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Selegiline Transdermal Selegiline Transdermal System System (STS)(STS)
FDA Psychopharmacologic Drugs FDA Psychopharmacologic Drugs Advisory CommitteeAdvisory Committee
October 26, 2005October 26, 2005
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IntroductionIntroductionMelissa Goodhead, BSc, RACMelissa Goodhead, BSc, RACGroup Director, Regulatory Affairs / Group Director, Regulatory Affairs / Quality AssuranceQuality AssuranceSomerset PharmaceuticalsSomerset Pharmaceuticals
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FDA QuestionsFDA Questions
Do the available data for the EMSAM 20 mg Do the available data for the EMSAM 20 mg patch support the reasonable safety of this patch support the reasonable safety of this formulation without the need for dietary formulation without the need for dietary restrictions?restrictions?
If the EMSAM 20 mg patch formulation could be If the EMSAM 20 mg patch formulation could be considered reasonably safe for marketing considered reasonably safe for marketing without the need for dietary restrictions, would without the need for dietary restrictions, would it be acceptable to market the 20 mg patch it be acceptable to market the 20 mg patch without dietary restrictions and at the same without dietary restrictions and at the same time require dietary restrictions for the 30 and time require dietary restrictions for the 30 and 40 mg patch strengths?40 mg patch strengths?
1.
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Selegiline – Presentation AgendaSelegiline – Presentation Agenda
OverviewOverview . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .
Safety Safety –– Tyramine Tyramine . . . . . . . . .. . . . . . . . .
Physician & PatientPhysician & PatientAwareness Program Awareness Program . . . . . . .. . . . . . .
Conclusion Conclusion –– Q&A Q&A. . . . . . . . . . . . . . . . . .
Sheldon Preskorn, MDSheldon Preskorn, MD
Lawrence F. Blob, MDLawrence F. Blob, MD
Chad VanDenBerg, PharmDChad VanDenBerg, PharmD
Melvin Sharoky, MDMelvin Sharoky, MD
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OverviewOverviewSheldon Preskorn, MDSheldon Preskorn, MDChairman, Department of PsychiatryChairman, Department of PsychiatryUniversity of Kansas, WichitaUniversity of Kansas, Wichita
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OverviewOverview
Clinical DepressionClinical Depression
Characteristics of MAOICharacteristics of MAOI
Oral MAOI and tyramineOral MAOI and tyramine
Medical need for MAOI without dietary Medical need for MAOI without dietary modificationsmodifications
Transdermal delivery of MAOITransdermal delivery of MAOI
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Facts About Clinical DepressionFacts About Clinical Depression
High prevalenceHigh prevalence
Significant morbidity and mortalitySignificant morbidity and mortality
Heterogeneous illness: No single antidepressant Heterogeneous illness: No single antidepressant works for every patientworks for every patient
30% do not respond to a series of different 30% do not respond to a series of different antidepressantsantidepressants
Need for additional effective optionsNeed for additional effective options
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Characteristics of Monoamine Oxidase InhibitorsCharacteristics of Monoamine Oxidase Inhibitors
First antidepressantsFirst antidepressants
Established efficacyEstablished efficacy
Affect three neurotransmittersAffect three neurotransmitters
Infrequently used despite their efficacy in Infrequently used despite their efficacy in part because of dietary restrictionspart because of dietary restrictions
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Infrequent MAOI UseInfrequent MAOI Use
IMS 2005 IMS 2005 – 0.1% of all antidepressant – 0.1% of all antidepressant prescriptionsprescriptions
APA guidelines 2000 cite dietary restrictions APA guidelines 2000 cite dietary restrictions as a reason to limit useas a reason to limit use
