Clinical trial NCT03292016
Conditions: Parkinson Disease
Keywords: Off Episodes Parkinson Disease
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2017-08-22; Completion date: 2019-03-05
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A study that compares the extent to which apomorphine becomes available in the body after taking either an investigational drug containing apomorphine or apomorphine that is injected under the skin in people with PD complicated by "OFF" episodes.

Detailed description:
This multi-center study will aim to evaluate the pharmacokinetics (PK) and comparative bioavailability of a single dose of APL-130277 sublingual thin film with subcutaneous (s.c.) APO-go® and s.c. APOKYN® in subjects with Parkinson's disease (PD). The dose of APOKYN® (≤ 5 mg) will be based on the subjects' current prescribed dose. The study is designed as an open-label, randomized, three-way crossover. Subjects will receive all three treatment arms with a minimum 1-day wash-out between each visit (excluding the screening visit) and will be randomly assigned to one of the six sequences

Arms: arm 1: APL-130277, sublingual thin film, once daily arm 2: Subcutaneous APO-go, once daily arm 3: Subcutaneous APOKYN, once daily
Interventions: intervention 1: APL-130277 intervention 2: APO-go intervention 3: Apokyn
Intervention descriptions: intervention 1: APL-130277 sublingual thin film intervention 2: Subcutaneous APO-go intervention 3: Subcutaneous APOKYN

Protocol documents:
Prot_000.pdf: 
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Sunovion Pharmaceuticals Inc. 
 
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RESTRICTED DISTRIBUTION OF PROTOCOLS 
This document contains information confidential and/or of proprietary interest to Sumitomo 
Dainippon Pharma Co. Ltd. and/or Sunovion Pharmaceuticals Inc. (including their 
The information cannot be disclosed to any third party or 
predecessors, subsidiaries or affiliates). 
used for any purpose other than the purpose for which it is being submitted without the prior 
written consent of the appropriate Sumitomo Dainippon Pharma company. 
This information is being provided to you for the purpose of conducting a clinical study for 
Sumitomo Dainippon Pharma Co. Ltd. and
 You may disclose 
/or Sunovion Pharmaceuticals Inc.
the contents of this protocol to the study personnel under your supervision and to your 
Institutional Review Board or Independent Ethics Committee for the above purpose. You may 
not disclose the contents of this protocol to any other parties, unless such disclosure is required 
by government regulations or laws, without the prior written permission of Sumitomo Dainippon 
Pharma Co. Ltd. and
 
/or Sunovion Pharmaceuticals Inc.
Any data gathered during the conduct of this protocol and supplemental information (eg, a 
 
protocol amendment) that may be added to this document is also proprietary to Sumitomo 
Dainippon Pharma Co. Ltd. and
, and should be handled 
/or Sunovion Pharmaceuticals Inc.
consistently with that stated above. 


Sunovion Pharmaceuticals Inc. 
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1.
EMERGENCY CONTACT INFORMATION
Role in Study 
Name 
Contact Information 
Responsible Physician 
 
 
Medical Monitor 
SAE Reporting 
 
 


Sunovion Pharmaceuticals Inc. 
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2.
INVESTIGATOR APPROVAL STATEMENT
I have read the protocol, CTH-203, Version 2.00, “A Comparative Bioavailability Study to 
Evaluate the Single Dose Pharmacokinetic Properties of APL-130277 with Two Different 
Formulations of Subcutaneous Apomorphine in a Randomized, 3-Period Crossover Design in 
Subjects with Parkinson’s Disease Complicated by Motor Fluctuations (“OFF” Episodes),” and 
agree that it contains all necessary details for conducting the study and to conduct the study in 
strict accordance with the specifications outlined herein. 
I agree that no additional procedure(s) will be added during the conduct of the study except 
through protocol amendment by Sunovion Pharmaceuticals Inc. and after documentation of 
IRB/REB/IEC approval. 
Principal Investigator 
Printed Name: 
Signature: 
Date: 
PROTOCOL 
A Comparative Bioavailability Study to Evaluate the Single Dose Pharmacokinetic 
Properties of APL-130277 with Two Different Formulations of Subcutaneous 
Apomorphine in a Randomized, 3-Period Crossover Design in Subjects with Parkinson’s 
Disease Complicated by Motor Fluctuations (“OFF” Episodes) 
Protocol: 10 May 2017 
Version 2.00 


Sunovion Pharmaceuticals Inc. 
 
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3. 
PROTOCOL SYNOPSIS 
TITLE 
A Comparative Bioavailability Study to Evaluate the Single Dose 
Pharmacokinetic Properties of APL-130277 with Two Different Formulations of 
Subcutaneous Apomorphine in a Randomized, 3-Period Crossover Design in 
Subjects with Parkinson’s Disease Complicated by Motor Fluctuations (“OFF” 
Episodes) 
STUDY PHASE 
Phase 2 
OBJECTIVES 
Primary Objective  
• 
To evaluate the pharmacokinetics (PK) and comparative bioavailability 
of a single dose of APL-130277 sublingual thin film with subcutaneous 
(s.c.) APO-go® and s.c. APOKYN® in subjects with Parkinson’s disease 
(PD) complicated by motor fluctuations (“OFF” Episodes). 
Secondary Objectives 
• 
To evaluate the safety and tolerability of the study drugs. 
NUMBER OF 
SUBJECTS 
The study plan will require approximately 12 subjects to complete the Three-
Way Crossover phase.  
PATIENT 
POPULATION 
Inclusion Criteria 
Patients who meet each of the following criteria will be eligible for participation 
in the study: 
1. Male or female ≥ 18 years of age. 
2. Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank 
Criteria (excluding the “more than one affected relative” criterion). 
3. Clinically meaningful response to Levodopa (L-Dopa) with well-defined 
“OFF” episodes, as determined by the Investigator. 
4. Receiving a stable dose of APOKYN® of ≤ 5 mg per dose for at least 4 
weeks before the Screening Visit. 
5. Receiving stable doses of L-Dopa/carbidopa (immediate or sustained 
release) administered at least 4 times per day OR Rytary™ administered 
3 times per day, for at least 4 weeks before the Screening Visit. 
Adjunctive PD medication regimens must be maintained at a stable dose 
for at least 4 weeks prior to the Screening Visit with the exception that 
MAO-B inhibitors must be maintained at a stable level for at least 
8 weeks prior to the Screening Visit. 
6. No planned medication change(s) or surgical intervention anticipated 
during the course of study. 
7. Patients must experience a well-defined “OFF” episode in the morning if 
they do not take their morning PD medications on schedule, and must be 
willing to delay morning doses on the 3 study dosing days. 
8. Stage III or less on the modified Hoehn and Yahr scale in the “ON” 
state. 
9. Mini–Mental State Examination (MMSE) score > 23. 
10. If female and of childbearing potential, must agree to use one of the 


Sunovion Pharmaceuticals Inc. 
 
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10 May 2017 
CONFIDENTIAL 
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following methods of birth control: 
• 
Oral contraceptive; 
• 
Contraceptive patch; 
• 
Barrier (diaphragm, sponge or condom) plus spermicidal 
preparations; 
• 
Intrauterine contraceptive system; 
• 
Levonorgestrel implant; 
• 
Medroxyprogesterone acetate contraceptive injection; 
• 
Complete abstinence from sexual intercourse; 
• 
Hormonal vaginal contraceptive ring; or 
• 
Surgical sterilization or partner sterile (must have documented 
proof). 
11. Male patients must be either surgically sterile, agree to be sexually 
abstinent or use a barrier method of birth control (eg, condom), or 
maintain a monogamous relationship with a person who is not of child-
bearing potential from first study drug administration until 30 days after 
final drug administration. 
12. Willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study-related procedures to complete the 
study. 
13. Able to understand the consent form, and to provide written informed 
consent. 
 
Exclusion Criteria 
Patients will be excluded from participation in the study for any of the following 
reasons: 
1. Atypical or secondary parkinsonism. 
2. Previous treatment with any of the following: continuous subcutaneous 
(s.c.) apomorphine infusion; or Duodopa/Duopa. 
3. Contraindications to APO-go® or APOKYN® or hypersensitivity to 
apomorphine hydrochloride or any macrolide antibiotic or any of the 
ingredients of APO-go® or APOKYN® (notably sodium metabisulfite).  
4. Female who is pregnant or lactating. 
5. Participation in a clinical trial within 30 days prior to the Screening 
Visit. 
6. Receipt of any investigational (ie, unapproved) medication within 
30 days prior to the Screening Visit. 
7. Any selective 5HT3 antagonists (ie, ondansetron, granisetron, 
dolasetron, palonosetron, alosetron), dopamine antagonists (excluding 
quetiapine and clozapine) or dopamine depleting agents within 30 days 
prior to the Screening Visit. 
8. Drug or alcohol dependency in the past 12 months. 
9. History of malignant melanoma. 
10. Clinically significant medical, surgical, or laboratory abnormality in the 


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CONCOMITANT 
AND 
CO-ANALGESIC 
TREATMENT 
All subjects: stable doses of a L-Dopa formulation and other stable adjunctive 
PD medications. If a subject is presently using an anti-emetic they can continue 
with this treatment at the prescribed dose, otherwise use of an anti-emetic will 
not be permitted. 
PROHIBITED 
TREATMENT 
• 
Treatment with any form of apomorphine other than study 
medication(s). 
• 
Any selective 5HT3 antagonist (ie, ondansetron, granisetron, dolasetron, 
palonosetron, alosetron). 
• 
Dopamine antagonists (excluding quetiapine or clozapine) or depleting 
drugs. 
• 
Deep brain stimulation or other neurosurgical PD treatment, continuous 
s.c. apomorphine infusion or Duodopa/Duopa. 
• 
Use of an anti-emetic is not permitted. In cases where a subject is 
presently using an anti-emetic they will be allowed to continue with this 
treatment at the prescribed dose. 
STUDY DURATION 
Participation is anticipated to be approximately 37 days for each subject. 
INVESTIGATIVE 
SITES OR 
COUNTRIES 
This is a multi-center study to be conducted in the United States. 
STUDY ENDPOINTS 
Primary endpoint 
The primary endpoint is the PK profile (plasma), including: Cmax, Tmax, λz, t½, 
AUClast, AUC∞, MRT, M/P Ratio, CL/F, V/F. Comparative bioavailability (FT/R) 
between the Test and Reference products will also be evaluated. 
Secondary endpoints 
The secondary endpoints are safety and tolerability: evaluation of clinical 
laboratory tests, 12-lead ECGs, physical examinations, vital signs (including 
blood pressure [BP], heart rate [HR], respiration rate [RR], body temperature and 
weight), and adverse events (AEs). 
STATISTICAL 
METHODS 
SUMMARY 
All subjects who receive at least one dose of APL-130277, APO-go®, or 
APOKYN® will be included in the safety analysis set. The PK analysis set 
includes all subjects with at least one PK evaluation.  
Primary Objective: 
AUClast, AUC∞, Cmax, Tmax, t½, and λz will be evaluated. Analysis of Variance 
(ANOVA) will be performed for log-transformed AUClast, AUC∞ and Cmax. Tmax 
will be analyzed using a non-parametric test (Wilcoxon test) while t½ will be 
analyzed using a t-test. Comparative bioavailability will be assessed by 
estimating the 90% confidence intervals (CI) for the formulation ratios 
(APL-130277 vs. APO-go® vs. APOKYN®) of geometric means for AUClast, 
AUC∞, Cmax and will be calculated based on the ratios of the least squares means 
and estimates from the ANOVA. 
Secondary Objectives: 
Safety and tolerability will be evaluated through summary tables and individual 
listings of all safety parameters collected in the study. 


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SAMPLE SIZE 
CALCULATION 
With a sample size of 12 subjects, a two-sided 90% confidence interval for the 
difference in paired PK parameter means on the log scale will have an interval 
that extends no more than 0.221 units from the observed difference with 90% 
coverage probability. This calculation assumes a coefficient of variation of 35% 
for the difference on the original scale. If the observed mean difference on the 
log scale were zero, this would correspond to a 90% confidence interval for the 
ratio of geometric means of (80.2%, 124.7%) on the original scale. 
 
 


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4. 
STUDY DESIGN FLOW CHART 
Table 1: 
Schedule of Events 
Procedures 
Screening Visit1 
Telephone 
Contact2 
Wash-Out 
Period 1 Visit 
Telephone 
Contact2 
Wash-Out 
Period 2 Visit 
Telephone 
Contact2 
Wash-Out 
Period 3 Visit 
Telephone 
Contact2 
Wash-Out 
End of Study  
Visit 
Study Visit 
SV 
TC 
W/O 
P1 
TC 
W/O 
P2 
TC 
W/O 
P3 
TC 
W/O 
EOS 
Day  
-21 to  
-3 
1 day 
prior 
to 
W/O 
1 day 
prior 
to P1 
1 
1 day 
prior 
to 
W/O 
1 day 
prior 
to P2 
3-5 
days 
after 
P1 
1 day 
prior 
to 
W/O 
1 day 
prior 
to P3 
3-5 
days 
after 
P2 
1 day 
prior 
to 
W/O 
1 day 
prior 
to EOS 
3-5 
days 
after 
P3 
-21 to 
-3 
-2 
-1 
1 
2 
3 
4-6 
7 
8 
9-11 
12 
13 
14-16 
Outpatient Visit 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Reconfirmation of Consent 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Review Entry Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review Prohibited Treatment & Study 
Restrictions 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Exam, including 
Oropharyngeal Exam & Injection Site 
Reaction3 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated Physical Exam, including 
Oropharyngeal Exam & Injection Site 
Reaction4 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
BMI, Weight and Height5 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 


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CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
Procedures 
Screening Visit1 
Telephone 
Contact2 
Wash-Out 
Period 1 Visit 
Telephone 
Contact2 
Wash-Out 
Period 2 Visit 
Telephone 
Contact2 
Wash-Out 
Period 3 Visit 
Telephone 
Contact2 
Wash-Out 
End of Study  
Visit 
Study Visit 
SV 
TC 
W/O 
P1 
TC 
W/O 
P2 
TC 
W/O 
P3 
TC 
W/O 
EOS 
Day  
-21 to  
-3 
1 day 
prior 
to 
W/O 
1 day 
prior 
to P1 
1 
1 day 
prior 
to 
W/O 
1 day 
prior 
to P2 
3-5 
days 
after 
P1 
1 day 
prior 
to 
W/O 
1 day 
prior 
to P3 
3-5 
days 
after 
P2 
1 day 
prior 
to 
W/O 
1 day 
prior 
to EOS 
3-5 
days 
after 
P3 
-21 to 
-3 
-2 
-1 
1 
2 
3 
4-6 
7 
8 
9-11 
12 
13 
14-16 
Vital Signs (BP, HR, RR and Temp)6,7 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
12-Lead ECG7,8 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Clinical Laboratory Tests9 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
PK7,10 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
MMSE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Modified Hoehn and Yahr11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS12 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Confirmation of “OFF” or full “ON” 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
In-Clinic Dosing 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
AEs/Serious AEs (SAEs) 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Previous/Current Concomitant Medications 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
1 All screening procedures to be conducted within 21 days prior to dosing (Period 1). 
2 Telephone contact as a reminder for subject to discontinue APOKYN® a minimum of 1-day prior to each study visit for the Wash-Out Interval (excluding SV).  
3 Physical examinations to include the following: head-eyes-ears-nose and throat; respiratory system; cardiovascular system; gastrointestinal system, including 
mouth – oral cavity; musculoskeletal system; central and peripheral nervous system; skin; and injection site. The oropharyngeal cavity examination should 
include a visual inspection of the inside of each cheek, the inside of the upper and lower lip, the surface of the tongue, and under the tongue. Examination for 
injection site reaction will be completed at the End of Study Visit (EOS). 


Sunovion Pharmaceuticals Inc. 
 
Page 13 
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
4 Abbreviated physical examinations to include head-eyes-ears-nose and throat; heart; lungs; abdomen; skin; mouth – oral cavity and injection site to be done at 
t = 0 (just prior to dosing) and 2 hours after dosing at Period 1, Period 2, and Period 3. The oropharyngeal cavity examination should include a visual inspection 
of the inside of each cheek, the inside of the upper and lower lip, the surface of the tongue, and under the tongue. 
5 Both height and weight captured at the Screening Visit to calculate BMI; only weight captured at all other indicated visits. 
6 Vital signs will be assessed at the Screening Visit and End of Study Visit; Period 1, Period 2 and Period 3 at t = 0 minutes (just prior to dosing), 15, 45 and 60 
minutes. Blood pressure to be measured supine and standing (measured within 3 minutes of standing) at all timepoints. 
7 Suggested Sequence of Assessments: PK – ECG – Vitals.  
8 12-lead ECG:  Obtain in triplicate at the Screening Visit. Period 1, Period 2 and Period 3 obtain at t = 0 (just prior to dosing) and 60 minutes after dosing. 
Obtain at the End of Study Visit.  
9 Blood and urine collection for clinical laboratory tests will occur at the Screening Visit and at the End of Study Visit. In addition, serum pregnancy test will be 
performed on all females of childbearing potential. 
10 PK will be assessed in Period 1, Period 2 and Period 3 at t = 0 (just prior to dosing), 15, 30, 45, 60 minutes and 1.5, 3, 6 hours after dosing.  
11 The modified Hoehn and Yahr will be used during the Screening Visit in the “ON” state to determine eligibility.  
12 C-SSRS “Screening” scale to be used at the Screening Visit; “Since Last Visit” scale to be used at End of Study Visit. 
 
 


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3K\VLFDO&KDUDFWHULVWLFVRI$3/ 
7DEOH 
5DQGRPL]HG7UHDWPHQW6HTXHQFHV 
7DEOH 
'RVLQJ$OJRULWKP 
7DEOH 
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Sunovion Pharmaceuticals Inc. 
 
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6. 
LIST OF ABBREVIATIONS 
Abbreviation or 
specialist term 
Explanation 
5HT3 
5-hydroxy tryptophan (serotonin) 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
APO-go®  
apomorphine hydrochloride injection marketed in the EU 
APOKYN® 
apomorphine hydrochloride injection marketed in the US 
API 
active pharmaceutical ingredients 
AUClast 
area under the concentration-time curve from time zero to the last measurable plasma 
concentration-time curve using the linear up log down trapezoidal rule. 
AUC∞  
area under the concentration-time curve from time zero extrapolated to infinity using 
the linear up log down trapezoidal rule. 
AST 
aspartate aminotransferase 
BLQ 
Below the limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CL/F 
Apparent total clearance of the drug from plasma after oral administration 
Cmax 
maximum observed plasma concentration 
COMT 
Catechol O-methyltransferase 
CR 
chronic release 
CRA 
Clinical Research Associate 
CRF 
case report form 
CSA 
clinical study agreement 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV% 
coefficient of variation 
ECG 
electrocardiogram 
EDC 
electronic data capture 
GCP 
Good Clinical Practice 
GRAS 
Generally Recognized as Safe 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 


Sunovion Pharmaceuticals Inc. 
 
Page 20 
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
Abbreviation or 
specialist term 
Explanation 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
Interactive Web Response System 
L-Dopa 
L-3,4-dihydroxyphenylalanine or Levodopa 
λz 
terminal-phase rate constant 
MAO-B 
monoamine oxidase B  
MCH 
mean corpuscular hemoglobin 
MCHC 
MCH concentration 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
mean residence time 
MMSE 
Mini-Mental State Examination 
OH 
Orthostatic Hypotension 
PD 
Parkinson’s disease 
PK 
pharmacokinetic 
QTc 
Corrected QT interval 
RBC 
red blood cell 
REB 
Research Ethics Board 
RR 
respiratory rate 
SAE 
serious adverse event 
s.c. 
subcutaneous 
SD 
standard deviation 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
Sunovion 
Sunovion Pharmaceuticals Inc. 
t½ 
Terminal-phase half-life 
TdP 
Torsades de Pointes 
Temp 
temperature 
Tmax 
observed time of the maximum concentration 
V/F 
Apparent volume of distribution after non-intravenous administration 


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10 May 2017 
CONFIDENTIAL 
Version 2.00 
Abbreviation or 
specialist term 
Explanation 
WBC 
white blood cell 
WHO-DD 
World Health Organization Drug Dictionary 


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Sunovion Pharmaceuticals Inc. 
 
Page 24 
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10 May 2017 
CONFIDENTIAL 
Version 2.00 
Table 2: 
Summary of Apomorphine Physico-Chemical Data 
Active Pharmaceutical 
Ingredients (API) Common Name 
Apomorphine Hydrochloride Hemihydrate 
Production Site 
Manufacturer of Active Pharmaceutical Ingredient for 
Clinical Batches: 
Sanofi Aventis (Aramon Site) 
SANOFI CHIMIE  
Route d’Avignon  
30390 Aramon  
France 
IUPAC nomenclature 
4H-Dibenzo [de, g] quinoline-10, 11-diol, 5, 6, 6a, 7-
tetrahydro-6-methyl hydrochloride, hemihydrate 
Synonyms, common names 
Apomorphine hydrochloride, SR94013A, 6a,beta-
aporphine-10,11-diol hydrochloride 
CAS number 
41372-20-7 
Formula 
C17H17NO2•HCl•1/2H2O 
Molecular weight 
312.79 g/mol 
Specific Rotation 
-60.5o to -63.0o 
pKa 
pKa: 7.0, 8.9 
pH 
4.3 
Water solubility 
Sparingly soluble in water and alcohol; slightly soluble 
in chloroform  
7.3. 
Drug Product (APL-130277 Sublingual Thin Film) 
The product under development, APL-130277, is a soluble thin film for sublingual 
administration. APL-130277 is designed to deliver apomorphine systemically through absorption 
from the oral cavity mucosa, thus bypassing the extensive first pass metabolism associated with 
gastrointestinal absorption of the compound. The product is intended to be an alternative to the 
injectable form of apomorphine hydrochloride, which is marketed in the United States as 
APOKYN® and in most of Europe and Asia as APO-go®. 
APL-130277 is manufactured for clinical studies as a bilayer thin film with one layer containing 
the active ingredient, apomorphine hydrochloride, and the other layer containing a buffer 
(pyridoxine). Dosage units of 10, 15, 20, 25, and 30 mg are achieved from a single formulation 
by cutting different sized rectangular thin films from sheets of bulk film as shown in the table 
below. Identifying marks are printed in white ink on the buffer side of the sublingual thin film. 


