# Presentation: 538634

## One Year Post Exclusivity Adverse Event ReviewCONCERTA®  Pediatric Advisory Committee Meeting June 30, 2005

**Susan K. McCune, M.D.****Medical Officer**
**Division of Pediatric Drug Development****Center for Drug Evaluation and Research **
**Food and Drug Administration**

## Overview

- Background
- Clinical Trials for Initial Approval (6-12 years of age)
- Clinical Trial for Exclusivity (Adolescents)
- Methylphenidate Use Information
- Adverse Event Reports for Concerta® (12/4/03-1/4/05)

## Background Drug Information 

**Drug: **Concerta®** (**Methylphenidate HCl Extended Release Tablets)
**Therapeutic Category: **Central nervous system stimulant
**Sponsor: **Alza Corporation** **
**Indication: **Treatment of Attention Deficit Hyperactivity Disorder (ADHD)
**Original Market Approval: **August 1, 2000
**Pediatric Exclusivity Granted: **December 4, 2003

## Background Drug Information 

- Therapeutic action of methylphenidate in ADHD is unknown.  Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

- http://www.learner.org/channel/courses/biology/units/neuro/images.html

**Mechanism of action**

## Concerta® Drug Delivery System

## Drugs to Treat ADHD From the Clinical Practice Guidelines

**Stimulants **
**(First-Line Treatment)**

**Non-Stimulants**

**Methylphenidate**

**Amphetamine**

**Pemoline **

**Short acting**
**Ritalin****®****, Methylin****®**
**Intermediate acting**
**Ritalin SR****®****, Metadate ER****®****, Methylin ER****®**
**Long acting**
_**Concerta**__**®**_**, Metadate CD****®****, Ritalin LA****®**

**Short acting**
**Dexedrine****®****, Dextrostat****®**
**Intermediate acting**
**Adderall****®****, Dexedrine spansule****®**
**Long acting**
**Adderall XR****®**

**Antidepressants***
**(Second-Line Treatment)**

**Atomoxetine**
**Strattera****®**

**Tricyclic antidepressants**
**Imipramine, Desipramine**
**Bupropion**
**Wellbutrin****®****, Wellbutrin SR****®**

*** Not FDA approved for ADHD treatment**

- Subcommittee on Attention-Deficit/Hyperactivity Disorder and Committee on Quality Improvement. 2001. Clinical Practice Guideline: Treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics 108:1033-1044.

**Cylert****®**** discontinued by Abbott**

- From: Rappley, MD, 2005, Attention deficit-hyperactivity disorder, N. Engl. J. Med. 352:165-173

## Initial Studies For Concerta® Approval

- Clinical Trials

- 3 double blind, active and placebo controlled studies in  416 patients 6-12 years of age
- Compared Concerta®  once daily (18, 36, or 54 mg) to methylphenidate given three times daily over 12 hours (15, 30 or 45 mg total daily dose) and placebo
- Studies 1 and 2 were single-center 3 week crossover studies
- Study 3 was a multi-center 4 week parallel-group comparison
- Primary comparison of interest in all trials was Concerta® vs placebo

**(Original Market Approval 8/1/00)**

## Initial Studies For Concerta®

- Results of Clinical Trials (Efficacy)

## Initial Studies For Concerta®

- Results of Clinical Trials (Adverse Events)

- Study 3
- Sadness (0.9%)
- Increase in tics (1%) (Placebo patient)
- Two Open Label Long-Term Safety Trials (24 months and 9 months)
- Overall rate (6.7%)
- Insomnia (1.5%)
- Twitching (1%)
- Nervousness (0.7%)
- Emotional lability (0.7%)
- Abdominal pain (0.7%)
- Anorexia (0.7%)

- _Discontinuation of Treatment_

## Initial Studies For Concerta®

- Results of Clinical Trials
- (Adverse Events From Study 3)

## Initial Studies For Concerta®

_**Contraindications**_
- Agitation (ie. marked anxiety, tension and agitation since the drug may aggravate these symptoms)
- Hypersensitivity to methylphenidate
- Glaucoma
- Tics or a family history or diagnosis of Tourette’s
- MAO inhibitors
_**Warnings**_
- Long-term suppression of growth
- May exacerbate behavior disturbance and thought disorder in psychotic patients
- Seizures
- Potential for gastrointestinal obstruction
- Hypertension and other cardiovascular conditions
- Visual disturbance
- Use in children under 6 years of age
**Drug dependence (tolerance, psychological dependence, psychotic episodes and severe depression) (Boxed Warning)**

