# Presentation: 697383

## SPARLONTM (Provigil ® / Modafinil)Cephalon Inc.NDA 20-717 (S-019)

- Psychopharmacologic Drugs Advisory Committee
- Gaithersburg, Maryland
- March 23, 2006
- Glenn B. Mannheim, M.D.
- Division of Psychiatry Products

**Center for Drug Evaluation and Research**** **

## OUTLINE

- Background
- Overview of Safety Database
- Common AE’s
- Other AE’s
- Psychiatric AE’s`
- Rashes
- Potential Public Health Impact
- Closing Comments

## Modafinil Background

- Approved as a wakefulness-promoting agent in adults with excessive daytime sleepiness (EDS) associated with narcolepsy [1998]
- Approved for EDS associated with Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS) and Shift Work Sleep Disorder (SWSD) [2003]
- Recommended Dosing:
- 200 mg once a day (2.67 mg/kg)
- Narcolepsy + OSAHS: single AM dose
- SWSD: 1 hr prior to the start of work shift
- Doses > 200 mg, no additional benefit
- Available Tablets: 100, 200 mg

## Current Submission

- ADHD
- Children (6-11 Yrs)
- Adolescents (12-17 Yrs)
- Dosage and Administration
-  Maintenance Dose
- <  30 kg 340 mg qd
- 21 mg/kg, highest dose; 7.9 times higher than adult dose
- _>_ 30 kg 425 mg qd
- 14 mg/kg, highest dose; 5.3 times higher than adult dose
- Titration
- Initial dose 85 mg
- Increase in steps of 85 mg q 2 – 7 days
- Availability: 85, 170, 255, 340 and 425 mg Tablets

## Study Population

- 6-17 yrs with DSM-IV ADHD, in full time school
- Moderately to severely ill or greater (CGI-S  4),
- WISC-III and WIAT-II-A 80: Minimal LD
- Excluded:
- Psychiatric co-morbidities
- Psychotic disorder, suicide risk, depression, mood, anxiety disorder, substance abuse, etc.)
- Stimulant non-responders  ( 2 courses)
- Abnormal labs (e.g. ANC  1000/mm3 )
- Clinically significant illness   4 wks baseline

## Studies

- Pivotal Studies:
- Studies 309 & 311
- Identical 9 week, DB, *flexible dose, weekly titration*
*170 mg, 255 mg, 340 mg, 425 mg*
- Study 310
- 7 week, DB, *fixed dose*
-  30 kg; 340 mg/day
- _>_ 30 kg: 425 mg/day
- 2 week randomized withdrawal
-           Modafinil to Modafinil or PBO
-           PBO to PBO

## * 358 received proposed labeled efficacious doses

| Extent of Exposure by Dose in Phase 3 Studies |  |  | Number of patients treated |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  |  |  | Modafinil (mg/day)a |  |  |  |
|  |  |  | ≤255 | 340 | 425 | PBO |
| 309 | Flexible-dosage, parallel-group | 9 weeks | 31 | 22 | 78 | 67 |
| 310 | Fixed-dosage, parallel-group | 9 weeks | 0 | 44 | 81 | 64 |
| 311 | Flexible-dosage, parallel-group | 9 weeks | 31 | 36 | 97 | 82 |
| Subtotal |  |  | 62  | 102  | 256  | 213  |
| Total  |  |  | 420 |  |  |  |

## Sponsor’s Summary Of Pediatric Trials (From Briefing Document)

## PK Exposure in Peds vs. Adultswith Therapeutic Doses

-     Obtained from Study C1538a/113/PK/US
- ** Obtained from Study C1538a/404/PK/US – Dose 400 mg

| Parameter | Analyte | Adults** |  Children and Adolescents* |  |
| --- | --- | --- | --- | --- |
|  |  |  | WT  30 kg | WT < 30 kg |
|  |  | N = 13 | N = 11 | N = 13 |
|  |  | PROVIGIL
Normalized to 200 mg QD
x 21 D | Modafinil
425 mg QD
x 14 D | Modafinil
340 mg QD
x 14 D |
| Cmax | Modafinil | 6.4  0.75 | 16.0  3.00 | 19.5  4.44 |
|  | Modafinil Acid | 2.65  0.5 | 5.4  1.09 | 4.9  1.28 |
|  | Modafinil Sulfone | 1.85  0.8 | 11.8  7.25 | 29.0  15.7 |
| AUCtau | Modafinil | 73.5  13.3 | 177  28.5 | 199  45.4 |
|  | Modafinil Acid | 26.7  5.0 | 61.3  11.4 | 54.7  61.3 |
|  | Modafinil Sulfone | 38.8  1.7 | 251  154 | 629  349 |
| Sulfone AUC Ratios
Sub-Population : Adults |  | 1.0 | 6.5 | 16.2 |
| Maximum Daily Dose (MDD) (mg/kg) |  | 2.67 | 14.2 | 21.25 |
| MDD Ratios |  | 1.0 | 5.3 | 8.0 |