Sunovion Pharmaceuticals Inc. 
 
Page 25 
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
Table 3: 
Physical Characteristics of APL-130277 
Apomorphine 
Hydrochloride 
Loading (mg) 
Length 
(mm) 
Width (mm) 
Area 
(mm2) 
Identifying 
Mark 
10 
22 
8.8 
193.6 
C1 
15 
22 
13.2 
290.4 
C2 
20 
22 
17.6 
387.2 
C3 
25 
22 
22 
484.0 
C4 
30 
22 
26.4 
580.8 
C5 
The APL-130277 finished drug product will be manufactured at ARx, LLC facilities at: 400 
Seaks Run Road Glen Rock, PA 17327, USA. 
The formulations for each of the dosage strengths have exactly the same proportions of active 
pharmaceutical ingredient and inactive excipients.  
The formulation consists of pharmaceutically acceptable cellulosic film formers along with 
glycerin as a plasticizer; and flavor, sweetener and colour additives for patient 
acceptability. Other excipients include sodium hydroxide to modify pH and sodium metabisulfite 
as an antioxidant/preservative. The formulation also includes pyridoxine HCL as a buffer 
component. The excipients used in formulating APL-130277 sublingual thin films, are 
compendial (USP, NF or FCC) items and/or are Generally Recognized as Safe (GRAS) and/or 
have precedent for use in pharmaceutical products approved in the US. 
7.4. 
Clinical Experience 
This is the thirteenth planned in-man study for APL-130277. Previous studies CTH-101, CTH-
102, CTH-103, CTH-104, CTH-106, CTH-107 and CTH-200 were performed in healthy 
volunteers in Malaysia, all at Info Kinetics. CTH-101 through CTH-104 and CTH-107 were 
conducted with prototype formulations.  The first study completed in a PD patient population, 
CTH-105, was conducted at 4 sites in North America. CTH-300 and CTH-301, both evaluating 
APL-130277 in a PD patient population, are being conducted concurrently in North America. 
CTH-201 and CTH-302 are planned in a PD patient population and will be conducted in Europe 
in early 2017. 
The clinical experience with APL-130277 in healthy volunteers is summarized in considerable 
detail in the Investigator's Brochure (IB). Adverse events were those expected to be seen with 
apomorphine, with the most common AEs being somnolence, dizziness and nausea. No dose 
limiting side effects were encountered with APL-130277 and no subjects discontinued 
APL-130277 treatment due to AE. 
The healthy volunteer studies confirmed the method of administration, allowed further 
refinement of the formulation and confirmed PK comparability of APL-130277 to s.c. 
apomorphine. The CTH-103 and CTH-104 PK study results demonstrated dose proportionality 
of the doses of APL-130277 tested (10 mg, 15 mg, 25 mg) and that the 25 mg dose is sustained 
over an extended period of time (162 minutes) above the minimal efficacious plasma 
concentration of apomorphine (approximately 3 ng/mL), believed to be a level demonstrating 


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7.6. 
Rationale 
This multi-center, Phase 2 study is designed to evaluate the pharmacokinetics (PK) and 
comparative bioavailability of a single dose of APL-130277 sublingual thin film with 
subcutaneous (s.c.) APO-go® and s.c. APOKYN® in subjects with Parkinson’s disease (PD) who 
experience motor fluctuations (“OFF” episodes). 
 


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8. 
ETHICS 
This study will be conducted in compliance with the principles established by the World Medical 
Assembly in the Declaration of Helsinki - Ethical Principles for Medical Research Involving 
Human Subjects and all applicable amendments, the ICH Principles of Good Clinical Practice 
(GCP) (including archiving of essential study documents), and applicable regulatory 
requirements and guidelines. 
A properly constituted, valid Institutional Review Board (IRB) or Research Ethics Board (REB) 
or Independent Ethics Committee (IEC) must review and approve the protocol, each 
Investigator’s Informed Consent Form (ICF), and related subject information before the start of 
the study, and any subject recruitment material(s) before they are provided to subjects. During 
the Clinical Trial, any amendment or modification to the protocol should be submitted to the 
IRB/REB/IEC. The IRB/REB/IEC should also be informed of any event likely to affect the 
safety of subjects or the continued conduct of the study, in particular any changes in safety. All 
updates to the IB will be sent to the IRB/REB/IEC. 
It is the responsibility of each Investigator to ensure that written informed consent is obtained 
from the patient before any study activity or procedure is undertaken. 


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9. 
OBJECTIVES AND STUDY ENDPOINTS 
9.1. 
Objectives  
The primary objective is to evaluate the pharmacokinetics (PK) and comparative bioavailability 
of a single dose of APL-130277 sublingual thin film with subcutaneous (s.c.) APO-go® and s.c. 
APOKYN® in subjects with Parkinson’s disease (PD) complicated by motor fluctuations (“OFF” 
episodes). 
The secondary objective is to evaluate the safety and tolerability of the study drugs. 
9.2. 
Study Endpoints 
9.2.1. 
Primary Endpoint 
PK profile (plasma), including: Cmax, Tmax, λz, t½, AUClast, AUC∞, MRT, M/P Ratio, CL/F, V/F. 
Comparative bioavailability (FT/R) between the Test and Reference products will also be 
evaluated. 
9.2.2. 
Secondary Endpoints 
Safety and tolerability: evaluation of clinical laboratory tests, 12-lead ECGs, physical 
examinations, vital signs (including blood pressure [BP], heart rate [HR], respiration rate [RR], 
body temperature and weight), and adverse events (AEs). 


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10. 
STUDY DESIGN 
This is a multi-center, phase 2, open-label, randomized, three-way crossover study designed to 
evaluate the pharmacokinetics (PK) and comparative bioavailability of a single dose of 
APL-130277 sublingual thin film with subcutaneous (s.c.) APO-go® and s.c. APOKYN® in 
subjects with Parkinson’s disease (PD). 
10.1. 
General Overview 
This study will commence with an initial Screening Visit, followed by an open-label, 
randomized, three-way crossover (Period 1, Period 2, and Period 3). Subjects will receive all 
three treatment arms with a minimum 1-day Wash-Out Interval between each visit (excluding the 
screening visit).  
10.2. 
Screening Visit 
Before any study procedures are performed on any person, informed consent must be obtained. 
Subjects, who have provided full consent to participate, will arrive at the clinic having taken 
their usual morning dose of PD medications; but before taking their next dose of medication. 
Their normally scheduled second dose of L-Dopa (without adjunctive PD medication) will be 
administered in the clinic following confirmation of an “OFF” episode by the Investigator, to 
ensure the subject experiences an “ON” response. Eligibility criteria will be assessed by the 
Investigator. Subjects, who are considered eligible, will be scheduled for the Period 1 Visit. 
10.3. 
Wash-Out Interval 
One (1) day before each Period Visit, at a minimum, subjects will be required discontinue 
subcutaneous APOKYN®; this is referred to as the wash-out interval. L-Dopa and any other 
adjunctive PD medication will be permitted during this time. 
10.4. 
Three-Way Open-Label Randomized Crossover (Period 1, Period 2, 
Period 3)  
Subjects will be asked to return to the clinic the morning of Period 1 (P1) after their usual 
morning dose of PD medications; but before taking their next dose of medication and will be 
randomized to one of the 6 treatment sequences.  
Subjects will be required to wait to take their normally scheduled second dose of PD medications 
until after confirmation by the Investigator that the subject is in the “OFF” state and will be 
dosed according to the randomized treatment sequence with APL-130277, APO-go®, or 
APOKYN®. All PD medications should be held until 60 minutes after dosing. 
Following the same procedures described above, subjects will return to clinic within 3-5 days 
after Period 1 and will be dosed for Period 2 with one of the other two treatments. Subjects will 
return to clinic within 3-5 days after Period 2 and will be dosed for Period 3 with the third and 
last treatment. 


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11. 
PATIENT POPULATION 
11.1. 
Selection of Study Population 
A screening log of potential study candidates and an enrollment log of enrolled subjects must be 
maintained at each study site.  
The study will require approximately 12 subjects to complete the Three-Way Crossover phase. 
Recruitment will continue until the required number of subjects complete the study.  
11.1.1. 
Inclusion Criteria  
Patients who meet each of the following criteria will be eligible for participation in the study: 
1. Male or female ≥ 18 years of age. 
2. Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank Criteria (excluding 
the “more than one affected relative” criterion). 
3. Clinically meaningful response to Levodopa (L-Dopa) with well-defined “OFF” 
episodes, as determined by the Investigator. 
4. Receiving APOKYN® of ≤ 5 mg per dose for at least 4 weeks before the Screening Visit. 
5. Receiving stable doses of L-Dopa/carbidopa (immediate or sustained release) 
administered at least 4 times per day OR Rytary™ administered 3 times per day, for at 
least 4 weeks before the Screening Visit. Adjunctive PD medication regimens must be 
maintained at a stable dose for at least 4 weeks prior to the Screening Visit with the 
exception that MAO-B inhibitors must be maintained at a stable level for at least 8 weeks 
prior to the Screening Visit. 
6. No planned medication change(s) or surgical intervention anticipated during the course of 
study. 
7. Patients must experience a well-defined “OFF” episode in the morning if they do not take 
their morning PD medications on schedule, and must be willing to delay morning doses 
on the 3 study dosing days. 
8. Stage III or less on the modified Hoehn and Yahr scale in the “ON” state. 
9. Mini–Mental State Examination (MMSE) score > 23. 
10. If female and of childbearing potential, must agree to use one of the following methods of 
birth control: 
• Oral contraceptive; 
• Contraceptive patch; 
• Barrier (diaphragm, sponge or condom) plus spermicidal preparations; 
• Intrauterine contraceptive system; 
• Levonorgestrel implant; 


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• Medroxyprogesterone acetate contraceptive injection; 
• Complete abstinence from sexual intercourse; 
• Hormonal vaginal contraceptive ring; or 
• Surgical sterilization or partner sterile (must have documented proof). 
11. Male patients must be either surgically sterile, agree to be sexually abstinent or use a 
barrier method of birth control (eg, condom) or maintain a monogamous relationship with 
a person who is not of child-bearing potential from first study drug administration until 
30 days after final drug administration. 
12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study-related procedures to complete the study. 
13. Able to understand the consent form, and to provide written informed consent 
11.1.2. 
Exclusion Criteria  
Patients will be excluded from participation in the study for any of the following reasons: 
1. Atypical or secondary parkinsonism. 
2. Previous treatment with any of the following:  continuous subcutaneous (s.c.) 
apomorphine infusion; or Duodopa/Duopa. 
3. Contraindications to APO-go® or APOKYN® or hypersensitivity to apomorphine 
hydrochloride or any macrolide antibiotic or any of the ingredients of APO-go® or 
APOKYN® (notably sodium metabisulfite).  
4. Female who is pregnant or lactating. 
5. Participation in a clinical trial within 30 days prior to the Screening Visit. 
6. Receipt of any investigational (ie, unapproved) medication within 30 days prior to the 
Screening Visit. 
7. Any selective 5HT3 antagonists (ie, ondansetron, granisetron, dolasetron, palonosetron, 
alosetron), dopamine antagonists (excluding quetiapine and clozapine) or dopamine 
depleting agents within 30 days prior to the Screening Visit. 
8. Drug or alcohol dependency in the past 12 months. 
9. History of malignant melanoma. 
10. Clinically significant medical, surgical, or laboratory abnormality in the opinion of the 
Investigator. 
11. Major psychiatric disorder including, but not limited to, dementia, bipolar disorder, 
psychosis, or any disorder that, in the opinion of the Investigator, requires ongoing 
treatment that would make study participation unsafe or make treatment compliance 
difficult. 
12. History of clinically significant hallucinations during the past 6 months. 
13. History of clinically significant impulse control disorder(s). 


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Sunovion Pharmaceuticals Inc. 
 
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11.3. 
Subject Withdrawal from the Study 
Subjects may be withdrawn from participating in this study for the following: 
• In order to protect their safety and/or well-being; 
• If they are unwilling or unable to comply with required study procedures; 
• If they withdraw their consent to participate in the study; 
• If the study is prematurely terminated by the Sponsor or Regulatory Authorities; 
• If they no longer meet the inclusion/exclusion criteria within the study. 
Subjects will be advised that they are free to withdraw from the study at any time, for any reason, 
and without prejudice. Every reasonable and appropriate effort should be made by the 
Investigator to keep subjects in the study. However, subjects must be withdrawn from the study 
if the subject withdraws his or her consent to participate. In the event of subject withdrawal, the 
Investigator should attempt to determine the reason for the subject’s withdrawal. 
The reason for discontinuation and the date of withdrawal from the study will be recorded in the 
appropriate CRF. The Investigator should make at least 3 documented attempts to contact a 
subject who is lost to follow-up, with at least 1 attempt made by a certified letter. Documentation 
of contact attempts must be made in the subject’s record. 
Neither subjects withdrawing from the study nor those removed by the Investigator or Sponsor 
will be replaced. Subjects who are withdrawn from this study may not re-enter the study at a later 
date. The screening number for a withdrawn subject will not be reassigned to another subject. 
If a subject is removed or withdraws from the study, the procedures outlined in the EOS Visit 
will be performed, where possible.  


Sunovion Pharmaceuticals Inc. 
 
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12. 
STUDY PROCEDURES 
This study will consist of the following: 
1. Screening Visit (SV) 
2. Telephone Contact 
3. Wash-Out Interval 
4. Three-Way Open-Label Randomized Crossover  
a. Period 1 Visit (P1) 
b. Period 2 Visit (P2) 
c. Period 3 Visit (P3)  
5. End of Study Visit (EOS) 
12.1. 
Screening Visit 
Potential subjects must sign an Informed Consent Form (ICF) before any screening-related 
procedures are performed. Subjects, who have provided full consent to participate, will arrive at 
the clinic after their usual morning dose of PD medications; but before taking their next dose of 
medication. Their normally scheduled second dose of L-Dopa (without adjunctive PD 
medication) will be administered in the clinic following confirmation of an “OFF” episode by the 
Investigator, to ensure the subject experiences an “ON” response. 
The following procedures will be performed by study staff at the Screening Visit: 
• Review the study and obtain written informed consent. Subjects may review the 
consent and return it at a later date, at which time the Screening Visit will take place. 
• Review inclusion/exclusion criteria. 
• Record demographics and detailed medical history, including review of medications 
taken within 6 months prior to the Screening Visit, current treatment regimens, drug, 
alcohol and smoking history. 
• Perform a complete physical examination, including an oropharyngeal examination. 
The oropharyngeal cavity examination should include a visual inspection of the inside 
of each cheek, the inside of the upper and lower lip, the surface of the tongue, and 
under the tongue. 
• Measure height and weight; calculate BMI. 
• Record vital signs (BP, HR, RR and Temp), after the subject has been in a supine 
position for 5 minutes. Subject BP to be measured both supine and standing (within 3 
minutes of standing). 
• Perform a standard 12-lead ECG in triplicate. 
• Collect blood and urine sample for clinical laboratory tests (hematology, chemistry, 
urinalysis and serology). Serum pregnancy test for females of child-bearing potential 
only.  


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Sunovion Pharmaceuticals Inc. 
 
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• Reconfirm consent. 
• Review prohibited treatment and study restrictions. 
• Perform randomization (at the Period 1 Visit only). 
• Perform an abbreviated physical examination, including oropharyngeal examination 
and of the injection site at t = 0 (just prior to dosing) and 2 hours after dosing. The 
oropharyngeal cavity examination should include a visual inspection of the inside of 
each cheek, the inside of the upper and lower lip, the surface of the tongue, and under 
the tongue.  
• Measure body weight. 
• Perform a standard 12-lead ECG t = 0 (just prior to dosing) and approximately 
60 minutes after dosing. 
• Record vital signs (BP, HR, RR and Temp) at t = 0 minutes (just prior to dosing), and 
at 15, 45, and 60 minutes after dosing. Blood pressure to be measured both supine and 
standing (measured within 3 minutes of standing). 
• Collection and processing of blood samples for PK assessment will occur at the 
following time points: t = 0 (just prior to dosing), 15, 30, 45, and 60 minutes after 
dosing and at 1.5, 3, and 6 hours after dosing. 
• Investigator confirmation of “OFF” or “ON”. The subject must be in an “OFF” state 
in order to proceed with dosing. 
• When subject is in the “OFF” state, proceed with dosing according to the 
randomization scheme. 
• Record any AEs/SAEs that have occurred since the last visit. 
• Record any new concomitant medications and/or changes to current concomitant 
medications being used by the subject since the last visit. 
If in the opinion of the Investigator the subject can no longer tolerate the “OFF” state at any 
point during the visit, the subject may receive rescue L-Dopa (+/- other adjunctive PD 
medication) at a dosage considered appropriate by the Investigator to achieve a full “ON” state. 
Where possible, administration of rescue L-Dopa should be delayed until 60 minutes after 
dosing. 
12.5. 
End of Study Visit 
Approximately 3-5 days following the completion of the study (after Period 3), subjects will be 
asked to return to the clinic for a final safety assessment visit having completed a 1-day wash-out 
prior to this visit. The following procedures will take place at this visit: 
• Reconfirm consent. 
• Review prohibited treatment and study restrictions. 
• Perform a complete physical examination, including an oropharyngeal examination 
and of the injection site. The oropharyngeal cavity examination should include a 


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Sunovion Pharmaceuticals Inc. 
 
Page 40 
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All physical examinations performed in this study, whether complete or abbreviated, will include 
an oropharyngeal cavity examination by the Investigator (or designate trained to perform this 
examination) and will include a visual inspection of the inside of each cheek, the inside of the 
upper and lower lip, the surface of the tongue, and under the tongue. Each location within the 
oropharyngeal examination will be scored and graded as follows: 
• Finding 
− None 
− Focal reddening 
− Multiple foci of reddening 
− Edema 
− Ulceration 
• Grade 
− Mild 
− Moderate 
− Severe 
All abnormal findings at baseline will be recorded on the Medical History/Concomitant 
Diagnoses page (or equivalent) of the CRF. New abnormal findings or a worsening of baseline 
conditions detected at follow-up physical examinations will be recorded as AEs on the CRF. 
The Investigator (or designate) should evaluate each finding against AE criteria and complete the 
AE CRF, as appropriate. Photographs for reference may be taken by the Investigator (or 
designate) provided the subject provides consent to do so. 
12.7.2.2. Vital Signs 
Vital signs (HR, RR, BP and body temperature) will be measured at various timepoints after the 
subject has been in a supine position for 5 minutes. Vital signs will be measured at the Screening 
Visit and End of Study Visit. In Period 1, Period 2 and Period 3 at t = 0 (just prior to dosing), 15, 
45 and 60 minutes after dosing at all scheduled study visits. Vital signs (BP only) will also be 
measured within three minutes of standing at all timepoints. 
Study personnel will carefully monitor subjects for signs of Orthostatic Hypotension; defined as: 
• a systolic BP decrease of ≥ 20 mmHg within three minutes of standing up from a 
supine position; and/or 
• a diastolic BP decrease of ≥ 10 mmHg within three minutes of standing up from a 
supine position. 
12.7.2.3. 12-Lead ECG 
A standard 12-lead ECG will be performed at all timepoints outlined in the protocol. A triplicate 
12-lead ECG will be performed at the Screening Visit.  
ECGs will be performed in a semi-recumbent position and after 5 minutes of rest.  


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Sunovion Pharmaceuticals Inc. 
 
Page 43 
CTH-203 
10 May 2017 
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Version 2.00 
− MAO-B inhibitors; 
− COMT inhibitors; 
− Amantadine; 
− Anti-cholinergics. 
12.7.2.10. Confirmation of “OFF” or “ON” Episodes 
At the Screening Visit, subjects will present to the clinic having taken their usual morning dose 
of L-Dopa and any other adjunctive PD medication; but before taking their next dose of 
medication. Their normally scheduled second dose of L-Dopa (without adjunctive PD 
medication) will be administered in the clinic.  
Prior to administration of their L-Dopa dose, subjects will be examined by the Investigator in 
order to verify that they are in the “OFF” state. If they are in the “OFF” state, subjects will then 
take their normal dose of L-Dopa and the Investigator will as well determine that the subject is 
experiences an “ON” state. Confirmation of “OFF”/”ON” state should be noted in the 
appropriate eCRF. 
Definitions of Full “ON” and “OFF” 
The following definitions will be used in this study: 
“OFF” – defined as: 
• A period of time when medication has worn off and is no longer providing benefit 
with regard to mobility, slowness, and stiffness; 
• Confirmed by the Investigator using their clinical judgement as “OFF”. 
• Confirmed by the subject as “OFF”. 
Full “ON” as assessed by the Investigator – defined as: 
• Based on clinical judgment, it is the period of time where the Investigator feels the 
medication is providing benefit with regard to mobility, stiffness and slowness and 
the subject has adequate motor function to allow them to perform their normal daily 
activities.  
Clinical confirmation of the “OFF” state must occur prior to dosing a subject with study 
medication (or their standard L-Dopa dose at the Screening Visit). The same assessor should be 
utilized for each subject throughout the study. 
12.7.2.11. Pharmacokinetic (PK) Evaluation 
Pharmacokinetic evaluation of APL-130277, subcutaneous APO-go® and APOKYN® will be 
completed in Period 1, Period 2, and Period 3. Blood draws for PK analyses will occur at t = 0 
(just prior to dosing), 15, 30, 45, and 60 minutes after dosing and at 1.5, 3, and 6 hours after 
dosing. Sampling should occur as close as possible to the target time. Actual sampling date and 
time should be recorded in CRF. 
Instructions specific to PK draws, sample preparation, storage and shipping will be outlined in 
the Pharmacokinetic Laboratory Manual. 