**Approved Labeling Following the Initial Clinical Trials**

## Nervousness
Insomnia
Hypersensitivity (skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with necrotizing vasculitis, and thrombocytopenic purpura)
Anorexia
Nausea
Dizziness
Palpitations
Headache
Dyskinesia
Drowsiness
Blood pressure and pulse changes both up and down

- Insomnia
- Hypersensitivity (skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with necrotizing vasculitis, and thrombocytopenic purpura)
- Anorexia
- Nausea
- Dizziness
- Palpitations
- Headache
- Dyskinesia
- Drowsiness
- Blood pressure and pulse changes both up and down

- Tachycardia
- Angina
- Cardiac arrhythmia
- Abdominal pain
- Weight loss with prolonged therapy
- Tourette’s
- Toxic psychosis
- Abnormal liver function (transaminase elevation to hepatic coma)
- Cerebral arteritis and/or occlusion
- Leukopenia and/or anemia
- Transient depressed mood
- Scalp hair loss
- Neuroleptic malignant syndrome

- In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia and tachycardia may occur more frequently

_**Adverse Events with Other Methylphenidate Products**_

**Initial Studies For Concerta****®**

**Approved Labeling Following the Initial Clinical Trials**

## Initial Studies For Concerta®

**Initial Studies For Concerta****®**

- Vomiting
- Agitation
- Tremors,
- Hyperreflexia
- Muscle twitching
- Convulsions (may be followed by coma)
- Euphoria
- Confusion
- Hallucinations
- Delirium

- Sweating
- Flushing
- Headache
- Hyperpyrexia
- Tachycardia
- Palpitations
- Cardiac arrhythmias
- Hypertension
- Mydriasis
- Dryness of mucous membranes

**Approved Labeling Following the Initial Clinical Trials**

## Exclusivity Study For Concerta® (Granted 12/4/03)

- Clinical Trial for Adolescents

- A randomized, double blind, multi-center, placebo controlled study of 177 patients 13-18 years of age
- Of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg/d) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness
- Patients who met the criteria were randomized to receive their individual dose (18-72 mg/d, n=87) or placebo (n=90) during a 2 week double blind phase
- Mean scores for the investigator rating on the ADHD Rating Scale demonstrated that Concerta® was significantly superior to placebo

## Exclusivity Study For Concerta®

- Results of the Clinical Trial for Adolescents (Adverse Events)

- No Concerta® patients discontinued treatment
- One placebo patient discontinued due to increased mood irritability

- _Discontinuation of Treatment (Adolescent Trial)_

## Exclusivity Study For Concerta®

- Results of the Clinical Trial for Adolescents (Adverse Events)

## Current Approved Indications for Concerta® Following the Initial Studies and the Study for Exclusivity

## Drug Use Trends: Methylphenidate (2002-2004)

**Drug Use Trends: Methylphenidate (2002-2004)**

- Overall increase from 25 million prescriptions (2002) to over 29 million (2004) _for single _ingredient and combination psychostimulant products1
- Methylphenidate products accounted for approximately half of all stimulant prescriptions in the past 3 years1
- Concerta® retained approximately half of the market share for methylphenidate products during all 3 years1
- 1IMS Health, National Prescription Audit *Plus*TM, Years 2002 - 2004, Data extracted Jan 2005

## Drug Use Trends: Concerta®

**Drug Use Trends: Concerta****®**

- Most frequent prescribers1
- Pediatrics (37.1%)
- Psychiatry (31%)
- Family practice (11.7%)
- Prescription Claim Characteristics – Patient Demographics2
- 80% of claims for pediatric patients (age 1-16 years)
- 75% of all pediatric claims to males
- Indication associated with use3 in pediatric patients
- Attention deficit disorder (> 96% of mentions during office-based physician visits)
- 1IMS Health, National Prescription Audit *Plus*TM, Year 2004, Data extracted Jan 2005
- 2Caremark Dimension RxTM, Years 2002 - 2004, Data extracted Feb 2005
- 3IMS Health, National Disease and Therapeutic IndexTM, Years 2002 - 2004, Data extracted Feb 2005

