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One Year Post Exclusivity Adverse Event Review:

Venlafaxine

Pediatric Subcommittee of the Anti-infective Drugs Advisory Committee Meeting

June 9, 2004

Hari Cheryl Sachs, MD, FAAPMedical OfficerDivision of Pediatric Drug DevelopmentCenter for Drug Evaluation and Research Food and Drug Administration

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Outline • Background Drug Information• Use Information• Pharmacologic and Clinical Review• Relevant Safety Labeling• Adverse Events

– Maternal: In utero and Breast feeding– Direct Exposure

• Comments

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Background Drug Information • Moiety: Effexor®, Effexor XR® (venlafaxine)• Therapeutic Category: Antidepressant• Sponsor: Wyeth-Ayerst • Adult Indications: Major depressive disorder,

generalized anxiety disorder, and social anxiety disorder – Adult Dosage: Effexor® 75-375 mg/day; Effexor XR® 75-

225 mg daily• Pediatric Indications: There are NO approved

pediatric indications• Original Market Approval: 12/28/93 (Effexor®)

10/20/97 (Effexor XR®) • Pediatric Exclusivity Granted: 12/2/02

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Background Drug Information

• Active metabolite: O-desmethylvenlafaxine• Potent inhibitor of serotonin and norepinephrine

reuptake (SNRI)• Weak inhibitor of dopamine reuptake• No significant muscarinic cholinergic, H1-

histaminergic and alpha-1 adrenergic effect• Half life: ~ 5 hrs parent and 11 hrs active

metabolite

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Drug Use Trends in Outpatient Settings: Venlafaxine

• Fourth most commonly used antidepressant in US 2003.1

• Both pediatric & adult prescriptions have increased steadily between 2001 and 2003.1,3

• Pediatric Diagnosis (off label): mood disorders (depression and bipolar), anxiety and ADHD.2

• Pediatric patients account for approximately 2.4 % of total U.S. prescriptions of Effexor® between Dec 2002 – Nov 2003 (462,441).1,3*

1IMS Health, National Prescription Audit Plus, On-Line Source Year Aug 1998 – Nov 2003, Data Extracted Feb 20042IMS Health, National Disease and Therapeutic Index, CD-Rom, Source 3 Year Jan 2001-Dec 2003 and Oct 2000- Sep 2003 3AdvancePCS Dimension Rx, On-Line*Calculation based on application of proportions of pediatric venlafaxine prescriptions in AdvancePCS to IMS Health, National Prescription Audit Plus to estimate number of venlafaxine prescriptions dispensed nationwide to pediatric population

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• http://www.fda.gov/cder/pediatric/Summaryreview.htm

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Pediatric Exclusivity Studies: Venlafaxine

Eight week, multicenter, double blind, placebo controlled parallel group, flexible dose studies performed for each indication. Dose= 37.5-225 mgAge= 6-17 years

Major Depressive Disorder (2 studies, n=353)Neither study showed significant difference from placebo

Generalized Anxiety Disorder (2 studies, n=313)One study demonstrated efficacy

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Clinical Review: Venlafaxine

• Safety- The four 8-week trials plus– 6 month open label study in MDD– 6 week phase II study in Conduct disorder

• Decreased weight gain and growth noted, unrelated to treatment emergent-anorexia.– Mean weight loss (0.45 kg) in treated patients

vs. weight gain (0.77 kg) in placebo– Mean height increase 0.3 cm in treated group

compared with 1.0 cm increase in placebo• Elevations in cholesterol and blood pressure

similar to those seen in adults

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• Category C• Discontinuation effects in newborn

– Complications requiring prolonged hospitalization, respiratory support, tube feeding

– Clinical findings including respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hyperreflexia, tremor, jitteriness, irritability and constant crying

Relevant Safety Labeling- Pregnancy

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• Clinical worsening and suicide risk– Close observation of adult and pediatric

patients– Potential worsening of depression– Emergence of behavioral symptoms, including

suicidal behavior• Sustained hypertension

Relevant Safety Labeling: Warnings

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– Insomnia and nervousness– Weight loss and slower rate of growth in

children- Treatment emergent anorexia – Activation of mania/hypomania- Hyponatremia- Mydriasis- Use caution in patients with seizures- Abnormal bleeding- Serum cholesterol elevation