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13. 
ADVERSE EVENTS 
Adverse events will be recorded from the time of signing of the ICF by the subject through to 
study completion or earlier, if warranted by a subject discontinuation. All AEs will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA). 
13.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject (or patient) or clinical investigation 
subject (or patient) administered a pharmaceutical product that does not necessarily have a causal 
relationship with the product. An AE can therefore be any unfavorable and unintended sign 
(including a new, clinically important abnormal laboratory finding), symptom, or disease, 
temporally associated with the product, whether or not related to the product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. 
13.2. 
Definition of Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life threatening; 
• Requires in-subject hospitalization (being admitted) or prolongation of existing 
hospitalization; 
• Results in permanent (persistent) disability/incapacity; 
• Is a congenital anomaly; 
• Is an important medical event. 
Medical and scientific judgment should be exercised in deciding whether it is appropriate to 
consider other situations serious, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
(or patient) or may require intervention to prevent another of the outcomes listed in the definition 
above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
An elective hospital admission to treat a condition present before exposure to the investigational 
drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the condition 
or event as an SAE. 
A spontaneous abortion or congenital anomaly in an infant born to a mother who was exposed to 
the investigational drug during pregnancy is an SAE. 


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Due to the nature of subjects being enrolled in this study, and the given study objectives, 
for subjects who are hospitalized to facilitate their study visit, “OFF” episodes will not be 
considered a SAE. 
13.3. 
Definition of Severity 
The clinical “severity” of an AE will be classified as: 
Mild 
Causes no limitation of usual activities. 
Moderate 
Causes some limitation of usual activities. 
Severe 
Prevents or severely limits usual activities. 
 
13.4. 
Definition of Start Date, Stop Date, and Duration 
Start Date 
The date at which the AE is first noted. 
Stop Date 
The date at which the AE is known to be resolved. If it is not known to 
have stopped, then indicate “ongoing”. 
Duration 
A time in days, hours or minutes (this is optional). 
13.5. 
Action(s) Taken 
Actions taken may consist of: 
None 
No actions taken. 
Discontinued Investigational 
Drug 
Investigational drug was permanently discontinued because 
of the AE. 
Change Investigational Drug 
Investigational drug was given at a lower dose, at a longer 
interval between doses, or was temporarily withheld 
because of the AE. 
Treatment 
Specified medication (to be listed on the concomitant 
medication chart) was used as a countermeasure. 
Others 
Other actions, such as an operative procedure, were 
required because of the AE. 


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13.6. 
Definition of Expectedness 
An expected AE is an AE for which the nature or severity is consistent with the known AE 
profile of the product. For an investigational drug, the known information is contained in the IB. 
For a marketed product, the known information is contained in the current package insert for the 
product. 
An unexpected AE is an AE for which the specificity or severity is not consistent with the 
current IB. For example, hepatic necrosis would be unexpected (greater severity) if the IB only 
listed elevated hepatic enzymes or hepatitis. Likewise, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (greater specificity) if the IB only listed cerebral vascular 
accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, 
already documented adverse reaction constitute unexpected events. Examples would be (a) acute 
renal failure as an expected adverse reaction with a subsequent new occurrence of interstitial 
nephritis and (b) hepatitis with a first occurrence of fulminate hepatitis. 
13.7. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) for APL-130277 are those pertaining to: 
• Hypotension, orthostatic hypotension  
• Syncope  
• Falls & injuries  
• Dyskinesias  
• Hallucinations and psychotic behaviors  
• Impulse control  
• Daytime sudden onset of sleep  
• QT prolongation and ventricular arrhythmias  
• Acute Coronary Syndrome, myocardial infarction, angina  
• Suicidal ideation & attempts  
• Melanoma  
• Stomatitis, oral ulcers, oral irritation  
• Allergic/sensitivity response to the formulation 
All AESIs should be reported to Sunovion as outlined in Section 13.13.  
13.8. 
Definition of Relationship to Investigational Drug(s) 
The categories for classifying the Investigator’s opinion regarding the relationship of an AE to 
investigational drug(s) are listed below: 


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Certain 
An AE occurring in a plausible time relationship to investigational drug 
administration and which cannot be explained by a concurrent disease or 
other drugs or events. The response to withdrawal of the drug 
(dechallenge) is clinically reasonable. 
Probable (likely) 
An AE with a reasonable time sequence to administration of the 
investigational drug and which is unlikely to be attributed to concurrent 
disease or other drugs or events. The response to withdrawal of the drug 
(dechallenge) is clinically reasonable. 
Possible 
An AE with a reasonable time sequence to administration of the 
investigational drug, but which could also be explained by concurrent 
disease or other drugs or events. Information on drug withdrawal may be 
lacking or unclear. 
Unlikely 
An AE, including laboratory test abnormality, with a temporal relationship 
to investigational drug administration that makes a causal relationship 
improbable and in which other drugs, events, or underlying disease 
provide plausible explanations. 
Not related 
An AE with sufficient evidence to accept that there is no causal 
relationship to investigational drug administration (eg, no temporal 
relationship to drug administration, because the drug was administered 
after onset of event; investigation shows that the drug was not 
administered; another cause was proven; etc.). 
13.9. 
Definition of Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as: 
• Resolved; 
• Resolved with sequelae; 
• Ongoing; 
• Death; 
• Unknown. 
Death should only be selected as an outcome when the AE resulted in death. If more than 1 AE is 
possibly related to the subject’s death, the outcome of death should be indicated for the AE 
attributed as the cause of death in the death certificate or summary. 
13.10. 
Documentation of Adverse Events 
The Investigator will monitor and/or ask about or evaluate AEs using non-leading questions at 
each visit or evaluation. The occurrence of all AEs will be documented in the CRF with the 
following information, where appropriate: 


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• AE name or term; 
• When the AE first occurred (start date); 
• When the AE stopped (stop date), or an indication of “ongoing”; 
• How long the AE persisted (optional); 
• Severity of the AE; 
• Seriousness; 
• Actions taken; 
• Outcome; 
• Investigator opinion regarding the relationship of AE to the investigational drug(s). 
13.11. 
Follow-up of Subjects with an Adverse Event 
Any AE will be followed to a satisfactory resolution, loss to follow-up, until it becomes stable, 
or until it can be explained by another known cause(s) (ie, concurrent condition or medication) 
and clinical judgment indicates that further evaluation is not warranted. All findings relevant to 
the final outcome of an AE must be reported in the subject’s medical record. 
13.12. 
Special Procedures for Managing AEs/SAEs  
If AEs occur in a subject which are not tolerable, or for which continued administration of 
investigational drug is not reasonable in view of the potential benefit to subject, the Investigator 
must decide whether to stop investigational treatment and/or treat the subject. Subject 
withdrawal should be avoided, if possible. If discontinuation of treatment occurs, every attempt 
should be made to restart study drug if medically appropriate, whatever the duration of 
discontinuation. 
13.13. 
Notification of Serious Adverse Events 
The Investigator must report all SAEs and pregnancies promptly to Sunovion or its designee, by 
completing the SAE form and submit by email (or fax) within 24 hours of first becoming aware of 
the event. Email: sunovionsafety@druginfo.com or Fax: 1-855-278-6344. 
The Investigator will be able to contact Dr. Poonam Hundal, the study Medical Monitor, at 
+1-919-592-1802 or Poonam.Hundal@incresearch.com.  
If a SAE is reported via telephone, the Investigator must follow up the initial telephone 
notification by completing the SAE form and submit by email (or fax). 
At the time of the first notification of an SAE, the study site should provide the following 
information to the Sunovion contact person, if available: 
• Subject’s study number and initials; 
• Subject’s date of birth; 
• Subject’s gender; 


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• Date of first dose of investigational drug(s); 
• Date of last dose of investigational drug(s), if applicable; 
• AE term; 
• Time and date of occurrence of the event; 
• A brief description of the event, outcome to date, and any actions taken; 
• The seriousness criteria(on) that were met; 
• Concomitant medication at onset of the event; 
• Relevant medical history information; 
• Relevant laboratory test findings; 
• Investigator’s opinion of the relationship to investigational drug(s). (“Is there a 
reasonable possibility that the investigational drug caused the SAE? Yes or No?”); 
• Whether and when the Investigator was unblinded as to the subject’s treatment 
assignment. 
Any missing or additional relevant information concerning the serious (or unexpected) AE 
should be provided in a written follow-up report. 
The Investigator is required to comply with applicable regulations regarding the notification of 
his/her IRB/REB/IEC. 


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Sunovion Pharmaceuticals Inc. 
 
Page 53 
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10 May 2017 
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14.7. 
Randomization and Blinding 
At Screening, the IWRS will assign a unique subject identification number to the subject known 
as the Screening Number. This number will be associated with the subject throughout the study. 
Every subject that signs an ICF must be entered into the IWRS regardless of eligibility in order 
to obtain a Screening Number. This 7-digit number will consist of a 4-digit site ID followed by a 
3-digit number assigned sequentially within each site starting at 001.  
Following Sponsor approval, subjects will be randomized centrally at a study level after the 
Screening Visit has been completed to one of the six randomization sequences using the 
Williams design.  
No stratification factors will be used. The randomization scheme will be designed by the study 
statistician. Once designed, an independent randomization expert will execute the randomization 
in the IWRS. The randomization number is used to identify the treatment sequence 
(APL-130277, APO-go®, APOKYN®) of the treatment that will be administered to the subject 
during the Three-Way Open-Label Randomized Crossover Phase (Period 1, Period 2, Period 3).  
A randomization number can only be assigned to one subject and cannot be reused once 
assigned. 


Sunovion Pharmaceuticals Inc. 
 
Page 54 
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
15. 
STATISTICAL ANALYSES  
15.1. 
Statistical Analysis Plan 
Full statistical considerations, table mock-ups and final analysis of safety and efficacy data 
collected in this study will be outlined in a formal Statistical Analysis Plan (SAP). The SAP will 
serve as a complement to the study protocol and supersedes it in case of differences. 
15.2. 
Summary of Statistical Methods 
Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. Descriptive statistics for categorical data will 
include frequency counts and percent. The total number of patients in the treatment group overall 
(N) will be used as the denominator for percent calculations, unless stated otherwise, 
Significance testing will be 2-sided using α = 0.05, unless otherwise specified. 
15.3. 
Analysis Populations 
15.3.1. 
Safety Population 
All subjects who receive at least one dose of study drug will be included in the safety analysis 
set. The safety analysis set will be used for the analysis of the safety endpoints and the subjects 
will be grouped according to the treatment that they received.  
15.3.2. 
Pharmacokinetic Population 
The PK analysis set includes all subjects with at least one PK evaluation. 
15.4. 
Sample Size Calculation 
With a sample size of 12 subjects, a two-sided 90% confidence interval for the difference in 
paired PK parameter means on the log scale will have an interval that extends no more than 
0.221 units from the observed difference with 90% coverage probability. This calculation 
assumes a coefficient of variation of 35% for the difference on the original scale.  If the observed 
mean difference on the log scale were zero, this would correspond to a 90% confidence interval 
for the ratio of geometric means of (80.2%, 124.7%) on the original scale.  
15.5. 
Safety Analysis 
Safety and tolerability will be evaluated through summary tables and individual listings of all 
safety parameters collected in the study. 
15.6. 
Pharmacokinetic Analysis  
Pharmacokinetic parameters will be derived using noncompartmental methods employing 
WinNonlin® Phoenix version 6.3 or higher (Pharsight, St Louis, MO). Pharmacokinetic analysis 
will be conducted using concentration-time data for apomorphine and metabolites. 


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Sunovion Pharmaceuticals Inc. 
 
Page 56 
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
The individual subject concentration-time data for apomorphine and metabolites will be listed 
and displayed graphically on linear and semi-log scales. Plasma apomorphine and metabolite 
concentration-time data will be summarized descriptively in tabular and graphical formats (linear 
and semi-log scales) overlaid by dose level. Individual PK parameters from the 
noncompartmental PK analysis will be tabulated, where calculable, and summarized 
descriptively. The following summary statistics will be presented for PK parameters: N, 
arithmetic mean, CV%, SD of the arithmetic mean, median, minimum, maximum, geometric 
mean and CV% of the geometric mean. Tmax will be presented as N, median, minimum and 
maximum. 
Figures illustrating the time course of mean drug concentration vs. time for each regimen will be 
overlaid and presented for relevant comparisons on linear and semi-logarithmic scales, as 
appropriate. Other analyses such as exploring the relationship between PK parameters and dose 
will be conducted, as appropriate. 
AUClast, AUC∞, Cmax, Tmax, t½ and λz will be evaluated for plasma apomorphine concentrations. 
Analysis of Variance (ANOVA) will be performed for log-transformed AUClast, AUC∞, and 
Cmax. Tmax will be analyzed using a non-parametric test (Wilcoxon test) while t½ will be analyzed 
using a t-test. Comparative bioavailability will be assessed by estimating the 90% confidence 
intervals (CI) for the formulation ratios (APL-130277 vs. APO-go® vs. APOKYN®) of geometric 
means for AUClast, AUC∞, Cmax and will be calculated based on the ratios of the least squares 
means and estimates from the ANOVA. 


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Sunovion Pharmaceuticals Inc. 
 
Page 58 
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
16.3. 
Study Documentation 
16.3.1. 
Investigator’s Regulatory Documents 
The regulatory documents listed below must be received from the Investigator and reviewed and 
approved by Sunovion or its designee before the clinical site can initiate the study and before 
Sunovion will authorize shipment of investigational drug to the clinical site. Copies of the 
Investigator’s regulatory documents must be retained at the clinical site in a secure location. 
Additional documents, including a copy of the protocol and applicable amendment(s), the 
APL-130277 IB, copies of regulatory references, copies of IRB/REB/IEC correspondence, and 
investigational drug accountability records must be retained as part of the Investigator’s 
regulatory documents. It is the Investigator’s responsibility to ensure that copies of all required 
regulatory documents are organized, current, and available for inspection. 
Documents Required for Regulatory Packet: 
Confidentiality Agreement 
Signed Clinical Trial Agreement 
Final Protocol 
PI CV 
Final Protocol Amendments (if any) 
PI Medical License 
Protocol Signature Pages 
Sub-Investigator CV 
Protocol Amendment Signature Pages  
(if applicable) 
Sub-Investigator License 
PI signed FDA Form 1572 
APL-130277 IB 
IRB Approvals 
Signed Financial Disclosure 
IRB Membership List / Assurance Statement  
Regulatory Agency Approval  
 
Approved Informed Consent Template(s) 
Additional documentation requirements may be communicated by Sunovion staff (or it’s 
designate). 
16.3.2. 
Case Report Forms 
If the study is managed using an Electronic Data Capture (EDC) system, the Investigator agrees 
to maintain accurate CRFs/EDC modules and source documentation as part of the case histories 
for all subjects who sign an ICF. 
CRFs/EDC modules are considered confidential documents and should be handled and stored 
accordingly. Sunovion or its designee will provide the necessary training on the use of the 
specific EDC system used during the study to ensure that the information is captured accurately 
and appropriately. 


Sunovion Pharmaceuticals Inc. 
 
Page 59 
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
In order to ensure data accuracy, EDC module data for individual subject visits should be 
completed as soon as possible following the visit and in accordance with the site Clinical Trial 
Agreement in place. EDC data will be reviewed by the CRA during monitoring visits. The CRA 
will verify data recorded with source documents. 
All corrections or changes requested to the study data must be made as soon as possible by the 
study site, and verified by the Investigator. When all incorrect and/or inconsistent data has been 
accounted for, EDC data will be considered complete. All corrections or changes made to any 
study data must be appropriately tracked in an audit trail. 
When applicable, the site is expected to notify the Study Medical Monitor before breaking the 
study blind, unless it is in the subject’s best interest if the blind is broken immediately.  
16.3.3. 
Source Documents 
All information recorded in the CRF must be supported by corresponding source documentation. 
Examples of acceptable source documentation include but are not limited to hospital records, 
clinic and office charts, laboratory notes, and recorded data from automated instruments, 
memoranda, and pharmacy dispensing records. If available, source documents for at least the 2 
years prior to screening will be reviewed by the CRA to verify the subject’s eligibility for the 
study. 
Original versions of the laboratory reports and ECG tracings will be retained at the clinical site 
with the subject’s source documents. 
16.4. 
Data Quality Assurance 
Sunovion and its designees will perform quality control and assurance checks on all clinical 
studies that it sponsors. Sunovion, or its designee, will be responsible for additional data quality 
assurance related to the clinical data being generated, entered and maintained as part of this 
clinical study. 
16.4.1. 
Monitoring the Study 
Clinical Research Associates (CRAs) will conduct site visits at the study facilities to monitor the 
study. The Investigator agrees to allow these CRA(s) and other authorized Sunovion personnel 
access. The clinical site will be monitored by Sunovion and/or it’s designate to ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines. As 
representatives of Sunovion, CRAs are responsible for following the study protocol closely and 
notifying project management of any noted deviations. The assigned CRA(s) will visit the 
Investigator and clinical site at periodic intervals and maintain periodic communication. The 
CRA(s) will maintain current knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
Investigator and staff. While on site, the CRA(s) will review regulatory documents, compare 
entries in the source documents, and review investigational drug accountability records. The 
CRA will ask for clarification and/or correction of any noted inconsistencies. 
By signing the protocol, the Investigator agrees to meet with the CRA during clinical site visits, 
to ensure that study staff is available to the CRA(s) as needed, to provide the CRA(s) access to 
all study documentation and medical records, to the clinical supplies dispensing and storage area, 


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and agrees to assist the monitors in their activities, if requested. The Investigator also agrees to 
allow inspectors from regulatory agencies to review records and to assist the inspectors in their 
duties, if requested. 
16.4.2. 
Routine Data Collection 
CRFs will be reviewed by the CRA during monitoring visits. The CRA will verify data with 
source documents. If the CRA’s comparison of the original CRF data with source documents 
reveals data discrepancies or omissions that require study staff to make corrections, corrections 
will be made. After the CRF data have been monitored and all corrections have been made, the 
Investigator must appropriately document within the data system his/her agreement with the data 
contained therein. If corrections are required subsequent to the Investigator’s signature, the 
Investigator must document his/her agreement with the CRF data to confirm the accuracy of the 
changed data. A copy of all CRF data will be retained at the clinical site. If corrections are 
required after all data have been electronically transferred, corrections that have been made must 
be verified in writing by the Investigator, and new data provided to Sunovion. 
Should an EDC system be implemented, the CRA will verify data with source documents. If the 
CRA’s comparison of the original EDC module data with source documents reveals data 
discrepancies or omissions that require study staff to make corrections, the corrections will be 
made as outlined in the Study Monitoring Plan. After the EDC module data have been monitored 
and all corrections have been made, the Investigator must appropriately document within the data 
system his/her agreement with the data contained therein. If corrections are required subsequent 
to the Investigator’s signature, the Investigator must document his/her agreement with the EDC 
module data to confirm the accuracy of the changed data. A copy of all EDC module data will be 
retained at the clinical site. If corrections are required after all data have been electronically 
transferred, the corrections must be made as instructed in site training. 
16.4.3. 
Data Management 
A vendor contracted by Sunovion will provide the data management system and data 
management services for the study. An EDC system may be implemented. 
Clinical site personnel will be responsible for providing resolutions to all data queries. The 
Investigator will be required to review and document data to ensure the accuracy of the corrected 
and/or clarified data. If an EDC system is implemented, this documentation will be electronic. 
Query forms or documentation must be generated and filed by the site. 
16.4.4. 
Study Termination 
The study may be terminated at Sunovion’s discretion at any time for any reason. If Sunovion 
discovers conditions that warrant early termination of the study, the Investigator will be notified 
by Sunovion or its designee. Examples of conditions that may warrant premature termination of 
the study include, but are not limited to the following: 
• The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study; and 
• The decision on the part of Sunovion to suspend or discontinue testing, evaluation, or 
development of the investigational product. 


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16.4.5. 
Clinical Site Closure 
On termination of the study, all screening and ongoing study related procedures conducted at the 
clinical site will be closed. Sunovion may terminate participation of the clinical site at any time. 
Examples of conditions that may warrant premature termination of a clinical site include, but are 
not limited to the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines; 
• Inadequate subject enrollment; 
• Administrative reasons. 


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17. 
GENERAL CONSIDERATIONS 
17.1. 
Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Sunovion. The protocol amendment must be signed by the 
Investigator and approved by the IRB/REB/IEC before it may be implemented. Protocol 
amendments will be filed with the appropriate regulatory agency(s) having jurisdiction over the 
conduct of the study. 
17.2. 
Use of Information and Publication 
All information concerning APL-130277, Sunovion’s operations, patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information supplied by 
Sunovion to the Investigator and not previously published, is considered confidential and 
remains the sole property of Sunovion. The CRFs also remain the property of Sunovion. The 
Investigator agrees to use this information for purposes of study execution through finalization. 
The information developed in this study will be used by Sunovion in connection with the 
continued development of APL-130277 and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. 
Publication or other public presentation of APL-130277 data resulting from this study requires 
prior review and written approval of Sunovion, which will not be unreasonably withheld. 
Abstracts, manuscripts, and presentation materials should be provided to Sunovion for review at 
least 30 days prior to the relevant submission deadline. 
After publication of the results of the multi-center study or 24 months after the clinical study 
report has been finalized, whichever comes first, the Sponsor acknowledges the Investigator's 
rights to publish results from this study. Any such scientific paper, presentation, communication, 
or other information concerning the study described in this protocol must be submitted to the 
Sponsor for review prior to submission for publication/presentation. 
17.3. 
Records Retention 
The Investigator shall retain and preserve 1 copy of all data generated in the course of the study, 
specifically including but not limited to those defined by GCP as essential, for the longer of: (1) 
2 years after the last marketing authorization for the investigational drug has been approved or 
Sunovion has discontinued its research with respect to such drug; or (2) such longer period as 
required by applicable global regulatory requirements. At the end of such period, the Investigator 
shall notify Sunovion in writing of its intent to destroy all such material. Sunovion shall have 
30 days to respond to the Investigator’s notice, and Sunovion shall have a further opportunity to 
retain such materials at Sunovion’s expense. 
17.4. 
Sample Retention 
Samples may be used for purposes related to this research. The samples will be stored until the 
study team has determined that specimens are no longer needed and the decision has been made 


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that there are no samples to be re-assayed. In addition, identifiable samples can be destroyed at 
any time at the request of the subject. 
17.5. 
Subject Injury 
In general, specific to provisions in the clinical trial agreement, if a subject is injured as a direct 
result of a test article and the site, its staff and Investigators have followed the protocol and all 
documentation supporting the proper running of the trial, Sunovion will pay for reasonable and 
necessary medical treatment for the injury. If laws or regulations of the locality in which the 
study is taking place require additional payment of expenses, Sunovion shall comply with such 
laws or regulations. Where applicable, Sunovion has taken specific national insurance. 


