Timothy Fagan, M.D. Professor of Medicine and Associate Professor of Pharmacology University of Arizona, Tucson, Arizona

1
Timothy Fagan, M.D. Professor of Medicine and
Associate Professor of PharmacologyUniversity
of Arizona, Tucson, Arizona
Uprima PresentationTAP Holdings Inc.
2
Hemodynamics

• Syncope
• Hypotension
• Nitrate Interaction
• Alcohol Interaction

3
Syncope
Safety-Syncope

• Definition A sudden transient loss of
  consciousness with spontaneous recovery1
• Signs Associated with hypotension, bradycardia
  or both which occur when a person is in the
  upright position
• Syncope may occur in up to 40 of the population
  during lifetime

1Murdock BD. South African Medical Journal. v 57
p.771-774
Williams RL. Aerospace Medicine. v 33. P.
545-551.
4
Non-Cardiogenic Etiologies of Syncope
Safety-Syncope

• Physiological Reflex Syncope (vasovagal)
• Most common type of syncope (50-80)1
• Biphasic
• Initial phase apprehension, anxiety, increased
  HR
• Vasodepressor phase decreased HR, BP, CO faint
• Prompt resolution when supine (self-limiting)
• Accommodation usually occurs (60-85 have only 1
  episode)2
• Many other types, but represent a small
  percentage of syncope

1Wayne, HH Am Journal Med. v30 p. 418-438. 1961
2Kapoor WN. Am Journal Med. V83 p.700-708. 1987
5
Evidence for Non-Cardiogenic Etiology
Safety-Syncope

• The syncope observed with Uprima is vasovagal
  in origin based on careful review of

• Timing and pattern of syncope in individuals
• Absence of association with known markers of CVD
• Data from continuous Holter monitoring

6
Evidence for Non-Cardiogenic Etiology
Safety-Syncope

• 1,702 Holter monitor recordings in 344
  subjects/patients,including those
• with diabetes
• on nitrates
• on anti-hypertensives
• with and without alcohol ingestion
• These groups demonstrated a similar incidence of
  arrhythmias in patients when they received
  Uprima compared to when they received placebo

7
Distribution of Syncopal Eventsfor all Uprima
Studies
Safety-Syncope
Dose
Fixed Dose
Dose-Optimization
Recommended Doses
2 mg 0.2 (2/964) N/A 4 mg 1.2 (7/590) 0.6
(4/690) 5 mg 0.8 (7/860) 1.1 (6/556) 6
mg 2.1 (13/621) 0.3 (2/631)
Higher Than Recommended Doses
8
Comparison of Syncope Patients vs. Non-Syncope
Patients
Safety-Syncope

• No apparent difference in age, height, weight or
  race
• No association with concurrent medications
• Prodromal symptoms (moderate or severe nausea,
  vomiting, sweating/hot flashes/vasodilatation,
  dizziness/lightheadedness and pallor) occurred in
  nearly all patients with syncope
• Any one or more symptoms constitutes the prodrome

9
Comparison of Prodrome in Syncope
vs.Non-Syncope Patients
Safety-Syncope
Phase IIII Studies

• Syncopal Non-Syncopal Episodes
  with Administrations Prodrome with Prodrome
• Per Administration2, 4, 5, 6 mg 85.4 2.92, 4
  mg 84.6 1.8

• Nearly all patients (85) who experienced syncope
  also had one or more of the prodromal vasovagal
  adverse events
• Among patients who did not experience syncope,
  only 2.9 of all Uprima administrations (1.8
  for 2 and 4 mg) resulted in one or more prodromal
  symptoms

(with at least 1 prodromal symptom)
10
Syncope 2 and 4 mg
Safety-Syncope

• Of 1,988 patients who received 2 and/or 4 mg of
  Uprima, 13 had syncope (1 per 2,700 doses)
• Onset (approximate time post dose) Median 35
  minutes Range 22 to 54 minutes
• Duration (approximate) Median 60
  seconds Range 1 second to 5 minutes
• Occurrence 7/13 (54) 1st dose 2/13 (15)
  Increase in dose 4/13 (31) Later dose (range
  3rd-11th dose)
• Rechallenge 7 patients were rechallenged and
  took a total of 150 additional doses without
  syncope

