1 neonatal adverse events associated with in utero ssri/snri exposure robert levin, m.d. medical...
TRANSCRIPT
1
Neonatal Adverse Events Associated with in utero SSRI/SNRI Exposure
Robert Levin, M.D.
Medical Reviewer
DNDP
FDA
2
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
¹SSRI/SNRI Toxicity in Adults
CNS & Neuromuscular: Irritability, jitteriness, tremor, restlessness, anxiety,
agitation, insomnia, dystonia, dyskinesia
GI: nausea, vomiting, diarrhea
¹ Mason PJ, et al. Serotonin Syndrome. Presentation of 2 cases and review of the literature. Medicine 2000 Jul, 79(4): 201-9
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
¹ Mason PJ, et al. Serotonin Syndrome. Presentation of 2 cases and review of the literature. Medicine 2000 Jul, 79(4): 201-9
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
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
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
¹ 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
18
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
¹ 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