Surveys have shown dietary restrictions as Surveys have shown dietary restrictions as a major deterrent to MAOI usagea major deterrent to MAOI usage
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MAO in the GutMAO in the Gut
Barrier preventing systemic absorption of Barrier preventing systemic absorption of tyramine tyramine
Virtually impossible to eat enough tyramine Virtually impossible to eat enough tyramine in food to overcome this barrierin food to overcome this barrier
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Oral MAOIs and Dietary TyramineOral MAOIs and Dietary Tyramine
Oral MAOIs substantially inhibit intestinal MAOOral MAOIs substantially inhibit intestinal MAO
Tyramine can enter systemic circulationTyramine can enter systemic circulation
Systemic tyramine causes release of NESystemic tyramine causes release of NE
Large dose of tyramine can cause dramatic Large dose of tyramine can cause dramatic rise in blood pressure via NErise in blood pressure via NE
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Hypertensive CrisisHypertensive Crisis
Not Not chronic or essential hypertensionchronic or essential hypertension
Medical emergency requiring immediate Medical emergency requiring immediate treatmenttreatment
Acute elevation in BP >180/120 mmHg leading Acute elevation in BP >180/120 mmHg leading to end-organ damageto end-organ damage
Tyramine-induced hypertensive crisisTyramine-induced hypertensive crisis
– onset between 10 minutes and 2 hours onset between 10 minutes and 2 hours after mealafter meal
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Current MAOI Diet RecommendationsCurrent MAOI Diet Recommendations
Avoid high tyramine foodsAvoid high tyramine foods
– Aged cheesesAged cheeses
– Fermented or spoiled meats Fermented or spoiled meats
– Some yeast extracts (e.g., marmite) Some yeast extracts (e.g., marmite)
Maximum tyramine content meal: 40 mg tyramineMaximum tyramine content meal: 40 mg tyramine
The need for the diet and the potential risk of The need for the diet and the potential risk of hypertensive crisis discourages MAOI usehypertensive crisis discourages MAOI use
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The Clinical NeedThe Clinical Need
The efficacy of the oral MAOIs without the The efficacy of the oral MAOIs without the need for a tyramine-restrictive dietneed for a tyramine-restrictive diet
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Oral versus Transdermal DeliveryOral versus Transdermal Delivery
20 mg 20 mg patchpatch
skinskin
Oral MAOI Transdermal Selegiline
16Mawhinney et al. Mawhinney et al. J Pharm PharmacolJ Pharm Pharmacol 2003. 2003.
Inhibition of MAO by Selegiline in Guinea Pigs Inhibition of MAO by Selegiline in Guinea Pigs
CortexCortex
Oral SelegilineOral Selegiline Transdermal SelegilineTransdermal Selegiline
DuodenumDuodenum LiverLiver
Per
cen
tag
e in
hib
itio
nP
erce
nta
ge
inh
ibit
ion
Daily dose (mg/kg)Daily dose (mg/kg)
0.10.1 1.01.0 10.010.0 100100
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
Daily dose (cmDaily dose (cm22/24 h)/24 h)
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
Per
cen
tag
e in
hib
itio
nP
erce
nta
ge
inh
ibit
ion
0.40.4 0.710.71 1.01.0 1.51.5 2.02.0 2.52.5
Can the 20 mg transdermal delivery system Can the 20 mg transdermal delivery system for selegiline provide antidepressant for selegiline provide antidepressant efficacy without the need for dietary efficacy without the need for dietary modification?modification?
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Positive Placebo-controlled Efficacy TrialsPositive Placebo-controlled Efficacy Trialswith Transdermal Selegilinewith Transdermal Selegiline
E106E106 P0052P0052 P9806P9806
DurationDuration 6 weeks6 weeks 8 weeks8 weeks 52 weeks52 weeks
NN 176176 265265 322322
EMSAM EMSAM DoseDose 20 mg20 mg 20, 30, or 40 20, 30, or 40
mgmg 20 mg20 mg
Primary Primary EndpointEndpoint
HAMD-17HAMD-17p = 0.018p = 0.018
HAMD-28HAMD-28p = 0.033p = 0.033
K-M RelapseK-M Relapse††
