# Presentation: 904785

## Assessing Drug Safety and ADHD Medications, Including AtomoxetineA. J. Allen, M.D., Ph.D.Child Psychiatrist, Pharmacologist Global Medical Director – StratteraEli Lilly and Company

## Thoughts re: Patients, Families, and Clinicians

- Re: public comments
- ADHD is a real medical condition with significant morbidity and needs treatment
- All treatment options have benefits and risks, some expected and some unexpected
- This includes medications, non-medication interventions, and no treatment
- Goal should be to inform patients and families of both benefits and risks so that they can decide the best treatment option for them.
- Goal is NOT to scare patients/families so much that they are afraid to seek treatment
- Goal is NOT to deny or prevent treatment out of fear

## Thoughts re: Patients, Families, and Clinicians (Continued)

- Clinicians know their individual patients and are in the best position to direct their treatment as needed – don’t tie their hands with a one size fits all solution
- Need for more research of ADHD, its causes and treatment options
- Access to mental health care for children and families is already a major concern, don’t make that problem worse

## “Scientific knowledge is a body of statements of varying degrees of certainty – some more unsure, some nearly sure, none absolutely certain.

- Richard P. Feynman, Ph.D.
- _The Pleasure of Finding Things Out_
- Chapter 6, The Value of Science

## Atomoxetine (ATX) ADHD Clinical Trials

- Most data are from trials initiated prior to first marketing approval, so no exclusion for ATX non-responders or patients unable to tolerate ATX in clinical practice
- No “run in” trial to select for ATX responders
- With the exception of trials that included a stimulant, trials allowed stimulant non-responders or patients unable to tolerate stimulants in clinical practice

## Atomoxetine (ATX) ADHD Clinical Trials (Continued)

- ADHD trials required diagnosis of ADHD (any subtype) and minimum symptom severity at baseline
- Most pediatric trials allowed common ADHD comorbidities:  oppositional defiant disorder, anxiety, depression, tics
- Exception: trials including a stimulant excluded labeled contraindications, as well as those with history of poor response to stimulants
- 3 trials required comorbidities: 1 anxiety, 1 depression, 1 tics
- Adult trials excluded anxiety, depression
- All trials excluded patients who had seizures, psychosis, mania, or who were suicidal

## Clinical Trial Data (All Ages)

|  | DB Exposure in patient-yrs (N, time) | OL Exposure in patient-yrs (N, days) | Total (DB+OL) Exposure in  patient-yrs |
| --- | --- | --- | --- |
| MPH products | 152.5 (2256,   25 days) | 2147.0 (4628, 169 days) | 2299.4 |
| Amphetamine Products | 77.2 (1236,     23 days) | 1767.5 (5177, 125 days) | 1844.7 |
| Modafinil | 85.5 (772,       40 days) | 383.5 (924,   152 days) | 469.0 |
| Total Above 3 | 315.2 (4264,   27 days) | 4298.0 (10,729,        146 days) | 4613.1 |
| Atomoxetine | 654.9 (2459,   97 days) | 5095.3 (5270, 353 days) | 5750.1 |

- Derived From:  Table 3, Mosholder, FDA Report PID: D060163, March 3, 2006

## Disclosure of Lilly Clinical Trial Data

- Required by our Principles of Medical Research and occurs via
- Presentations and posters at scientific meetings
- Publications in peer-reviewed, scientific journals
- Clinical trial registry:  www.lillytrials.com

## Lilly Code of Business Conduct

- “Lilly is committed to maintaining the quality and safety of its products. Therefore, all employees are required to report the following:
-    Adverse Event - any undesirable medical occurrence in a patient administered a Lilly product (drug or device), including side effects already listed in the package insert.”

## Reporter type for atomoxetine spontaneous AE reports

- Most AE reports from consumers come through The Lilly Answer Center (1-800-LillyRx) Notes: All atomoxetine spontaneous cases through 3/14/2006. HCP = health care professional.

## Some Limitations of Post-Marketing Adverse Event Reports

- Differences between companies in methods and efficiency for collecting events
- Medication history, clinician experience and comfort affect reporting rates
- Many reports that are received are sketchy or lack important information

## Some Limitations of Post-Marketing Adverse Event Reports (continued)

- Lack of control group
- Especially important in pediatric population due to developmental changes
- Confounded by multiple factors
- Coexisting diagnoses
- Other treatments (meds, psychotherapy, etc.)
- Psychosocial factors (e.g., academic problems)
- Life events (e.g., death of a loved one)

## Putting Risks in Context: Odds of Death Due to Injury, US, 2002

| Type of Accident or Manner of Injury | One Year Odds |
| --- | --- |
| MVA: Pedestrian | 1 in 47,273 |
| MVA: Car Occupant | 1 in 17,625 |
| Airplane Accident | 1 in 440,951 |
| Fall (any type) | 1 in 17,712 |
| Accidental drowning and submersion | 1 in 83,534 |
| Due to Smoke or Fire | 1 in 91,149 |
| Lightning | 1 in 4,362,746 |
| Intentional Self-Harm (suicide) | 1 in 9,096 |
| Assault by Firearm | 1 in 24,342 |