## Concerta® Prescription Claims By Age, 2002-2004

- Caremark Dimension RxTM, Years 2002 - 2004, Data extracted Feb 2005

## Review of AERS Data Submitted to the FDA Prior to January 4, 2005

- Comparison of Methylphenidate Products
- Brief comparison of adverse event reports for Concerta® and all other methylphenidate products (short and long acting) in children 0-16 years during the one year post exclusivity period
- Discussion of Concerta® Adverse Event Reports
- Raw counts of adverse events for Concerta® following exclusivity
- In depth review of unduplicated reports for Concerta® in children 0-16 years of age during the one year post exclusivity period
- Raw counts of adverse events for Concerta® following market approval

## Adverse Event Reports for the Methylphenidate Products

| Characteristic |  | Concerta® | Other Methylphenidate |
| --- | --- | --- | --- |
| Total |  | 135 | 96 |
| Origin | Foreign | 77 | 49 |
|  | U.S. | 58 | 47 |
| Gender | Female | 26 | 17 |
|  | Male | 108 | 77 |
|  | Unknown | 1 | 2 |
| Age | 0-1 year | 0 | 1 |
|  | 2-5 years | 1 | 9 |
|  | 6-11 years | 82 | 50 |
|  | 12-16 years | 52 | 36 |

- December 4, 2003 – January 4, 2005

## Adverse Event Reports for the Methylphenidate Products

| Characteristic |  | Concerta®  (N=135) | Other Methylphenidate Products (N=96) |
| --- | --- | --- | --- |
| Outcome box checked on MedWatch form
(multiple boxes may be checked on one report)
 | Death | 1* | 1 |
|  | Hospitalization | 39 | 15 |
|  | Life-threatening | 5 | 2 |
|  | Disability | 5 | 4 |
|  | Required intervention | 1 | 9 |
|  | Other/Medically important | 95 | 65 |
|  | None selected | 7 | 8 |

**Adverse Event Reports for the Methylphenidate Products**

- December 4, 2003 – January 4, 2005

- * One case in a 16 year old male who had been off Concerta® for 7 days who had cardiac arrest and was found with cocaine powder

## Deaths in Pediatric Patients Taking Methylphenidate Products

- December 4, 2003 – January 4, 2005

- 16-year-old male received Concerta® for bipolar disorder for 2 days.  Concerta® was replaced with Adderall®.  Seven days after discontinuing Concerta®, the patient was found in cardiac arrest with cocaine powder in his lap and was pronounced brain dead.

## Deaths in Pediatric Patients Taking Methylphenidate Products

- December 4, 2003 – January 4, 2005

- 12-year-old male received Ritalin SR® from May 2002, which was changed to Ritalin LA® in July 2003.  He also received medications for asthma.  He collapsed on the playground in August 2003 and could not be resuscitated.  No acute history of asthma exacerbation was reported.  Autopsy showed mild lung inflammation and cerebral edema but was inconclusive regarding cause of death.

## Non-fatal Cardiac Arrest in a Pediatric Patient Taking Methylphenidate Products

- December 4, 2003 – January 4, 2005

- 13-year-old male with coarctation of the aorta and two mitral valve replacements who was on the heart transplant list because of long-standing dilated cardiomyopathy with a history of sick sinus syndrome and ventricular fibrillation who received Concerta® for an “extended duration”.  The patient experienced a cardiac arrest, was resuscitated, and had a pacemaker defibrillator inserted.  Concerta® was continued for 2 more weeks.

## Categories of Adverse Events Reported for Methylphenidate ProductsDecember 4, 2003 – January 4, 2005

| AE Category | Concerta® | Other Methylphenidate Products |
| --- | --- | --- |
| Total | 135 | 96 |
| Psychiatric | 36 | 16 |
| Cardiovascular | 20 | 4 |
| Neurological | 16 | 18 |
| Gastrointestinal | 11 | 5 |
| Hematological | 10 | 4 |
| Miscellaneous | 7 | 8 |
| Special Senses | 7 | 2 |
| Cerebrovascular | 2 | 4 |
| Overdose/abuse | 3 | 2 |
| Lack of effect | 3 | 13 |
| Skin | 0 | 4 |
| Thyroid | 1 | 4 |
| Respiratory | 0 | 5 |
| Significant Confounding Variables | 19 | 7 |