p = 0.006p = 0.006
††K-M Relapse = Kaplan Meier time to relapse analysis
19
Safety – TyramineSafety – TyramineLawrence Blob, MDLawrence Blob, MDMedical Director, Medical Director, Somerset PharmaceuticalsSomerset Pharmaceuticals
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Safety of Transdermal Selegiline Safety of Transdermal Selegiline
Oral selegiline: 16 years of safe use withOral selegiline: 16 years of safe use withnormal dietnormal diet
Tyramine challenge program shows oral and Tyramine challenge program shows oral and transdermal selegiline have equally low transdermal selegiline have equally low intestinal MAO inhibitionintestinal MAO inhibition
Food challenges demonstrate tyramine safety of Food challenges demonstrate tyramine safety of 20 mg transdermal selegiline20 mg transdermal selegiline
Phase III safety data found no hypertensive Phase III safety data found no hypertensive crises in 2,503 MDD patients at 20, 30, and 40 mgcrises in 2,503 MDD patients at 20, 30, and 40 mg
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10 mg Oral and 20 mg Transdermal Selegiline10 mg Oral and 20 mg Transdermal Selegiline
Same active ingredientSame active ingredient
Unlike oral, transdermal selegiline achieves Unlike oral, transdermal selegiline achieves antidepressant levels in CNS antidepressant levels in CNS
Like oral, transdermal maintains the intestinal Like oral, transdermal maintains the intestinal barrier to tyraminebarrier to tyramine
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Safety of Oral Selegiline (Eldepryl) Safety of Oral Selegiline (Eldepryl)
16 years of safe use in Parkinson’s disease16 years of safe use in Parkinson’s disease
– Approved in 1989Approved in 1989
– No dietary modificationsNo dietary modifications
– 1.5 million patients exposed1.5 million patients exposed
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AERS & IMS Health Records for Oral SelegilineAERS & IMS Health Records for Oral Selegiline
Pharmacovigilance data (1997-2005)Pharmacovigilance data (1997-2005)
Rate of hypertensive crisis per 100,000 Rate of hypertensive crisis per 100,000 exposure-yearsexposure-years
EldeprylEldepryl ParnateParnate
1.561.56 43.3643.36
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AERS: 4 Reports of Hypertensive CrisisAERS: 4 Reports of Hypertensive Crisis
3 determined not related to tyramine3 determined not related to tyramine
– Case 1: tolcapone, levodopa, carbidopa, Case 1: tolcapone, levodopa, carbidopa, bromocriptine, ropinirole bromocriptine, ropinirole
– Case 2: ephedrine, theophylline, Case 2: ephedrine, theophylline, levodopa, carbidopa, lisuride, maprotilinelevodopa, carbidopa, lisuride, maprotiline
– Case 3: levodopa, bromocriptine, Case 3: levodopa, bromocriptine, talipexoletalipexole
One report: no details availableOne report: no details available
– Must consider tyramine-relatedMust consider tyramine-related Tyramine-related hypertensive crisisTyramine-related hypertensive crisis
– <0.4 per 100,000 exposure-years<0.4 per 100,000 exposure-years
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DATATOP: Controlled Safety Data DATATOP: Controlled Safety Data
Study of oral selegiline and Vitamin E for the Study of oral selegiline and Vitamin E for the treatment of Parkinsonismtreatment of Parkinsonism
N = 800N = 800
2,970 patient-years of exposure2,970 patient-years of exposure
No increase in mortality (2.1%) compared to No increase in mortality (2.1%) compared to a matched population (2.7%)a matched population (2.7%)
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DATATOP:DATATOP:Cardiovascular/Cerebrovascular EventsCardiovascular/Cerebrovascular Events
Incidence perIncidence per1000 patient-years1000 patient-years Oral SelegilineOral Selegiline PlaceboPlacebo
MIMI 6.46.4 8.18.1
CVA / TIACVA / TIA 6.76.7 13.013.0
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Safety of Transdermal Selegiline Safety of Transdermal Selegiline
Oral selegiline: 16 years of safe use withOral selegiline: 16 years of safe use withnormal dietnormal diet