## Adverse Events

## Incidence of Common Treatment-Emergent Adverse Experiences in Phase 3 Double-Blind Placebo Controlled Studies By 2 % Subjects Treated With Modafinil That Were More Frequent Than Placebo Group

| Body System | Preferred Term | Modafinil
(n = 420) | Placebo
(n = 213) |
| --- | --- | --- | --- |
| Body as a Whole | Headache | 20% | 13% |
|  | Abdominal Pain | 10% |   8% |
|  | Fever |   5% |   3% |
|  | Pain |   3% |   2% |
| Nervous | Insomnia | 27% |   4% |
|  | Nervousness |   5% |   4% |
|  | Dizziness |   2% |   1% |
| Digestive | Nausea |   4% |   2% |
|  | Dry Mouth |   2% |   1% |
|  | Dyspepsia |   2%                                        |   1% |
|  | Gastroenteritis |   2% |   1% |
|  | Anorexia  | 16% |   3% |
| Metabolic/Nutritional | Weight Loss |   4% |   1% |
| Hemic/Lymphatic | Ecchymosis |   2% |   0% |
| Skin/Appendages | Rash |   4% |   2% |

**Incidence of **_**Common**_** Treatment-Emergent ****Adverse Experiences in Phase 3**** Double-Blind Placebo Controlled Studies By 2 % Subjects Treated With Modafinil That Were More Frequent Than Placebo Group**
** **

## NOTABLE PSYCHIATRIC AE’S

- Psychosis: 5/933 (0.5 %)
- Formication (one day after d/cing drug)
- Command auditory hallucinations with suicidal ideation requiring hospitalization
- Other hallucinations (two cases)
-  Ideas of referential control (abnormal thinking)
- Suicidal Events 6/933 (0.6%)
- 5 ideation
- 1 attempt
- None completed
- Suicidal behavior was infrequent among non–medicated ADHD PBO subjects (Mosholder Review).

## Other Clinically Significant Adverse Events 

**Other Clinically Significant Adverse Events**

## RASHES

- Phase 3, Double-Blind: 4 % (Modafinil), 2 % PBO
- All subjects exposed: 49/933 (5 %) had rash
- Dropouts Phase III PC Studies:
- Modafinil: 1/420 (0.24%); PBO: 0/213 (0%)
- Dropouts, All Studies:
- 26/101 (26 %) subjects who dropped out had a rash as an AE
- 13/933 (1.4 %) drop-out due to _rash_
- Rashes varied in spectrum of severity
- 	-   8 with rash also had fever
- 	-   2 with rash also had elevated LFT's
- 		  (17x ULN-ALT and 3.5 ULN-GGT )

## SERIOUS SKIN REACTIONS

- Erythema multiforme, Steven Johnson Syndrome (EM/SJS):  2
- Peeling and blistering over entire body with lips and urinary tract involvement (Study 311)
- _Drug stopped but rash progressed_ to peeling, blistering, mucosal involvement over days.
- Maculopapular, morbilliform, pruritic (Study 207)
- _Drug stopped but rash progressed_
- _Hospitalized_
- Other Rashes
- Vesiculobullae cheeks with severe lip blisters (Study 207)
- Unspecified rash in 7 yr. old with a _positive re-challenge_: day 24 onset; TX. Prednisone, Benadryl; recurred when restarted at 85 mg on day 34 (Study 312)

## OTHER SKIN REACTIONS	

- Possible Allergic Events: 22/933 (2.4 %)
- Hives, urticaria
- Facial Edema
- Pruritus
- Allergic Reactions
- Red lips
- Eczema with LFTs
- Probable Non-Allergic Events
- Alopecia
- Tongue blotches
- Herpes zoster
- Plantar warts
- Ringworm

## Case 1: Subject ID 062338, Study 311 

- 7 y.o. female with unremarkable medical Hx
-  started, titrated to 340 or 425 mg/day X 2 weeks (d 14)
- 2 days later (d 16), fever (101.9 deg), sore throat, mild rash (red bumps)
- Next day (d 17) received 1 dose of amoxicillin, stopped
- Next day (d 18) _modafinil stopped__ _
- Over next 4 days _rash worsens and progresses_
- D 19: Multiple pruritic areas arms/stomach
- D 22: Rash *progresses *to face
- D 23: Mucosal involvement in 2 areas
- Urethral meatus: burning on urination
- Swollen, crusty lips
- D :  Extensive skin pealing; palms and soles later involved
- D 30: No new lesions, event resolved
- D 31 (or, d 26): Given 1 dose of modafinil, itching worsens
- D 44: Withdrawn from Study: SJS resolved, EM *continues*

