Deaths In Children Using Promethazine (PHENERGAN) Increase; FDA Issues a Safety Alert and a Stronger Black Box Warning

The Food and Drug Administration (FDA) issued a safety alert on April 25, warning that more deaths from decreased rate or depth of breathing (respiratory depression) had been reported in children given products containing promethazine (PHENERGAN) and that the warnings in the drug’s professional product labeling had been strengthened.

Promethazine is widely used in children as an antihistamine, an antinausea drug and as a sedative. The drug is available in many forms, including syrups, suppositories, tablets and injectables, and the warning applies to all forms of the drug.  

Since 1969, when the FDA first started to keep track of adverse drug reaction cases, the agency has received reports of serious adverse events linked to this drug, including seven deaths and 22 cases of respiratory depression in children younger than 2 years of age.

The major points in the FDA safety alert are:

All products containing promethazine HCl — syrups, suppositories, injectables and tablets — should not be prescribed for patients younger than 2 years of age because of the potential for fatal respiratory depression.

Caution should also be exercised when administering promethazine HCl medications to patients from two years of age until 16 years of age. The full text of the safety alert can be found on the FDA's web site.

Promethazine is a very old drug that was first approved for use in the United States in 1951. It belongs to the family of drugs known as phenothiazines, which include the antipsychotic products chlorpromazine (THORAZINE), trifluoperazine (STELAZINE) and a number of others.

Since promethazine’s approval, serious and often life-threatening problems, including respiratory depression, oversedation, agitation, hallucinations, seizures and impairment of muscle movement have been reported with the drug’s use in children.

The drug’s labeling was revised in January 2005 to include a black box warning about cases of respiratory depression and deaths (see Worst Pills, Best Pills News, April 2005).

A black box warning is the strongest type of risk information that the FDA can request from a manufacturer for a drug’s professional product labeling. It is usually reserved for those products that are known to cause death or serious injury. Unfortunately, black box warnings alone are not very effective in changing a physician’s prescribing habits and thus protecting patients from preventable harm. There is no requirement that a physician tell a patient about the existence of a black box warning or that pharmacists give patients the FDA-approved labeling for a drug with a black box warning at the time of dispensing.

In the April 2005 edition of Worst Pills, Best Pills News, we wrote about the absurdity of the FDA in requiring a black box warning in a drug’s professional labeling that is, in general, only seen by pharmacists and physicians — neither of whom is at risk of harm from promethazine. Only the patient or the patient’s child faces the possibility of severe, sometimes fatal, adverse reactions from promethazine, but this group is left in the dark because a drug’s professional label is not routinely distributed to consumers at the time a prescription is dispensed.

The FDA has had the regulatory authority since 1998 to require that pharmacies distribute written drug-risk information with each new and refill prescription for drugs that present significant public health hazards, such as promethazine. The written information is known as a medication guide, which is an FDA-approved patient label containing pertinent information for the patients’ understanding of how to safely use a medicinal product.

At this time, there are at least 75 drugs that require a medication guide but promethazine is not one of them. The FDA should have required that a medication guide be distributed with each new and refill prescription for promethazine because the drug clearly presents serious public health concerns. It is irresponsible of the FDA not to require a medication guide for promethazine to inform consumers and the parents of patients about the risks of this drug.  

A word of caution: most prescription drug consumers now receive written drug information at the pharmacy that is written by commercial information vendors. In two large surveys, the information produced by commercial vendors failed to meet minimum voluntary content quality guidelines.

In other words, the commercially produced information distributed by pharmacies is not reliable, and unreliable drug information is potentially harmful.

What You Can Do

You should not administer promethazine products to children two years of age or younger, and it is advisable that the drug should not be given to children less than 16 years of age.