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MPH Label: An opportunity

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US should invest more in safety monitoring ... because of MPH-related AEs that kicked in at 5 mg TID, which differed from schoolage children ... – PowerPoint PPT presentation

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Title: MPH Label: An opportunity


1
MPH Label An opportunity
  • Good that FDA is considering a clarification of
    the MPH label for safety
  • US should invest more in safety monitoring
  • Problems of evaluating a signal from spontaneous
    reports
  • Need a denominator
  • Studies that should be encouraged

2
Challenges of interpretation
  • Spontaneous reports for AERS weaknesses
  • Under-reporting
  • Duplicate reports
  • Clinicians dont use standardized elicitation
  • Clinicians dont use standard coding
  • Trials designed for efficacy underpowered to
    determine safety
  • Cant tell how strong or how specific a signal is

3
Comorbidity Can Affect Side Effects
  • Rate of comorbidity high in ADHD 75
  • Dont know if AE is an effect of medication or a
    symptom of the other disorder
  • Important for parents and clinicians to be aware
    that treatment with stimulants may impact on
    comorbidity put in label?

4
Comorbidity in the MTA Sample (N 579)
ADHD alone
ODD
179 (31)
126 (21)
15
Tic
14
12
8
AnxietyODD
5
4
67 (12)
2
1
11
3
Mood
Conduct
5
43 (7)
26
Anxiety
58 (10)
5
Need to know denominator
  • Adverse events risks should be based on
    prevalence not only the severity of the risk
  • Evidence based medicine requires Number Need to
    Treat (NNT) and the Number needed to Harm (NNH)
    to evaluate the balance of benefit to risk

6

Swanson et al. for the MTA Cooperative Group
7
Questions about the MTA from a Clinician
(engaged in treatment as usual)
  • What percentage of the next 100 ADHD patients
    will improve if I switch from treatment as usual
    to the MTA medication algorithm?
  • increase from 25 (CC) to over 55.6 (MedMgt)
  • How many additional patients will respond if I
    then add intensive behavioral treatment?
  • Increase from 55.6 (MedMgt) to 67.6 (Comb)
  • If the MTA medication algorithm is not an
    option, will behavioral treatment alone improve
    my success rate?
  • variable, depending on local conditions

Swanson et al. for the MTA Cooperative Group
8
Good that FDA is examining challenge / dechallenge
  • MTA titration trial looked for a dose response in
    side effects to attribute a problem to the
    medidation
  • MTA found that parents more sensitive than
    teachers in seeing the D/R or dose
    proportionality of MPH

9
Parents MPH Side Effects ( Patients)
40
35
30
Placebo
25
5mg
10mg
20
15/20 mg
15
10
5
0
Crabby
Appetite
Dull
Insomnia
10
Teachers MPH Side Effects (Patients)
30
25
Placebo
20
5mg
10mg
15
15/20 mg
10
5
0
Crabby
Appetite
Dull
Worried
11
FDA clarifying risks a good thing
  • Putting the risks of psychotic reaction in clear
    language
  • But should also give more information on more
    common adverse events
  • Growth delay is now more clearly an initial
    effect of stimulants in preschoolers and
    schoolage children should be highlighted

12
MTA Study Growth Rates per Year
13
Mean Weight (kg) Across Time (month)
14
Weight Gain (2.4 3.0 kg/yr) Vs. Mean Dose
(31.2 12.0 mg), r-0.3d
Dplt0.0001, n212
15
FDA should be encouraged to review entire MPH
label
  • The labeling anomaly for MPH
  • Warning against use of MPH in children under 6
    years of age
  • Approval of d-amphetamine for use down to age 3

16
Adverse Events for lead-in titration
  • A total of 16/183 (8.7) patients dropped from
    the study (n14) or could not tolerate proposed
    dosing (n2) due to AEs associated with study
    drug for both lead-in titration phases

Note Most patients reported multiple AEs
17
Adverse Events in Titration Trial (1)
18
Adverse Events in Titration Trial (2)
19
Growth tiles ? over 540 days on MPH (n95)
  • Significant effect
  • for time for both
  • weight and BMI
  • tiles, Plt0.001

20
Preschoolers Need Lower MPH Doses
PK studies comparing Preschoolers and School-Aged
Subjects
Wigal et. al., 2004
21
Conclusions
  • MPH effect sizes were small to moderate (Cohen,
    1988) for composite measures of efficacy in
    preschoolers using best dose mean estimate of
    14.1 8.1 mg (0.75 mg/kg/day) total daily dose
  • Best MPH dose (0.75 mg/kg/day) from controlled
    PATS titration trial differed from weight
    adjusted dose (0.96 mg/kg/day) in schoolage
    children with ADHD reported in MTA Study
  • 8.7 of patients discontinued because of
    MPH-related AEs that kicked in at 5 mg TID, which
    differed from schoolage children
  • Growth data over 375 days shows drop in expected
    growth, gaining 1.5 cm less and 2.5 kg less than
    expected on MPH
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