11
Uprima Development - Patient Safety
Safety-Syncope

• Early syncopal events were unexpected and in some
  cases resulted in interventions in 2 cases,
  injury occurred
• With patient/physician education (instructions to
  lie down if lightheaded, dizzy or faint), there
  have been fewer medical interventions and no
  serious injuries

12
Summary of Syncope at 2 - 4 mg
Safety-Syncope

• Incidence is 0.6 per patient when dose is
  optimized to 4 mg
• Incidence is 1 syncope per 2,700 administrations
  of Uprima 2 or 4 mg
• 11 out of 13 patients with syncope had prodromal
  symptoms
• All syncope occurred within 1 hour of dosing
• The context of usage and instructions to remain
  recumbent in the event of prodromal symptoms
  should minimize the risk of syncope. This was
  further evaluated in the current home-use study
  with 863 patients submitted to the FDA on March
  30, 2000.

13
Syncope Conclusion
Safety-Syncope

• Of patients who experience syncope, most will
  experience vasovagal prodromal symptoms before
  the syncopal event
• When Uprima is used, most people will be
• Recumbent
• Accompanied by a sympathetic partner
• Very unlikely to be driving a car or operating
  heavy machinery
• Syncope is reported with other approved drugs
• Bupropion HCl (Wellbutrin/Zyban) 1.2 Depression/
  smoking cessation
• Alpha blockers 0.5-1 BPH/hypertension
• MUSE 0.9 Erectile dysfunction

14
Hemodynamics

• Syncope
• Hypotension
• Nitrate Interaction
• Alcohol Interaction

15
Definition of Mean Maximum Decrease in Blood
Pressure
Safety - Hypotension

• For vital signs measurements at multiple
  timepoints, the greatest decrease from baseline
  in each patient is determined
• These changes are then averaged across patients
• These changes will be greater than the mean
  change at any point in time
• Placebo represents random variation
• Using the mean maximum decrease in blood pressure
  provides a conservative (worst-case) estimate of
  mean changes in blood pressure
• Note Vital signs will be presented both as mean
  maximum decreases from baseline (tables) and
  mean changes from baseline over time (graphs)

16
Vital Signs and Hypotension in the Phase III
Studies
17
Mean Maximum Decrease fromBaseline in Blood
Pressure
Phase III CrossoverM98-941
Safety - Hypotension
M98-941
Higher Than Recommended Dose
Recommended Doses
4 mg (N 145)
2 mg (N 148)
5 mg (N 138)
Uprima
Uprima
Placebo
Placebo
Uprima
Placebo
Supine (mm Hg) Systolic Diastolic Standing (mm
Hg) Systolic Diastolic
-9.1 -4.9 -8.8 -4.7
-11.7 -5.7 -11.1 -5.4
-9.8 -5.7 -9.8 -5.7
-9.9 -5.3 -10.2 -5.3
-15.1 -7.5 -14.4 -7.3
-8.2 -5.5 -8.1 -4.8
, , Statistically significant at p 0.05,
0.01 or 0.001 levels, respectively, compared to
placebo.
18
2 mg Arm Mean Change from Baseline in Systolic
and Diastolic Blood Pressure
Phase III CrossoverM98-941
Safety - Hypotension
M98-941
Changein SBP(mm Hg)



Changein DBP(mm Hg)

Time  Post-dosing (Minutes)
Statistically significant at the p 0.05 level.
19
4 mg Arm Mean Change from Baseline in Systolic
and Diastolic Blood Pressure
Phase III CrossoverM98-941
Safety - Hypotension
M98-941
Changein SBP(mm Hg)




Changein DBP(mm Hg)
Time  Post-dosing (Minutes)
Statistically significant at the p 0.05 level.
20
Mean Changes in Supine Systolic Blood
PressureComparison of Uprima to Viagra
Safety - Hypotension
4 mg Uprima
100 mg Viagra
M98-941
Changein SBP(mm Hg)
Changein SBP(mm Hg)