Tyramine challenge program shows oral and Tyramine challenge program shows oral and transdermal selegiline have equally low transdermal selegiline have equally low intestinal MAO inhibitionintestinal MAO inhibition
Food challenges demonstrate tyramine safetyFood challenges demonstrate tyramine safetyof 20 mg transdermal selegilineof 20 mg transdermal selegiline
Phase III safety data found no hypertensive Phase III safety data found no hypertensive crises in 2,503 MDD patients at 20, 30, and 40 mgcrises in 2,503 MDD patients at 20, 30, and 40 mg
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Tyramine Challenge StudiesTyramine Challenge Studies
14 tyramine challenge studies (N=214)14 tyramine challenge studies (N=214)
Time of exposure, up to 96 daysTime of exposure, up to 96 days
Dose (20 to 40 mg transdermal selegiline)Dose (20 to 40 mg transdermal selegiline)
Fasting versus fed conditionsFasting versus fed conditions
Comparator drugs Comparator drugs
– Oral selegiline (Eldepryl)Oral selegiline (Eldepryl)
– Fluoxetine (Prozac)Fluoxetine (Prozac)
– Tranylcypromine (Parnate)Tranylcypromine (Parnate)
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Tyramine Pressor Test ModelTyramine Pressor Test Model
Endpoint: 30 mmHg SBPEndpoint: 30 mmHg SBP
BaselineBaselinetyraminetyraminechallengechallenge
Active Active drugdrugtreatmenttreatment
On-drugOn-drugtyramine tyramine challengechallenge
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Model: Minimum Pressor DoseModel: Minimum Pressor Dose
ExampleExampleMinimumMinimumPressorPressordose 200 mgdose 200 mg
MinimumMinimumPressorPressordose 400 mgdose 400 mg
Minimum Pressor Dose:Minimum Pressor Dose: Smallest oral tyramine dose Smallest oral tyramine dose to cause 30 mmHg SBPto cause 30 mmHg SBP
BaselineBaselinetyraminetyraminechallengechallenge
Active Active drugdrugtreatmenttreatment
On-drugOn-drugtyramine tyramine challengechallenge
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Model: Tyramine Sensitivity Factor (TSF)Model: Tyramine Sensitivity Factor (TSF)
Example: Drug 1Example: Drug 1
400/200 = TSF of 2400/200 = TSF of 2
MinimumMinimumPressorPressordose 200 mgdose 200 mg
MinimumMinimumPressorPressordose 400 mgdose 400 mg
BaselineBaselinetyraminetyraminechallengechallenge
Active Active drugdrugtreatmenttreatment
On-drugOn-drugtyramine tyramine challengechallenge
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Model: Tyramine Sensitivity Factor (TSF)Model: Tyramine Sensitivity Factor (TSF)
Example: Drug 2Example: Drug 2MinimumMinimumPressorPressordose 10 mgdose 10 mg
MinimumMinimumPressorPressordose 400 mgdose 400 mg
400/10 = TSF of 40400/10 = TSF of 40
BaselineBaselinetyraminetyraminechallengechallenge
Active Active drugdrugtreatmenttreatment
On-drugOn-drugtyramine tyramine challengechallenge
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Comparator StudiesComparator Studies
Crossover studiesCrossover studies
– Transdermal selegiline 20 mg vs.Transdermal selegiline 20 mg vs.oral selegiline 10 mg (Eldepryl)oral selegiline 10 mg (Eldepryl)
– Transdermal selegiline 20 mg vs. Transdermal selegiline 20 mg vs. tranylcypromine 30 mg (Parnate)tranylcypromine 30 mg (Parnate)
Negative controlNegative control
– Fluoxetine 60 mg (Prozac)Fluoxetine 60 mg (Prozac)
34
TSF: Transdermal 20 mg vs. Oral Selegiline 10 mgTSF: Transdermal 20 mg vs. Oral Selegiline 10 mgMean Pressor DoseMean Pressor Dose(mg Tyramine)(mg Tyramine) 338338 385385
1.75 ± 0.54 1.67 ± 1.04
TransdermalSelegiline
20 mg
Oral Selegiline10 mg
Tyramine Sensitivity
Factor
Crossover data
35
0
2
4
6
8
10
Tyramine Sensitivity
Factor
338338 385385
Fluoxetine60 mg
408408
1.43 ± 0.561.75 ± 0.54 1.67 ± 1.04
TSF of Fluoxetine 60 mgTSF of Fluoxetine 60 mg
TransdermalSelegiline
20 mg
Oral Selegiline10 mg
Mean Pressor DoseMean Pressor Dose(mg Tyramine)(mg Tyramine)
36
0
10
20
30
40
50
60
270270 1010
TSF of Tranylcypromine 30 mg (Parnate)TSF of Tranylcypromine 30 mg (Parnate)
TransdermalSelegiline
