1. Pediatric AC 6/9/041 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

2. Pediatric AC 6/9/042 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

3. Pediatric AC 6/9/043 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

4. Pediatric AC 6/9/044 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

5. Pediatric AC 6/9/045 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

6. Pediatric AC 6/9/046 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

7. Pediatric AC 6/9/047 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

8. Pediatric AC 6/9/048 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”

9. Pediatric AC 6/9/049 Neonatal withdrawal syndrome case definition applied 1 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 1 Schatzberg AF, et al. Serotonin reuptake inhibitor discontinuation syndrome: A hypothetical definition. J Clin Psychiatry 1997;58[suppl 7]5-10.

10. AERS case counts Drug (t½ hours)2001Met definition 2001-4 Venlafaxine (5-11)22335 Fluvoxamine (15)929 Paroxetine (21)7835141 Sertraline (26)33812 Citalopram (35)12518 Fluoxetine (4-16 days)56422

11. Pediatric AC 6/9/0411 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

12. Pediatric AC 6/9/0412 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)

13. Pediatric AC 6/9/0413 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)

14. 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)

15. Reported signs of SRI neonatal withdrawal not mutually exclusive (N) CNSNeuromuscularGI/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)

16. Pediatric AC 6/9/0416 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.

17. Pediatric AC 6/9/0417 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)

18. Pediatric AC 6/9/0418 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.

19. Pediatric AC 6/9/0419 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.

20. Pediatric AC 6/9/0420 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