## Pediatric Adverse Event Reports for Concerta® December 4, 2003 – January 4, 2005

## Raw Counts of Adverse Event Reports for Concerta®#December 4, 2003 – January 4, 2005

| Age | All Reports (U.S.) | Serious (U.S.) | Death (U.S.) |
| --- | --- | --- | --- |
| All Ages (Includes age not specified) | 265 (144) | 243 (123) | 13 (13) |
| Adults 
(>17 years) | 56 (46) | 51 (41) | 10 (10) |
| Pediatric 
(0-16 years) | 164 (77) | 149 (63) | 3 (3)* |

- * Two deaths occurred in adults (17 year olds), and one death attributable to cocaine use

- # Includes duplicate reports

## Pediatric Adverse Event Reports for Concerta® December 4, 2003 – January 4, 2005

- 164 Total Reports
- 2 involved adults
- 5 are duplicate reports
- 14 involve non-Concerta® methylphenidate products
- 143 Unduplicated Reports
- 8 cases where no adverse event was reported
- Leaving 135 Reports

## Confounding Variables in 19 Cases

- Adverse event started before Concerta® (1)
- Adverse event started after Concerta® discontinued (2)
- Adverse event consistent with pre-existing or familial illness (4)
- Adverse event temporal to use of another drug for which the event is a known effect (7)
- Adverse event resolved during ongoing Concerta® use (5)

**Pediatric Adverse Event Reports for Concerta****®**** ****December 4, 2003 – January 4, 2005**

**Notes:**
This slide summarizes the reasons that 19 Concerta cases were categorized as strongly confounded by the FDA Safety Evaluator who performed the review.  

These are the primary reasons for confounding.  Some cases have multiple factors.  For example, in the Concerta death case described earlier, the adverse event occurred after Concerta was discontinued AND was temporal to cocaine use.  There may be secondary reasons not described here for some cases as well.  For example, a case of diabetes mellitus type 1 developing during Concerta use was confounded by the patient’s family history of diabetes mellitus type 1 but the absence of other cases also contributed to the decision to consider this case confounded.

## Characteristics of Pediatric Adverse Event Report Outcomes and Indications for Concerta® December 4, 2003 – January 4, 2005N=135 Unduplicated Reports

| Characteristic |  | Number of Reports |
| --- | --- | --- |
| Origin | Foreign | 77 |
|  | U.S. | 58 |
| Gender | Female | 26 |
|  | Male | 108 |
|  | Unknown | 1 |
| Age | 0 - <1 month | 0 |
|  | 1 month - < 2 years | 0 |
|  | 2-5 years | 1 |
|  | 6-11 years | 82 |
|  | 12-16 years | 52 |

## Characteristics of the Pediatric Adverse Event Reports for Concerta® December 4, 2003 – January 4, 2005N=135 Reports

| Characteristic |  | Number of Reports |
| --- | --- | --- |
| Outcome box checked on MedWatch form
(multiple boxes may be checked on one report)
 | Death | 1 |
|  | Hospitalization | 39 |
|  | Life Threatening | 5 |
|  | Required Intervention | 1 |
|  | Medically Important/Other | 95 |
|  | Disability | 5 |
|  | No Outcome Selected | 7 |
| Indication for methylphenidate use | ADHD/Hyperactivity/ADD | 108 |
|  | Disturbance in attention;
Learning disability; Oppositional defiant; Developmental disorder; Tourette’s | 6 |
|  | Unknown | 21 |

## Categories of Adverse Event Reports for Concerta®December 4, 2003 – January 4, 2005N=135 Reports

| Adverse Event Category | Number of Reports |
| --- | --- |
| Psychiatric adverse events | 36 |
| Cardiovascular adverse events | 20 |
| Neurological adverse events | 16 |
| Gastrointestinal adverse events | 11 |
| Hematologic adverse events | 10 |
| Miscellaneous adverse events | 8 |
| Special senses adverse events | 7 |
| Cerebrovascular adverse events | 2 |
| Overdose/abuse | 3 |
| Lack of effect | 3 |
| Significant Confounding Variables | 19 |

