Division of Pediatric Drug Development by HC12072710047

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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, FAAP
                Medical Officer
                Division of Pediatric Drug Development
                Center for Drug Evaluation and Research
                Food and Drug Administration       1
                   Outline
•   Background Drug Information
•   Use Information
•   Pharmacologic and Clinical Review
•   Relevant Safety Labeling
•   Adverse Events
    – Maternal: In utero and Breast feeding
    – Direct Exposure
• Comments



                                              2
    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
                                                        3
   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
                                                4
             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


                                                                                                                  5
• http://www.fda.gov/cder/pediatric/Summaryreview.htm




                                                    6
    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

                                                              7
   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             8
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
                                                     9
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



                                              10
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
                                                11
 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

                                                12
          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
                                                                        13
 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       14
          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)



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




                                            16
         In utero Exposure-
              Other (4)
• Cardio-respiratory arrest, somnolence and
  regurgitation
• Weak cry and fluid in lungs
• Jaundice (2)




                                              17
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                   18
               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



                                             19
        Direct Exposure (n=30)

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




                                 20
         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)

                                                        21
        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)

                                             22
         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)

                                                  23
                Overdose
                 (n=4)
• Accidental (1)
• Non-accidental (3)




                           24
Other Pediatric Adverse Events
            (n=3)
• Hypertension (1)
• Growth retardation (1)
• Drug interaction (Augmentin decreased
  effectiveness) (1)




                                          25
Discontinuation or Decrease in
         Dose (n=6)
Both physical symptoms and/or emergence of
 psychiatric symptoms described




                                         26
            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                                  27

								
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