## Case 2: Subject ID 315, Study 207 

- 11 y.o. female with inattentive ADHD, Turner’s syndrome, nocturnal enuresis on somatotropin (7.5 yrs) & desmopressin (4 mths)
- Started/titrated modafinil 200 mg/day for 1st week, then 100 mg/day for 2nd week
- D 4: Fever, abdominal pain, diarrhea lasting 9 days
- D 14: ER for pruritic urticaria: face, chest; _Drug Stopped_
- Tx. Diphenhydramine
- D 15: _Rash Worsens_
- _Hospitalized_ with provisional diagnosis of SJS
- No mucosal involvement
- Diagnosed as moderate morbiliform rash
- Tx. Hydroxyzine
- Rash resolved in 1 week
- Accepted by sponsor as compatible with SJS

## Case: Subject ID 18004, Study 213 

- 8 y.o. male with ADHD
- Started/titrated modafinil 200/200 mg/day for 2.5 wks (19 days)
- D 14: Fever, moderate rash on cheeks
- _Rash Progressed_
- D 17: Severe blistering on lips
- Vesiculobullous rash
- D 19: _Modafinil stopped_
- Recovered
- Time Course Not Specified
- Treatment: cephalexin (rash), Tylenol with codeine (fever, pain)

## FDA DERMATOLOGY CONSULTATION  (Dr. Porres)

- Definite Cases Representing EM/SJS
- All Studies (2/933; 0.2 %)
- Early Prodromal EM/SJS
- All Studies (3/933; 0.32 %)
- Insufficient Information But History Suggestive of Prodromal EM/SJS
- All Studies (7/933; 0.75 %)

## SPONTANEOUS U.S. POST-MARKETING REPORTS OF SERIOUS SKIN REACTIONS FOR MODAFINIL

- 6 Reports of Serious Skin Reactions
- All Adults (18 and Over):
- 5 EM/SJS,  Biopsy Confirmed
- 4 Hospitalized
- 1 Death, Confounded By Concomitant Drugs and Medical Conditions
- 1 Dermatitis Bullous
- Because of under-reporting the true number of cases is likely to be greater

## Erythema Multiforme – 
Stevens Johnson Syndrome

Possible Hypersensitivity Reactions ?

- Stevens Johnson Syndrome
- Possible Hypersensitivity Reactions ?

## Possible Cross-Sensitivity with Sulfa Drugs

- Subject ID’s 056003-Study 311; 056180, Study 312
- 9 y.o. male
- H/O sulfamethoxazole trimethoprim allergy
- Normal labs and physical at baseline and during DB PBO (Study 311)
- Open label modafinil started (Study 312)
- After 10 days: urticaria, face edema, fever (99.6oF), vomiting
- After 14 days: increased ALT (17 X ULN), AST (10 X ULN)
- After stopping drug and supportive treatment, recovers

## Potential Public Health Impact

- EM/SJS Background Rate: 1-2/ 1,000, 000/Yr (0.00015 %)
- (Rzany B, et al. Lancet 1999; 353: 2190-94; Rzany B, et al. J Clin Epi 49: 7:769-773, 1996)
- EM/SJS Observed: 2/933 (0.214%)
- Compatible/Suggestive of Early EM/SJS: 3/933 (0.3 %, 3/1,000)
- Insufficient Information, But Hx Suggesting Prodromal EM/SJS: 7/933 (0.75 %, 7/1,000)
- Definite + Possible Cases: 12/933 (1.3 %, 13/1,000)
- Range of  Risk: 0.2% - 1.3 %

## ESTIMATED USAGE

- 2.5 million Children (4-17 Years) On ADHD Meds
- (CDC Study-2003; MMWR Prevalence of Diagnosis and Medication Tx for ADHD-U.S. 2003,  09/02/05, pp. 842-847)
- Assumed Market Share of Provigil: 10 %
- Basis for Assumption: Atomoxetine at 16.4 % is currently at low end compared to other stimulants (dispensed prescriptions for ages < 19 years, Jan-Jun 2005)*

- *Vector One®: National, Dispensed Prescriptions Jan-Jun 2005, Extracted January 2006.