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18. 
REFERENCES  
Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as 
estimated from the cumulative literature. Mov Disord. 2001;16(3):448-58. 
APOMORPHINE treatment for morphine addiction. Br J Addict Alcohol Other Drugs. 
1949;46(2):93-101. 
Corsini GU, Del Zompo M, Gessa GL, Mangoni A. Therapeutic efficacy of apomorphine 
combined with an extracerebral inhibitor of dopamine receptors in Parkinson's disease. Lancet. 
1979;1(8123):954-6. 
Cotzias GC, Papavasiliou PS, Fehling C, Kaufman B, Mena I. Similarities between neurologic 
effects of L-dipa and of apomorphine. N Engl J Med. 1970;282(1):31-3. 
Hornykiewicz O. Basic research on dopamine in Parkinson's disease and the discovery of the 
nigrostriatal dopamine pathway:  the view of an eyewitness. Neurodegener Dis. 2008;5:114–7. 
Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A. Differential 
actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate 
analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J 
Pharmacol Exp Ther. 2002;303(2):791-804. 
Mouradian MM, Heuser IJ, Baronti F, et al. Pathogenesis of dyskinesias in Parkinson's disease. 
Ann Neurol. 1989;25(5):523-6. 
Schwab RS, Amador LV, Lettvin JY. Apomorphine in Parkinson's disease. Trans Am Neurol 
Assoc. 1951;56: 251–3. 
Stocchi F, Vacca L, Ruggieri S, et al. Intermittent vs. continuous levodopa administration in 
patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol. 
2005;62(6):905-10. 
Tanner CM, Goldman SM. Epidemiology of Parkinson's disease. Neurol Clin. 1996;14:317-35. 


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19. 
APPENDICES 
19.1. 
APPENDIX I: APOKYN® Prescribing Information 
 
 


 
- 1 - 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
APOKYN® safely and effectively.  See full prescribing information for 
APOKYN®.   
 
APOKYN® (apomorphine hydrochloride injection) 
For Subcutaneous Use Only  
Initial U.S. Approval: 2004 
 
---------------------------RECENT MAJOR CHANGES--------------------------- 
Dosage and Administration, Premedication  
and Concomitant Medication (2.2) 
 
 
03/2017 
Warnings and Precautions, Nausea and Vomiting (5.2)  
03/2017 
 
----------------------------INDICATIONS AND USAGE--------------------------- 
APOKYN is a non-ergoline dopamine agonist indicated for the acute, 
intermittent treatment of hypomobility, “off” episodes (“end-of-dose wearing 
off” and unpredictable “on/off” episodes) associated with advanced 
Parkinson’s disease (1)  
 
----------------------DOSAGE AND ADMINISTRATION----------------------- 
• For subcutaneous use only (2.1) 
• Always express APOKYN dose in mL to minimize dosing errors (2.1) 
• The starting dose of APOKYN is 0.2 mL (2 mg); give the first dose under 
medical supervision; titrate the dose to effect and tolerance; the maximum 
recommended dose is 0.6 mL (2.3) 
• Treatment with a concomitant antiemetic, e.g., trimethobenzamide, is 
recommended, starting 3 days prior to the first dose of APOKYN. 
Treatment with trimethobenzamide should only be continued as long as 
necessary to control nausea and vomiting, and generally no longer than two 
months (2.2, 5.2, 6.1, 17) 
• APOKYN doses must be separated by at least 2 hours (2.6) 
• Renal impairment: reduce test dose, and reduce starting dose to 0.1 mL     
(1 mg) (2.4, 8.6, 12.3) 
 
---------------------DOSAGE FORMS AND STRENGTHS---------------------- 
Multi-dose glass cartridges, 30 mg/3 mL (10 mg/mL) for use with a multiple-
dose pen injector (APOKYN Pen) (3, 16) 
 
-------------------------------CONTRAINDICATIONS------------------------------ 
• Concomitant use of APOKYN with 5HT3 antagonists, including 
antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and 
alosetron, is contraindicated (4) 
• Hypersensitivity to apomorphine, its excipients or sodium metabisulfite (4)  
 
-----------------------WARNINGS AND PRECAUTIONS------------------------ 
• For subcutaneous use only; thrombus formation and pulmonary embolism 
have followed intravenous administration of APOKYN (5.1)  
• Falling asleep during activities of daily living, and daytime somnolence 
may occur (5.3)  
• Syncope and hypotension/orthostatic hypotension may occur (5.4, 5.5) 
• Falls may occur, or increase (5.6)  
• May cause hallucinations and psychotic-like behavior (5.7) 
• May cause dyskinesia or exacerbate pre-existing dyskinesia (5.8) 
• May cause problems with impulse control and impulsive behaviors (5.9) 
• May cause coronary events (5.10) 
• May prolong QTc and cause torsades de pointes or sudden death (5.11) 
 
------------------------------ADVERSE REACTIONS------------------------------- 
Most common adverse reactions (incidence at least 10% greater on APOKYN 
than on placebo) were yawning, drowsiness/somnolence, dyskinesias, 
dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, 
hallucination/confusion, and edema/swelling of extremities (6.1) 
 
To report SUSPECTED ADVERSE REACTIONS, contact US 
WorldMeds at 1-877-727-6596 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch. 
 
------------------------------DRUG INTERACTIONS------------------------------- 
• Concomitant use of antihypertensive medications and vasodilators: 
increased risk for hypotension, myocardial infarction, pneumonia, falls, and 
injuries (7.2) 
• Dopamine antagonists such as neuroleptics or metoclopramide, may 
diminish the effectiveness of APOKYN (7.3)  
 
-----------------------USE IN SPECIFIC POPULATIONS------------------------ 
• Pregnancy: Based on animal data, may cause fetal harm (8.1) 
• Geriatric Use:  In clinical trials, patients  65 years of age and older were 
more likely to experience certain adverse events (8.5) 
 
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling. 
 
 
 
 
Revised: 03/2017
_____________________________________________________________________________________________________________________________  
 
FULL PRESCRIBING INFORMATION: CONTENTS* 
1 
INDICATIONS AND USAGE 
2 
DOSAGE AND ADMINISTRATION 
2.1 
Important Administration Instructions 
2.2 
Premedication and Concomitant Medication 
2.3 
Dosing Information 
2.4 
Dosing in Patients with Renal Impairment 
2.5 
Dosing in Patients with Hepatic Impairment 
2.6 
Re-treatment and Interruption in Therapy  
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Serious Adverse Reactions after Intravenous Administration 
5.2 
Nausea and Vomiting 
5.3 
Falling Asleep During Activities of Daily Living and 
Somnolence 
5.4 
Syncope 
5.5 
Hypotension/Orthostatic Hypotension 
5.6 
Falls 
5.7 
Hallucinations/Psychotic-Like Behavior 
5.8 
Dyskinesias 
5.9 
Impulse Control/Compulsive Behaviors 
5.10 
Coronary Events 
5.11 
QTc Prolongation and Potential for Proarrhythymic Effects 
5.12 
Withdrawal-Emergent Hyperpyrexia and Confusion 
5.13 
Melanoma 
5.14 
Fibrotic Complications 
5.15 
Priapism 
5.16 
Retinal Pathology in Albino Rats  
6 
ADVERSE REACTIONS 
6.1 
Clinical Trial Experience   
7 
DRUG INTERACTIONS 
7.1 
5HT3 Antagonists  
7.2 
Antihypertensive Medications and Vasodilators 
7.3 
Dopamine Antagonists 
7.4 
Drugs Prolonging the QT/QTc Interval 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
8.2          Lactation 
8.4          Pediatric Use 
8.5 
Geriatric Use 
8.6 
Renal Impairment 
8.7 
Hepatic Impairment 
9 
DRUG ABUSE AND DEPENDENCE 
9.2 
Abuse 
10 OVERDOSAGE 
11 DESCRIPTION 
12  CLINICAL PHARMACOLOGY 
12.1   
Mechanism of Action 
12.2 
 
Pharmacodynamics 
12.3 
Pharmacokinetics  
13  NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
14  CLINICAL STUDIES 
16  HOW SUPPLIED/STORAGE AND HANDLING 
17  PATIENT COUNSELING INFORMATION 
 
*Sections or subsections omitted from the Full Prescribing Information are not 
listed
 
_______________________________________________________________________________________________________________________________________  


 
- 2 - 
FULL PRESCRIBING INFORMATION 
 
1 
INDICATIONS AND USAGE 
APOKYN (apomorphine hydrochloride injection) is indicated for the acute, intermittent treatment of 
hypomobility, “off” episodes (“end-of-dose wearing off” and unpredictable “on/off” episodes) in 
patients with advanced Parkinson’s disease. APOKYN has been studied as an adjunct to other 
medications [see Clinical Studies (14)]. 
 
2 
DOSAGE AND ADMINISTRATION 
 
2.1 
Important Administration Instructions 
APOKYN is indicated for subcutaneous administration only [see Warnings and Precautions (5.1)] and 
only by a multiple-dose APOKYN Pen with supplied cartridges.  The initial dose and dose titrations 
should be performed by a healthcare provider. Blood pressure and pulse should be measured in the 
supine and standing position before and after dosing.   
 
A caregiver or patient may administer APOKYN if a healthcare provider determines that it is 
appropriate. Instruct patients to follow the directions provided in the Patients Instructions For Use. 
Because the APOKYN Pen has markings in milliliters (mL), the prescribed dose of APOKYN should be 
expressed in mL to avoid confusion.   
 
Visually inspect the APOKYN drug product through the viewing window for particulate matter and 
discoloration prior to administration.  The solution should not be used if discolored (it should be 
colorless), or cloudy, or if foreign particles are present.  Rotate the injection site and use proper aseptic 
technique [see How Supplied/Storage and Handling (16) and Patient Counseling Information (17)].    
 
2.2 
Premedication and Concomitant Medication 
Because of the high incidence of nausea and vomiting with APOKYN treatment, an antiemetic, e.g., 
trimethobenzamide 300 mg three times a day, should be started 3 days prior to the initial dose of 
APOKYN [see Warnings and Precautions (5.2)]. Treatment with trimethobenzamide should only be 
continued as long as necessary to control nausea and vomiting, and generally no longer than two months 
after initiation of treatment with APOKYN, as trimethobenzamide increases the incidence of 
somnolence, dizziness and falls in patients treated with APOKYN [see Warnings and Precautions 
(5.2)]. 
 
Based on reports of profound hypotension and loss of consciousness when apomorphine was 
administered with ondansetron, the concomitant use of apomorphine with drugs of the 5HT3 antagonist 
class including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and 
alosetron are contraindicated [see Contraindications (4)]. 
 
2.3  
Dosing Information 
The recommended starting dose of APOKYN is 0.2 mL (2 mg).  Titrate on the basis of effectiveness and 
tolerance, up to a maximum recommended dose of 0.6 mL (6 mg) [see Clinical Studies (14)].  
 
There is no evidence from controlled trials that doses greater than 0.6 mL (6 mg) gave an increased 
effect and therefore, individual doses above 0.6 mL (6 mg) are not recommended. The average 
frequency of dosing in the development program was 3 times per day. There is limited experience with 
single doses greater than 0.6 mL (6 mg), dosing more than 5 times per day and with total daily doses 
greater than 2 mL (20 mg).  
 


 
- 3 - 
Begin dosing when patients are in an “off” state.  The initial dose should be a 0.2 mL (2 mg) test dose in 
a setting where medical personnel can closely monitor blood pressure and pulse. Both supine and 
standing blood pressure and pulse should be checked pre-dose and at 20 minutes, 40 minutes, and 60 
minutes post-dose (and after 60 minutes, if there is significant hypotension at 60 minutes). Patients who 
develop clinically significant orthostatic hypotension in response to this test dose of APOKYN should 
not be considered candidates for treatment with APOKYN.  
 
If the patient tolerates the 0.2 mL (2 mg) dose, and responds adequately, the starting dose should be    
0.2 mL (2 mg), used on an as needed basis to treat recurring “off” episodes. If needed, the dose can be 
increased in 0.1 mL (1 mg) increments every few days on an outpatient basis.  
 
The general principle guiding subsequent dosing (described in detail below) is to determine that the 
patient needs and can tolerate a higher test dose, 0.3 mL or 0.4 mL (3 mg or 4 mg, respectively) under 
close medical supervision.  A trial of outpatient dosing may follow (periodically assessing both efficacy 
and tolerability), using a dose 0.1 mL (1 mg) lower than the tolerated test dose.  
 
If the patient tolerates the 0.2 mL (2 mg) test dose but does not respond adequately, a dose of              
0.4 mL (4 mg) may be administered under medical supervision, at least 2 hours after the initial test dose, 
at the next observed “off” period.  If the patient tolerates and responds to a test dose of 0.4 mL (4 mg), 
the initial maintenance dose should be 0.3 mL (3 mg) used on an as needed basis to treat recurring “off” 
episodes as an outpatient. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few 
days on an outpatient basis.  
 
If the patient does not tolerate a test dose of 0.4 mL (4 mg), a test dose of 0.3 mL (3 mg) may be 
administered during a separate “off” period under medical supervision, at least 2 hours after the previous 
dose.  If the patient tolerates the 0.3 mL (3 mg) test dose, the initial maintenance dose should be 0.2 mL 
(2 mg) used on an as needed basis to treat existing “off” episodes.  If needed, and the 0.2 mL (2 mg) 
dose is tolerated, the dose can be increased to 0.3 mL (3 mg) after a few days. In such a patient, the dose 
should ordinarily not be increased to 0.4 mL (4 mg) on an outpatient basis.  
 
2.4 
Dosing in Patients with Renal Impairment 
For patients with mild and moderate renal impairment, the test dose and starting dose should be reduced 
to 0.1 mL (1 mg) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].  
 
2.5. 
Dosing in Patients with Hepatic Impairment 
Closely monitor patients with mild and moderate hepatic impairment [see Clinical Pharmacology (12.3) 
and Use in Specific Populations (8.7)].   
 
2.6  
Re-treatment and Interruption in Therapy 
If a single dose of APOKYN is ineffective for a particular “off” period, a second dose should not be 
given for that “off” episode. The efficacy of the safety of administering a second dose for a single “off” 
episode has not been studied systematically. Do not administer a repeat dose of APOKYN sooner than 2 
hours after the last dose. 
 
Patients who have an interruption in therapy of more than a week should be restarted on a 0.2 mL (2 mg) 
dose and gradually titrated to effect and tolerability.  
 
3 
DOSAGE FORMS AND STRENGTHS 
APOKYN 30 mg/3 mL (10 mg/mL) containing apomorphine hydrochloride (as apomorphine 
hydrochloride hemihydrate), USP is supplied as a clear, colorless, sterile, solution in a 3 mL (30 mg) 
cartridge. The 3 mL (30 mg) glass cartridge is used with a manual reusable, multiple-dose pen injector 


 
- 4 - 
(APOKYN Pen). A single cartridge, pen and needle can deliver doses up to 1 mL (10 mg) in 
0.02 mL (0.2 mg) increments.  The multiple-dose pen injector is provided in a package with six needles.  
 
4 
CONTRAINDICATIONS 
APOKYN is contraindicated in patients: 
 
• Using concomitant drugs of the 5HT3 antagonist class including antiemetics (e.g., ondansetron, 
granisetron, dolasetron, palonosetron) and alosetron [see Drug Interactions (7.1)]. There have been 
reports of profound hypotension and loss of consciousness when APOKYN was administered with 
ondansetron. 
 
• With hypersensitivity/allergic reaction characterized by urticaria, rash, pruritus, and/or various 
manifestations of angioedema to apomorphine or to any of the excipients including a sulfite (i.e., 
sodium metabisulfite). Patients with a sulfite sensitivity may experience various allergic-type 
reactions, including anaphylactic symptoms and life-threatening asthmatic attacks. Patients who 
experience any hypersensitivity/allergic reaction to APOKYN should avoid taking APOKYN again. 
 
5 
WARNINGS AND PRECAUTIONS 
 
5.1 
Serious Adverse Reactions After Intravenous Administration  
Following intravenous administration of APOKYN, serious adverse reactions including thrombus 
formation and pulmonary embolism due to intravenous crystallization of apomorphine have occurred.  
Consequently, APOKYN should not be administered intravenously.  
 
5.2 
Nausea and Vomiting  
APOKYN causes severe nausea and vomiting when it is administered at recommended doses. Because 
of this, in domestic clinical studies, 98% of all patients were pre-medicated with trimethobenzamide, an 
antiemetic, for three days prior to study enrollment, and were then encouraged to continue 
trimethobenzamide for at least 6 weeks. Even with the use of concomitant trimethobenzamide in clinical 
studies, 31% and 11% of the APOKYN-treated patients had nausea and vomiting, respectively, and 3% 
and 2% of the patients discontinued APOKYN due to nausea and vomiting, respectively.  Among 522 
patients treated, 262 (50%) discontinued trimethobenzamide while continuing APOKYN. The average 
time to discontinuation of trimethobenzamide was about 2 months (range: 1 day to 33 months). For the 
262 patients who discontinued trimethobenzamide, 249 patients continued apomorphine without 
trimethobenzamide for a duration of follow-up that averaged 1 year (range: 0 years to 3 years). 
 
The effect of trimethobenzamide on reducing nausea and vomiting during treatment with APOKYN was 
evaluated in a 12-week, placebo-controlled study in 194 patients. The study suggests that 
trimethobenzamide reduces the incidence of nausea and vomiting during the first 4 weeks of APOKYN 
treatment (incidence of nausea and vomiting 43% on trimethobenzamide vs. 59% on placebo). However, 
over the 12-week period, compared with placebo, patients treated with trimethobenzamide had a greater 
incidence of somnolence (19% for trimethobenzamide vs. 12% for placebo), dizziness (14% for 
trimethobenzamide vs. 8% for placebo), and falls (8% for trimethobenzamide vs. 1% for placebo). 
Therefore, the benefit of treatment with trimethobenzamide must be balanced with the risk for those 
adverse events, and treatment with trimethobenzamide should only be continued as long as necessary to 
control nausea and vomiting, and generally no longer than two months. 
 
The ability of concomitantly administered antiemetic drugs (other than trimethobenzamide) has not been 
studied. Antiemetics with anti-dopaminergic actions (e.g., haloperidol, chlorpromazine, promethazine, 
prochlorperazine, metaclopramide) have the potential to worsen the symptoms in patients with 
Parkinson’s disease and should be avoided.  


 
- 5 - 
 
5.3 
Falling Asleep During Activities of Daily Living and Somnolence  
There have been reports in the literature of patients treated with APOKYN subcutaneous injections who 
suddenly fell asleep without prior warning of sleepiness while engaged in activities of daily living. 
Somnolence is commonly associated with APOKYN, and it is reported that falling asleep while engaged 
in activities of daily living always occurs in a setting of pre-existing somnolence, even if patients do not 
give such a history. Somnolence was reported in 35% of patients treated with APOKYN and in none of 
the patients in the placebo group. Prescribers should reassess patients for drowsiness or sleepiness, 
especially since some of the events occur well after the start of treatment. Prescribers should also be 
aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about 
drowsiness or sleepiness during specific activities.  
 
Before initiating treatment with APOKYN, advise patients of the risk of drowsiness and ask them about 
factors that could increase the risk with APOKYN, such as concomitant sedating medications and the 
presence of sleep disorders. If a patient develops significant daytime sleepiness or falls asleep during 
activities that require active participation (e.g., conversations, eating, etc.), APOKYN should ordinarily 
be discontinued. If a decision is made to continue APOKYN, patients should be advised not to drive and 
to avoid other potentially dangerous activities. There is insufficient information to determine whether 
dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.  
 
5.4 
Syncope 
In clinical studies, approximately 2% of APOKYN-treated patients experienced syncope.   
 
5.5 
Hypotension / Orthostatic Hypotension   
Dopamine agonists, including APOKYN, may cause orthostatic hypotension at any time but especially 
during dose escalation. Patients with Parkinson’s disease may also have an impaired capacity to respond 
to an orthostatic challenge. For these reasons, Parkinson’s disease patients being treated with 
dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic 
hypotension, especially during dose escalation, and should be informed of this risk. 
 
Patients undergoing titration of APOKYN showed an increased incidence (from 4% pre-dose to 18% 
post-dose) of systolic orthostatic hypotension (≥ 20 mmHg decrease) when evaluated at various times 
after in-office dosing. A small number of patients developed severe systolic orthostatic hypotension     
(≥ 30 mmHg decrease and systolic BP ≤ 90 mmHg) after subcutaneous apomorphine injection. In 
clinical trials of APOKYN in patients with advanced Parkinson’s disease, 59 of 550 patients (11%) had 
orthostatic hypotension, hypotension, and/or syncope. These events were considered serious in               
4 patients (< 1%) and resulted in withdrawal of APOKYN in 10 patients (2%). These events occurred 
both with initial dosing and during long-term treatment. Whether or not hypotension contributed to other 
significant adverse events seen (e.g., falls), is unknown. APOKYN causes dose-related decreases in 
systolic (SBP) and diastolic blood pressure (DBP) [see Clinical Pharmacology (12.2)]. 
 
The hypotensive effects of APOKYN may be increased by the concomitant use of alcohol, 
antihypertensive medications, and vasodilators (especially nitrates). Patients should avoid alcohol when 
using APOKYN. Check blood pressure for hypotension and orthostatic hypotension in patients 
APOKYN with concomitant antihypertensive medications and/or vasodilators [see Drug Interactions 
(7.2)].  
 