20 mg
Tranylcypromine30 mg
40.00 40.00 ± 7.07± 7.07
1.86 1.86 ± ± 0.420.42
Mean Pressor DoseMean Pressor Dose(mg Tyramine)(mg Tyramine)
Tyramine Sensitivity
Factor
Crossover data
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TSF Stability Over Time (40 mg dose)TSF Stability Over Time (40 mg dose)
0
5
10
15
20
25
30
35
40
45
50
Tyramine Tyramine Sensitivity Sensitivity
FactorFactor
8484 6666 8888 1010
11.45 ± 6.59 (8.17, 14.73)
11.36 ± 5.13 (8.40, 14.33)
9.33 ± 5.20(5.84, 12.82)
40.00 ± 7.07(34.56, 45.44)
Tranylcypromine30 mg/d
Day 8
Transdermal Selegiline40 mgDay 60
40 mgDay 90
40 mgDay 30
Mean Pressor DoseMean Pressor Dose(mg Tyramine)(mg Tyramine)
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Safety of Transdermal Selegiline Safety of Transdermal Selegiline
Oral selegiline: 16 years of safe use withOral selegiline: 16 years of safe use withnormal dietnormal diet
Tyramine challenge program shows oral and Tyramine challenge program shows oral and transdermal selegiline have equally low transdermal selegiline have equally low intestinal MAO inhibitionintestinal MAO inhibition
Food challenges demonstrate tyramine safety of Food challenges demonstrate tyramine safety of 20 mg transdermal selegiline20 mg transdermal selegiline
Phase III safety data found no hypertensive Phase III safety data found no hypertensive crises in 2,503 MDD patients at 20, 30, and 40 mgcrises in 2,503 MDD patients at 20, 30, and 40 mg
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Pharmacodynamic Effect of Food onPharmacodynamic Effect of Food onPressor Dose Pressor Dose
0
50
100
150
200
250
Pressor DosePressor Dose(mg Tyramine)(mg Tyramine)
Transdermal SelegilineTransdermal Selegiline40 mg40 mg
FastingFasting
Transdermal SelegilineTransdermal Selegiline40 mg40 mg
FedFed
6464 172172Mean Pressor DoseMean Pressor Dose
pp = 0.0023 = 0.0023
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Tyramine Content in a High-Tyramine MealTyramine Content in a High-Tyramine Meal
Sample MealSample MealPortionPortion
(g or mL)(g or mL)Tyramine contentTyramine content
(mg/portion)(mg/portion)
Bottled beerBottled beerSauerkrautSauerkrautBoiled potatoesBoiled potatoesGreen and yellow peppers Green and yellow peppers Roast PorkRoast PorkPepper saucePepper sauceCheeseCheese CamembertCamembert Danish blueDanish bluePinot NoirPinot Noir
700700454454454454250250454454150150
30303030
700700
1.01.016.716.71.91.91.81.83.23.23.03.0
1.41.48.88.82.02.0
Total tyramine in mealTotal tyramine in meal 39.839.8
41
0
20
40
60
Transdermal Transdermal SelegilineSelegiline
20 mg21 Days
Tranylcypromine30 mg
1010
Tyramine Sensitivity
Factor
Mean Pressor DoseMean Pressor Dose(mg Tyramine) (mg Tyramine)
TransdermalTransdermalSelegilineSelegiline
20 mg30 Days
204204256256
Pressor Dose Range at Steady State Pressor Dose Range at Steady State
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Safety Margin: 20 mg Transdermal, ExtremesSafety Margin: 20 mg Transdermal, Extremes(Calculated for Fed Conditions)(Calculated for Fed Conditions)
0
20
40
60
80
100
120
140
TransdermalSelegiline
Tranylcypromine High TyramineMeal
20 mgN = 2
N = 10
Minimum = 125 mgMinimum = 125 mg
Minimum = 25 mgMinimum = 25 mg
40 mg40 mg
TyramineTyramine(mg)(mg)
< 5 mg < 5 mg Tyramine Tyramine Typical Typical MealMeal
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Tyramine Challenge Program ConclusionsTyramine Challenge Program Conclusions
20 mg transdermal and oral selegiline and fluoxetine 20 mg transdermal and oral selegiline and fluoxetine all have similar TSF, about 14-20 times less than that all have similar TSF, about 14-20 times less than that of tranylcypromine of tranylcypromine
40 mg transdermal selegiline has a TSF 4 times less 40 mg transdermal selegiline has a TSF 4 times less than tranylcyprominethan tranylcypromine
Patients taking 20 mg transdermal selegiline will be Patients taking 20 mg transdermal selegiline will be unable to eat enough tyramine-rich food to cause a unable to eat enough tyramine-rich food to cause a hypertensive crisishypertensive crisis
