Neonatal Adverse Events Associated with in utero SSRI/SNRI Exposure

1. Neonatal Adverse Events Associated with in utero SSRI/SNRI Exposure Robert Levin, M.D. Medical Reviewer DNDP FDA

3. SSRIs and SNRI • Selective Serotonin Reuptake Inhibitors: • fluoxetine, sertraline, paroxetine, paroxetine CR, fluvoxamine, citalopram • Serotonin Norepinephrine Reuptake Inhibitor: venlafaxine, venlafaxine ER

4. 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

5. Sources of Information re: SSRI/SNRI & Neonatal AE • Postmarketing reports (AERS) • Retrospective studies • Prospective studies • Medical literature

6. 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

7. 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)

8. 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

9. Terms Used for Neonatal SSRI/SNRI Syndromes • - SRI Withdrawal • - SRI Toxicity • - Poor Neonatal Adaptation • - Serotonergic Excess • - Serotonergic CNS Adverse Effects • - Serotonin Syndrome

10. 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.

11. 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

12. 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

13. 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

14. 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 & Adult Discontinuation Symptoms

15. 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 Similarities Between Neonatal AE & Toxicity in Adults

16. 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

17. 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

19. 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

20. 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)

21. 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

22. 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