 
- 6 - 
5.6 
Falls  
Patients with Parkinson’s disease (PD) are at risk of falling due to underlying postural instability, 
possible autonomic instability, and syncope caused by the blood pressure lowering effects of the drugs 
used to treat PD. Subcutaneous APOKYN might increase the risk of falling by simultaneously lowering 
blood pressure and altering mobility [see Clinical Pharmacology (12.2)].  
 
In clinical trials, 30% of patients had events that could reasonably be considered falls and about 5% of 
patients had falls that were considered serious.  
 
5.7 
Hallucinations / Psychotic-Like Behavior  
In clinical studies, hallucinations were reported by 14% of the APOKYN-treated patients. In one 
randomized, double-blind, placebo-controlled study, hallucinations or confusion occurred in 10% of 
patients treated with APOKYN and 0% of patients treated with placebo. Hallucinations resulted in 
discontinuation of APOKYN in 1% of patients.  
 
Postmarketing reports indicate that patients may experience new or worsening mental status and 
behavioral changes, which may be severe, including psychotic-like behavior after starting or increasing 
the dose of APOKYN.  Other drugs prescribed to improve the symptoms of Parkinson’s disease can 
have similar effects on thinking and behavior.  This abnormal thinking and behavior can consist of one 
or more of a variety of manifestations, including paranoid ideation, delusions, hallucinations, confusion, 
disorientation, aggressive behavior, agitation, and delirium. 
 
Patients with a major psychotic disorder should ordinarily not be treated with APOKYN because of the 
risk of exacerbating psychosis.  In addition, certain medications used to treat psychosis may exacerbate 
the symptoms of Parkinson’s disease and may decrease the effectiveness of APOKYN [see Drug 
Interactions (7.3)]. 
 
5.8 
Dyskinesias 
APOKYN may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical studies, dyskinesia or 
worsening of dyskinesia was reported in 24% of patients. Overall, 2% of APOKYN-treated patients 
withdrew from studies due to dyskinesias. 
 
5.9 
Impulse Control/Compulsive Behaviors 
Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, 
intense urges to spend money uncontrollably, and other intense urges and the inability to control these 
urges while taking one or more of the medications, including APOKYN, that increase central 
dopaminergic tone and that are generally used for the treatment of Parkinson’s disease.  In some cases, 
although not all, these urges were reported to have stopped when the dose was reduced or the medication 
was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for 
prescribers to specifically ask patients or their caregivers about the development of new or increased 
gambling urges, sexual urges, uncontrolled spending or other urges while being treated with APOKYN. 
Physicians should consider dose reduction or stopping the medication if a patient develops such urges 
while taking APOKYN.  
 
5.10 
Coronary Events 
In clinical studies, 4% of patients treated with APOKYN experienced angina, myocardial infarction, 
cardiac arrest and/or sudden death; some cases of angina and myocardial infarction occurred in close 
proximity to APOKYN dosing (within 2 hours), while other cases of cardiac arrest and sudden death 
were observed at times unrelated to dosing. APOKYN has been shown to reduce resting systolic and 
diastolic blood pressure and may have the potential to exacerbate coronary (and cerebral) ischemia in 


 
- 7 - 
patients with known cardiovascular and cerebrovascular disease. If patients develop signs and symptoms 
of coronary or cerebral ischemia, prescribers should re-evaluate the continued use of APOKYN.  
 
5.11 
QTc Prolongation and Potential for Proarrhythymic Effects  
There is a small dose related prolongation of QTc interval with doses of APOKYN greater than 6 mg 
[See Clinical Pharmacology (12.2)].  Doses greater than 6 mg do not provide additional clinical benefit 
and are not recommended.  
 
Drugs that prolong the QTc interval have been associated with torsades de pointes and sudden death. 
The relationship of QTc prolongation to torsades de pointes is clearest for larger increases (20 msec and 
greater), but it is possible that smaller QTc prolongations may also increase risk, or increase it in 
susceptible individuals, such as those with hypokalemia, hypomagnesemia, bradycardia, concomitant 
use of other drugs that prolong the QTc interval, or genetic predisposition (e.g., congenital prolongation 
of the QT interval). Although torsades de pointes has not been observed in association with the use of 
APOKYN at recommended doses in clinical studies, experience is too limited to rule out an increased 
risk. Palpitations and syncope may signal the occurrence of an episode of torsades de pointes.  
 
The risks and benefits of APOKYN treatment should be considered prior to initiating treatment with 
APOKYN in patients with risk factors for prolonged QTc. 
 
5.12 
Withdrawal-Emergent Hyperpyrexia and Confusion  
A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated 
temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious 
etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in 
antiparkinsonian therapy.  
 
5.13  Melanoma 
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to 
approximately 6-fold higher) of developing melanoma than the general population. Whether the 
increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat 
Parkinson’s disease, is unclear. 
 
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently 
and on a regular basis when using APOKYN for any indication. Ideally, periodic skin examinations 
should be performed by appropriately qualified individuals (e.g., dermatologists).   
 
5.14  Fibrotic Complications 
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac 
valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While 
these complications may resolve when the drug is discontinued, complete resolution does not always 
occur. Although these adverse reactions are believed to be related to the ergoline structure of these 
dopamine agonists, whether other, nonergot derived dopamine agonists, such as APOKYN, can cause 
these reactions is unknown.  
 
5.15 
Priapism  
APOKYN may cause prolonged painful erections in some patients. In clinical studies, painful erections 
were reported by 3 of 361 APOKYN-treated men, and one patient withdrew from APOKYN therapy 
because of priapism. Although no patients in the clinical studies required surgical intervention, severe 
priapism may require surgical intervention.  
 
 


 
- 8 - 
5.16 
Retinal Pathology in Albino Rats  
In a 2-year carcinogenicity study of apomorphine in albino rat, retinal atrophy was detected at all 
subcutaneous doses tested (up to 0.8 mg/kg/day or 2 mg/kg/day in males or females, respectively; less 
than the maximum recommended human dose of 20 mg/day on a body surface area [mg/m2] basis). 
Retinal atrophy/degeneration has been observed in albino rats treated with other dopamine agonists for 
prolonged periods (generally during 2-year carcinogenicity studies). Retinal findings were not observed 
in a 39-week subcutaneous toxicity study of apomorphine in monkey at doses up to 1.5 mg/kg/day, a 
dose similar to the MRHD on a mg/m2 basis. The clinical significance of the finding in rat has not been 
established but cannot be disregarded because disruption of a mechanism that is universally present in 
vertebrates (e.g., disk shedding) may be involved.  
 
6 
ADVERSE REACTIONS 
 
 
 
The following adverse reactions are discussed in more detail in the Warnings and Precautions section of 
labeling: 
 
  
• Nausea and Vomiting [see Warnings and Precautions (5.2)] 
• Syncope [see Warnings and Precautions (5.4)] 
• Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.5)] 
• Falls [see Warnings and Precautions (5.6)] 
• Hallucinations/Psychotic-Like Behavior [see Warnings and Precautions (5.7)] 
• Dyskinesias [see Warnings and Precautions (5.8)] 
• Coronary Events [see Warnings and Precautions (5.10)] 
• Priapism [see Warnings and Precautions (5.15)] 
 
6.1  
Clinical Trial Experience 
Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions 
(number of unique patients experiencing an adverse reaction associated with treatment per total number 
of patients treated) observed in the clinical trials of a drug cannot be directly compared to the incidence 
of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse 
reactions observed in practice. 
 
In placebo-controlled trials, most patients received only one subcutaneous dose of APOKYN. All 
patients received concomitant levodopa and 86% received a concomitant dopamine agonist. All patients 
had some degree of spontaneously occurring periods of hypomobility (“off episodes”) at baseline. 
 
The most common adverse reactions (APOKYN incidence at least 10% greater than placebo incidence) 
observed in a placebo-controlled trial were yawning, drowsiness/somnolence, dyskinesias, 
dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and 
edema/swelling of extremities.   
 
Table 1 presents the most common adverse reactions reported by APOKYN-naïve Parkinson’s disease 
patients who were enrolled in a randomized placebo-controlled, parallel group trial and who were 
treated for up to 4 weeks (Study 1) [see Clinical Studies (14)]. Individual APOKYN doses in this trial 
ranged from 2 mg to 10 mg, and were titrated to achieve tolerability and control of symptoms.  
 
 
 
 
 


 
- 9 - 
 
Table 1: Adverse Reactions Occurring in Two or More APOKYN-Treated Patients in Study 1 
 
 
APOKYN (n = 20) 
PLACEBO (n = 9) 
% 
% 
Yawning 
40 
0 
Dyskinesias 
35 
11 
Drowsiness or Somnolence 
35 
0 
Nausea and/or Vomiting 
30 
11 
Dizziness or Postural Hypotension 
20 
0 
Rhinorrhea 
20 
0 
Chest Pain/Pressure/Angina 
15 
11 
Hallucination or Confusion 
10 
0 
Edema/Swelling of Extremities 
10 
0 
 
Other Adverse Reactions  
 
Injection Site Reactions 
Patients treated with APOKYN subcutaneous injections during clinical studies, 26% of patients had 
injection site reactions, including bruising (16%), granuloma (4%), and pruritus (2%). 
 
In addition to those in Table 1, the most common adverse reactions in pooled APOKYN trials (occurring 
in at least 5% of the patients) in descending order were injection site reaction, fall, arthralgia, insomnia, 
headache, depression, urinary tract infection, anxiety, congestive heart failure, limb pain, back pain, 
Parkinson’s disease aggravated, pneumonia, confusion, sweating increased, dyspnea, fatigue, 
ecchymosis, constipation, diarrhea, weakness, and dehydration. 
 
7 
DRUG INTERACTIONS 
 
7.1 
5HT3 Antagonists 
Based on reports of profound hypotension and loss of consciousness when APOKYN was administered 
with ondansetron, the concomitant use of APOKYN with 5HT3 antagonists including antiemetics (for 
example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron, is contraindicated.  
 
7.2 
Antihypertensive Medications and Vasodilators 
The following adverse events were experienced more commonly in patients receiving concomitant 
antihypertensive medications or vasodilators (n = 94) compared to patients not receiving these 
concomitant drugs (n = 456): hypotension 10% vs 4%, myocardial infarction 3% vs 1%, serious 
pneumonia 5% vs 3%, serious falls 9% vs 3%, and bone and joint injuries 6% vs 2%. The mechanism 
underlying many of these events is unknown, but may represent increased hypotension [see Warnings 
and Precautions (5.5, 5.6)].  
 
7.3 
Dopamine Antagonists 
Since APOKYN is a dopamine agonist, it is possible that concomitant use of dopamine antagonists, such 
as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish 
the effectiveness of APOKYN. Patients with major psychotic disorders, treated with neuroleptics, 
should be treated with dopamine agonists only if the potential benefits outweigh the risks.  
 
7.4 
Drugs Prolonging the QT/QTc Interval 
Caution should be exercised when prescribing APOKYN concomitantly with drugs that prolong the 
QT/QTc interval [see Warnings and Precautions (5.11)].  
 


 
- 10 - 
8 
USE IN SPECIFIC POPULATIONS 
 
8.1 
Pregnancy  
Risk Summary 
There are no adequate data on the developmental risk associated with use of APOKYN in pregnant 
women. In animal reproduction studies, apomorphine had adverse developmental effects in rats 
(increased neonatal deaths) and rabbits (increased incidence of malformation) when administered during 
pregnancy at clinically relevant doses. These doses were also associated with maternal toxicity [see 
Data]. In the U.S. general population, the estimated background risk of major birth defects and 
miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The 
background risk of major birth defects and miscarriage for the indicated population is unknown. 
 
Data 
 
Animal Data 
No adverse developmental effects were observed when apomorphine (0.3, 1, or 3 mg/kg/day) was 
administered by subcutaneous injection to pregnant rats throughout organogenesis; the highest dose 
tested is 1.5 times the maximum recommended human dose (MRHD) of 20 mg/day on a mg/m2 basis. 
Administration of apomorphine (0.3, 1, or 3 mg/kg/day) by subcutaneous injection to pregnant rabbits 
throughout organogenesis resulted in an increased incidence of malformations of the heart and/or great 
vessels at the mid and high doses; maternal toxicity was observed at the highest dose tested. The no-
effect dose for adverse developmental effects is less than the MRHD on a mg/m2 basis.  
 
Apomorphine (0.3, 1, or 3 mg/kg/day), administered by subcutaneous injection to females throughout 
gestation and lactation, resulted in increased offspring mortality at the highest dose tested, which was 
associated with maternal toxicity. There were no effects on developmental parameters or reproductive 
performance in surviving offspring. The no-effect dose for developmental toxicity (1 mg/kg/day) is less 
than the MRHD on a mg/m2 basis. 
 
8.2 
Lactation 
 
Risk Summary 
  
There are no data on the presence of apomorphine in human milk, the effects of apomorphine on the 
breastfed infant, or the effects of apomorphine on milk production. The developmental and health 
benefits of breastfeeding should be considered along with the mother’s clinical need for APOKYN and 
any potential adverse effects on the breastfed infant from APOKYN or from the underlying maternal 
condition.  
 
8.4 
Pediatric Use  
Safety and effectiveness in pediatric patients have not been established.  
 
8.5 
Geriatric Use  
In the APOKYN clinical development program, there were 239 patients less than age 65 treated with 
APOKYN and 311 patients who were age 65 years of age or older. Confusion and hallucinations were 
reported more frequently with patients age 65 and older compared to patients with less than age 65. 
Serious adverse reactions (life-threatening events or events resulting in hospitalization and/or increased 
disability) were also more common in patients age 65 and older. Patients age 65 and older were more 
likely to fall (experiencing bone and joint injuries), have cardiovascular events, develop respiratory 
disorders, and have gastrointestinal events. Patients age 65 and above were also more likely to 
discontinue APOKYN treatment as a result of one or more adverse reactions.  
 


 
- 11 - 
8.6 
Renal Impairment 
The starting APOKYN dose should be reduced in patients with mild or moderate renal impairment 
because the concentration and exposure (Cmax and AUC) are increased in these patients. Studies in 
subjects with severe renal impairment have not been conducted [see Dosage and Administration (2.4) 
and Clinical Pharmacology (12.3)].  
 
8.7 
Hepatic Impairment  
Caution should be exercised when administrating APOKYN to patients with mild and moderate hepatic 
impairment due to the increased Cmax and AUC in these patients. Studies of subjects with severe hepatic 
impairment have not been conducted [see Dosage and Administration (2.5) and Clinical Pharmacology 
(12.3)].  
 
9 
DRUG ABUSE AND DEPENDENCE 
 
9.2 
Abuse  
In premarketing clinical experience, APOKYN did not reveal any tendency for a withdrawal syndrome or 
any drug-seeking behavior. However, there are rare postmarketing reports of abuse of medications 
containing APOKYN or levodopa. In general, these reports consist of patients taking increasing doses of 
medication in order to achieve a euphoric state. 
 
10 
OVERDOSAGE 
A 62-year-old man accidentally injected 25 mg of APOKYN subcutaneously. After 3 minutes, the 
patient felt nauseated and lost consciousness for 20 minutes. Afterwards, he was alert with a heart rate 
40/minute and a supine blood pressure of 90/50. He recovered completely within an hour. 
 
11 
DESCRIPTION 
APOKYN (apomorphine hydrochloride injection) contains apomorphine hydrochloride, a non-ergoline 
dopamine agonist. Apomorphine hydrochloride is chemically designated as 6aβ-Aporphine-10,11-diol 
hydrochloride hemihydrate with a molecular formula of C17H17NO2 • HCL • ½ H2O. Its structural 
formula and molecular weight are: 
 
 
Figure 1: Structural Formula and Molecular Weight of Apomorphine 
 
M.W. 312.79 
 
Apomorphine hydrochloride appears as minute, white or grayish-white glistening crystals or as white 
powder that is soluble in water at 80°C. 
 
APOKYN is a clear, colorless, sterile solution for subcutaneous injection and is available in 
3 mL (30 mg) multi-dose cartridges. Each mL of solution contains 10 mg of apomorphine 
hydrochloride, USP as apomorphine hydrochloride hemihydrate, 1 mg of sodium metabisulfite, NF and 
5 mg of benzyl alcohol, NF (preservative) in water for injection, USP. In addition, each mL of solution 
may contain sodium hydroxide, NF and/or hydrochloric acid, NF to adjust the pH of the solution. 


 
- 12 - 
12 
CLINICAL PHARMACOLOGY 
 
12.1 
Mechanism of Action 
APOKYN is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D4 
receptor, and moderate affinity for the dopamine D2, D3, and D5, and adrenergic α1D, α2B, α2C 
receptors. The precise mechanism of action of APOKYN as a treatment for Parkinson’s disease is 
unknown, although it is believed to be due to stimulation of post-synaptic dopamine D2-type receptors 
within the caudate-putamen in the brain.  
 
12.2 
Pharmacodynamics  
Prolongation of the QTc Interval: In a placebo-controlled study in which patients received increasing 
single doses of APOKYN from 2 mg to up to 10 mg, the mean difference in QTc (measured by Holter 
monitor) between APOKYN and placebo was 0 msec at 4 mg, 1 msec at 6 mg, and 7 msec at 8 mg. Too 
few patients received a 10 mg dose to be able to adequately characterize the change in QTc interval at 
that dose.  
 
In a controlled trial in which patients were administered placebo or a single dose of APOKYN (mean 
dose of 5.2 mg; range of 2 mg to 10 mg), the mean difference between APOKYN and placebo in the 
change in QTc was about 3 msec at 20 minutes and 90 minutes. In the entire database, 2 patients (one at 
2 mg and 6 mg, one at 6 mg) exhibited large QTc increments (> 60 msecs from pre-dose) and had QTc 
intervals greater than 500 msecs acutely after dosing. Doses of 6 mg or less thus are associated with 
minimal increases in QTc.  
 
Decreases in blood pressure 
Dose-dependent mean decrements in systolic blood pressure ranged from 5 mmHg after 2 mg to           
16 mmHg after 10 mg. Dose-dependent mean decrements in diastolic blood pressure ranged from          
3 mmHg after 2 mg to 8 mmHg after 10 mg. These changes were observed at 20 minutes, and were 
maximal between 20 and 40 minutes after dosing. Lesser, but still noteworthy blood pressure 
decrements persisted up to at least 90 minutes after dosing.  
 
12.3 
Pharmacokinetics  
Absorption  
Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed (time to peak 
concentration ranges from 10 minutes to 60 minutes) following subcutaneous administration into the 
abdominal wall. After subcutaneous administration, apomorphine appears to have bioavailability equal 
to that of an intravenous administration. Apomorphine exhibits linear pharmacokinetics over a dose 
range of 2 mg to 8 mg following a single subcutaneous injection of APOKYN into the abdominal wall in 
patients with idiopathic Parkinson’s disease. 
 
Distribution  
The plasma-to-whole blood apomorphine concentration ratio is equal to one. Mean (range) apparent 
volume of distribution was 218 L (123 L to 404 L). Maximum concentrations in cerebrospinal fluid 
(CSF) are less than 10% of maximum plasma concentrations and occur 10 minutes to 20 minutes later.  
 
Metabolism and Elimination  
The mean apparent clearance (range) is 223 L/hr (125 L/hr to 401 L/hr) and the mean terminal 
elimination half-life is about 40 minutes (range about 30 minutes to 60 minutes).  
 
The route of metabolism in humans is not known. Potential routes of metabolism in humans include 
sulfation, N-demethylation, glucuronidation and oxidation. In vitro, apomorphine undergoes rapid 
autooxidation. 


 
- 13 - 
 
 
Special Populations 
The clearance of apomorphine does not appear to be influenced by age, gender, weight, duration of 
Parkinson’s disease, levodopa dose or duration of therapy. 
 
Renal Impairment  
In a study comparing renally-impaired subjects (moderately impaired as determined by estimated 
creatinine clearance) to healthy matched volunteers, the AUC0-∞ and Cmax values were increased by 
approximately 16% and 50%, respectively, following a single subcutaneous administration of APOKYN 
into the abdominal wall. The mean time to peak concentrations and the mean terminal half-life of 
apomorphine were unaffected by the renal status of the individual. Studies in subjects with severe renal 
impairment have not been conducted. The starting dose for patients with mild or moderate renal 
impairment should be reduced [see Dosage and Administration (2.4) and Use in Specific Populations 
(8.6)]. 
 
Hepatic Impairment  
In a study comparing subjects with hepatic impairment (moderately impaired as determined by the 
Child-Pugh classification method) to healthy matched volunteers, the AUC0-∞ and Cmax values were 
increased by approximately 10% and 25%, respectively, following a single subcutaneous administration 
of APOKYN into the abdominal wall. Studies in subjects with severe hepatic impairment have not been 
conducted [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)]. 
 
Drug-Drug Interactions  
Carbidopa/levodopa: Levodopa pharmacokinetics were unchanged when subcutaneous APOKYN and 
levodopa were co-administrated in patients. However, motor response differences were significant. The 
threshold levodopa concentration necessary for an improved motor response was reduced significantly, 
leading to an increased duration of effect without a change in the maximal response to levodopa therapy.  
 
Other Drugs Eliminated Via Hepatic Metabolism  
Based upon an in vitro study, cytochrome P450 enzymes play a minor role in the metabolism of 
apomorphine. In vitro studies have also demonstrated that drug interactions are unlikely due to 
apomorphine acting as a substrate, an inhibitor, or an inducer of cytochrome P450 enzymes.  
 
COMT Interactions 
A pharmacokinetic interaction of APOKYN with catechol-O-methyl transferase (COMT) inhibitors or 
drugs metabolized by this route is unlikely since apomorphine appears not to be metabolized by COMT. 
 
