# Presentation: 023017

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

**Uprima****®**** ****Presentation****TAP Holdings Inc.**

## Hemodynamics

- Syncope
- Hypotension
- Nitrate Interaction
- Alcohol Interaction

## 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

- Safety-Syncope

- 1Murdock BD. *South African Medical Journal. *v 57: p.771-774

- Williams RL. *Aerospace Medicine*. v 33. P. 545-551.

## Non-Cardiogenic Etiologies of 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

- Safety-Syncope

## Evidence for Non-Cardiogenic Etiology

- 	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

- Safety-Syncope

## Evidence for Non-Cardiogenic Etiology

- 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

- Safety-Syncope

## Distribution of Syncopal Eventsfor all Uprima® Studies 

**Fixed Dose**

**Dose-Optimization**

**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)****	**

- Distribution of Syncopal Eventsfor all Uprima® Studies

***Recommended Doses***

***Higher Than Recommended Doses***

- Safety-Syncope

## Comparison of Syncope Patients vs. Non-Syncope Patients

- 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

- Safety-Syncope

## Comparison of Prodrome* in Syncope vs.Non-Syncope Patients

**	****	****Syncopal****	****Non-Syncopal****	****Episodes with****	****Administrations****	****Prodrome****	****with Prodrome**
**Per Administration****2, 4, 5, 6 mg****	****85.4%****	****2.9%****2, 4 mg****	****84.6%****	****1.8%**

*Phase I–III Studies*

- 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

- Safety-Syncope

- *(with at least 1 prodromal symptom)

## Syncope: 2 and 4 mg

- 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

- Safety-Syncope

## Uprima Development - Patient Safety

- 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

- Safety-Syncope

## Summary of Syncope at 2 - 4 mg

- 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.

- Safety-Syncope

## Syncope Conclusion

- 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

- Safety-Syncope

## Hemodynamics

- Syncope
- Hypotension
- Nitrate Interaction
- Alcohol Interaction

## Definition of Mean Maximum Decrease in Blood Pressure

- 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)

- Safety - Hypotension

## Vital Signs and Hypotension in the Phase III Studies

## Mean Maximum Decrease fromBaseline in Blood Pressure

**	****Systolic**
**	****Diastolic**
**Standing (mm Hg)**
**	****Systolic**
**	****Diastolic**

**Uprima****®**

**Uprima****®**

**Placebo**

**4 mg**
**(N = 145)**

- *, **, *** Statistically significant at p = 0.05, 0.01 or 0.001 levels, respectively, compared to placebo.

**	****-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**

- Mean Maximum Decrease fromBaseline in Blood Pressure

**2 mg**
**(N = 148)**

** ****Placebo**

- Phase III – CrossoverM98-941

**Uprima****®**

**Placebo**

**5 mg**
**(N = 138)**

**	****-15.1*** **
**	****-7.5* **
**	****-14.4*****
**	****-7.3****

**	****-8.2**
**	****-5.5**
**	****-8.1**
**	****-4.8**

*M98-941*

***Recommended Doses***

***Higher Than ******Recommended Dose***

- Safety - Hypotension

## 2 mg Arm – Mean Change from Baseline in Systolic and Diastolic Blood Pressure

- 2 mg Arm – Mean Change from Baseline in Systolic and Diastolic Blood Pressure

- Changein SBP(mm Hg)

- Time — Post-dosing (Minutes)

- Changein DBP(mm Hg)

- Phase III – CrossoverM98-941

- * Statistically significant at the p = 0.05 level.

- ®

- ®

- *

- *

*M98-941*

- Safety - Hypotension

## 4 mg Arm – Mean Change from Baseline in Systolic and Diastolic Blood Pressure

- 4 mg Arm – Mean Change from Baseline in Systolic and Diastolic Blood Pressure

- Changein SBP(mm Hg)

- Time — Post-dosing (Minutes)

- Changein DBP(mm Hg)

- Phase III – CrossoverM98-941

- * Statistically significant at the p = 0.05 level.

