Antidepressant pregnancy exposure risks should be communicated in patient labeling, FDA's Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee recommended June 9.

"We've all been talking about giving the information out to the doctors, and that's important, but you also have to give it to the mother. The mothers have to have this information given to them," subcommittee member Judith O'Fallon, PhD, Mayo Clinic, said.

The subcommittee said that the potential risks of prenatal exposure to selective serotonin and norepinephrine reuptake inhibitors should be communicated to patients even though a conclusive link to toxicity has not be determined. [To ¹ watch a webcast of this meeting, go to FDAAdvisoryCommittee.com.]

FDA has received reports of neurological, neuromuscular and autonomic effects in newborns whose mothers were taking SSRI/SNRIs such as Prozac , Paxil , Celexa , Effexor , Zoloft and Luvox .

FDA's search of its adverse events reporting system found 210 reports of neonatal withdrawal in 2001. However, only 57 of the cases met the definition of neonatal withdrawal syndrome as applied by FDA.

The definition required either a physician diagnosis of withdrawal or all four of the following: maternal antidepressant use at birth; non-attribution to other causes; onset in hours to days after birth; and resolution of withdrawal in days to weeks.

Neonatal SSRI/SNRI withdrawal is distinguished from toxicity by onset of symptoms. Withdrawal usually manifests in 10 to 36 hours while toxicity onset is immediate to within several hours.

Drug Risk Evaluation Division Safety Evaluator Katherine Phelan said that 37 "cases were excluded because the adverse event was present at birth. This contributed to the new drug review division decision not to distinguish withdrawal from toxicity."

FDA has created proposed class labeling for SSRI/SNRI prenatal exposure that to be added to the pregnancy precautions section.

The proposed precaution states: "Neonates exposed to SSRI/SNRI late in 3rd trimester have developed AE requiring prolonged hospitalization, respiratory support, tube feeding. AE may arise immediately upon delivery."

Adverse events that have been reported include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.

The proposed dosage and administration section advises physicians to taper treatment late in the 3rd trimester.

"There's some suggestion that when treating a woman with SSRI/SNRI one might decrease the risk of both SSRI withdrawal and toxicity by carefully tapering the drug roughly 10 to 14 days before the expected due date, and in the case of fluoxetine perhaps abruptly discontinuing the drug," Neuropharmacological Drug Products Division Medical Reviewer Robert Levin, MD, said.

The suggestion to taper the dose was not unanimously supported by the subcommittee. "I still have reservations about" tapering the dosage. "I think that's a leap of faith that we don't have information about," subcommittee member Richard Gorman, MD, Pediatric Partners (Ellicott City, Md.) said.

Levin noted that the tapering recommendation "may be a bit controversial" because it was not based on controlled studied.

Subcommittee member Katherine Wisner, MD, Western Psychiatric Institute & Clinic (Pittsburg) also cautioned about grouping serotonin withdrawal and toxicity together. "We really have to understand how to diagnose this because the treatments are exactly opposite," she said.

The class labeling changes have been incorporated into the labels for Paxil, Effexor, Celexa and Luvox. Lilly has verbally accepted the class labeling for Prozac. Pfizer is currently in discussions with FDA about incorporating the changes into Zoloft's label.

"Probably each company did request making modifications to it," but "in the end they accepted the verbatim language that we proposed," Levin said.

The subcommittee recommended against the issuance of a public health advisory by FDA for fear that it would unduly scare patients away from depression therapy based on inconclusive information.

"I just worry about the meta-message. When this organization says something, it can pack a big wallop and that meta-message may lead to more negative outcomes then we hope," Wisner said.

The committee also felt that a public health advisory was inappropriate because of the lack of definitive information or recommendations for specific action.

"This doesn't sound like there's enough concrete information to where sending that out wouldn't send up an alarm and everybody would go, 'What do I do about it?' And the answer is, 'We don't know," which would strike me as crying wolf, subcommittee member Robert Nelson, MD, University of Pennsylvania, said.

The subcommittee supported physician education on potential risks to newborns from SSRI/SNRIs but recommended against the issuance of a "Dear Doctor" letter due to the intricacies of the risk/benefit equation.

Although most committee members felt that prenatal exposure probably does not create long-term negative effects on a baby, a study presented by Philip Zeskind, PhD, University of North Carolina, suggested that babies born to women taking SSRIs during pregnancy may have longer term neurobehavioral disturbances.

Further studies are needed in this area, the subcommittee said, beginning with an update of more recent AERS data. FDA has raw AERS data showing 237 reports of neonatal withdrawal between the end of 2001 and the beginning of 2004. "At the very least an update of the 2004 data - cleaned - would probably make sense," Nelson said.

"Population-based prospective studies" are "absolutely important and essential through whatever mechanism," subcommittee chair Patricia Chesney, MD, University of Tennessee College of Medicine, said. Randomized placebo controlled clinical trials were not recommended.

A National Institute of Mental Health study is underway to compare pregnant women who taper antidepressant dose, those who continue on full doses through term, those who are depressed but not on drugs and normal controls.

The study will collect maternal serum/cord blood drug levels, and cry analysis, neurological exams and modified Finnegan Scale at birth and week two.

SSRI Pregnancy Exposure Risks Should Be Communicated To Patient – Cmte.

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