## Reported Concerta® Adverse Event Signs/Symptoms Compared to Labeling

**Labeled**

**Exact Wording**

**Similar **
**Wording/Meaning**
**(e.g., tremors - **
**shaking, trembling)**

**Unlabeled**

**Open to interpretation**
**(e.g., anxiety as mentioned**
** ****in contraindications)**

**Not Mentioned**

## Psychiatric Adverse Events Reported with Concerta®December 4, 2003 – January 4, 2005 (N=36 cases)

**Agitation/behavior disturbance (15)**
- Resolved/improved when d/c Concerta**®** (9)
- Improved when d/c Concerta**®** & alternative therapy (1)
**Psychosis/hallucination/visual hallucination (12)**
- Resolved/improved when d/c Concerta**®** (8)
**Suicidal ideation / suicide attempt (11)**
- Resolved when d/c Concerta**®** (5)
- Improved when d/c Concerta**®** & alternative therapy (1)
**Anxiety (8)**
- Resolved/improved when d/c Concerta**®** (6)
- Resolved when d/c Concerta**®** & alternative therapy (1)
- Resolved when Concerta**®** dose decreased (1)
- NOTE:  A case may report more than one adverse event

## Psychiatric Adverse Events Reported with Concerta®December 4, 2003 – January 4, 2005 (N=36 cases) (Cont.) 

**Sleep disturbance (6)**
- Resolved/improved when d/c Concerta**®** (3)
- Resolved when d/c Concerta**®** & alternative therapy (1)
**Obsessive/Compulsive reaction (4)**
- Resolved/improved when d/c Concerta**®** (3)
**Mania (1)**
- Resolved when d/c Concerta**®** (1)
**Euphoria (2)**
- Resolved when d/c Concerta**®** (1)
**Depression (2)**
- Resolved when d/c Concerta**®** (2)
- NOTE:  A case may report more than one adverse event

## Psychiatric Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=36 Cases

- Reported events
- Anxiety (fearfulness, phobia, panic attack)
- Agitation/Behavioral Disturbance (violent behavior, aggression, self-injurious behavior, crying, disinhibition, abnormal behavior, change in behavior, irritability, and social withdrawal)
- Psychotic behavior, and abnormal thinking
- Contraindications in Concerta® Label
- Concerta® is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms
- Warnings in Concerta® Label
- Clinical experience suggests that in psychotic patients, administration of methylphenidate may exacerbate symptoms of behavior disturbance and thought disorder

## Psychiatric Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=36 Cases

- Events Labeled Under Adverse Reactions:
- Sadness, insomnia, anorexia, increased waking, decreased appetite, sleep disorder, and headache
- Events Labeled Under Other Methylphenidate Products:
- Choreoathetoid movements
- Transient depressed mood (depression)
- Toxic psychosis (hallucinations, visual hallucinations)
- Events Labeled Under Overdosage:
- Euphoria,
- Hallucinations (visual hallucinations)
- Tremor (trembling, shaking)
- Events Labeled Under Information for Patients:
- Psychosis (abnormal thinking or hallucinations)

## Psychiatric Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=36 Cases

- Unlabeled Events:
- _Suicidal ideation_, _suicide attempt_,
- _Obsessive compulsive reaction_ (_trichotillomania_, _pica_, _rumination_),
- _Bad dreams_,
- _Listlessness_,
- _Psychomotor slowdown_,
- _Mania_

- _Underlined_ = Not labeled

## Cardiovascular Adverse Events Reported with Concerta®December 4, 2003 – January 4, 2005 (N=20 cases)

- Hypertension / increased blood pressure (5)
- Resolved when d/c Concerta**®** (4)
- Tachycardia (5)
- Resolved when d/c Concerta**®** (2)
- Syncope (2)
- Resolved when d/c Concerta**®** (1)
- Chest pain (7)
- Resolved when d/c Concerta**®** (4)
- NOTE:  A case may report more than one adverse event

## Cardiovascular Adverse Events Reported with Concerta®December 4, 2003 – January 4, 2005 (N=20 cases) (Cont.)

- Left atrial enlargement per EKG (1)
- Dizziness (2)
- Headache (3)
- Dyspnea / dyspnea on exertion (4)
- Vomiting (1)
- Sweating (1)
- Abnormal EKG (1)
- Increased QT interval (2)
- Supraventricular extrasystoles per EKG (1)
- Peripheral vasoconstriction / obstruction (2)
- NOTE:  A case may report more than one adverse event

## Cardiovascular Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=20 Cases

- Events Labeled Under Warnings:
- Hypertension, and tachycardia
- Events Labeled Under Adverse Reactions:
- Dizziness
- Events Labeled Under Other Methylphenidate Products:
- Chest pain, supraventricular extrasystoles, cardiac arrhythmia, and AV block