Relevant Safety Labeling- Precautions

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Relevant Safety Labeling- Adverse Reactions and Post-

Marketing Reports

Adverse reactions• with abrupt discontinuation

– agitation, anxiety, dizziness, sensory disturbance, nausea and sweating

Post marketing reports• Dyskinesia and rhabdomyolysis

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Adverse Event Reports:Venlafaxine

12/02/02 – 01/02/04• Total number of reports, all ages:

– 1490 reports (824 U.S.)serious-1421 (776)deaths- 166 (116)

• Pediatric reports: – 55 reports (31 U.S.)

serious- 54 (31)death- 2 (2)

Raw counts (US reports are in parenthesis)- includes duplicates

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Gender and Age Distribution by Mode of Exposure (n=49)

Gender In utero (19) Direct (30) Male 12 13 Female 4 16 Unknown 3 1

Age 0- 1 month 18 0 1 mo- <2 yr 1 0 2-5 yr 0 2 6- 11 yr 0 6 12-16 yr0 22

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In utero Exposure 19 total in utero

– 3 breast feeding and in utero exposure

No deathsCongenital anomaly (4)

– Cardiac (2)– Hypospadias (1)– Hand malformation (1)

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In utero Exposure Neurologic Events (n=11)

• Hypotonia (2)• Seizures (3)• Tremor/jittery/myoclonus/dyskinesia (6)

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In utero Exposure- Other (4)

• Cardio-respiratory arrest, somnolence and regurgitation

• Weak cry and fluid in lungs • Jaundice (2)

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Comorbid Conditions/Medications • Neonatal withdrawal (2)• Prematurity (4, unknown gestation-8)• Breast feeding (3)• Substance use (tobacco, alcohol) (1)• Concomitant medications

– Total (10, other psychotropic-4)– None ( 2)– Unknown (7)

Many pertinent negatives and comorbid conditions not recorded

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Comments• Many neonatal AEs reflect events labeled

for adults (e.g., tremor, convulsion, hypotonia)

• Adverse events may also be related to:– Concomitant medications or substances– Comorbid conditions ( prematurity)– Withdrawal syndrome/serotonin toxicity

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Direct Exposure (n=30)

• Psychiatric (14)• Neurologic (9)• Overdose (4)• Other (3)

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Direct Exposure (n=30)• Dose range 37.5- 300 mg/day (mean = 137.5 mg, n=17)• Indication for use (n=20):

– Depression 12– Depression and anxiety 3– Depression and ADHD 2– ADHD 2– ADHD and anxiety 1

• Reporter type: – Health Provider 17– Consumer 12– Lawyer 1

• Concomitant medications: 20 (psychotropic 10)

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Psychiatric Events (n=14)• Completed suicide (2)• Attempted suicide (4)• Suicidal ideation with self-injury (1)• Self-injury (2)• Aggression/agitation (3)• Behavior change (2)

Concomitant medications 8 (6 psychotropic)

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Neurologic Events (n=9)• Seizures (2)• Loss of consciousness (2)• Motor and/or sensory impairment (5)

– Tremor (2)– Myoclonic jerks (1)– Impaired motor skills, decreased reflexes,

vertigo (1)– Vertigo, nausea, diarrhea (1)

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Overdose (n=4)

• Accidental (1)• Non-accidental (3)

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Other Pediatric Adverse Events (n=3)

• Hypertension (1)• Growth retardation (1)• Drug interaction (Augmentin decreased

effectiveness) (1)

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Discontinuation or Decrease in Dose (n=6)

Both physical symptoms and/or emergence of psychiatric symptoms described

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Final Remarks• Most events labeled or related to labeled

events Exception: neonates• New class warning: Close observation for

clinical worsening and suicide • New labeling added as a result of

exclusivity studies regarding effect on growth (May 2004)

• Class labeling regarding maternal exposure and neonatal withdrawal/serotonin toxicity.

• Safety of venlafaxine will continue to be monitored