13  
NONCLINICAL TOXICOLOGY 
 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
 
Carcinogenesis 
Lifetime carcinogenicity studies of apomorphine were conducted in male (0.1, 0.3, or 0.8 mg/kg/day) 
and female (0.3, 0.8, or 2 mg/kg/day) rats. Apomorphine was administered by subcutaneous injection for 
22 months or 23 months, respectively.  In males, there was an increase in Leydig cell tumors at the 
highest dose tested, which is less than the MRHD (20 mg) on a mg/m2 basis. This finding is of 
questionable significance because the endocrine mechanisms believed to be involved in the production 
of Leydig cell tumors in rats are not relevant to humans. No drug-related tumors were observed in 
females; the highest dose tested is similar to the MRHD on a mg/m2 basis.    
 


 
- 14 - 
In a 26-week carcinogenicity study in P53-knockout transgenic mice, there was no evidence of 
carcinogenic potential when apomorphine was administered by subcutaneous injection at doses up to   
20 mg/kg/day (male) or 40 mg/kg/day (female). 
 
Mutagenesis 
Apomorphine was mutagenic in the in vitro bacterial reverse mutation (Ames) and the in vitro mouse 
lymphoma tk assays. Apomorphine was clastogenic in the in vitro chromosomal aberration assay in 
human lymphocytes and in the in vitro mouse lymphoma tk assay. Apomorphine was negative in the in 
vivo micronucleus assay in mice.  
 
Impairment of Fertility 
Apomorphine was administered subcutaneously at doses up to 3 mg/kg/day (approximately 1.5 times the 
MRHD on a mg/m2 basis) to male and female rats prior to and throughout the mating period and 
continuing in females through gestation day 6. There was no evidence of adverse effects on fertility or 
on early fetal viability. A significant decrease in testis weight was observed in a 39-week study in 
cynomolgus monkey at all subcutaneous dose tested (0.3, 1, or 1.5 mg/kg/day); the lowest dose tested is 
less than the MRHD on a mg/m2 basis. 
 
In a published fertility study, apomorphine was administered to male rats at subcutaneous doses of      
0.2, 0.8, or 2 mg/kg prior to and throughout the mating period. Fertility was reduced at the highest dose 
tested. 
 
14   
CLINICAL STUDIES 
The effectiveness of APOKYN in the acute symptomatic treatment of the recurring episodes of 
hypomobility, “off” episodes (“end-of-dose wearing off” and unpredictable “on/off” episodes), in 
patients with advanced Parkinson’s disease was established in three randomized, controlled trials of 
APOKYN given subcutaneously (Studies 1, 2, and 3). At baseline in these trials, the mean duration of 
Parkinson’s disease was approximately 11 years. Whereas all patients were using concomitant L-dopa at 
baseline, 86% of patients were using a concomitant oral dopaminergic agonist, 31% were using a 
concomitant catechol-ortho-methyl transferase (COMT) inhibitor, and 10% were using a concomitant 
monoamine B oxidase inhibitor. Study 1 was conducted in patients who did not have prior exposure to 
APOKYN (i.e., APOKYN naïve) and Studies 2 and 3 were conducted in patients with at least 3 months 
of APOKYN use immediately prior to study enrollment. Almost all patients without prior exposure to 
APOKYN began taking an antiemetic (trimethobenzamide) three days prior to starting APOKYN and 
50% of patients were able to discontinue the concomitant antiemetic, on average 2 months after 
initiating APOKYN. 
 
The change from baseline in Part III (Motor Examination) of the Unified Parkinson’s Disease Rating 
Scale (UPDRS) served as the primary outcome assessment measure in each study. Part III of the 
UPDRS contains 14 items designed to assess the severity of the cardinal motor findings (e.g., tremor, 
rigidity, bradykinesia, postural instability, etc.) in patients with Parkinson’s disease.  
 
Study 1 
Study 1 was a randomized, double-blind, placebo-controlled, parallel-group trial in 29 patients with 
advanced Parkinson’s disease who had at least 2 hours of “off” time per day despite an optimized oral 
regimen for Parkinson’s disease including levodopa and an oral dopaminergic agonist. Patients with 
atypical Parkinson’s disease, psychosis, dementia, hypotension, or those taking dopamine antagonists 
were excluded from participation.  In an office setting, hypomobility was allowed to occur by 
withholding the patients’ Parkinson’s disease medications overnight. The following morning, patients 
(in a hypomobile state) were started on study treatment in a 2:1 ratio (2 mg of APOKYN or placebo 
given subcutaneously).  At least 2 hours after the first dose, patients were given additional doses of 


 
- 15 - 
study medication until they achieved a “therapeutic response” (defined as a response similar to the 
patient’s response to their usual dose of levodopa) or until 10 mg of APOKYN or placebo equivalent 
was given. At each injection re-dosing, the study drug dose was increased in 2 mg increments up to 4 
mg, 6 mg, 8 mg, 10 mg of APOKYN) or placebo equivalent.  
 
Of the 20 patients randomized to APOKYN, 18 achieved a “therapeutic response” at about 20 minutes. 
The mean APOKYN dose was 5.4 mg (3 patients on 2 mg, 7 patients on 4 mg, 5 patients on 6 mg,         
3 patients on 8 mg, and 2 patients on 10 mg). In contrast, of the 9 placebo-treated patients, none reached 
a “therapeutic response.” The mean change-from-baseline for UPDRS Part III score for APOKYN group 
(highest dose) was statistically significant compared to that for the placebo group (Table 2). 
 
Table 2: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 1 
 
Treatment 
Baseline UPDRS Motor 
Score 
Mean Change from Baseline 
Difference from placebo 
Placebo 
36.3 
-   0.1 
NA 
APOKYN 
39.7 
- 23.9 
- 23.8 
 
Study 2 
Study 2 used a randomized, placebo-controlled crossover design of 17 patients with Parkinson’s disease 
who had been using APOKYN for at least 3 months. Patients received their usual morning doses of 
Parkinson’s disease medications and were followed until hypomobility occurred, at which time they 
received either a single dose of subcutaneous APOKYN (at their usual dose) and placebo on different 
days in random order. UPDRS Part III scores were evaluated over time. The mean dose of APOKYN 
was 4 mg (2 patients on 2 mg, 9 patients on 3 mg, 2 patients on 4 mg, and 1 patient each on 4.5 mg,       
5 mg, 8 mg, and 10 mg). The mean change-from-baseline UPDRS Part III score for the APOKYN group 
was statistically significant compared to that for the placebo group (Table 3).  
 
 
Table 3: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 2 
 
Treatment 
Baseline UPDRS Motor 
Score 
Mean Change from Baseline 
Difference from placebo 
Placebo 
40.1 
-   3.0 
NA 
APOKYN 
41.3 
- 20.0 
- 17.0 
 
 
Study 3 
Study 3 used a randomized withdrawal design in 4 parallel groups from 62 patients (APOKYN-35; 
Placebo-27) with Parkinson’s disease who had been using APOKYN for at least 3 months. Patients were 
randomized to one of the following 4 treatments dosed once by subcutaneous administration: APOKYN 
at the usual dose (mean dose 4.6 mg), placebo at a volume matching the usual APOKYN dose, 
APOKYN at the usual dose + 2 mg (0.2 mL) (mean dose 5.8 mg), or placebo at a volume matching the 
usual APOKYN dose + 0.2 mL. Patients received their usual morning doses of Parkinson’s disease 
medications and were followed until hypomobility occurred, at which time they received the randomized 
treatment. APOKYN doses ranged between 2 mg – 10 mg. The mean change-from-baseline for the 
APOKYN group for UPDRS Part III scores at 20 minutes post dosing was statistically significant 
compared to that for the placebo group (Table 4). Figure 2 describes the mean change from baseline in 
UPDRS Motor Scores over time for pooled APOKYN and placebo administration.   
 
 
 


 
- 16 - 
Table 4: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 4 
 
Treatment 
Baseline UPDRS Motor 
Score 
Mean Change from Baseline 
Difference from placebo 
Placebo (Pooled) 
40.6 
-   7.4 
NA 
APOKYN (Pooled) 
42.0 
- 24.2 
- 16.8 
 
 
Figure 2: Mean Change from Baseline in UPDRS Motor Scores of Pooled APOKYN Groups and Placebo Group in 
Study 3  
 
 
 
In Study 3, the mean changes-from-baseline for UPDRS Part III scores at 20 minutes post dosing for the 
APOKYN and higher dose APOKYN groups were 24 and 25, respectively. This result suggests that 
patients chronically treated at a dose of 4 mg might derive little additional benefit from a dose increment 
of 2 mg. There was also an increased incidence of adverse reactions in patients randomized to higher 
APOKYN dose.   
 
16   
HOW SUPPLIED/STORAGE AND HANDLING 
 
APOKYN is supplied as a 10 mg/mL clear, colorless, sterile, solution in 3 mL (30 mg) glass cartridges.  
 
NDC 27505-004-05 
Cartons of five 3 mL cartridges 
 
APOKYN Pen 
The pen injector is provided in a package with six needles and a carrying case.  
 
 
Store at 25°C (77°F).  Excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room 
Temperature] 
 
17   
PATIENT COUNSELING INFORMATION   
 
See FDA-approved patient labeling (Patient Information and Instructions for Use) 
 
 
 


 
- 17 - 
Administration with the APOKYN Pen 
 
Instruct patients and caregivers to read the “APOKYN Pen Instructions for Use” and Patient 
Information. Instruct patients to use APOKYN only as prescribed [See Dosage and Administration (2)].  
 
Instruct patients and caregivers that the APOKYN Pen is dosed in milliliters, not milligrams.  
 
Inform patients and caregivers that it is possible to dial in their usual dose of APOKYN even though the 
cartridge may contain less than that amount of drug. In this case, they will receive only a partial dose 
with the injection, and the amount left to inject will appear in the dosing window. To complete the 
correct dose, patients/caregivers will need to “re-arm” the device and dial in the correct amount of the 
remaining dose. Patients and caregivers should be alerted to the fact that there may be insufficient drug 
left in the cartridge to deliver a complete dose (for example, patients and caregivers should be urged to 
keep records of how many doses they have delivered for each cartridge, so that they can replace any 
cartridge that has an inadequate amount of drug remaining).  
 
Instruct patients to rotate the injection site and to observe proper aseptic technique.  
 
Advise patients that APOKYN is intended only for subcutaneous injection and must not be given 
intravenously because of the risk of serious complications such as thrombus formation and pulmonary 
embolism due to crystallization [see Warnings and Precautions (5.1)]. 
 
Avoidance of Concomitant Antiemetic Drugs of 5HT3 Antagonist Class 
 
Advise patients that they should not use concomitant drugs of the 5HT3 antagonist class including 
antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron with APOKYN. Use 
of APOKYN with concomitant antiemetic drugs of the 5HT3 antagonist class is contraindicated because 
there have been reports of profound hypotension and loss of consciousness when APOKYN was 
administered with ondansetron [see Contraindications (4)]. 
 
Hypersensitivity / Allergic Reactions 
 
Advise patients that hypersensitivity/allergic reaction characterized by urticaria, rash, pruritus, and/or 
various manifestations of angioedema may occur because of APOKYN or any of its excipients including 
a sulfite (i.e., sodium metabisulfite). Inform patients with a sulfite sensitivity that they may experience 
various allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic attacks. 
Advise patients who experience any hypersensitivity/allergic reaction to APOKYN that they should 
avoid taking APOKYN again [see Contraindications (4)].  
 
Nausea and Vomiting  
 
Advise patients that they may experience severe nausea and/or vomiting and that they should begin 
taking trimethobenzamide 300 mg orally 3 times per day for 3 days prior to starting APOKYN 
injections. Advise patients that APOKYN taken with trimethobenzamide may increase the risks for 
somnolence, dizziness, and falls. Inform patients that their healthcare provider will tell them when 
trimethobenzamide can be discontinued [see Warnings and Precautions (5.2)]. 
 
Falling Asleep Suddenly and Sedation / Sleepiness 
 
Alert patients to the potential sedating effects of APOKYN, including somnolence and falling asleep 
while engaged in activities of daily living. Instruct patients not to drive a car or engage in other 


 
- 18 - 
potentially dangerous activities until they have gained sufficient experience with APOKYN to gauge 
whether or not it affects their mental and/or motor performance adversely. Advise patients that if 
increased somnolence or episodes of falling asleep during activities of daily living (e.g., watching 
television, passenger in a car, etc.) occur, they should not drive or participate in potentially dangerous 
activities until they have contacted their physician. Because of possible additive effects of alcohol use, 
advise patients to limit their alcohol intake [see Warnings and Precautions (5.3)]. 
 
Syncope 
 
Advise patients that APOKYN may cause syncope [see Warnings and Precautions (5.4)]. 
 
Hypotension / Orthostatic Hypotension 
 
Advise patients that they may develop postural (orthostatic) hypotension with or without symptoms such 
as dizziness, nausea, syncope, and sometimes sweating. Hypotension and/or orthostatic symptoms may 
occur more frequently during initial therapy or with an increase in dose at any time (cases have been 
seen after months of treatment). Instruct patients to rise slowly after sitting or lying down after taking 
APOKYN. Instruct patients to limit their alcohol intake because it may potentiate the hypotensive effect 
of APOKYN [see Warnings and Precautions (5.5)]. 
 
Falls 
 
Alert patients that they may have increased risk for falling when using APOKYN [see Warnings and 
Precautions (5.6)]. 
 
Hallucinations and/or Psychotic-Like Behavior 
 
Inform patients that hallucinations or other manifestations of psychotic-like behavior can occur.  Tell 
patients if they have a major psychotic disorder, ordinarily they should not use APOKYN because of the 
risk of exacerbating the psychosis. Patients with a major psychotic disorder should also be aware that 
many treatments for psychosis may decrease the effectiveness of APOKYN [see Warnings and 
Precautions (5.7)].  
 
Dyskinesia 
 
Inform patients that APOKYN may cause and/or exacerbate pre-existing dyskinesias [see Warnings and 
Precautions (5.8)].  
 
Impulse Control / Compulsive Behaviors  
 
Patients and their caregivers should be alerted to the possibility that they may experience intense urges 
to spend money uncontrollably, intense urges to gamble, increased sexual urges, binge eating and/or 
other intense urges and the inability to control these urges while taking APOKYN [see  Warnings and 
Precautions (5.9)]. 
 
Coronary Events  
 
Inform patients that APOKYN may cause coronary events including angina and myocardial infarction 
and these outcomes could possibly be related to significant hypotension/orthostatic hypotension [see 
Warnings and Precautions (5.10)]. 
 


 
- 19 - 
QTc Prolongation and Potential for Proarrhythymic Effects  
 
Alert patients that APOKYN may cause QTc prolongation and might produce proarrhythmic effects that 
could cause torsades de pointes and sudden death. Palpitations and syncope may signal the occurrence of 
an episode of torsades de pointes [see Warnings and Precautions (5.11)]. 
 
Withdrawal-Emergent Hyperpyrexia and Confusion  
 
Advise patients to contact their healthcare provider if they wish to discontinue APOKYN or decrease the 
dose of APOKYN [see Warnings and Precautions (5.12)]. 
Melanoma 
 
Advise patients with Parkinson’s disease that they have a higher risk of developing melanoma. Advise 
patients to have a qualified healthcare provider examine that patient’s skin periodically for melanomas 
on a regular basis when using APOKYN [see Warnings and Precautions (5.13)]. 
 
Priapism 
 
Advise patients that APOKYN may cause prolonged painful erections and that if this occurs that they 
should seek medical attention immediately [see Warnings and Precautions (5.15)]. 
 
Injection Site Reactions 
 
Inform patients that injections of APOKYN may result in injection site reactions including bruising, 
granuloma, and pruritus [see Adverse Reactions (6.1)]. 
 
Distributed by: 
 
US WorldMeds, LLC 
4441 Springdale Rd 
Louisville, KY 40241 
 
US WorldMeds, LLC is the exclusive licensee and distributor of APOKYN in the United States and Its territories.  
© 2017. APOKYN is a registered trademark of BRITUSWIP. 


Sunovion Pharmaceuticals Inc.  
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
19.2. 
APPENDIX II: APOKYN® Pen Instructions 
 
 


APOKYN® Pen Instructions for Use
Designed to be used only with 
3 mL APOKYN® (apomorphine hydrochloride injection) Cartridges
For more information, call your specialty pharmacy provider
or 1-877-7APOKYN (727-6596).
(apomorphine hydrochloride injection)




APOKYN Pen
3


• APOKYN
® (apomorphine hydrochloride injection) is for under the skin (subcutaneous)
injection only.  
• Do not inject APOKYN into a vein.
• Do not use the APOKYN
® Pen unless you and your care partner have been taught the right
way to use it and both of you understand all of the instructions.
• The APOKYN Pen is for use only with 3 mL APOKYN
® (apomorphine hydrochloride
injection) Cartridges.
• The APOKYN Pen is only for use by 1 patient and should not be shared.
4


Gray Pen Body
a
b
d e
c
L
01
f. Outer Needle Shield
g. Pink Inner Needle Shield
h. Pen Needle
i. Pink Paper Tab
j. Rubber Septum
k. Metal Cap
l. Cartridge Plunger
j k
l
f
i
g
h
b. Black Rod
c. White Dose Window
d. White Dose Knob
e. Teal Injection Button
Pen Needle Unit
Cartridge
Gray Pen Cap
a. Clip
Teal Cartridge
Holder
5


Read First: Important Safety Information
◆The APOKYN Pen is a medicine delivery device. It is very important that you or your care
partner read this Instructions for Use and follow the instructions for using the APOKYN Pen
correctly to receive the correct APOKYN dose.
◆Always perform a flow check (prime) before every injection and after loading a new cartridge.
◆The liquid in the APOKYN Cartridge can cause irritation if it gets on your skin or in your eyes.
Flush your eyes with cold water and wash the liquid off your skin right away if this happens.
6


◆The BD pen needle unit is sterile. Avoid contaminating the needle after opening. Do not place it
on a surface or touch other items with the needle.
◆Do not dial the dose or try to correct a dialing error with the pen needle in the skin. You could
receive the wrong dose.
◆Be careful when removing the needle. Accidental needle sticks can transmit serious infections.
7


Never store or carry the APOKYN Pen with a pen needle attached.
Storing or carrying the APOKYN Pen with a pen needle attached
may let:
◆Air enter the cartridge
◆Medicine leak out
This can affect your APOKYN dose.
Never recap pen with 
needle attached.
8


New Needle
Reused Needle
You must use a new, sterile BD pen needle with each injection.
Magnification: 50x
The APOKYN Pen should only be used with pen needles (29G x 1/2"). These needles are
available through your specialty pharmacy provider or your local pharmacy.
9


How to Use the APOKYN Pen
2
Preparing the APOKYN Pen for 
Cartridge Loading
Step 1. Remove the gray pen cap by pulling it straight off.
Step 2. Unscrew the teal cartridge holder from the gray
pen body by turning it clockwise.
1
10


Loading a Cartridge
Step 3. Only use APOKYN that is clear and colorless. Do not use an APOKYN
Cartridge that contains medicine that is cloudy, green, or contains
particles. Call your specialty pharmacy provider for replacement
cartridges. Insert the APOKYN Cartridge, metal cap first, into the teal
cartridge holder.
Step 4. Lower the gray pen body onto the teal cartridge holder so that the black
rod presses against the cartridge plunger. Screw the teal cartridge holder
onto the gray pen body. Tighten the pieces by turning the teal cartridge
holder clockwise until no gap remains and 1 of the white arrows line up
with the white marker on the gray pen body.
3
11
4
4


5
Step 5. If you already have a cartridge in the pen and have used the pen,
you should check the cartridge through the window in the teal
cartridge holder to make sure there is enough APOKYN solution in
the cartridge to provide your next dose. If the gray cartridge
plunger has reached the red line on the cartridge, remove the
cartridge and insert a new cartridge into the pen before attaching
the pen needle and preparing the dose.
12


Attaching the Pen Needle
Step 6. Remove the pink paper tab from the back of a new pen needle.
Use a new needle for each injection. Never reuse needles.
Step 7. Holding the APOKYN Pen by the teal cartridge holder, push the pen
needle unit onto the pen. Screw the threaded hub of the pen needle
onto the teal cartridge holder counter-clockwise. When the needle
unit is attached, remove the outer shield that protects the needle with
a gentle pull. Save the outer shield. You will use it to remove the
needle from the pen after the injection is finished. Do not remove the
inner needle shield at this time. The needle is sterile and must stay
clean. After opening, do not place the needle on a surface or let it
touch anything.
6
7
13


Preparing (Priming) the APOKYN Pen for Use
IMPORTANT – Prior to each injection, it is important that the APOKYN Pen be properly primed.
For a new APOKYN Cartridge (1 that has not been used before), repeat the priming procedure
described on the next page (Steps 8-9) 3 or 4 times to make sure all the air has been removed from 
the needle and cartridge.
For an APOKYN Cartridge you have used before (1 that has been previously primed), repeat the
priming procedure described on the next page (Steps 8-9) 1 time to make sure all the air has been
removed from the needle and cartridge.
14


99
Step 8. You must prepare (prime) the APOKYN Pen for use before injecting the
medicine. To prime the APOKYN Pen, set the dose by turning the dose
knob to 0.1 mL. This is important so you can get rid of any air bubbles
in the cartridge.
Step 9. Remove the inner needle shield. Remember, do not let the needle touch any-
thing. With the needle pointing up, firmly push the injection button in as far
as it will go and hold for at least 5 seconds. A small stream of medicine must
come out of the end of the needle. If it does not, reset the dose by repeating
Step 8. Repeat these steps (Steps 8-9) until a small stream of medicine
comes out the end of the needle. When medicine comes out of the end of
the needle, the APOKYN Pen is primed for injection and ready to use.
APOKYN medicine can cause staining to fabric and other surfaces it touches.
Be careful where you prime the APOKYN Pen.
8
L
.06
15


10a.
L
0.1
Setting the Dose
Step 10. To set the dose, turn the white dose knob until the correct
dose (number of mLs) is shown in the window. The dose will
appear as a red number between two black lines that will line
up next to the letters “mL” on the pen body. Make sure the
correct number (dose) appears in the window.
10b.
2
1
1
2
2
16


