# Presentation: 493985

## Neonatal withdrawal syndrome with Serotonin Reuptake InhibitorsOffice of Drug Safety Review

- Kathleen Phelan, R.Ph., Safety Evaluator
- Division of Drug Risk Evaluation
- Office of Drug Safety

- Pediatric AC 6/9/04

## Outline

- FDA Adverse Event Reporting system (AERS)
- Contents
- Limitations
- Value
- Office of Drug Safety adverse event reviews
- Review of neonatal withdrawal syndrome after *in utero* exposure to serotonin reuptake inhibitors (SRIs)
- Conclusions

- Pediatric AC 6/9/04

## Adverse Event Reporting System (AERS)

- Contains > 3 million reports of suspected adverse drug and biological product events
- Sources include healthcare professionals, consumers, medical literature, postmarketing clinical studies
- No reporting requirements for healthcare professionals
- Reporting requirements for manufacturers vary with event severity and expectedness
- Expectedness is determined by drug labeling

- Pediatric AC 6/9/04

## AERS data limitations

- Voluntary; therefore, underreporting
- Estimated or no denominators available – usage during pregnancy is not available
- Cannot accurately determine incidence rate
- Information is often incomplete
- Reporting biases differ between drugs
- Cannot confirm that a drug caused an adverse event or that drugs differ in relatedness to an adverse event

- Pediatric AC 6/9/04

## Value of AERS data

- Discovery of previously unknown adverse drug events
- Adverse events too rare to be seen in trials
- Adverse events in population not exposed to drug in trials (pregnant women)
- Greater severity than adverse events seen in trials
- Triggers further investigation – call for follow-up, review available data, request study

- Pediatric AC 6/9/04

## Office of Drug Safety Reviews

- Monitor adverse event reports as they are entered into AERS database
- For selected cases, contact reporters for additional information
- Search AERS and medical literature
- Evaluate reports and develop case series
- Office of Drug Safety reports findings to new drug review divisions and recommends action

- Pediatric AC 6/9/04

## AERS reports of neonatal withdrawal with Serotonin Reuptake Inhibitors

- SRIs  citalopram (Celexa), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), venlafaxine (Effexor)
- SRI discontinuation syndrome known adverse event in adults
- Review of reports with MedDRA code “drug withdrawal neonatal” suggested neurological, neuromuscular, autonomic events
- AERS search broadened

- Pediatric AC 6/9/04

## AERS search strategies

- Either MedDRA High Level Group Term: “neonatal neurological system disorders” OR Preferred Term: “drug withdrawal syndrome neonatal”
- A large group of MedDRA terms encompassing various neurological, neuromuscular, and autonomic system adverse events AND age 0 to 3 months
- Both MedDRA Preferred Terms: “complications of maternal exposure to therapeutic drugs” AND “drug withdrawal syndrome”

- Pediatric AC 6/9/04

## Neonatal withdrawal syndrome case definition applied1

- EITHER all four of the following:
- Maternal SRI use at birth
- Not attributable to other cause
- Onset hours to days after birth
- Resolved in days to weeks
- OR
- Reported as SRI withdrawal
- 1Schatzberg AF, et al. Serotonin reuptake inhibitor discontinuation syndrome:  A hypothetical definition.  J Clin Psychiatry 1997;58[suppl 7]5-10.

- Pediatric AC 6/9/04

## AERS case counts

| Drug (t1⁄2 hours) | 2001 | Met definition | 2001-4  |
| --- | --- | --- | --- |
| Venlafaxine (5-11) | 22  | 3 | 35 |
| Fluvoxamine (15) | 9 | 2 | 9 |
| Paroxetine (21) | 78 | 35 | 141 |
| Sertraline (26) | 33 | 8 | 12 |
| Citalopram (35) | 12 | 5 | 18 |
| Fluoxetine (4-16 days) | 56 | 4 | 22 |