- National Safety Council:  http://www.nsc.org/lrs/statinfo/odds.htm

## Bottom Line Regarding Post-Marketing Adverse Events

- Important, but imperfect pharmacovigilance tool
- Efficiency of collecting events differs depending on medication and company
- Cases often difficult to assess
- Need to compare to background rate of events in relevant population
- Need to put risks in context

## Pharmacology

## Binding Affinity of Atomoxetine & Psychostimulants for the NE & DA Transporters

| Compound | NET 
Ki, nM, mean | DAT
Ki, nM, mean | Ratio DAT/NET |
| --- | --- | --- | --- |
| Atomoxetine | 3.5 (5a, 2.0e) | 1266 (1451a, 1080e) | 362 |
| Methylphenidate | 427 (339a, 514b) | 46 (34a, 84b, 21c) | 0.11 |
| D-Amphetamine | 257d | 190c | 0.7 |

- aBymaster et al. 2002   bGatley et al. 1996 cPristupa et al. 1994   dCheetham et al. 1996 eTatsumi et al. 1997

## Effects of Atomoxetine (●) or Vehicle (o) on Locomotor Activity in Sham-lesioned (n=13) and 6-OHDA-lesioned (n=13) rats 

**Effects of Atomoxetine (****●****) or Vehicle (****o****) on Locomotor Activity in Sham-lesioned (*****n*****=13) and 6-OHDA-lesioned (*****n*****=13) rats**

- From Moran-Gates et al., *Int J Neuropsychopharmacol* 2005; 8(3)439–444.

## Subject Rating: “Do you like the drug effect you are feeling now?”

- ***

- *

********P*****<.05, ********p*****<.001.**
**Note: MPH90 was significantly different from A45, A90, and A180 (*****p*****<.001).**

**PBO: placebo**
**MPH90: methylphenidate, 90 mg**
**PH60: phentermine, 60 mg**
**D100: desipramine, 100 mg**
**D200: desipramine, 200 mg**
**A45: atomoxetine, 45 mg**
**A90: atomoxetine, 90 mg**
**A180: atomoxetine, 180 mg**

- From Jasinski et al. Poster presented at: The XXIVth Congress of the Collegium Internationale Neuro-Psychopharmacologicum; June 20–24, 2004; Paris, France.

## Morphine-Benzedrine Group Scale

**********p*****<.001.**
**Note: MPH90 was significantly different from A45, A90, and A180 (*****p*****<.001).**

- ***

- ***

**PBO: placebo**
**MPH90: methylphenidate, 90 mg**
**PH60: phentermine, 60 mg**
**D100: desipramine, 100 mg**
**D200: desipramine, 200 mg**
**A45: atomoxetine, 45 mg**
**A90: atomoxetine, 90 mg**
**A180: atomoxetine, 180 mg**

- From Jasinski et al. Poster presented at: The XXIVth Congress of the Collegium Internationale Neuro-Psychopharmacologicum; June 20–24, 2004; Paris, France.

## Cardiovascular

## Changes in Heart Rate and Systolic BP 1.5 h Post Dose

**PBO: placebo**
**MPH90: methylphenidate, 90 mg**
**PH60: phentermine, 60 mg**
**D100: desipramine, 100 mg**
**D200: desipramine, 200 mg**
**A45: atomoxetine, 45 mg**
**A90: atomoxetine, 90 mg**
**A180: atomoxetine, 180 mg**

- From Jasinski et al. Poster presented at: The XXIVth Congress of the Collegium Internationale Neuro-Psychopharmacologicum; June 20–24, 2004; Paris, France.

- Heart Rate

- Systolic BP

## Suicidal Ideation or Behaviors

## General Methodology for Conducting Meta-Analyses of Psychiatric AEs

- Text string search of database fields for visits in window of time
- Remove clear false positive “hits”
- Prepare data for review
- Raw data (line listings)
- One page patient summaries (OPPS)
- Health care professionals blind to treatment assess cases and categorize using predefined criteria (for suicidality, all are variants of Columbia Univ. criteria)
- Statistical analysis of categorized cases

## Suicidal Behavior or Ideation in Pediatric Trials: Risk Ratios for Atomoxetine vs Placebo Using FDA Methods

## Suicidal Behavior or Ideation in Pediatric Trials: Risk Ratios for Atomoxetine vs Methylphenidate Using FDA Methods

- ----------------------->  Disadvantage Atomoxetine

- 1 case

- 1 case

## Suicidal Ideation or Behaviors Analysis Summary

- Suicidal ideation or behaviors were uncommon in atomoxetine-treated pediatric patients with most categorized as “suicidal ideation.”
- Incidence of suicidal ideation was statistically greater in atomoxetine-treated pediatric patients compared with placebo.
- The risk of suicidal ideation or behaviors with atomoxetine was not significantly different from that seen with methylphenidate (MHRR=0.52, 95% CI: 0.06, 4.54).
- Data does not demonstrate increased risk for suicidal ideation or behaviors in adults taking atomoxetine for ADHD.
- Label change (black box warning and medication guide) has been implemented.