Pre-dose
Time  Post-dosing (Minutes)
Time  Post-dosing (Hours)
1 Phase III crossover studies (M96-470, M97-658
M98-941). 2 Viagra Package Insert, June, 1999.
21
Adverse Event of Hypotension
Phase III M96-470, M97-658, M97-763, M98-941
M98-876

• In the Phase III Crossover Studies, hypotension
  was reported as an adverse event in less than 5
  of patients overall
• Crossover studies Dose-optimization studies
• 3/429 (0.7) at 2 mg 0/146 (0) at 2, 4, 5 mg
• 18/426 (4.2) at 4 mg 6/242 (2.5) at 2, 4, 5,
  6 mg
• 14/282 (5.0) at 5 mg
• 12/262 (4.6) at 6 mg
• Nearly all patients (52 of 53) who had an adverse
  event of hypotension reported one or more
  concurrent vasovagal adverse events (prodrome)

22
Phase III Hypotension Summary
Phase III
Safety-Hypotension

• No clinically significant mean decreases in blood
  pressure were observed for the recommended dose
  of 2 mg
• No clinically significant mean decreases in blood
  pressure were observed for the recommended dose
  of 4 mg
• The higher than recommended dose of 5 mg resulted
  in statistically significant mean decreases from
  baseline in standing and supine blood pressure
  only within the first hour of dosing
• Mean decreases in BP observed following Viagra
  100 mg were both larger in magnitude and longer
  in duration than those seen with Uprima 4 mg
• Hypotension was reported as an adverse event by
  less than 5 of patients in the Phase III
  crossover studies, and 98 of these patients
  experienced one or more prodromal vasovagal
  adverse events

23
DiabetesStudy M97-804
24
Mean Maximum Decrease from Baseline in Blood
Pressure
Phase III Diabetes
Safety-Diabetes
M97-804
Supine (mm Hg)
Systolic Diastolic
-6.8 -3.9
-6.3 -2.4
-7.9 -3.0
-5.0 -2.5
Standing (mm Hg)
Systolic Diastolic
-8.4 -3.8
-7.8 -2.9
-6.2 -3.0
-6.9 -3.0

• No significant blood pressure differences between
  Uprima and placebo in diabetic patients

25
Diabetes Safety Conclusion
Phase III
Safety-Diabetes

• Adverse event profile at maximum recommended dose
  or higher in diabetic patients similar to adverse
  event profile in Phase III studies
• No abnormalities noted in the subset of patients
  with Holter monitoring
• Syncope in 3 of 205 patients

26
Hemodynamics

• Syncope
• Hypotension
• Nitrate Interaction
• Alcohol Interaction

27
Nitrate InteractionStudy M98-930
28
Antihypertensives and Nitrates Study
M98-930

• Objective To evaluate potential pharmacodynamic
  interactions between Uprima and commonly used
  cardiovascular medications
• Study design Multi-center, double-blind,
  randomized placebo-controlled, fixed-dose,
  crossover
• Dose Uprima 5 mg, chronic therapeutic doses
  of antihypertensives and/or nitrates
• Number of patients 162 with hypertension and/or
  coronary disease
• Measurements Supine and standing blood pressure
  (BP) by Dinamap, Holter monitor recordings and
  adverse events (AE)

29
Uprima Antihypertensives and Nitrate
Interaction Studies
Safety-Nitrates
M98-930

• Higher than recommended dose of Uprima (5 mg)
• Multiple concurrent drugs capable of decreasing
  blood pressure
• Patients with cardiovascular diseases were
  subject to frequent orthostatic maneuvers

30
Patients Taking Nitrates
Safety-Nitrates
M98-930

• Average age of 67.4 years and average weight of
  186 lbs.
• The majority of patients were on a variety of
  concurrent cardiovascular medications in addition
  to nitrates(e.g., 75 on antihypertensives, 12
  on digitalis, 52 on lipid lowering agents, 18
  on antidiabetic agents)
• Patients had expected CVD risk factors including
  hypertension, previous MI, previous
  CABG/angioplasty, previous stroke, diabetes,
  congestive heart failure and atrial fibrillation

