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One Year Post Exclusivity Adverse Event Review: Venlafaxine Pediatric Subcommittee of the Anti-infective Drugs Advisory

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, FAAP Medical Officer Division of Pediatric Drug Development Center for Drug Evaluation and Research

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One Year Post Exclusivity Adverse Event Review: Venlafaxine Pediatric Subcommittee of the Anti-infective Drugs Advisory

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  1. One Year Post Exclusivity Adverse Event Review:VenlafaxinePediatric Subcommittee of the Anti-infective Drugs Advisory Committee Meeting June 9, 2004 Hari Cheryl Sachs, MD, FAAPMedical Officer Division of Pediatric Drug DevelopmentCenter for Drug Evaluation and Research Food and Drug Administration

  2. Outline • Background Drug Information • Use Information • Pharmacologic and Clinical Review • Relevant Safety Labeling • Adverse Events • Maternal: In utero and Breast feeding • Direct Exposure • Comments

  3. 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

  4. 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

  5. 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 2004 2IMS 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

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

  7. Pediatric Exclusivity Studies: Venlafaxine Eight week, multicenter, double blind, placebo controlled parallel group, flexible dose studies performed for each indication. Dose= 37.5-225 mg Age= 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

  8. 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

  9. Relevant Safety Labeling- Pregnancy • 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

  10. Relevant Safety Labeling: Warnings • 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

  11. Relevant Safety Labeling- Precautions • 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

  12. 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

  13. Adverse Event Reports:Venlafaxine12/02/02 – 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

  14. 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 yr 0 22

  15. In utero Exposure 19 total in utero • 3 breast feeding and in utero exposure No deaths Congenital anomaly (4) • Cardiac (2) • Hypospadias (1) • Hand malformation (1)

  16. In utero Exposure Neurologic Events (n=11) • Hypotonia (2) • Seizures (3) • Tremor/jittery/myoclonus/dyskinesia (6)

  17. In utero Exposure- Other (4) • Cardio-respiratory arrest, somnolence and regurgitation • Weak cry and fluid in lungs • Jaundice (2)

  18. 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

  19. 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

  20. Direct Exposure (n=30) • Psychiatric (14) • Neurologic (9) • Overdose (4) • Other (3)

  21. 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)

  22. 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)

  23. 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)

  24. Overdose (n=4) • Accidental (1) • Non-accidental (3)

  25. Other Pediatric Adverse Events (n=3) • Hypertension (1) • Growth retardation (1) • Drug interaction (Augmentin decreased effectiveness) (1)

  26. Discontinuation or Decrease in Dose (n=6) Both physical symptoms and/or emergence of psychiatric symptoms described

  27. 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

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