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

2. 2

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

4. 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. 5 Sources of Information re: SSRI/SNRI & Neonatal AE Postmarketing reports (AERS) Retrospective studies Prospective studies Medical literature

6. 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. 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. 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. 9 Terms Used for Neonatal SSRI/SNRI Syndromes - SRI Withdrawal - SRI Toxicity - Poor Neonatal Adaptation - Serotonergic Excess - Serotonergic CNS Adverse Effects - Serotonin Syndrome

10. 10 SSRI/SNRI Discontinuation Symptoms in Adults 1 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 1 Schatzberg AF, et al. Serotonin reuptake inhibitor discontinuation syndrome: A hypothetical definition. J Clin Psychiatry 1997; 58 [suppl 7] 5-10.

11. 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. 12 ¹SSRI/SNRI Toxicity in Adults CNS & Neuromuscular: Irritability, jitteriness, tremor, restlessness, anxiety, agitation, insomnia, dystonia, dyskinesia GI: nausea, vomiting, diarrhea ¹Mason PJ, et al. Serotonin Syndrome. Presentation of 2 cases and review of the literature. Medicine 2000 Jul, 79(4): 201-9

13. 13 ¹Serotonin 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 ¹Mason PJ, et al. Serotonin Syndrome. Presentation of 2 cases and review of the literature. Medicine 2000 Jul, 79(4): 201-9

14. 14 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

15. 15 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

16. 16 ¹Exposure 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 ¹Laine K et al. Arch Gen Psychiatry 2003 Jul Vol 60: 720-6

17. 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

18. 18

19. 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. 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. 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 delivery 1 Lack of consensus about interpretation and management of these neonatal AE Controlled trials are needed in this important field ¹Wisner et al. Pharmacologic Treatment of Depression During Pregnancy. JAMA 1999, Vol. 282 (13): 1264-9

22. 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