## Psychosis/Mania

## General Methodology for Conducting Meta-Analyses of Psychiatric AEs

- Text string search of database fields for visits in window of time
- Remove clear false positive “hits”
- Prepare data for review
- Raw data (line listings)
- One page patient summaries (OPPS)
- Health care professionals blind to treatment assess cases and categorize using predefined criteria (for suicidality, all are variants of Columbia Univ. criteria)
- Statistical analysis of categorized cases

## Some Phenomena That May Be Reported Clinically as Hallucinations in Young Children, But that Are NOT Psychosis/Mania

- Imaginary friends
- Hypnagognic hallucinations
- Auras associated with migraine headaches
- Images of loved ones who have died
- Some obsessive thoughts in OCD
- Flashbacks in PTSD
- Other sensory phenomena (e.g., scary images from horror movies)

## Psychosis/Mania Events

- Patient 2
- 12 yr M
- Diagnoses:  ADHD, Oppositional Defiant Disorder
- ATX dose:  0.70 mg/kg/day
- Time to onset:  2 days
- Event:  “Hallucinations, seeing things,” mild severity, 1 day duration
- Other Events:  Intermittent headaches (mild), Decreased appetite (moderate), Nausea (mild), Tiredness (mild), mood swings (moderate), decreased sleep (mild), clouded thinking (moderate), mouth sores (mild).
- Outcome:  Discontinued due to Lack of Efficacy at day 346.

## Psychosis/Mania Events

- Patient 4
- 9 yr M
- Diagnoses:  ADHD, Oppositional Defiant Disorder
- ATX dose:  35 mg (1.16 mg/kg/day)
- Time to onset:  212 days
- Event:  “Psychosis,” severe severity, unknown duration
- Other Events:  blood in urine, knot in groin region, knot above right eye, sore throat.  Patient was sexually assaulted earlier in the study.
- Outcome:  Discontinued from study and hospitalized due to this severe adverse event.

## Trial in ADHD with Comorbid DepressionTreatment-Emergent Mania:YMRS Total Score

**Treatment-emergent mania defined as YMRS total score <15 at baseline and ********15 postbaseline.**
**At baseline, 5 patients in the ATX group and 2 patients in the PBO group had YMRS scores >15. At endpoint, all but 1 patient in the ATX group had YMRS scores <15.**

|  | n | % |
| --- | --- | --- |
| Atomoxetine, N=68 | 2 | 2.9 |
| Placebo, N=67 | 2 | 3.0 |

- From Bangs et al. Poster presented at: The 45th Annual Meeting of the New Clinical Drug Evaluation Unit; June 6–9, 2005; Boca Raton, Fla.

## Case Series: Atomoxetine Use in Children with Bipolar Disorder & Comorbid ADHD

- 7 outpatients w/ pediatric BPD and comorbid ADHD
- Treated w/ ATX; all but 1 also receiving mood stabilizers
- All but 1 showed significant improvement in ADHD Sx severity
- No episodes of hypomania or mania during Rx
- AEs included sedation, nausea, decreased appetite
- Conclusion: “ATX may be a safe and effective treatment for ADHD in conjunction w/ mood stabilizers in children w/ BPD.”

- From Hah & Chang, *J Child Adolesc Psychopharmacol* 2005; 15(6): 996-1004.

## Psychosis/Mania Summary

- Clinician review of pediatric cases identified via text string search of the double-blind clinical trial adverse event database found that only 1 of 4 cases appeared to be true psychosis/mania and resulted in discontinuation of treatment due to the adverse event, but that case was confounded by a history of sexual assault
- Event context, duration and/or severity were important considerations in evaluating cases
- In double-blind, placebo-controlled trial for pediatric ADHD patients with comorbid depression, equal number of treatment emergent mania cases in ATX and placebo treated groups as assessed by YMRS
- The literature suggests that ADHD meds can benefit some patients with ADHD and comorbid pediatric bipolar disorder

## Aggression/Hostility

## Aggression/Hostility Analysis Summary

- Events were generally infrequent during these trials.
- Majority of events were isolated reports of non-specific aggression and did not result in discontinuation of medication
- Children and adolescents treated with atomoxetine showed a potentially higher risk of aggression or hostility events based on a numerically (but not statistically significantly) higher risk compared with placebo (MHRR=1.33, 95% CI: 0.67, 2.64).
- The risk of hostility or aggression events with atomoxetine was not significantly different from that seen with methylphenidate (MHRR=0.96, 95% CI: 0.29, 3.19).
- Children and adolescents taking atomoxetine for ADHD should be monitored closely for the emergence or worsening of aggressive behavior or hostility.

## Conclusion: Lilly Key Points

- ADHD is a real medical condition with significant morbidity and needs treatment
- Put benefits and risks of all treatment options in context
- Inform patients/families, but don’t try to scare them and don’t limit access out of fear
- Clinicians know their individual patients and are in the best position to direct their treatment as needed
- Strattera (atomoxetine) is generally safe and effective for the treatment of ADHD
- Lilly is committed to continued study of Strattera’s benefits and risks, and to appropriate labeling

**QUESTIONS?**