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Neonatal Adverse Events Associated with in utero SSRI/SNRI Exposure

Robert Levin, M.D.

Medical Reviewer

DNDP

FDA

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SSRIs and SNRI

• Selective Serotonin Reuptake Inhibitors: fluoxetine, sertraline, paroxetine, paroxetine CR,

fluvoxamine, citalopram

• Serotonin Norepinephrine Reuptake Inhibitor:

venlafaxine, venlafaxine ER

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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

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Sources of Information re: SSRI/SNRI & Neonatal AE

• Postmarketing reports (AERS)• Retrospective studies• Prospective studies

• Medical literature

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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

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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)

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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

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Terms Used for Neonatal SSRI/SNRI Syndromes

- SRI Withdrawal

- SRI Toxicity

- Poor Neonatal Adaptation

- Serotonergic Excess

- Serotonergic CNS Adverse Effects

- Serotonin Syndrome

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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