31
Nitrates Plus Uprima 5 mg Mean Maximum Decrease
from Baseline in Blood Pressure
Safety-Nitrates
M98-930
Long-Acting Nitrates (N 20)
Short-ActingNitrates (N 20)
Uprima
Uprima
Placebo
Placebo
Supine (mm Hg) Systolic Diastolic Standing (mm
Hg) Systolic Diastolic
-13.5 -6.0 -22.1 -8.9
-15.1 -6.7 -18.9 -9.9
-11.5 -4.9 -10.6 -5.1
-22.1 -11.6 -22.3 -13.9

• Statistically significant differences only
  occurred in the standing position

Statistically significant at p 0.05 level
compared to placebo.
32
Short-Acting Nitrates Mean Change from Baseline
in Systolic and Diastolic Blood Pressure
Safety-Nitrates
M98-930
Changein SBP(mm Hg)


Changein DBP(mm Hg)
Time  Post-dosing (Minutes)

• No statistically significant mean changes
  compared to sublingual nitroglycerin alone (N20)

30 minute timepoint Baseline
33
Long-Acting Nitrates Mean Change fromBaseline
in Systolic and Diastolic Blood Pressure
Safety-Nitrates
M98-930
Changein SBP(mm Hg)






Changein DBP(mm Hg)


Time  Post-dosing (Minutes)

• Statistically significant changes occurred only
  in the standing position (N20)

, Statistically significant at p0.001,
p0.05 level compared to placebo.
34
Short-Acting NitratesChanges in Systolic Blood
PressureComparison of Uprima to Viagra
Safety-Nitrates
Uprima 5 mg Standing (N20)(higher than
recommended dose)
Viagra 50 mg Sitting (N16)
Sitting Systolic Blood Pressure (mm Hg)
Standing Systolic Blood Pressure (mm Hg)
Treatment
Treatment

2
Sildenafil 50 mg GTN
1
Placebo GTN
1
2
Baseline
0.50
1.00
1.50
2.00
Baseline
0.17
0.33
0.5
1.0
1.5
Time Post Dose (hours)
Time Post Dose (hours)
1 19 on 0.4 mg sublingual nitroglycerin and 1
patient on 0.3 mg sublingual nitroglycerin. 2 Stud
y 148-231 A double-blind, placebo-controlled,
randomized, two way crossover study to
investigate theeffects of a single dose of
Sildenafil (50 mg) in patients with stable angina
taking sublingual glyceryl trinitrate 0.5 mg.
35
Short-Acting NitratesChanges in Diastolic Blood
PressureComparison of Uprima to Viagra
Safety-Nitrates
Uprima 5 mg Standing (N20)(higher than
recommended dose)
Viagra 50 mg Sitting (N16)
Sitting Diastolic Blood Pressure (mm Hg)
Standing Diastolic Blood Pressure (mm Hg)
Treatment
Treatment

2
1
Sildenafil 50 mg GTN
1
Placebo GTN
2
Baseline
0.17
0.33
0.5
1.0
1.5
Time Post Dose (hours)
Time Post Dose (hours)
1 19 on 0.4 mg sublingual nitroglycerin and 1
patient on 0.3 mg sublingual nitroglycerin. 2 Stud
y 148-231 A double-blind, placebo-controlled,
randomized, two way crossover study to
investigate theeffects of a single dose of
Sildenafil (50 mg) in patients with stable angina
taking sublingual glyceryl trinitrate 0.5 mg.
36
Long-Acting NitratesChanges in Standing Systolic
Blood PressureComparison of Uprima to Viagra
Safety-Nitrates
Uprima 5 mg Standing (N20)(higher than
recommended dose)
Viagra 50 mg Standing (N16)
Treatment
2
Sildenafil 50 mg ISMN 20 mg
Placebo ISMN 20 mg
2
Standing Systolic Blood Pressure (mm Hg)
Standing Systolic Blood Pressure (mm Hg)
Treatment

