Neonatal toxicity and withdrawal: FDA considers SSRI label change

OB/GYN News, July 1, 2004 by Elizabeth Mechcatie

ROCKVILLE, MD. -- A Food and Drug Administration advisory panel supported the addition of information to the professional label and patient package insert of serotonin reuptake inhibitors concerning neonatal withdrawal syndrome and toxicity reports in newborns exposed to the drugs during the third trimester.

At a meeting of the FDA's Pediatric Subcommittee Panel last month. the panel agreed that the class labeling changes for the selective serotonin reuptake inhibitors (SSRIs) and for venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI), were reasonable. The changes, which had been proposed by the FDA, have already been added to the labels of several such agents; others have agreed to or are considering the changes.

The panel also agreed that enhancing the existing patient information leaflet--or including this information in an insert if the drug package has none--would be helpful for pregnant women taking these medications, and could help counteract the less well-balanced risk-benefit information that can be found by searching the Internet.

At the meeting--held to discuss reports of neonatal withdrawal after in utero exposure to a serotonin reuptake inhibitor (SRI), and other issues related to pediatric adverse events reports associated with certain drugs--the panelagreed that there should be further education of physicians about the information added in the label, through medical societies or some other venue.

Panel members did not support the idea of a "Dear Health Care Professional" letter, issued by pharmaceutical companies, or a public health advisory, issued by the FDA. The panel didn't make any formal votes.

A consultant to the panel, Dr. Katherine Wisner, professor of psychiatry, ob.gyn., and reproductive sciences and epidemiology at the University of Pittsburgh, said the point of adding this information is to help patients recognize that there are adverse effects that newborns may develop when these drugs are taken in the third trimester, which needs to be considered in the context of a risk-benefit decision.

The class labeling change includes the statement that neonates who have been exposed to an SRI, which includes both SSRIs and the SNRI venlafaxine, late in the third trimester have developed adverse events that have required prolonged hospitalization, respiratory support, and tube feeding. A list of symptoms includes respiratory distress, cyanosis, apnea, feeding difficulties, vomiting, hypoglycemia, tremors, jitteriness, irritability, and constant crying, which the label says are "consistent with SSRI/SNRI discontinuation symptoms or direct toxic effects of the drug," said Dr. Robert Levin, who is a reviewer in the FDA's division of neuropharmacologic drug products.

The dosage section includes the statement that the potential risks and benefits should be "carefully" considered when treating a woman with these drugs during the third trimester, which Dr. Levin acknowledged "may be controversial," and that physicians "may consider tapering" the drug late in the third trimester.

The change reflects reports of neonatal adverse events associated with all drugs in this class, which are "analogous" to symptoms of discontinuation and toxicity that have been described in adults, Dr. Levin explained. He acknowledged the difficulties in interpreting adverse events in newborns. which can be confounded by factors such as maternal psychiatric illnesses, and the unknown background rate of these adverse events. "Despite the uncertainties, we feel there's enough to put in the label," making clear that these symptoms are associated only with third-trimester exposure, he said.

To date, the changes have been made to the labels for paroxetine (Paxil, Paxil CR). citalopram (Celexa), fluvoxamine (Luvox), and venlafaxine and venlafaxine ER (Effexor). Eli Lilly & Co., the manufacturer of fluoxetine (Prozac), has agreed to include the changes in its label, and Pfizer Inc., the manufacturer of sertraline (Zoloft), is currently discussing this with the FDA, according to Dr. Levin.

Supporting the existence of a withdrawal syndrome in newborns exposed to SRIs late in pregnancy are reports to the FDA's Adverse Event Reporting System (AERS). Katherine Phelan, a safety evaluator in the FDA's office of drug safety, told the panel. Health care professionals need to be made aware that possible cases of neonatal withdrawal have been reported for all approved SRIs, "suggesting a class effect," she said.

A search of the 2001 AERS reports identified 57 cases of possible neonatal withdrawal syndrome that met the FDA's case definition: maternal SRI use up to the time of delivery; symptoms that could not be attributed to another cause, with an onset hours to days after delivery, which resolved in days or weeks; or a case that was reported specifically as SRI withdrawal. Symptoms began in a median of hours up to 2 days.

CNS symptoms that were reported included irritability and agitation, the two symptoms that also describe the discontinuation syndrome seen in adults, Dr. Phelan said. Other symptoms reported were crying, neuromuscular symptoms such as hypertonia, and seizures, as well as GI/autonomic symptoms such as trouble feeding, vomiting, tachypnea, and trouble breathing. The FDA has gotten reports since 2001, but they have not been analyzed yet, she said.