## Cardiovascular Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=20 Cases

- Unlabeled Events:
- _Increased QT interval_
- _Syncope_
- _Left atrial enlargement on EKG_
- _Dyspnea_, _exertional dyspnea_
- _Peripheral vascular obstruction with cyanosis in toes_, _peripheral vasoconstriction_

- _Underlined_ = Not labeled

## Neurological Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=16 Cases

- Events Labeled Under Warnings:
- Seizures, epilepsy, focal epilepsy, and absence seizures
- Events Labeled Under Adverse Reactions:
- Visual disturbance, dystonia, tics, sleep disorder, dyskinesia, restlessness,  and headache
- Events Labeled Under Overdosage:
- Disorientation, tremor (shaking), and confusion

## Neurological Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=16 Cases

- Unlabeled Events:
- _Aching extremities_, _leg numbness_, _asthenia_, _retrograde amnesia_, _sleep walking_, _eye pain_, _decreased consciousness_, and _brain tumor and cyst_

- _Underlined_ = Not labeled

## Special Senses Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=7 Cases

- Reported event
- Increased intraocular pressure
- Contraindications in Concerta® Label
- Concerta® is contraindicated in patients with glaucoma

## Special Senses Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=7 Cases

- Events Labeled Under Warnings:
- Visual disturbance (transient blindness, loss of color vision)
- Diplopia (strabismus)

## Special Senses Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=7 Cases

- Unlabeled Events:
- _Abnormal eye movements_
- _Retinopathy_
- _Nystagmus and vertigo_

- _Underlined_ = Not labeled

## Cerebrovascular Adverse Events Reported with Concerta®December 4, 2003 – January 4, 2005 (N=2 cases)

- One case each:
- Cerebral aneurysm
- Unspecified cerebrovascular disorder with hallucinations

## Cerebrovascular Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=2 Cases

- Events Labeled Under Other Methylphenidate Products:
- Cerebrovascular disorder

## Cerebrovascular Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=2 Cases

- Unlabeled Events:
- _Cerebral aneurysm_

- Underlined = Not labeled

## Concerta® Timeline

- August 1, 2000
- Market Approval

- December 4, 2003
- Pediatric Exclusivity Granted

- January 4, 2005
- One Year Post-Exclusivity Review

- Post-Exclusivity

- Post-Marketing

## Raw Counts of Adverse Event Reports for Concerta®#August 1, 2000 – January 4, 2005

| Age | All Reports (U.S.) | Serious (U.S.) | Death (U.S.) |
| --- | --- | --- | --- |
| All Ages (Includes age not specified) | 936 (711) | 862 (639) | 52 (47) |
| Adults 
(>17 years) | 162 (136) | 152 (126) | 35 (32) |
| Pediatric 
(0-16 years) | 642 (479) | 599 (438) | 16 (14) |

- # Includes duplicate reports

## Deaths in Pediatric Patients Taking Concerta® Following Market ApprovalAugust 1, 2000 (N=7)

- Suicide/Overdose (3)
- 14 y.o. on Zoloft® and Concerta® committed suicide
- 13 y.o. on Wellbutrin® and Concerta® died of methylphenidate overdose
- 15 y.o. with Tourette’s and autism on Concerta® committed suicide by hanging
- Cardiovascular (2)
- 13 y.o. on Zyrtec® and Concerta® died in sleep (cardiac arrhythmia)
- 13 y.o. on Concerta® with a history of syncope died a sudden cardiac death with polymorphic ventricular tachycardia
- Other (2)
- 9 y.o. with a history of asthma on Claritin®, Flovent® and Concerta® had viral symptoms with vomiting and coughing.  Arrested after increased respiratory distress.  Methylphenidate level 156ng/mL (therapeutic 3.7-6.8ng/mL)
- 16 y.o. off Concerta® for 7 days found dead with cocaine powder

## Summary:  Concerta® Adverse Event Report ProfileDecember 4, 2003 – January 4, 2005

- 135 unduplicated pediatric reports
- Majority of use and adverse events seen in the 6-11 year old population

## Summary:  Concerta® Adverse Event Report ProfileDecember 4, 2003 – January 4, 2005 (Cont.)

- Psychiatric adverse events
- Anxiety and agitation
- _Contraindications_ section states contraindicated in patients with marked anxiety, tension, and agitation since the drug may aggravate these symptoms
- Thought and behavior disturbance, psychosis, visual hallucination and visual disturbance
- _Warnings_ section states methylphenidate may exacerbate symptoms of behavior disturbance and thought disorder
- _Warnings_ section states visual disturbances have been rarely encountered
- Toxic psychosis, transient depressed mood
- _Adverse Events With Other Methylphenidate Products_ section
- Psychosis (abnormal thinking or hallucinations)
- _Information for Patients Taking Concerta__®_ section
- Suicidal ideation is unlabeled