1
1
Baseline
0.17
0.33
0.5
0.67
0.83
1.0
1.5
2.0
Baseline
0.50
0.75
1.00
1.25
1.50
1.75
2.00
0.25
Time Post Dose (hours)
Time Post Dose (hours)
1 16 patients on isosorbide mononitrate and 4
patients on minitran patch. 2 Viagra Study
148-231 A double-blind, placebo-controlled,
randomized, two way crossover study to
investigate theeffects of a single dose of
Sildenafil (50 mg) in patients with stable angina
taking isosorbide mononitrate 20 mg oral therapy.
37
Long-Acting NitratesChanges in Standing
Diastolic Blood PressureComparison of Uprima to
Viagra
Safety - Nitrates
Uprima 5 mg Standing (N20)(higher than
recommended dose)
Viagra 50 mg Standing (N16)
Treatment
2
Sildenafil 50 mg ISMN 20 mg
Placebo ISMN 20 mg
2
Standing Diastolic Blood Pressure (mm Hg)
Standing Diastolic Blood Pressure (mm Hg)
Treatment
1

1
Baseline
0.50
0.75
1.00
1.25
1.50
1.75
2.00
0.25
Baseline
0.17
0.33
0.5
0.67
0.83
1.0
1.5
2.0
Time Post Dose (hours)
Time Post Dose (hours)
1 16 patients on isosorbide mononitrate and 4
patients on minitran patch. 2 Viagra Study
148-231 A double-blind, placebo-controlled,
randomized, two way crossover study to
investigate theeffects of a single dose of
Sildenafil (50 mg) in patients with stable angina
taking isosorbide mononitrate 20 mg oral therapy.
38
Nitrate Interaction Conclusion
Safety-Nitrates

• No syncopal events
• No Holter monitor changes attributed to Uprima
• Compared to Viagra, blood pressure decreases
  were considerably smaller in magnitude and
  shorter in duration
• The 4 of 40 patients taking nitrates who had
  clinically significant decreases in blood
  pressure also had prodromal symptoms
• With adequate patient instruction (lie down if
  you experience prodomal symptoms), Uprima can be
  administered to patients taking nitrates

39
Antihypertensive Interaction Study M98-930
40
Antihypertensives Plus Uprima 5 mg Mean Maximum
Decrease from Baseline in Blood Pressure
Safety-Antihypertensives
M98-930
Calcium Channel Blockers (N 26)
Alpha1 Blockers (N 24)
Diuretics (N 21)
ACE Inhibitors (N 25)
Beta Blockers (N 26)
Supine (mm Hg) Systolic Diastolic Standing (mm
Hg) Systolic Diastolic
Statistically significant at p 0.05 level
compared to placebo.
41
Antihypertensive Interaction Conclusion
Safety-Antihypertensives

• No clinically significant mean changes from
  baseline in blood pressure or pulse rate for
  patients receiving ACE Inhibitors, beta
  blockers, calcium channel blockers, alpha1
  blockers, and/or diuretics
• Incidence and type of adverse events reported
  were similar to other Uprima Phase I, II and
  III studies
• No Holter monitor changes attributed to Uprima
  except those consistent with vasovagal effects
• One of 122 patients had syncope (0.8 at 5 mg)

42
Hemodynamics

• Syncope
• Hypotension
• Nitrate Interaction
• Alcohol Interaction

43
History of Alcohol Interaction
Safety - Alcohol

• In an early Phase III trial, a syncopal event
  occurred in a patient who consumed excessive
  alcohol. For this reason Uprima/ethanol
  interaction studies were conducted.
• In the first alcohol interaction study (M97-745)
  at high doses of Uprima (5 mg) and ethanol (0.6
  g/kg), two serious adverse event (SAE) occurred.
  There were no sequelae. However, ethanol
  interaction studies were redesigned, starting
  with lower doses of ethanol
• With 6 mg of Uprima and 0.15 g/kg of ethanol
  (M97-762) there were no SAEs after experiencing
  nausea or pallor, 4 subjects received oxygen as a
  precaution
• Further trials were conducted with 6 mg of
  Uprima and 0.3 g/kg (M98-838) and 0.6 g/kg
  (M98-891) of ethanol

