# Presentation: 487369

## Neonatal Adverse Events Associated with in utero SSRI/SNRI Exposure

- Robert Levin, M.D.
- Medical Reviewer
- DNDP
- FDA

## Slide 2

## SSRIs and SNRI

- Selective Serotonin Reuptake Inhibitors:
- fluoxetine, sertraline, paroxetine, paroxetine CR, fluvoxamine, citalopram
- Serotonin Norepinephrine Reuptake Inhibitor:
-    venlafaxine, venlafaxine ER

## Objectives

- 1. Highlight language in SSRI/SNRI class
-     labeling
- a) PRECAUTIONS- Pregnancy non-teratogenic
-      section
-     b) DOSAGE and ADMINISTRATION section
- 2. Provide rationale for proposing class labeling

## Sources of Information re: SSRI/SNRI & Neonatal AE

- Postmarketing reports (AERS)
- Retrospective studies
- Prospective studies
- Medical literature

## PRECAUTIONS- Pregnancy             non-teratogenic

- 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
- Respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying

## Precautions- Pregnancy (continued)

- AE reported are consistent with SSRI/SNRI discontinuation symptoms or direct toxic effects of the drug
- In some cases, neonatal adverse events are consistent with serotonin syndrome                   (see WARNINGS)

## Dosage and Administration

- When treating a pregnant woman with SSRI/SNRI during 3rd trimester, carefully consider potential risks and benefits
- Physician may consider tapering SSRI/SNRI     late in the 3rd trimester

## Terms Used for Neonatal SSRI/SNRI Syndromes

- - SRI Withdrawal
- - SRI Toxicity
- - Poor  Neonatal Adaptation
- - Serotonergic Excess
- - Serotonergic CNS Adverse Effects
- - Serotonin Syndrome

## SSRI/SNRI Discontinuation Symptoms in Adults1 

- Dysequilibrium: dizziness, vertigo, ataxia
- GI: nausea, vomiting
- Flu-like: fatigue, lethargy, myalgia, chills
- Sensory disturbance: paresthesia, electric shock sensation
- Sleep disturbance: insomnia, vivid disturbing dreams
- Neuropsychiatric symptoms
- 1Schatzberg AF, et al. Serotonin reuptake inhibitor discontinuation syndrome:  A hypothetical definition.  J Clin Psychiatry 1997; 58 [suppl 7] 5-10.

## Neuropsychiatric SSRI/SNRI Discontinuation Symptoms in Adults

- Anxiety, agitation, irritability, crying spells, hypomania, depressed mood, confusion, impaired memory, impaired concentration, slowed thinking, tremor
- Some AE may resemble symptoms of the patient’s illness
- Other neuropsychiatric symptoms may be new for the patient

## SSRI/SNRI Toxicity in Adults 

- CNS & Neuromuscular:
- Irritability, jitteriness, tremor, restlessness, anxiety, agitation, insomnia, dystonia, dyskinesia
- GI: nausea, vomiting, diarrhea
- Mason PJ, et al.  Serotonin Syndrome. Presentation of 2 cases and review of the literature. Medicine 2000 Jul, 79(4): 201-9

## Serotonin Syndrome in Adults 

- CNS: convulsions, disorientation, cognitive impairment
- Neuromuscular: hypertonia, rigidity, myoclonus, hyperreflexia, paresthesia
- Autonomic Instability & Temperature Instability:
- Respiratory distress, tachypnea, hyperthermia, temperature instability, rigors, chills, diaphoresis, tachycardia
- Mason PJ, et al.  Serotonin Syndrome. Presentation of 2 cases and review of the literature. Medicine 2000 Jul, 79(4): 201-9

## Similarities Between Neonatal AE & Adult Discontinuation Symptoms

- Neonatal “Withdrawal”
- Irritability, jitteriness, agitation, insomnia, poor feeding, crying
- AE onset: 10 to 36 hours
- Resolution: 1 to 14 days