## Excluded cases:  fluoxetine (N=52)

- 12 exposure to other drugs assoc with withdrawal
- 10 adverse event present at birth
- 8 timing of adverse event vs. birth unclear
- 8 adverse event not consistent with withdrawal
- 6 fluoxetine discontinued early in pregnancy
- 3 adverse event persisting months after birth
- 2 adverse event occurred *in utero*
- 1 adverse event after discontinue breastfeeding
- 1 timing of fluoxetine use unclear
- 1 admin of fluoxetine not relieve symptoms

- Pediatric AC 6/9/04

## Maternal information

- 56 mothers, 1 twin pregnancy, 57 neonates
- Ages unknown in large majority of cases
- Diagnoses for SRI use: unknown (28), depression (21), schizophrenia (3), anxiety (2)
- SRI dosage within labeled recommendations except for venlafaxine 450 mg/day (1)
- Confounders:  alcohol occasional (4), cigarettes (7), marijuana (2)

- Pediatric AC 6/9/04

## Neonate information (N=57)

- Gestation ≥ 37 wks (30), < 37 wks (5)
- Gender:  male (25), female (17)
- Birth weight:  range 860 grams – 4.23 kg,
- 	mean 3.04 kg, median 3.12 kg (28)
- Apgar scores:
- 	1 minute range 1-9, mean 7.4, median 8 (20)
- 	5 minute range 6-10, mean 8.6, median 9 (19)
- 	10 minute range 6-10, mean 9, median 9 (9)

- Pediatric AC 6/9/04

## Adverse event information (N=57)

| Drug | T1/2 hours | Median time to onset (N) | Median duration (N) |
| --- | --- | --- | --- |
| Venlafaxine | 5-11 | 10 hours (1) | 2 days (1) |
| Fluvoxamine | 15 | hours-2 days (2) | 5 days (1) |
| Paroxetine | 21 | 18 hours (19) | 1.5-2 wks (17) |
| Sertraline | 26 | 21 hours (6) | 1 day (7) |
| Citalopram | 35 | 12 hours (5) | 7 days (5) |
| Fluoxetine | 4-16 days | 1.5 days (4) | 1 week (3) |

## Reported signs of SRI neonatal withdrawal not mutually exclusive (N)

| CNS | Neuromuscular  | GI/autonomic |
| --- | --- | --- |
| irritability (20) | hypertonia (17) | trouble feed (13) |
| jitteriness (14) | tremor (13) | vomiting (4) |
| agitation (8) | seizures (8) | tachypnea (7) |
| crying (5) | posturing (6) | trouble breathe (5) |
| screaming (4) | hypotonia (4) | resp distress (3) |
| high-pitch cry (3) | jerkiness (3) | hypothermia (3) |
| EEG abnorm (2) | hyperreflexia (3) | shivering (3) |

## Labeled signs and symptoms of discontinuation in adults

-  dysphoric mood, *irritability*, *agitation*, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania.

- Pediatric AC 6/9/04

## Treatments and outcomes (N=57)

- Treatments [*not mutually exclusive*]
- Hospitalization (37)
- Phenobarbital (9) or benzodiazepine (2)
- Oxygen/ventilation (5)
- Antibiotic (3)
- Tube feeding (4)
- Intravenous fluids (3)
- Outcomes:  resolved (31), improved (12), ongoing (3), unknown (11)

- Pediatric AC 6/9/04

## Conclusions

- AERS data support the existence of a withdrawal syndrome in neonates exposed to SRI medications *in utero* at the end of pregnancy.
- Reports of cases possibly related to drug have been received for citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine, suggesting a class effect.

- Pediatric AC 6/9/04

## Conclusions

- Excitatory nervous and neuromuscular events are the most frequently reported signs of neonatal SRI withdrawal.
- Breathing and feeding difficulties have required supportive care.
- Healthcare providers should be made aware that adverse events may be seen in neonates exposed to SRI medications just prior to birth.

- Pediatric AC 6/9/04

## Neonatal withdrawal syndrome with Serotonin Reuptake InhibitorsOffice of Drug Safety Review

- Kathleen Phelan, R.Ph., Safety Evaluator
- Division of Drug Risk Evaluation
- Office of Drug Safety

- Pediatric AC 6/9/04