44
EthanolInteraction Studies M98-838 M98-891
45
Ethanol Interaction Studies
Phase I
Safety-Alcohol
M98-838 M98-891

• Study Design Double-blind, randomized,
  placebo-controlled, three- period crossover
  studies in healthy male subjects
• Crossover periods Ethanol Beverage Uprima
  Placebo Beverage Uprima Ethanol
  Beverage Placebo
• Dose Uprima 6 mg M98-838, M98-891 Ethanol 0.
  3 g/kg M98-838 0.6 g/kg M98-891
• Day 1-3 Uprima or placebo tablet
• Day 3 Ethanol or placebo beverage, 1hr. before
  tablet
• Washout Four days

46
Ethanol Interaction Studies
Phase I
Safety-Alcohol

• Higher than recommended dose of Uprima (6 mg)
• High dose of ethanol (0.6 g/kg in M98-891),
  equivalent to 5 one-ounce shots, consumed within
  30 minutes
• Healthy male volunteers were subjected to
• frequent orthostatic maneuvers
• frequent blood draws

47
Ethanol Plus Uprima 6 mg Mean Maximum Decrease
from Baseline in Blood Pressure
Phase I
Safety-Alcohol
M98-891(0.6 g/kg Ethanol) (N61)
M98-838(0.3 g/kg Ethanol)(N64-66)
Uprima Ethanol
Uprima Ethanol
Uprima
Uprima
Ethanol
Ethanol
Supine (mm Hg) Systolic Diastolic Standing (mm
Hg) Systolic Diastolic
-14.0 -8.9 -16.6 -9.5
-10.9 -6.5 -21.8 -12.6
-14.7 -8.6 -23.2 -10.6
-13.2 -7.8 -19.3 -12.1
-15.9 -9.1 -26.8 -16.9
-15.2 -7.1 -22.3 -14.2

• Changes for Uprima ethanol greater than
  ethanol alone in the standing position

Statistically significant at p 0.05 level
compared to Uprima plus ethanol.
48
Mean Change from Baseline inSystolic Blood
Pressure
Phase I
Safety-Alcohol
M98-838
SupineSBP(mm Hg)
Uprima 6 mg EtOH 0.3 g/kg Uprima 6 mg
Placebo Placebo EtOH 0.3 g/kg
StandingSBP(mm Hg)
Time  Post-dosing (Minutes)

• No statistically significant differences from
  ethanol alone (N66)

49
Mean Change from Baseline inDiastolic Blood
Pressure
Phase I
Safety-Alcohol
M98-838
SupineDBP(mm Hg)

Uprima 6 mg EtOH 0.3 g/kg Uprima 6 mg
Placebo Placebo EtOH 0.3 g/kg
StandingDBP(mm Hg)
Time  Post-dosing (Minutes)

• No clinically meaningful changes (N66)

Statistically significant compared to Uprima
ethanol at the p 0.05 levels.
50
Mean Change from Baseline inSystolic Blood
Pressure
Phase I
Safety-Alcohol
M98-891



SupineSBP(mm Hg)





Uprima 6 mg EtOH 0.6 g/kg Uprima 6 mg
Placebo Placebo EtOH 0.6 g/kg

StandingSBP(mm Hg)


Time  Post-dosing (Minutes)

• Of the statistically significant changes seen,
  some may be attributable to ethanol alone as
  well as the combination of Uprima and ethanol
  (N61)

, , Statistically significant compared to
Uprima ethanol at the p 0.05, 0.01 and 0.001
levels, respectively.
51
Mean Change from Baseline inDiastolic Blood
Pressure
Phase I
Safety-Alcohol
M98-891




SupineDBP(mm Hg)
Uprima 6 mg EtOH 0.6 g/kg Uprima 6 mg
Placebo Placebo EtOH 0.6 g/kg





StandingDBP(mm Hg)
Time  Post-dosing (Minutes)

• Of the statistically significant changes seen,
  some may be attributable to ethanol alone as
  well as the combination of Uprima and ethanol
  (N61)