- Adult Withdrawal
- Irritability, anxiety, agitation, insomnia, anorexia, GI distress
- AE onset: 24 to 72 hours
- Resolution: 1 to 14 days

## Similarities Between Neonatal AE & Toxicity in Adults

- Neonatal “Toxicity”
- Jitteriness, insomnia, hypertonia, myoclonus, hyperreflexia, convulsions, temperature dysregulation, autonomic instability, tachypnea
- Onset: immediate to several hours
- Resolution: hours to weeks
- May have high serum SSRI/SNRI levels

- Adult Toxicity
- Jitteriness, insomnia, hypertonia, myoclonus, hyperreflexia, akathisia, convulsions, temperature dysregulation, autonomic instability, tachypnea, cognitive symptoms
- Onset: highly variable
- Resolution: hours to several days
- May have high serum SSRI/SNRI levels

## Exposure to SSRI During Pregnancy- Serotonergic Symptoms in Newborns

- Prospective, non-randomized, controlled study; N=40
- Pregnant women with Depression or Panic vs. controls
- Fluoxetine or citalopram (20-40 mg) through delivery
- Outcome Measures: AE, maternal and neonatal SSRI & metabolite levels, monoamine levels, vital signs
- Specific AE Assessment of 7 serotonergic symptoms:
- myoclonus, tremor, rigidity, hyperreflexia, shivering, restlessness, incoordination
- Laine K et al. Arch Gen Psychiatry 2003 Jul Vol 60: 720-6

## Findings of Laine Study

- SSRI group: 4-fold increase in serotonergic symptom score during Days 1-4
- Tremor, restlessness, rigidity
- Mean neonatal SSRI serum levels were in the usual adult range
- Symptom resolution correlated with decreasing serum   SSRI level
- SSRI group had lower cord 5-HIAA concentration, indicating increased CNS serotonin activity
- Serotonergic symptom score correlated inversely with      5-HIAA concentration

## Slide 18

## Difficulty in Interpreting Neonatal AE

- Confounded by psychiatric & other medical illnesses, obstetric factors, concomitant medications, etc.
- Background rates of AE unknown
- SSRI/SNRI use in pregnant women unknown
- Limited data from cases (maternal & gestational age,  timing of AE onset & resolution, serum drug levels, duration & doses of SSRI/SNRI Rx, etc).
- Limited repertoire of neonatal behaviors
- Overlap of SSRI/SNRI WD & Toxicity symptoms

## Rationale for Proposing Class Labeling

- Neonatal AE associated with SSRI/SNRI exposure during 3rd trimester have been reported for all drugs in the class
- AE are consistent with SSRI/SNRI discontinuation symptoms or direct toxic effects of drug
-  Some neonatal AE are serious requiring special care
- Clinicians need to be aware of the potential for
- development of these neonatal AE
- Awareness could impact management
- (prevention, diagnosis, treatment)

## Treating Depression During Pregnancy

- Morbidity of depression (mother & neonate)
- Prevalence of depression during pregnancy: 10% to 16%
- Clinicians and patient can weigh potential risks & benefits for mother and neonate when deciding upon treatment
- Might reduce risk of neonatal SSRI/SNRI exposure by tapering near term; might reduce the risk of depression relapse by restarting SSRI/SNRI upon delivery1
- Lack of consensus about interpretation and management of these neonatal AE
- Controlled trials are needed in this important field
- Wisner et al. Pharmacologic Treatment of Depression During Pregnancy. JAMA 1999, Vol. 282 (13): 1264-9

## Status of Proposed SSRI/SNRI Class Labeling 

- Labeling for paroxetine, paroxetine CR, venlafaxine, venlafaxine ER, citalopram, and fluvoxamine include the new class labeling
- The sponsor of fluoxetine has accepted the class labeling
- The Division is having discussions with the sponsor of sertraline