Step 11. Dose Correction. If you turn the dose knob past your dose, do not
dial backwards. If you dial backwards, APOKYN will be pushed
through the needle and you will lose medicine. Continue to turn the
dial until it is fully turned. Press the injection button fully. This will
reset the dial to zero without pushing medicine out of the needle.
Repeat Step 10 to redial your dose.
11
L
0.6
0.5
–.56
–.46
–.54
–.64
17


Giving the Injection
Step 12. APOKYN is only for injection under the skin (subcutaneous injection).
Choose an injection site on your stomach area, upper arm or upper leg.
Change the site with each injection. Do not inject APOKYN into skin that
is red or sore.
Clean the site with an alcohol swab and allow to air dry. Pinch about an
inch of skin and fat tissue of your injection site between your thumb and
forefinger. With the other hand, insert the needle all the way into the
pinched skin.
Step 13. Fully push the teal injection button on the APOKYN Pen. A clicking sound
will be heard while the dose is injected. Push the injection button firmly
for 5 seconds. Remove the needle from your skin. If medicine keeps
dripping from the needle, keep the needle in the skin longer the next time
you inject APOKYN.
13
0
0
12
18


IMPORTANT – If you set your dose and cannot depress the teal injection button, the cartridge is
empty. Remove the pen needle and cartridge and prepare the pen as described in Steps 2-9 with a
new cartridge. Set the dose and give the injection.  
If you set your dose and the injection button stops before you receive a complete dose, note the
number in the window, remove the pen needle and cartridge, and prepare the pen as described in
Steps 2-9 with a new cartridge. Set the dose to the number that last appeared in the window and
administer the injection. This completes the dose.
Before attempting to replace a cartridge, be sure that a needle unit is not attached to the 
APOKYN Pen.
19


Removing the Pen Needle
Step 14. Carefully replace the outer needle shield. Be careful to avoid a
needle-stick. Place the outer needle shield in the notch located on
the far left side of your carrying case. The opening of the needle
shield should be pointing up. Carefully insert the needle (attached
to the pen) into the opening of the shield. Without holding onto
the shield, push down firmly. 
1414
20


Step 15. Hold the pen by the teal cartridge holder and unscrew the pen
needle from the cartridge holder. Recap the pen. Never recap the
pen with a needle attached. Safely dispose of used pen needles
in a “sharps” container. Your specialty pharmacy provider will
provide you with a “sharps” container. Do not throw used
needles in a trash can.
   15
Storage Information
–Store APOKYN cartridges at room temperature, 68°F to 77°F (20°C to 25°C)
Excursions permitted to 59 to 86°F (15 to 30°C) [See USP Controlled Room Temperature]
21


Proper Disposal
◆Put your used needles and syringes in an FDA-cleared sharps disposal container right away after
use. Do not throw away (dispose of) loose needles and syringes in your household trash.
◆If you do not have an FDA-cleared sharps disposal container, you may use a household container
that is:
– made of a heavy-duty plastic
– able to be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out
– upright and stable during use
– leak-resistant
– properly labeled to warn of hazardous waste inside the container
22


◆When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be state or
local laws about how you should throw away used needles and syringes. For more information
about safe sharps disposal, and for specific information about sharps disposal in the state that
you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
◆Do not dispose of your used sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your used sharps disposal container.
23


Care and Storage
The APOKYN Pen can now be stored in its carrying case. Never store or carry the APOKYN Pen with
a pen needle attached.
You must store and care for your pen the right way:
◆Avoid exposure to dust, moisture, and cold or hot temperatures.
◆Never wash the pen in water or use strong disinfectants. Only a clean, damp cloth should be used
for cleaning.
◆Do not try to repair the pen if it is damaged or if you cannot solve a problem shown in the
following “Troubleshooting” section.
◆Do not use pen for more than 1 year after the first use or after the expiration date on the carton. 
For more information, call your specialty pharmacy provider or 1-877-7APOKYN (727-6596).
24


Troubleshooting
Replace the cartridge as described in Steps 3-5.
Replace the pen needle as described in Steps 14 & 6-7.
Turn the dial past the highest setting on the pen.
Wipe all exposed pen surfaces with a clean, 
damp cloth.
PROBLEM
POSSIBLE CAUSE
HOW TO FIX THE PROBLEM
No medicine comes out of the pen (the
dosage dial moves freely, but no click is
heard).
The dosage dial does not return to zero
during an injection.
The dosage dial does not turn easily.
Pen does not close.
The pen is in dose correction mode.
The cartridge is empty.
The pen needle is clogged.
Cartridge is inserted incorrectly.
Dust or dirt is on the pen.
Push the injection button all the way in so the
dial returns to zero. 
Remove cartridge and reload it. See Steps 3-4.
25


Troubleshooting
PROBLEM
Injection button will not depress.
Injection button stops before a
complete dose is delivered.
Pen does not work.
Dose numbers and/or white
markers wear off.
Cartridge is empty.
Not enough medication in
cartridge to complete the dose.
Repeated use over extended
period of time.
Mechanical failure.
POSSIBLE CAUSE
HOW TO FIX THE PROBLEM
Replace cartridge. See Steps 3-5.
Replace cartridge. See Steps 3-5.
Replace pen.
Call your specialty pharmacy provider or
1-877-7APOKYN (727-6596).
Replace pen.
Call your specialty pharmacy provider or
1-877-7APOKYN (727-6596).
26


Troubleshooting
For more information, call your specialty pharmacy provider or 1-877-7APOKYN (727-6596).
PROBLEM
Too much force needed to depress
injection button.
Unable to read the dose numbers through
the dose window.
Defective cartridge.
Incorrect cleaning or improper
handling.
POSSIBLE CAUSE
HOW TO FIX THE PROBLEM
Replace cartridge. See Steps 3-5.
Replace pen.
Call your specialty pharmacy provider or
1-877-7APOKYN (727-6596).
27


Patient Information
APOKYN
® (AY-po-kin) (apomorphine hydrochloride injection)
Read this Patient Information before you start using APOKYN and each time you get a refill. There may be new
information. This information does not take the place of talking to your healthcare provider about your medical
condition or your treatment.
What is APOKYN?
APOKYN is a prescription medicine used to treat acute, intermittent episodes of poor mobility called
“off” episodes (end-of-dose wearing “off” or unpredictable “on-off” episodes) in people with advanced
Parkinson’s disease (PD).
It is not known if APOKYN is safe and effective in children.
28


Who should not take APOKYN?
Do not take APOKYN if you are:
• taking certain medicines to treat nausea called 5HT3 antagonists including, ondansetron, granisetron, dolasetron,
palonosetron, and alosetron. People taking ondansetron together with apomorphine, the active ingredient in
APOKYN, have had very low blood pressure and lost consciousness or “blacked out.”
• allergic to apomorphine hydrochloride or to any of the ingredients in APOKYN and experience hives, itching, rash,
or swelling (e.g., eyes, tongue, etc.). APOKYN also contains a sulfite called sodium metabisulfite. Sulfites can
cause severe, life-threatening allergic reactions in some people. An allergy to sulfites is not the same as an allergy
to sulfa. People with asthma are more likely to be allergic to sulfites. Call your healthcare provider if you have
hives, itching, rash, swelling of the eyes, tongue, lips, chest pain, trouble breathing or swallowing. See the end of
this leaflet for a complete list of ingredients in APOKYN.
29


What should I tell my healthcare provider before taking APOKYN?
Before you start using APOKYN, tell your healthcare provider if you:
• have difficulty staying awake during the daytime
• have dizziness
• have fainting spells
• have low blood pressure
• have asthma
• are allergic to any medicines containing sulfites
• have liver problems
• have kidney problems
• have heart problems
• have had a stroke or other brain problems
• have a mental problem called a major psychotic disorder
30


• drink alcohol
• are pregnant or plan to become pregnant. It is not known if APOKYN will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if APOKYN passes into your breast milk. You and your
healthcare provider should decide if you will take APOKYN or breastfeed. You should not do both.
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription
medicines, vitamins, and herbal supplements.
Using APOKYN with certain other medicines may affect each other. Using APOKYN with other medicines can cause
serious side effects.
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a
new medicine.
31


How should I use APOKYN?
• Read the Instructions for Use starting on page 6 of this leaflet for specific information about the right way
to use APOKYN.
• Use APOKYN exactly as your healthcare provider tells you to use it.
• Your healthcare provider will tell you how much APOKYN to use and teach you the right way to use it.
• Your healthcare provider may change your dose if needed.
• Do not change your dose of APOKYN or use it more often than prescribed unless your healthcare provider has told
you to.
• Do not give another dose of APOKYN sooner than 2 hours after the last dose.
• Your healthcare provider will prescribe APOKYN that comes in prefilled glass cartridges that are used with a special
multiple-dose injector pen.
• Your APOKYN pen is dosed in milliliters (mL), not milligrams (mg). Make sure your prescription tells you how
many milliliters (mL) to use.
• Inject APOKYN under your skin (subcutaneously). Do not inject APOKYN into a vein.
32


• Keep a record of how much APOKYN you have used each time you inject or your care partner gives you
an injection.
• Use a new needle with each injection. Never reuse a needle.
• APOKYN is a clear and colorless liquid. Do not use APOKYN if it appears cloudy, colored, or to contain particles,
and call your pharmacist.
• Your healthcare provider may prescribe another medicine called an antiemetic to take while you are using APOKYN.
Antiemetic medicines help to decrease the symptoms of nausea and vomiting that can happen with APOKYN.
• If you take too much APOKYN, call your healthcare provider. If you experience severe or serious side effects such as
chest pain or prolonged erection lasting more than 4 hours, go to the nearest hospital emergency room.
What should I avoid while using APOKYN?
• Do not drink alcohol while you are using APOKYN. It can increase your chance of developing serious side effects.
• Do not take medicines that make you sleepy while you are using APOKYN.
33


• Do not drive, operate machinery, or do other dangerous activities until you know how APOKYN affects you.
• Do not change your body position too fast. Get up slowly from sitting or lying. APOKYN can lower your blood
pressure and cause dizziness or fainting.
What are the possible side effects of APOKYN?
APOKYN may cause serious side effects. Call your healthcare provider right away if you have any of the serious
side effects, including:
• allergic reaction. An allergic reaction with side effects of hives, itching, rash, swelling (e.g., eyes, tongue, etc.);
trouble breathing and/or swallowing may occur after injecting APOKYN.
• blood clots. Injecting APOKYN into a vein (intravenous) can cause blood clots. Do not inject APOKYN in your vein.
• nausea and vomiting. Severe nausea and vomiting can happen with APOKYN. Your healthcare provider may
prescribe a medicine called trimethobenzamide (Tigan
®) to help prevent nausea and vomiting. Some patients can
stop taking Tigan after using APOKYN for several months. Some patients may need to keep taking Tigan to help
prevent nausea and vomiting. Talk to your healthcare provider before you stop taking Tigan.
34


• sleepiness or falling asleep during the day.Some people treated with APOKYN may get sleepy during the day or
fall asleep without warning while doing everyday activities such as talking, eating, or driving a car.
• dizziness. APOKYN can lower your blood pressure and cause dizziness. Dizziness can happen when APOKYN
treatment is started or when the APOKYN dose is increased. Do not get up too fast from sitting or after lying down,
especially if you have been sitting or lying down for a long period of time.
• falls. The changes that can happen with Parkinson’s disease (PD), and the effects of some PD medicines, can
increase the risk of falling. APOKYN may also increase your risk of falling.
• hallucinations or psychotic-like behavior. APOKYN can cause or worsen psychotic-like behavior including
hallucinations (seeing or hearing things that are not real), confusion, excessive suspicion, aggressive behavior,
agitation, delusional beliefs (believing things that are not real), and disorganized thinking.
• sudden uncontrolled movements (dyskinesias). Some people with PD may get sudden, uncontrolled movements
after treatment with some PD medicines. APOKYN can cause or make dyskinesias worse.
• intense urges. Some people with PD have reported new or increased gambling urges, increased sexual urges, and
other intense urges, while taking PD medicines, including APOKYN.
35


36
• heart problems. If you have shortness of breath, fast heartbeat, or chest pain while taking APOKYN, call your
healthcare provider or get emergency help right away.
• serious heart rhythm changes (QT prolongation). Tell your healthcare provider right away if you have a change in
your heartbeat (a fast or irregular heartbeat), or if you faint.
• injection site problems. Bruising, swelling, and itching can happen at the site where you inject APOKYN.
• fever and confusion. This can happen in some people when their PD medicine is stopped or there is a fast
decrease in the dose of their PD medicine.
• skin cancer (melanoma). Some people with PD may have an increased chance of getting a skin cancer called
melanoma. People with PD should have a healthcare provider check their skin for skin cancer regularly.
• tissue changes (fibrotic complications). Some people have had changes in the tissues of their pelvis, lungs, and
heart valves when taking medicines called nonergot derived dopamine agonists like APOKYN.
• prolonged painful erections (priaprism). APOKYN may cause prolonged, painful erections in some people. If you
have an erection that lasts more than 4 hours you should call your healthcare provider or go to the nearest hospital
emergency room right away.


• swelling of ankles/legs. APOKYN may cause swelling, especially in the ankles or legs. Tell your healthcare provider
if you notice any swelling.
Other common side effects of APOKYN include:
• yawning
• runny nose
• confusion
• swelling of your hands, arms, legs, and feet
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of APOKYN. For more information, ask your healthcare provider
or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
37


How should I store APOKYN?
• Store APOKYN at room temperature, 68°F to 77°F (20°C to 25°C).
• Safely throw away medicine that is out of date or no longer needed.
Keep APOKYN and all medicines out of the reach of children.
General information about the safe and effective use of APOKYN.
Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use
APOKYN for a condition for which it was not prescribed. Do not give APOKYN to other people, even if they have the
same symptoms that you have. It may harm them.
This Patient Information leaflet summarizes the most important information about APOKYN. If you would like more
information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information
about APOKYN that is written for health professionals.
For more information, go to www.apokyn.com or call 1-877-727-6596.
38


What are the ingredients in APOKYN?
Active ingredient: apomorphine hydrochloride, USP
Inactive ingredients: sodium metabisulfite, NF, benzyl alcohol, NF, water for injection, USP. It may also contain
sodium hydroxide, NF and/or hydrochloric acid, NF.
This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.
39
Distributed by: US WorldMeds, LLC
Louisville, KY 40207
Revised: July 2014


INS10001.01
US WorldMeds, LLC is the exclusive licensee and distributor
of APOKYN in the United States and Its territories.
© 2015 Britannia Pharmaceuticals Limited. APOKYN is a
registered trademark of Britannia Pharmaceuticals Limited.
BD and BD Logo are trademarks of Becton, Dickinson and Company.
©2015 BD
BD Medical  
1 Becton Drive
Franklin Lakes, NJ 07417, USA
Pharmaceutical Systems  


Sunovion Pharmaceuticals Inc.  
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
19.3. 
APPENDIX III: APO-go® Summary of Product Characteristics 