, , Statistically significant compared to
Uprima ethanol at the p 0.05, 0.01 and 0.001
levels, respectively.
52
Possibly Related Treatment-Emergent Adverse
Events gt5 in Uprima (6 mg) Plus Ethanol (0.3
and 0.6 g/kg)
Phase I
Safety-Alcohol
M98-891
M98-838
Uprima (6 mg) Ethanol0.3 g/kg N 68
Uprima (6 mg) Ethanol 0.6 g/kg N 64
Uprima (6 mg) N 67
Ethanol 0.3 g/kgN 64
Ethanol 0.6 g/kgN 63
Event
Uprima (6 mg) N 67
Nausea 34 (50.0) 21 (31.3) 1 (1.6)
31 (48.4) 23 (34.3) 2 (3.2) Dizziness 30 (44.1) 15
(22.4) 6 (9.4) 22 (34.4) 12 (17.9) 6 (9.5) Pallor
21 (30.9) 18 (26.9) 1 (1.6)
19 (29.7) 10 (14.9) 0 Sweating
18 (26.5) 12 (17.9) 0
9 (14.1) 6 (9.0) 1 (1.6) Vomiting
11 (16.2) 5 (7.5) 0
17 (26.6) 13 (19.4) 1 (1.6) Hypotension 9 (13.2)
5 (7.5) 1 (1.6) 24 (37.5) 9 (13.4) 9 (14.3) Head
ache 9 (13.2) 6 (9.0) 5 (7.8) 9 (14.1) 4 (6.0) 9 (
14.3) Asthenia 4 (5.9) 10 (14.9) 2 (3.1) 10 (15.6
) 7 (10.5) 5 (7.9) Yawning 3 (4.4) 6 (9.0) 2
(3.1) 0 0
0 Somnolence
3 (4.4) 2 (3.0) 3 (4.7) 3 (4.7) 2 (3.0) 4 (6.4) Va
sodilatation 3 (4.4) 3 (4.5) 0
8 (12.5) 5 (7.5) 0
53
Patient Instructions in Phase III Trials
Safety-Alcohol

• You should limit yourself to a minimal amount of
  alcoholic beverages during the six hours prior to
  taking study medication. For most people, a
  minimal amount of alcoholic beverages is 2
  glasses of beer, or 2 glasses of wine or 1 ounce
  of hard liquor.

54
Related Treatment-Emergent Adverse Events ³10
Phase II/III Studies
Safety-Alcohol
Alcohol Use Phase II/III Studies
Includes Higher Than Recommended Dose
Recommended Dose
2 and 4 mg doses
All doses (2, 4, 5, 6 mg)
Alcohol Users(? 1 drink/day) N350 n
()
Alcohol Users(? 1 drink/day) N414 n
()
Non-Alcohol Users N685n ()
Non-Alcohol Users N858n ()
Adverse Event
Nausea Somnolence Dizziness Sweating Yawning Synco
pe
62 (17.7) 32 (9.1) 25 (7.1) 19 (5.4) 22 (6.3)
3 (0.9)
140 (33.8) 70 (16.9) 66 (15.9) 49 (11.8) 43 (
10.4) 6 (1.4)
99 (14.5) 50 (7.3) 67 (9.8) 38 (5.5) 35 (5.1)
5 (0.7)
261 (30.4) 101 (11.8) 137 (16.0) 115 (13.4) 7
7 (9.0) 12 (1.4)

55
Ethanol Interaction Conclusion
Safety-Alcohol

• Subjects were stressed with high doses of
  Uprima, high doses of ethanol, frequent
  orthostatic maneuvers and blood draws
• Between 30 and 60 minutes post-dosing, mean
  decreases in standing blood pressure were greater
  when Uprima 6 mg was combined with ethanol 0.6
  g/kg than with ethanol administered alone. No
  clinically meaningful changes in supine blood
  pressure were noted
• An increased incidence of adverse events was
  associated with Uprima 6 mg when combined with
  ethanol
• Modest changes in apomorphine pharmacokinetic
  parameters were observed with ethanol 0.6 g/kg
  but not 0.3 g/kg. No clinically significant
  changes were seen in ethanol pharmacokinetics
• In all Phase II/III studies, the adverse event
  profiles in alcohol users vs. non-alcohol users
  were comparable, and the syncope rates were the
  same

56
Ethanol Interaction Conclusion (cont.)
Safety-Alcohol

• No holter monitor changes due to Uprima except
  those attributed to vasovagal effects
• No increased vasovagal Holter monitor changes
  with Uprima and ethanol compared to Uprima
  alone