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1 One Year Post Exclusivity Adverse Event Review: Venlafaxine Pediatric Subcommittee of the Anti-infective Drugs Advisory Committee Meeting June 9, 2004.

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Presentation on theme: "1 One Year Post Exclusivity Adverse Event Review: Venlafaxine Pediatric Subcommittee of the Anti-infective Drugs Advisory Committee Meeting June 9, 2004."— Presentation transcript:

1 1 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 Food and Drug Administration

2 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 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 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 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* 1 IMS Health, National Prescription Audit Plus , On-Line Source Year Aug 1998 – Nov 2003, Data Extracted Feb 2004 2 IMS Health, National Disease and Therapeutic Index , CD-Rom, Source 3 Year Jan 2001-Dec 2003 and Oct 2000- Sep 2003 3 AdvancePCS  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 6 http://www.fda.gov/cder/pediatric/Summaryreview.htm

7 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 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 9 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

10 10 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

11 11 –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

12 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 13 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

14 14 Gender and Age Distribution by Mode of Exposure (n=49) GenderIn utero (19)Direct (30) Male1213 Female416 Unknown31 Age 0- 1 month180 1 mo- <2 yr10 2-5 yr02 6- 11 yr06 12-16 yr022

15 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 16 In utero Exposure Neurologic Events (n=11) Hypotonia (2) Seizures (3) Tremor/jittery/myoclonus/dyskinesia (6)

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

18 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 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 20 Direct Exposure (n=30) Psychiatric (14) Neurologic (9) Overdose (4) Other (3)

21 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 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 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 24 Overdose (n=4) Accidental (1) Non-accidental (3)

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

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

27 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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