- ®

- ®

- *

- *

*M98-941*

- Safety - Hypotension

## Mean Changes in Supine Systolic Blood PressureComparison of Uprima® to Viagra®

- Changein SBP(mm Hg)

- Time — Post-dosing (Minutes)

- 4 mg Uprima®

- Mean Changes in Supine Systolic Blood PressureComparison of Uprima® to Viagra®

- 100 mg Viagra®

- Time — Post-dosing (Hours)

- Changein SBP(mm Hg)

- ®

- Pre-dose

***M98-941***

- Safety - Hypotension

- 1	Phase III crossover studies (M96-470, M97-658 & M98-941).
- 2 Viagra® Package Insert, June, 1999.

## Adverse Event of Hypotension

- 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)

- Phase III  M96-470, M97-658, M97-763, M98-941 & M98-876

## Phase III Hypotension Summary

- 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

- Safety-Hypotension

- Phase III

## DiabetesStudy M97-804

## Mean Maximum Decrease from Baseline in Blood Pressure

**Diastolic**

**-6.8**
**-3.9**

**-6.3 **
**-2.4**

**-7.9**
**-3.0**

**-5.0**
**-2.5**

- Mean Maximum Decrease from Baseline in Blood Pressure

- Phase III – Diabetes

**Systolic**
**Diastolic**

**-8.4 **
**-3.8**

**-7.8**
**-2.9**

**-6.2**
**-3.0**

**-6.9**
**-3.0**

**Supine (mm Hg)**

**Standing (mm Hg)**

*M97-804*

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

- Safety-Diabetes

## Diabetes Safety Conclusion

- 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

- Safety-Diabetes

## Hemodynamics

- Syncope
- Hypotension
- Nitrate Interaction
- Alcohol Interaction

## Nitrate InteractionStudy M98-930

## Antihypertensives and Nitrates Study

- 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)

*M98-930*

## Uprima® Antihypertensives and Nitrate Interaction Studies

- 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

- Safety-Nitrates

*M98-930*

## Patients Taking Nitrates

- 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

- Safety-Nitrates

*M98-930*

## Nitrates Plus Uprima® 5 mg Mean Maximum Decrease from Baseline in Blood Pressure

**	****Systolic**
**	****Diastolic**
**Standing (mm Hg)**
**	****Systolic**
**	****Diastolic**

**Uprima****®**

**Uprima****®**

**Placebo**

**Long-Acting**
**Nitrates**
**(N = 20)**

- * Statistically significant at p = 0.05 level compared to placebo.

**	****-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***

*M98-930*

- Nitrates Plus Uprima® 5 mg Mean Maximum Decrease from Baseline in Blood Pressure

**Short-Acting****Nitrates**
**(N = 20)**

** ****Placebo**

- Statistically significant differences only occurred in the standing position

- Safety-Nitrates

## Short-Acting Nitrates Mean Change from Baseline in Systolic and Diastolic Blood Pressure

- Short-Acting Nitrates Mean Change from Baseline in Systolic and Diastolic Blood Pressure

- 30 minute timepoint = Baseline

- Changein SBP(mm Hg)

- Time — Post-dosing (Minutes)

*M98-930*

- Changein DBP(mm Hg)

- ®

- ®

- No statistically significant mean changes compared to sublingual nitroglycerin alone (N=20)

- Safety-Nitrates

## Long-Acting Nitrates Mean Change fromBaseline in Systolic and Diastolic Blood Pressure

- Long-Acting Nitrates Mean Change fromBaseline in Systolic and Diastolic Blood Pressure

- ***,* Statistically significant at p=0.001, p=0.05 level compared to placebo.