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Safety of Transdermal Selegiline Safety of Transdermal Selegiline
Oral selegiline: 16 years of safe use withOral selegiline: 16 years of safe use withnormal dietnormal diet
Tyramine challenge program shows oral and Tyramine challenge program shows oral and transdermal selegiline have equally low transdermal selegiline have equally low intestinal MAO inhibitionintestinal MAO inhibition
Food challenges demonstrate tyramine safety of Food challenges demonstrate tyramine safety of 20 mg transdermal selegiline20 mg transdermal selegiline
Phase III safety data found no hypertensive Phase III safety data found no hypertensive crises in 2,503 MDD patients at 20, 30, and 40 mgcrises in 2,503 MDD patients at 20, 30, and 40 mg
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Phase III SafetyPhase III Safety
Exposure in 2500 patientsExposure in 2500 patients
– 20, 30, 40 mg transdermal selegiline20, 30, 40 mg transdermal selegiline
– No dietary modificationNo dietary modification
No serious adverse events of No serious adverse events of hypertensive crisishypertensive crisis
No deathsNo deaths
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Events of Interest Review ProcessEvents of Interest Review ProcessStep I: Comprehensive Computer Term SearchStep I: Comprehensive Computer Term Search
COSTART terms: Amblyopia, arrhythmia, COSTART terms: Amblyopia, arrhythmia, bradycardia, chest pain, coma, headache (severe), bradycardia, chest pain, coma, headache (severe), hypertension, migraine, neck rigidity, palpitation, hypertension, migraine, neck rigidity, palpitation, stupor, tachycardiastupor, tachycardia
Blood Pressure: Occurrence of blood pressure Blood Pressure: Occurrence of blood pressure 160/100 mmHg anytime during the study 160/100 mmHg anytime during the study
Step II: AlgorithmStep II: Algorithm Any patient with AE term hypertension, migraine or Any patient with AE term hypertension, migraine or
severe headachesevere headache Any AE terms judged at least moderate in intensityAny AE terms judged at least moderate in intensity Any AE requiring treatmentAny AE requiring treatment Occurrence of blood pressure Occurrence of blood pressure 160/100 mmHg 160/100 mmHg
anytime during the studyanytime during the study
Results: No events of hypertensive crisisResults: No events of hypertensive crisis
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Analysis of Blood Pressure Increases in Analysis of Blood Pressure Increases in Placebo-Controlled TrialsPlacebo-Controlled Trials
N = 1430 subjects in controlled trialsN = 1430 subjects in controlled trials
↑↑ 20 mmHg over baseline SBP and SBP >16020 mmHg over baseline SBP and SBP >160
Transdermal SelegilineTransdermal Selegiline PlaceboPlacebo
1.4% 1.4% 1.9% 1.9%
Incidence of AE HypertensionIncidence of AE Hypertension
Transdermal SelegilineTransdermal Selegiline PlaceboPlacebo
0.6% 0.6% 0.7% 0.7%
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Safety ConclusionsSafety Conclusions
20 mg transdermal selegiline is effective and 20 mg transdermal selegiline is effective and safe without dietary modificationssafe without dietary modifications
20 mg transdermal selegiline shows a low 20 mg transdermal selegiline shows a low inhibition of intestinal MAOinhibition of intestinal MAO
– Equivalent to 10 mg oral selegiline and Equivalent to 10 mg oral selegiline and 60 mg fluoxetine60 mg fluoxetine
No hypertensive crisis in Phase III programNo hypertensive crisis in Phase III program
Education program will instruct physicians and Education program will instruct physicians and patients on proper use of drugpatients on proper use of drug
49
Provider / Patient AwarenessProvider / Patient AwarenessChad VanDenBerg, Pharm.D., BCPPChad VanDenBerg, Pharm.D., BCPPDirector, Clinical Affairs & Product InformationDirector, Clinical Affairs & Product Information
Somerset Pharmaceuticals, Inc.Somerset Pharmaceuticals, Inc.