## Summary:  Concerta® Adverse Event Report ProfileDecember 4, 2003 – January 4, 2005 (Cont.)

- Cardiovascular adverse events
- Increase in pulse and blood pressure
- _Warnings_ section
- Blood pressure and pulse changes (both up and down), angina, and cardiac arrhythmia
- _Adverse Events With Other Methylphenidate Products_ section
- Tachycardia, palpitations, cardiac arrhythmias, and hypertension
- _Overdosage_ section
- Prolonged QT interval and syncope are unlabeled

## Summary:  Concerta® Adverse Event Report ProfileDecember 4, 2003 – January 4, 2005(Cont.)

- Need to examine adverse event reports in other stimulant products with respect to the psychiatric adverse events
- Need to characterize the cardiovascular risks for all stimulant drug products
- Plan to revise the label to ensure clarity so that all prescribers and patients are appropriately informed

## Acknowledgements

_**DDRE/ODS**_
- Kathleen M. Phelan, R.Ph.
- Mark Avigan, M.D.

_**DNDP**_
- Glenn Mannheim, M.D.
- Paul Andreason, M.D.
_**DSRCS/ODS**_
- Laura Governale, Pharm, D., MBA
- Sigal Kaplan, Ph.D., B.Pharm.
- Gerald Dal Pan, M.D., MHS

## Additional Slides

## Hematologic Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=10 Cases

- Events Labeled Under Other Methylphenidate Products:
- Iron deficiency anemia
- Neutropenia, and granulocytopenia
- Hypersensitivity (Henoch-Schonlein purpura, thrombocytopenia, petechiae, eosinophilia)

## Hematologic Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=10 Cases

- Unlabeled Events:
- _Hematoma_
- _Lymphocytosis_
- _Leukocytosis_

- _Underlined_ = Not labeled

## Gastrointestinal Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=11 Cases

- Events Labeled Under Other Methylphenidate Products:
- Increased liver function tests, hepatitis, and lack of weight gain
- Events Labeled Under Adverse Reactions:
- Anorexia, stomachache (esophagitis), and diarrhea

## Gastrointestinal Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=11 Cases

- Unlabeled Events:
- _Gallstones_
- _Acute cholecystitis_
- _Appendicitis_

- _Underlined_ = Not labeled

## Miscellaneous Adverse Events Reported with Concerta® December 4, 2003 – January 4, 2005N=8 Cases

- Events Labeled Under Warnings:
- Growth retardation
- Events Labeled Under Other Methylphenidate Products:
- Erythematous rash, peripheral swelling and fever
- _Unlabeled Events:_
- _Acute pulmonary edema_, and _bradycardia_ (after intranasal phenylephrine)
- _Acute renal failure_
- _Hyperthyroidism_
- _Hypoglycemia_
- _Pregnancy and spontaneous abortion_
- _Increased incidence of herpetic eye infections_

- _Underlined_ = Not labeled

## Adverse Findings in Clinical Trials With Concerta®

## Contraindications in Concerta® Label 

## Warnings in Concerta® Label 

## Warnings in Concerta® Label 

## Warnings in Concerta® Label 

## Warnings in Concerta® Label

## Concerta® Label for Adverse Events with Other Methylphenidate Products

## Overdosage in Concerta® Label

## Pediatric Adverse Event Reports for Concerta® December 4, 2003 – January 4, 2005Re-challenge Information

- Psychiatric adverse events
- 15 year old psychiatric and non-psychiatric adverse events reported.  Unspecified symptoms recurred on restarting Concerta®
- 10 year old with hallucination, diplopia and headache with Concerta®, events resolved off Concerta®, re-challenge with one dose resulted in chest pain and back pain, events resolved off Concerta®
- Cardiovascular adverse events
- 11 year old with hypertension, dizziness, chest pain, left atrial enlargement after 4-5 months of Concerta®, events resolved off Concerta®, no recurrence at 9 days after re-challenge
- 14 year old with cardiac arrhythmia, AV block, and increased QT interval after more than a year of Concerta®, no recurrence on re-challenge after the addition of a beta-blocker