- Time — Post-dosing (Minutes)

- *

- *

- *

- ***

- ***

- *

- Changein SBP(mm Hg)

- Changein DBP(mm Hg)

- ®

- ®

*M98-930*

- Statistically significant changes occurred only in the standing position (N=20)

- Safety-Nitrates

## Short-Acting NitratesChanges in Systolic Blood PressureComparison of Uprima® to Viagra® 

- Short-Acting NitratesChanges in Systolic Blood PressureComparison of Uprima® to Viagra®

- 1	19 on 0.4 mg sublingual nitroglycerin and 1 patient on 0.3 mg sublingual nitroglycerin.
- 2	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 sublingual glyceryl trinitrate 0.5 mg.

- Time Post Dose (hours)

- Standing Systolic Blood Pressure (mm Hg)

**Uprima****®**** 5 mg – Standing (N=20)****(higher than recommended dose)**

**Viagra****®**** 50 mg – Sitting (N=16)**

- Sitting Systolic Blood Pressure (mm Hg)

- Baseline

- 0.50

- 1.00

- 1.50

- 2.00

- Time Post Dose (hours)

- Sildenafil 50 mg + GTN

- Placebo + GTN

- Treatment:

- Baseline

- 0.17

- 0.33

- 0.5

- 1.0

- 1.5

- ®

- 1

- 1

- 2

- 2

- Treatment:

- Safety-Nitrates

## Short-Acting NitratesChanges in Diastolic Blood PressureComparison of Uprima®  to Viagra®

- Short-Acting NitratesChanges in Diastolic Blood PressureComparison of Uprima®  to Viagra®

- 1	19 on 0.4 mg sublingual nitroglycerin and 1 patient on 0.3 mg sublingual nitroglycerin.
- 2	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 sublingual glyceryl trinitrate 0.5 mg.

- Standing Diastolic Blood Pressure (mm Hg)

- Sitting Diastolic Blood Pressure (mm Hg)

- Time Post Dose (hours)

- Baseline

- 0.17

- 0.33

- 0.5

- 1.0

- 1.5

- Time Post Dose (hours)

- ®

- 1

- 1

- Treatment:

- Sildenafil 50 mg + GTN

- Placebo + GTN

- Treatment:

- 2

- 2

**Uprima****®**** 5 mg – Standing (N=20)****(higher than recommended dose)**

**Viagra****®**** 50 mg – Sitting (N=16)**

- Safety-Nitrates

## Long-Acting NitratesChanges in Standing Systolic Blood PressureComparison of Uprima® to Viagra® 

- Long-Acting NitratesChanges in Standing Systolic Blood PressureComparison of Uprima® to Viagra®

- 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.

- Standing Systolic Blood Pressure (mm Hg)

- Standing Systolic Blood Pressure (mm Hg)

- Time Post Dose (hours)

- Sildenafil 50 mg + ISMN 20 mg

- Placebo + ISMN 20 mg

- Treatment:

- Time Post Dose (hours)

- 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

- 2

- 2

- ®

- 1

- 1

- Treatment:

**Uprima****®**** 5 mg – Standing (N=20)****(higher than recommended dose)**

**Viagra****®**** 50 mg – Standing (N=16)**

- Safety-Nitrates

## Long-Acting NitratesChanges in Standing Diastolic Blood PressureComparison of Uprima® to Viagra®

- 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.

- Standing Diastolic Blood Pressure (mm Hg)

- Standing Diastolic Blood Pressure (mm Hg)

- Time Post Dose (hours)

- Time Post Dose (hours)

- Baseline

- 0.50

- 0.75

- 1.00

- 1.25

- 1.50

- 1.75

- 2.00

- 0.25

- Sildenafil 50 mg + ISMN 20 mg

- Placebo + ISMN 20 mg

- Treatment:

- 2

- 2

- Treatment:

- 1

- 1

- ®

**Uprima****®**** 5 mg – Standing (N=20)****(higher than recommended dose)**

**Viagra****®**** 50 mg – Standing (N=16)**

- Baseline

- 0.17

- 0.33

- 0.5

- 0.67

- 0.83

- 1.0

- 1.5

- 2.0

- Safety - Nitrates

## Nitrate Interaction Conclusion

- 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

- Safety-Nitrates

## Antihypertensive Interaction Study M98-930

## Antihypertensives Plus Uprima® 5 mg Mean Maximum Decrease from Baseline in Blood Pressure

**ACE Inhibitors**
**(N = 25)**

**Beta Blockers**
**(N = 26)**

**Calcium Channel**
**Blockers**
**(N = 26)**

**Alpha****1**** Blockers**
**(N = 24)**

**Diuretics**
**(N = 21)**

*M98-930*

- Antihypertensives Plus Uprima® 5 mg Mean Maximum Decrease from Baseline in Blood Pressure

**Supine (mm Hg) **
**	****Systolic**
**	****Diastolic**
**Standing (mm Hg)**
**	****Systolic**
**	****Diastolic**

- * Statistically significant at p = 0.05 level compared to placebo.

- Safety-Antihypertensives

## Antihypertensive Interaction Conclusion

- 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)

- Safety-Antihypertensives

## Hemodynamics

- Syncope
- Hypotension
- Nitrate Interaction
- Alcohol Interaction

## History of Alcohol Interaction

- 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

- Safety - Alcohol

## EthanolInteraction Studies M98-838 & M98-891

## Ethanol Interaction Studies

- 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

- Phase I

*M98-838 & M98-891*

- Safety-Alcohol

## Ethanol Interaction Studies

- 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

- Safety-Alcohol

- Phase I

## Ethanol Plus Uprima® 6 mg Mean Maximum Decrease from Baseline in Blood Pressure 

**	****Systolic**
**	****Diastolic**
**Standing (mm Hg)**
**	****Systolic**
**	****Diastolic**

**Uprima****®**

**Uprima****®**

** ****Ethanol**

**M98-891****(0.6 g/kg Ethanol) ****(N=61)**

- * Statistically significant at p = 0.05 level compared to Uprima® plus ethanol.

**	****-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**

- Ethanol Plus Uprima® 6 mg Mean Maximum Decrease from Baseline in Blood Pressure

**M98-838****(0.3 g/kg Ethanol)****(N=64-66)**

** ****Ethanol**

**Uprima****®**** +****Ethanol**

**Uprima****®**** +****Ethanol**

**	****-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

- Safety-Alcohol

- Phase I

## Mean Change from Baseline inSystolic Blood Pressure

- Mean Change from Baseline inSystolic Blood Pressure

- Time — Post-dosing (Minutes)

*M98-838 *

- SupineSBP(mm Hg)

- StandingSBP(mm Hg)

- Uprima® 6 mg + EtOH 0.3 g/kg
- Uprima® 6 mg + Placebo
- Placebo + EtOH 0.3 g/kg

- No statistically significant differences from ethanol alone (N=66)

- Safety-Alcohol

- Phase I

## Mean Change from Baseline inDiastolic Blood Pressure

- Mean Change from Baseline inDiastolic Blood Pressure

- StandingDBP(mm Hg)

- Time — Post-dosing (Minutes)

- SupineDBP(mm Hg)

- * Statistically significant compared to Uprima® + ethanol at the p = 0.05 levels.

- *

*M98-838*

- Uprima® 6 mg + EtOH 0.3 g/kg
- Uprima® 6 mg + Placebo
- Placebo + EtOH 0.3 g/kg

- No clinically meaningful changes (N=66)

- Phase I

- Safety-Alcohol

## Mean Change from Baseline inSystolic Blood Pressure

- Mean Change from Baseline inSystolic Blood Pressure

- StandingSBP(mm Hg)

- Time — Post-dosing (Minutes)

*M98-891*

- SupineSBP(mm Hg)

- *, **, *** Statistically significant compared to Uprima® + ethanol at the p = 0.05, 0.01 and 0.001 levels, respectively.