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FDA Question #2FDA Question #2
If the EMSAM 20 mg patch formulation could be If the EMSAM 20 mg patch formulation could be considered reasonably safe for marketing considered reasonably safe for marketing without the need for dietary restrictions, would without the need for dietary restrictions, would it be acceptable to market the 20 mg patch it be acceptable to market the 20 mg patch without dietary restrictions and at the same without dietary restrictions and at the same time require dietary restrictions for the 30 and time require dietary restrictions for the 30 and 40 mg patch strengths?40 mg patch strengths?
51
Education PlanEducation Plan
Goal: 100% awareness of the need for dietaryGoal: 100% awareness of the need for dietarymodifications at the higher strengthsmodifications at the higher strengths(30 and 40 mg patches)(30 and 40 mg patches)
Major elementsMajor elements Multiple education and outreach toolsMultiple education and outreach tools
– PrescribersPrescribers
– PharmacistsPharmacists
– PatientsPatients Uniquely designed packagingUniquely designed packaging
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Objective and ConsiderationsObjective and Considerations
Primary ObjectivePrimary Objective
– Dietary modification instructionsDietary modification instructions
Implementation ConsiderationsImplementation Considerations
– Prevent simultaneous use of multiple Prevent simultaneous use of multiple patchespatches
– Appropriate titration instructionsAppropriate titration instructions
53
Study of Physician and Patient Comprehension Study of Physician and Patient Comprehension of the Need for Dietary Modificationsof the Need for Dietary Modifications
MethodologyMethodology
75 Physicians75 Physicians
– Psychiatrists and primary care physiciansPsychiatrists and primary care physicians
70 Patients70 Patients
Results after only one exposure Results after only one exposure
96% of physicians and 94% of patients correctly 96% of physicians and 94% of patients correctly identify the need for dietary modifications at higher identify the need for dietary modifications at higher dosesdoses
Plan calls for multiple exposuresPlan calls for multiple exposures
54
Prescriber EducationPrescriber EducationKey ElementsKey Elements
Instructions for appropriate product usage Instructions for appropriate product usage consistent with labelconsistent with label
Patient education materialsPatient education materials Verbally communicateVerbally communicate
– Use as prescribedUse as prescribed
– Apply one patch at a timeApply one patch at a time
– Stay on modified diet for two weeks after Stay on modified diet for two weeks after discontinuationdiscontinuation
Write Write dietary modificationsdietary modifications requiredrequired on prescriptions on prescriptions
Continual Monitoring Continual Monitoring Bi-weekly assessment of awareness and practicesBi-weekly assessment of awareness and practices
55
Pharmacist EducationPharmacist Education
Key Elements Key Elements
Educational programs including Educational programs including teleconferences and mailingsteleconferences and mailings
Up-to-date product information available Up-to-date product information available through 3rd party data sourcesthrough 3rd party data sources
56
Patient EducationPatient Education
Patient education materialsPatient education materials
Patient information leaflet Patient information leaflet
Patient starter packPatient starter pack
EMSAM websiteEMSAM website
Dietary Modifications RequiredDietary Modifications Required
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58
Pharmacovigilance ProgramPharmacovigilance Program
Education and outreach program Education and outreach program
Pharmacovigilance procedures and reportingPharmacovigilance procedures and reporting
Targeted follow up on specific adverse eventsTargeted follow up on specific adverse events
– Hypertensive crisis and other CV eventsHypertensive crisis and other CV events
59
Provider / Patient Awareness SummaryProvider / Patient Awareness Summary
Multi-faceted planMulti-faceted plan
Enhanced education programEnhanced education program
– PrescribersPrescribers
– PharmacistsPharmacists
– PatientsPatients
Distinctive packagingDistinctive packaging
Enhanced pharmacovigilanceEnhanced pharmacovigilance
60
ConclusionsConclusionsMelvin Sharoky, MDMelvin Sharoky, MDCEO and PresidentCEO and President
Somerset Pharmaceuticals, Inc.Somerset Pharmaceuticals, Inc.
60
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