## ESTIMATED CASES EM/SJS

- 250,000 children switched to Modafinil
- 2.5 million children receiving medication for ADHD
- 10% market share
- 500 – 3250 Cases EM/SJS
- 0.2% - 1.3% incidence
- 25 – 488 Deaths / each 10% market share
- 5% - 15% mortality (Dermatol Online J 2002 Jun; 8 (1): 5)

## “There is no satisfactory method for determining who is at greatest risk for developing drug associated SJS and TEN and hence of preventing it, short of avoiding drugs altogether. There has been a single study suggesting that early withdrawal of the agent at the first sign of the illness may improve the outcome (Mittman N, et. al. Drug Safety 2004; 27 (7): 477-87). Although this intuitively makes sense, this study needs to be replicated. Even if it is proven correct, its practical application will be limited because it is very difficult to identify the very earliest lesion in a timely manner because of the rapidly progressive nature of this illness and the non-specific features of its prodrome.”

La Grenade L, ET. Al. Comparison of Reporting of Stevens - Johnson syndrome and Toxic Epidermal Necrolysis in Association with Selective COX-2 Inhibitors.  Drug Safety 2005: 28 (10): 917-924

- La Grenade L, ET. Al. Comparison of Reporting of Stevens - Johnson syndrome and Toxic Epidermal Necrolysis in Association with Selective COX-2 Inhibitors.  Drug Safety 2005: 28 (10): 917-924

- WILL LABELING WORK?

## CLOSING COMMENTS

- ADHD is a serious condition usually not considered to be associated with a fatal outcome.
- Exposure to a sulfone metabolite is significantly greater (up to 16 times) in children than adults. This raises questions about the relevancy of the adult safety experiences to pediatric use.

## CLOSING COMMENTS (CONT)

- The relationship of this metabolite to rash is speculative, but it has structural similarities to drugs known to cause EM/SJS which can be fatal.
- The incidence of EM/SJS observed in these studies is at minimum hundreds of times background.
- The age ranges of the rashes appear skewed towards subjects  12 years, those having a higher sulfone exposure.
- Doses lower than 340 mg has been shown to limit efficacy, hence dose reduction is not a reliable option.

## CLOSING COMMENTS (CONT)

- Although some cases with rash got better (positive dechallenge), one severe case _progressed after discontinuing_ the drug.
- One subject with rash was _hospitalized_ but there was disagreement about the diagnosis.
- One child with a H/O of reactions to sulfa drugs developed a _hypersensitivity reaction_ with transaminase elevation  (17 X ULN) with urticaria, fever and facial edema, 10 days after starting modafinil which raises the hypothesis of cross-sensitivity with sulfa drugs.

## CLOSING COMMENTS (CONT)

- Psychosis and suicidality, although not statistically significant were more frequent in subjects on modafinil than with PBO.
- Insomnia was present in 27 % subjects on modafinil vs. 4 % in PBO, and anorexia occurred in 16 % vs. 3 % in the DB, Phase 3 trials.

## CDER FDA Review Team

_**Regulatory Project Manager (DPP)**_** **
- Richardae Araojo, Pharm. D.
- Susan Player,  RN, MS, APRN, BC
_**Clinical**_**  **
_**(DPP)**_**	**
- Glenn B. Mannheim, M.D. (Initial Review)
- June Cai, M.D. (Response to Approv. Ltr)
- Gregory M. Dubitsky, M.D. (Consultant)
- Paul Andreason, M.D., Act Deputy Director
- Thomas Laughren, M.D., Director
_**(DNP**_**)**
- Judith A. Racoosin, M.D., M.P.H. (Safety)
- Marc B. Stone, M.D. (Safety)
- Norman Hershkowitz, M.D., Ph.D.
- Russell G. Katz, M.D., Director
_**Dermatology**_
- Joseph M. Porres, M.D., Ph.D.
- Markham C. Luke, M.D., Ph.D
_**Office of Pharmacoepidemiology**_ _**(OPaSS)**_
- John R. Senior, M.D.
- .

_**Division of Drug Risk Evaluation **_
- Andrew D. Mosholder, M.D., M.P.H.
- Kate Gelperin, M.D., M.P.H.
- Lois La Grenade, M.D., M.P.H.
- Cindy Kortepeter, Pharm.D.
- Marilyn R. Pitts, Pharm.D. (Safety Evaluator), Team Leader
_**Pharm/Tox (DPP)**_
- Aisar Atrakchi, Ph.D.
- Barry Rosloff, Ph.D., Team Leader
_**Clinical Pharmacology (OCBP)**_
- Christine Garnett, Ph.D.
- Ramana Uppoor, Ph.D., Team Leader
- Joga Gobburu, Ph.D., Team Leader
- Ron Kavanagh, B.S.Pharm., Pharm.D., Ph.D.
_**Division of Biometrics **_
- Tristan Massie, Ph.D.
- Peiling Yang, Ph.D., Act. Team Leader