- *

- **

- *

- *

- ***

- ***

- **

- *

- *

- *

- *

- Uprima® 6 mg + EtOH 0.6 g/kg
- Uprima® 6 mg + Placebo
- Placebo + EtOH 0.6 g/kg

- Of the statistically significant changes seen, some may be attributable to ethanol alone as well as the combination of Uprima® and ethanol (N=61)

- Phase I

- Safety-Alcohol

## Mean Change from Baseline inDiastolic Blood Pressure

- Mean Change from Baseline inDiastolic Blood Pressure

- StandingDBP(mm Hg)

- SupineDBP(mm Hg)

- *, **, *** Statistically significant compared to Uprima® + ethanol at the p = 0.05, 0.01 and 0.001 levels, respectively.

- ***

- ***

- **

- **

- *

- *

- *

- *

- *

*M98-891*

- Uprima® 6 mg + EtOH 0.6 g/kg
- Uprima® 6 mg + Placebo
- Placebo + EtOH 0.6 g/kg

- Time — Post-dosing (Minutes)

- Phase I

- Safety-Alcohol

## Possibly Related Treatment-Emergent Adverse Events >5% in Uprima® (6 mg) Plus Ethanol (0.3 and 0.6 g/kg)

**Event**

***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)****	**
**Headache****	****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)**
***Vasodilatation******	****** 3******	******(4.4)******	******3******	******(4.5)******	******      0     ******	******  ******	******8******	******(12.5)******	******5******	******(7.5)******	******       0       ***

**Uprima****®**** (6 mg) ****+ Ethanol****0.3 g/kg**
**N = 68**

**Ethanol**
** ****0.3 g/kg****N = 64**

**Uprima****®**** (6 mg)**
**N = 67**

**Uprima****®**** (6 mg) ****+ Ethanol**
**0.6 g/kg**
**N = 64**

**Uprima****®**** (6 mg)**
**N = 67**

**Ethanol**
**0.6 g/kg****N = 63**

**M98-891**

**M98-838**

- Phase I

- Safety-Alcohol

## Patient Instructions in Phase III Trials

- 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.

- Safety-Alcohol

## Related Treatment-Emergent Adverse Events 10%

- Phase II/III Studies

*Alcohol Use – Phase II/III Studies*

**Alcohol Users****(******** 1 drink/day) ****N=350**** n         (%)**

**Non-Alcohol Users**
**N=685****n         (%)**

**Adverse Event**

**Nausea**
**Somnolence**
**Dizziness**
**Sweating**
**Yawning**
**Syncope**

**2 and 4 mg doses **

**	****140****	****(33.8)**
**	****70****	****(16.9)**
**	****66****	****(15.9)**
**	****49****	****(11.8)**
**	****43****	****(10.4)**
**	****6****	****(1.4)**

**	****261****	****(30.4)**
**	****101****	****(11.8)**
**	****137****	****(16.0)**
**	****115****	****(13.4)**
**	****77****	****(9.0)**
**	****12****	****(1.4)**

**Alcohol Users****(******** 1 drink/day) **
**N=414**** n         (%)**

**Non-Alcohol Users**
**N=858****n         (%)**

**All doses (2, 4, 5, 6 mg) **

**	****62****	****(17.7)**
**	****32****	****(9.1)**
**	****25****	****(7.1)**
**	****19****	****(5.4)**
**	****22****	****(6.3)**
**	****3****	****(0.9)**

**	****99****	****(14.5)**
**	****50****	****(7.3)**
**	****67****	****(9.8)**
**	****38****	****(5.5)**
**	****35****	****(5.1)**
**	****5****	****(0.7)**

***Recommended Dose***

***Includes Higher Than Recommended Dose***

- 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

- 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

- Ethanol Interaction Conclusion

- 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

- No increased vasovagal Holter monitor changes with Uprima ®  and ethanol compared to Uprima® alone

- Ethanol Interaction Conclusion (cont.)

- Safety-Alcohol