpropanolamine use and hemorrhagic stroke in women. The increase in risk of hemorrhagic stroke was found for women using

phenylpropanolamine for weight control in the 3 days after starting use of the drug and for women using phenylpropanolamine as a nasal decongestant product in the first day of use. Although the study showed that the risk of hemorrhagic stroke was found mostly in women, men may also be at risk.

DISCUSSION

On October 19, 2000, FDA’s Nonprescription Drugs Advisory Committee (NDAC) discussed this report and other information on phenylpropanolamine. NDAC determined that there is an association between phenylpropanolamine and hemorrhagic stroke and recommended that phenylpropanolamine not be considered generally recognized as safe for OTC use as a nasal decongestant or for weight control.

FDA has reviewed the report and believes there is an association between phenylpropanolamine use and hemorrhagic stroke. Although this risk of hemorrhagic stroke is very low, FDA has significant concerns because of the seriousness of this adverse event (the irreversible outcome) and the inability to predict who is at risk. FDA does not consider the conditions for which phenylpropanolamine is used as justifying the risk of this serious event. FDA agrees with NDAC’s recommendation that phenylpropanolamine not be considered generally recognized as safe for use in OTC drug products. FDA also has concerns about the safe use of phenylpropanolamine in prescription drug products. Alternate nasal decongestants which do not contain phenylpropanolamine are available both OTC and by prescription.

OUTCOME

FDA plans to act to remove phenylpropanolamine as an ingredient in OTC and prescription drug products. FDA has notified all manufacturers, repackers, and distributors of any prescription or OTC drug product containing phenylpropanolamine of this new information and requested that they discontinue marketing drug products containing phenylpropanolamine. If applicable, products may be reformulated without phenylpropanolamine.