APO-go Pen 10mg/ml Solution for Injection
Summary of Product Characteristics Updated 04-Jan-2017 | Britannia Pharmaceuticals Limited
1. Name of the medicinal product
APO-go PEN 10 mg/ml Solution for Injection*
* Abbreviated to APO-go Pen in the text
2. Qualitative and quantitative composition
1ml contains 10mg apomorphine hydrochloride
Each 3ml PEN contains 30mg apomorphine hydrochloride
Excipient: Sodium bisulphite 0.93mg per ml
For a full list of excipients, see Section 6.1
3. Pharmaceutical form
Solution for injection.
The solution is clear, practically colourless, odourless and free from visible particles.
pH = 3.0 to 4.0
4. Clinical particulars
4.1 Therapeutic indications
The treatment of motor fluctuations ('on-off' phenomena) in patients with Parkinson's disease which are not 
sufficiently controlled by oral anti-Parkinson medication.
4.2 Posology and method of administration
Selection of patients suitable for APO-go injections:
Patients selected for treatment with APO-go should be able to recognise the onset of their 'off' symptoms and be 
capable of injecting themselves or else have a responsible carer able to inject for them when required.
Patients treated with apomorphine will usually need to start domperidone at least two days prior to initiation of 
therapy. The domperidone dose should be titrated to the lowest effective dose and discontinued as soon as 
possible. Before the decision to initiate domperidone and apomorphine treatment, risk factors for QT interval 
prolongation in the individual patient should be carefully assessed to ensure that the benefit outweighs the risk (see 
section 4.4).
Apomorphine should be initiated in the controlled environment of a specialist clinic. The patient should be 
supervised by a physician experienced in the treatment of Parkinson's disease (e.g. neurologist). The patient's 
treatment with levodopa, with or without dopamine agonists, should be optimised before starting APO-go treatment.
Adults
Administration
APO-go Pen 10mg/ml Solution for Injection is for subcutaneous use by intermittent bolus injection.
Apomorphine must not be used via the intravenous route. 
Do not use if the solution has turned green. The solution should be inspected visually prior to use. Only clear, 
colourless and particle free solution should be used.
Determination of the threshold dose.
The appropriate dose for each patient is established by incremental dosing schedules. The following schedule is 
suggested:
1mg of apomorphine HCl (0.1ml), that is approximately 15-20 micrograms/kg, may be injected subcutaneously during 
a hypokinetic, or 'off' period and the patient is observed over 30 minutes for a motor response.
If no response, or an inadequate response, is obtained a second dose of 2 mg of apomorphine HCl (0.2ml) is injected 
subcutaneously and the patient observed for an adequate response for a further 30 minutes.
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The dosage may be increased by incremental injections with at least a forty minute interval between succeeding 
injections, until a satisfactory motor response is obtained.
Establishment of treatment.
Once the appropriate dose is determined a single subcutaneous injection may be given into the lower abdomen or 
outer thigh at the first signs of an 'off' episode. It cannot be excluded that absorption may differ with different injection 
sites within a single individual. Accordingly, the patient should then be observed for the next hour to assess the quality 
of their response to treatment. Alterations in dosage may be made according to the patient's response.
The optimal dosage of apomorphine hydrochloride varies between individuals but, once established, remains 
relatively constant for each patient.
Precautions on continuing treatment.
The daily dose of APO-go varies widely between patients, typically within the range of 3-30mg, given as 1-10 
injections and sometimes as many as 12 separate injections per day.
It is recommended that the total daily dose of apomorphine HCl should not exceed 100mg and that individual bolus 
injections should not exceed 10mg.
In clinical studies it has usually been possible to make some reduction in the dose of levodopa; this effect varies 
considerably between patients and needs to be carefully managed by an experienced physician.
Once treatment has been established domperidone therapy may be gradually reduced in some patients but 
successfully eliminated only in a few, without any vomiting or hypotension.
Children and adolescents:
APO-go Pen 10mg/ml Solution for Injection is contra-indicated for children and adolescents under 18 years of age 
(see section 4.3).
Elderly:
The elderly are well represented in the population of patients with Parkinson's disease and constitute a high 
proportion of those studied in clinical trials of APO-go. The management of elderly patients treated with APO-go has 
not differed from that of younger patients. However, extra caution is recommended during initiation of therapy in 
elderly patients because of the risk of postural hypotension.
Renal impairment:
A dose schedule similar to that recommended for adults, and the elderly, can be followed for patients with renal 
impairment (see section 4.4).
4.3 Contraindications
In patients with respiratory depression, dementia, psychotic diseases or hepatic insufficiency.
Apomorphine HCl treatment must not be administered to patients who have an 'on' response to levodopa which is 
marred by severe dyskinesia or dystonia.
APO-go should not be administered to patients who have a known hypersensitivity to apomorphine or any excipients
of the medicinal product.
APO-go is contraindicated for children and adolescents under 18 years of age.
4.4 Special warnings and precautions for use
Apomorphine HCl should be given with caution to patients with renal, pulmonary or cardiovascular disease and 
persons prone to nausea and vomiting.
Extra caution is recommended during initiation of therapy in elderly and/or debilitated patients. 
Since apomorphine may produce hypotension, even when given with domperidone pre-treatment, care should be 
exercised in patients with pre-existing cardiac disease or in patients taking vasoactive medicinal products such as 
anti-hypertensives, and especially in patients with pre-existing postural hypotension. 
Since apomorphine, especially at high dose, may have the potential for QT prolongation, caution should be exercised 
when treating patients at risk for torsades de pointes arrhythmia.
When used in combination with domperidone, risk factors in the individual patient should be carefully assessed. This 
should be done before treatment initiation, and during treatment. Important risk factors include serious underlying 
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heart conditions such as congestive cardiac failure, severe hepatic impairment or significant electrolyte disturbance. 
Also medication possibly affecting electrolyte balance, CYP3A4 metabolism or QT interval should be assessed. 
Monitoring for an effect on the QTc interval is advisable. An ECG should be performed: 
- prior to treatment with domperidone 
- during the treatment initiation phase 
- as clinically indicated thereafter
The patient should be instructed to report possible cardiac symptoms including palpitations, syncope, or near-
syncope. They should also report clinical changes that could lead to hypokalaemia, such as gastroenteritis or the 
initiation of diuretic therapy. 
At each medical visit, risk factors should be revisited.
Apomorphine is associated with local subcutaneous effects. These can sometimes be reduced by the rotation of 
injection sites or possibly by the use of ultrasound (if available) in order to avoid to areas of nodularity and induration.
Haemolytic anaemia and thrombocytopenia have been reported in patients treated with apomorphine. Haematology 
tests should be undertaken at regular intervals as with levodopa, when given concomitantly with apomorphine.
Caution is advised when combining apomorphine with other medicinal products, especially those with a narrow 
therapeutic range (see section 4.5).
Neuropsychiatric problems co-exist in many patients with advanced Parkinson's disease. There is evidence that for 
some patients neuropsychiatric disturbances may be exacerbated by apomorphine. Special care should be exercised 
when apomorphine is used in these patients.
Apomorphine has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with 
Parkinson's disease. Patients must be informed of this and advised to exercise caution whilst driving or operating 
machines during treatment with apomorphine. Patients who have experienced somnolence and/or an episode of 
sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dosage may be 
considered.
Impulse control disorders
Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should 
be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased 
libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients 
treated with dopamine agonists including apomorphine. Dose reduction/tapered discontinuation should be considered 
if such symptoms develop.
Dopamine dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in 
some patients treated with apomorphine. Before initiation of treatment, patients and caregivers should be warned of 
the potential risk of developing DDS.
APO-go Pen 10mg/ml Solution for Injection contains sodium bisulphite which may rarely cause severe allergic 
reactions and bronchospasm.
This medicinal product contains less than 1 mmol sodium (23 mg) per 10ml, i.e. essentially “sodium-free”.
4.5 Interaction with other medicinal products and other forms of interaction
Patients selected for treatment with apomorphine HCl are almost certain to be taking concomitant medications for 
their Parkinson's disease. In the initial stages of apomorphine HCl therapy the patient should be monitored for 
unusual side-effects or signs of potentiation of effect.
Neuroleptic medicinal products may have an antagonistic effect if used with apomorphine. There is a potential 
interaction between clozapine and apomorphine, however clozapine may also be used to reduce the symptoms of 
neuropsychiatric complications.
The possible effects of apomorphine on the plasma concentrations of other medicinal products have not been 
studied. Therefore caution is advised when combining apomorphine with other medicinal products, especially those 
with a narrow therapeutic range.
Antihypertensive and Cardiac Active Medicinal Drugs 
Even when co-administered with domperidone, apomorphine may potentiate the antihypertensive effects of these 
medicinal products (See section 4.4).
It is recommended to avoid the administration of apomorphine with other drugs known to prolong the QT interval.
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4.6 Fertility, pregnancy and lactation
There is no experience of apomorphine usage in pregnant women. 
Animal reproduction studies do not indicate any teratogenic effects, but doses given to rats which are toxic to the 
mother can lead to failure to breathe in the newborn. The potential risk for humans is unknown. See Section 5.3.
APO-go should not be used during pregnancy unless clearly necessary.
It is not known whether apomorphine is excreted in breast milk. A decision on whether to continue/discontinue 
breastfeeding or to continue/discontinue therapy with APO-go should be made taking into account the benefit of 
breast-feeding to the child and the benefit of APO-go to the woman.
4.7 Effects on ability to drive and use machines
Apomorphine HCl has minor or moderate influence on the ability to drive and use machines.
Patients being treated with apomorphine and presenting with somnolence and/or sudden sleep episodes must be 
informed to refrain from driving or engaging in activities (e.g. operating machines) where impaired alertness may put 
themselves or others at risk of serious injury or death until such recurrent episodes and somnolence have resolved 
(see Section 4.4). 
“This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is 
in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, 
patients should be told:
• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called 'statutory defence') if:
o The medicine has been prescribed to treat a medical or dental problem and
o You have taken it according to the instructions given by the prescriber and in the information provided with the 
medicine and
o It was not affecting your ability to drive safely”
4.8 Undesirable effects
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)
Blood and lymphatic system disorders 
Uncommon:
Haemolytic anaemia and thrombocytopenia have been reported in patients treated with apomorphine.
Rare:
Eosinophilia has rarely occurred during treatment with apomorphine HCl.
Immune system disorders 
Rare:
Due to the presence of sodium metabisulphite, allergic reactions (including anaphylaxis and bronchospasm) may 
occur.
Psychiatric disorders 
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Very Common:
Hallucinations 
Common:
Neuropsychiatric disturbances (including transient mild confusion and visual hallucinations) have occurred during 
apomorphine HCl therapy.
Not known:
Impulse control disorders: Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, 
binge eating and compulsive eating can occur in patients treated with dopamine agonists including apomorphine (see 
section 4.4).
Aggression, agitation
Nervous system disorders 
Common:
Transient sedation with each dose of apomorphine HCl at the start of therapy may occur; this usually resolves over 
the first few weeks.
Apomorphine is associated with somnolence.
Dizziness / light-headedness have also been reported.
Uncommon:
Apomorphine may induce dyskinesias during 'on' periods, which can be severe in some cases, and in a few patients 
may result in cessation of therapy.
Apomorphine has been associated with sudden sleep onset episodes (see section 4.4).
Not known:
Syncope
Vascular disorders 
Uncommon:
Postural hypotension is seen infrequently and is usually transient (see section 4.4).
Respiratory, thoracic and mediastinal disorders 
Common:
Yawning has been reported during apomorphine therapy.
Uncommon:
Breathing difficulties have been reported.
Gastrointestinal disorders 
Common:
Nausea and vomiting, particularly when apomorphine treatment is first initiated, usually as a result of the omission of 
domperidone (see section 4.2).
Skin and subcutaneous tissue disorders 
Uncommon:
Local and generalised rashes have been reported.
General disorders and administration site conditions 
Very common:
Most patients experience injection site reactions, particularly with continuous use. These may include subcutaneous 
nodules, induration, erythema, tenderness and panniculitis. Various other local reactions (such as irritation, itching, 
bruising and pain) may also occur.
Uncommon:
Injection site necrosis and ulceration have been reported.
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Not known:
Peripheral oedema has been reported.
Investigations 
Uncommon:
Positive Coombs' tests have been reported for patients receiving apomorphine.
Reporting of side effects
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued 
monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any 
suspected adverse reactions via the:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
HPRA Pharmacovigilance, 
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie
Malta
ADR Reporting
Website: www.medicinesauthority.gov.mt/adrportal
4.9 Overdose
There is little clinical experience of overdose with apomorphine by this route of administration. Symptoms of overdose 
may be treated empirically as suggested below:-
Excessive emesis may be treated with domperidone.
Respiratory depression may be treated with naloxone.
Hypotension: appropriate measures should be taken, e.g. raising the foot of the bed.
Bradycardia may be treated with atropine.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmatherapeutic group: Dopamine agonists
ATC Classification: N04B C07
Apomorphine is a direct stimulant of dopamine receptors and while possessing both D1 and D2 receptor agonist 
properties does not share transport or metabolic pathways with levodopa.
Although in intact experimental animals, administration of apomorphine suppresses the rate of firing of nigro-striatal 
cells and in low dose has been found to produce a reduction in locomotor activity (thought to represent pre-synaptic 
inhibition of endogenous dopamine release) its actions on parkinsonian motor disability are likely to be mediated at 
post-synaptic receptor sites. This biphasic effect is also seen in humans.
5.2 Pharmacokinetic properties
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After subcutaneous injection of apomorphine its fate can be described by a two-compartment model, with a 
distribution half-life of 5 (± 1.1) minutes and an elimination half-life of 33 (± 3.9) minutes. Clinical response correlates 
well with levels of apomorphine in the cerebrospinal fluid; the drug distribution being best described by a two- 
compartment model. Apomorphine is rapidly and completely absorbed from subcutaneous tissue, correlating with the 
rapid onset of clinical effects (4-12 minutes), and that the brief duration of clinical action of the drug (about 1 hour) is 
explained by its rapid clearance. The metabolism of apomorphine is by glucuronidation and sulphonation to at least 
ten per cent of the total; other pathways have not been described.
5.3 Preclinical safety data
Repeat- dose subcutaneous toxicity studies reveal no special hazard for humans, beyond the information included in 
other sections of the SmPC.
In vitro genotoxicity studies demonstrated mutagenic and clastogenic effects, most likely due to products formed by 
oxidation of apomorphine. However, apomorphine was not genotoxic in the in vivo studies performed.
The effect of apomorphine on reproduction has been investigated in rats. Apomorphine was not teratogenic in this 
species, but it was noted that doses which are toxic to the mother can cause loss of maternal care and failure to 
breathe in the newborn.
No carcinogenicity studies have been performed.
6. Pharmaceutical particulars
6.1 List of excipients
Sodium bisulphite (E222)
Hydrochloric Acid (37%), concentrated (to adjust pH to 3.0 –4.0)
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
2 years
48 hours after first opening.
6.4 Special precautions for storage
Do not store above 25°C.
Keep the container in the outer carton to protect from light.
The product should be stored at the same conditions after opening and between withdrawals.
6.5 Nature and contents of container
Cartridge.
APO-go Pen 10 mg/ml is a disposable multiple dose pen injector system incorporating a clear glass (type I) cartridge 
containing a clear solution for injection. The glass cartridge is sealed at one end with a bromobutyl rubber piston, and 
at the other end with a bromobutyl rubber/aluminium membrane. 
Each pen contains 3ml of solution for injection.
Packs containing 1, 5, or 10 x 3ml pens in a moulded plastic tray in an outer cardboard carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
APO-go PEN
Do not use if solution has turned green.
Discard each pen no later than 48 hours from first use.
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(see attached diagram)
* This pack does NOT contain needles for use with your Pen.
Use pen needles not more than 12mm (½”) in length and not finer than 0.33mm (29 G). Pen needles recommended 
for use with insulin pens are compatible with APO-go® Pen.
IMPORTANT: Do not pull the red capped dial (see 1) before you have set the dosage (see 'Selecting the 
correct dosage').
Attaching the needle
(a) Before using APO-go Pen you will need some surgical wipes and one needle in its protective cone (see 2). 
(b) Take the Pen out of its box and remove the outer sleeve (see 3).
(c) Wipe the membrane of the Pen (see 4) with a surgical wipe.
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(d) Peel off the paper from the needle cone (see 2).
(e) It is important to bring the needle to the Pen in a straight line, as shown above. If the needle is presented at an 
angle it may cause the Pen to leak.
(f) Screw the cone (see 2) clockwise onto the membrane until it is tight. This securely attaches the needle.
(g) Remove the protective cone (see 5), but do not throw it away. Do not remove the needle protector (see 6) at this 
stage.
(h) Replace the Pen's outer sleeve (see 3).
Selecting the correct dose
(i) Press the red capped dosage dial (see 1) and whilst holding it down, turn the dial clockwise until the arrow points to 
the dose your doctor chose for you (see 7&8). Release the downward pressure on the red capped dial. The dose is 
now set and you do not need to redial for subsequent injections.
Important: If you pass your prescribed dose while turning the dial, just continue pressing and turning in the same 
direction until the arrow points to the dose your doctor chose for you.
Never pull and turn the red capped dosage dial at the same time.
If your dose is 1 mg, start by emptying a 1 mg dose onto a paper tissue and discarding it. This is called 'priming' and 
is important because it ensures you get a full dose the first time you use your Pen. Then, set the dose you require for 
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injection and inject it in the usual way (see “Injecting”). If the first dose required is more than 1 mg, you do not need to 
prime the Pen.
Injecting
(j) Once you have set the dose, gently pull out the red capped dosage dial as far as it will go. Check the red scale on 
the plunger (see 9) and inject only if the line that is just visible matches the intended dose.
(k) Using a surgical wipe, clean the area of skin where you plan to inject the medicine and around it.
(l) Remove the Pen's outer sleeve (see 3).
(m) Remove the needle protector (see 6).
(n) Insert the needle (see 10) into the skin as shown by your doctor.
(o) To inject, press the red capped dosage dial (see 1) down as far as it will go, using your thumb if possible. Once 
the red capped dosage dial is fully depressed, count to three before withdrawing the needle.
(p) Replace the protective cone (see 5) onto the used needle and push gently into place. Once secure, turn the 
needle anti-clockwise to unscrew it. 
Keep the needle in its protective cone and discard it in a safe place, such as a “Sharps” bin or an empty coffee jar.
Preparing for the next injection
(q) Remove the outer sleeve of the Pen and check there is enough apomorphine left in the cartridge for your next 
injection. If there is, put a new needle in place in the same way as before.
(r) If there is not enough apomorphine left for another injection, prepare another pen.
(s) Finally, replace the outer sleeve of your Pen.
7. Marketing authorisation holder
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Address
200 Longwater Avenue, Green Park, Reading, 
Berkshire, RG2 6GP, UK
Medical Information Direct Line
+44 (0)870 851 0207
Telephone
+44 1189209500
Medical Information e-mail
enquiries@medinformation.co.uk
Britannia Pharmaceuticals Limited
200 Longwater Avenue,
Green Park,
Reading,
Berkshire
RG2 6GP
United Kingdom
8. Marketing authorisation number(s)
PL 04483/0073
PA 356/10/1
MA 957/00102
9. Date of first authorisation/renewal of the authorisation
31 March 1999 / 27 July 2009
10. Date of revision of the text
10/2016
Company Contact Details
Britannia Pharmaceuticals Limited
http://www.britannia-pharm.co.uk/
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Sunovion Pharmaceuticals Inc.  
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
19.4. 
APPENDIX IV: Regulations and Guidelines 
19.4.1. 
Declaration of Helsinki 
The Policy of the World Medical Association is available at URL: https://www.wma.net/policies-
post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-
subjects/ 
19.4.2. 
Approval by an IRB/REB/IEC 
This protocol must be reviewed and approved by a valid IRB/REB/IEC prior to initiation of the 
study. Written notification of approval is to be submitted by the Investigator to Sunovion 
monitor prior to shipment of investigational drug supplies, and will include the date of the 
committee's approval and the chairperson's signature. This written approval will consist of a 
completed Institutional Review Board Approval form or Research Ethics Board Approval form, 
or written documentation from the IRB or REB containing the same information. 
Until written approval by the IRB/REB/IEC has been received by the Investigator, no subject 
may undergo any procedure solely for determining eligibility for this study. 
Protocol amendments must also be reviewed and approved by the IRB/REB/IEC. Written 
approval from the IRB/REB/IEC, or a designee, must be received by Sunovion, before 
implementation. This written approval will consist of a completed approval form, or written 
documentation from the IRB/REB/IEC containing the same information. 
19.4.3. 
Regulatory Authority/Agency 
For Investigational New Drug (IND) studies, the minimum standards of study conduct and 
requirements for informed consent are defined in the applicable regulations of the country in 
which the study is conducted. 
This protocol must be reviewed and approved by the country specific Regulatory 
Authority/Agency prior to initiation of the study. The Sponsor or authorized delegate will be 
responsible for the submission.  
 
 
 


Sunovion Pharmaceuticals Inc.  
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
19.5. 
APPENDIX V: Modified Hoehn and Yahr Scale 
Modified Hoehn & Yahr 
0: 
Asymptomatic. 
1:  
Unilateral involvement only. 
1.5:  
Unilateral and axial involvement 
2:  
Bilateral involvement without impairment of balance. 
2.5:  
Mild bilateral disease with recovery on pull test. 
3:  
Mild to moderate involvement; some postural instability but physically 
independent; needs assistance to recover from pull test. 
4:  
Severe disability; still able to walk or stand unassisted. 
5:  
Wheelchair bound or bedridden unless aided. 
 
 
 


Sunovion Pharmaceuticals Inc.  
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
19.6. 
APPENDIX VI: Columbia Suicide Severity Rating Scale (C-SSRS) 
 
 
 


 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Screening 
Version 1/14/09 
 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Past  
X Months 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
 
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…..and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe). Ask about time he/she was feeling the most suicidal.  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Screening (Version 1/14/09)    
 
 
                                             Page 1 of 2 


SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Past X Years 
or 
Lifetime  
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly lethal 
act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if 
someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get sympathy, 
or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes    No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck 
but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you actually did 
anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a specific 
method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Answer for Actual Attempts Only 
Most Recent  
Attempt 
Date: 
Most Lethal         
Attempt 
Date: 
Initial/First  
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with 
reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-
degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, 
had potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; 
laying on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Screening (Version 1/14/09)    
 
 
                                             Page 2 of 2 


 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Since Last 
Visit 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe).  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time                                                                    
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit (Version 1/14/09)    
 
 
                          Page 1 of 2       


SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Suicide: 
   Yes    No 
□   □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns 
less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit (Version 1/14/09)    
 
 
                          Page 2 of 2                  


Sunovion Pharmaceuticals Inc.  
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
19.7. 
APPENDIX VII: United Kingdom Parkinson’s Disease Brain Bank 
Clinical Diagnostic Criteria 
Step 1 - Diagnosis of Parkinsonian Syndrome 
• Bradykinesia 
• At least one of the following 
− Muscular rigidity 
− 4-6 Hz rest tremor 
− Postural instability not caused by primary visual, vestibular, cerebellar, or 
proprioceptive dysfunction 
Step 2 - Exclusion criteria for PD 
• History of repeated strokes with stepwise progression of Parkinsonian features 
• History of repeated head injury 
• History of definite encephalitis 
• Oculogyric crises 
• Neuroleptic treatment at onset of symptoms 
• Sustained remission 
• Strictly unilateral features after 3 years 
• Supranuclear gaze palsy 
• Cerebellar signs 
• Early severe autonomic involvement 
• Early severe dementia with disturbances of memory, language, and praxis 
• Babinski sign 
• Presence of cerebral tumor or communication hydrocephalus on imaging study 
• Negative response to large doses of L-Dopa in absence of malabsorption 
• MPTP exposure 
Step 3 - Supportive prospective positive criteria for PD 
Three or more required for diagnosis of definite Parkinson’s disease in combination with step 
one 
• Unilateral onset 
• Rest tremor present 
• Progressive disorder 
• Persistent asymmetry affecting side of onset most 


Sunovion Pharmaceuticals Inc.  
CTH-203 
10 May 2017 
CONFIDENTIAL 
Version 2.00 
• Excellent response (70-100%) to L-Dopa 
• Severe L-Dopa-induced chorea 
• L-Dopa response for 5 years or more 
• Clinical course of ten years or more 
 
Reference: Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of 
idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg 
Psychiatry. 1992;55(3):181-4. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03   
  INC Research © LLC 
Page 1 of 45 
Sponsor Name:
Sunovion Pharmaceuticals Inc. 
Protocol Number and Title:
CTH-203: A Comparative Bioavailability Study 
to Evaluate the Single Dose Pharmacokinetic 
Properties of APL-130277 with Two Different 
Formulations of Subcutaneous Apomorphine in 
a Randomized, 3-Period Crossover Design in 
Subjects with Parkinson’s Disease Complicated 
by Motor Fluctuations (“OFF” Episodes) 
Protocol Version and Date:
Version 2.0 10 May 2017
INC Research Project Code:
1009488
Author(s): 
Lead Biostatistician 
SAP Version: 
1.0
SAP Version Date: 
7 January, 2019
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Sunovion 
Pharmaceuticals Inc. Acceptance of this document constitutes agreement by the recipient that 
no information contained herein will be published or disclosed without prior written 
authorization from an official of Sunovion Pharmaceuticals Inc.  However, this document may be 
disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized 
representatives of a national regulatory authority under the condition that they are requested to 
keep it confidential. In the event of an actual or suspected breach of this obligation, INC 
Research should be notified promptly. 


Statistical Analysis Plan 
Protocol # CTH-203
Version 1.0 
INC Research #1009488
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 2 of 45 
Revision History 
 
Versio
n # 
Date 
(dd-mmm-yyyy) 
Document 
Owner 
Revision Summary 
V0.1 
16May2017 
 
Initial Release Version 
V1.0 
 
 
Final Version
 
 


Statistical Analysis Plan 
Protocol # CTH-203
Version 1.0 
INC Research #1009488
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
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I confirm that I have reviewed this document and agree with the content. 
 
APPROVALS
INC Research
 
Lead Biostatistician  
 
Date (dd-Mmm-yyyy) 
Senior Reviewing Biostatistician 
 
Date (dd-Mmm-yyyy) 
Sunovion Pharmaceuticals, Inc.
 
Assoc. Dir., Biostatistics 
 
Date (dd-Mmm-yyyy) 
Sr. Dir., Biostatistics 
Date (dd-Mmm-yyyy) 
Sr. Dir. Clinical Development 
Date (dd-Mmm-yyyy) 
PK Scientist 
Assoc. Director, Clinical Pharmacology/TMED 
Date (dd-Mmm-yyyy) 
 
 
 


Statistical Analysis Plan 
Protocol # CTH-203
Version 1.0 
INC Research #1009488
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 4 of 45 
TABLE OF CONTENTS 
Contents 
 
GLOSSARY OF ABBREVIATIONS ................................................................. 7 
 
PURPOSE ........................................................................................................ 9 
 
Responsibilities ................................................................................................................... 9 
 
Timings of Analyses ............................................................................................................ 9 
 
STUDY OBJECTIVES ................................................................................... 10 
 
Primary Objective .............................................................................................................. 10 
 
Secondary Objective ......................................................................................................... 10 
 
Brief Description ................................................................................................................ 10 
 
Subject Selection ............................................................................................................... 12 
 
Determination of Sample Size .......................................................................................... 12 
 
Treatment Assignment & Blinding ................................................................................... 12 
 
Study Procedures .............................................................................................................. 13 
 
ENDPOINTS .................................................................................................. 14 
 
Pharmacokinetic Endpoints ............................................................................................. 14 
 
Safety Endpoints ................................................................................................................ 14 
 
ANALYSIS POPULATIONS .......................................................................... 15 
 
Safety Population ............................................................................................................... 15 
 
Pharmacokinetic Population ............................................................................................ 15 
 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 16 
 
General Methods ................................................................................................................ 16 


Statistical Analysis Plan 
Protocol # CTH-203
Version 1.0 
INC Research #1009488
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 5 of 45 
 
Key Definitions ................................................................................................................... 16 
 
Baseline ....................................................................................................................... 16 
 
Study Day .................................................................................................................... 16 
 
Missing Data ....................................................................................................................... 17 
 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION................................................................................................. 18 
 
Subject Disposition and Withdrawals .............................................................................. 18 
 
Demographic and Other Baseline Characteristics ......................................................... 18 
 
Medical History and Concomitant Diseases ................................................................... 19 
 
Medication .......................................................................................................................... 19 
 
Prior Medication .......................................................................................................... 19 
 
Concomitant Medication .............................................................................................. 19 
 
Medications with Missing or Incomplete Start/End Date ............................................. 20 
 
ANALYSIS OF PHARMACOKINETICS ........................................................ 21 
 
PK sampling schedule....................................................................................................... 21 
 
Plasma PK endpoint .......................................................................................................... 21 
 
Handling of Dropouts, Missing Data or Data Below the Lower Limit of Quantification
 
24 
 
PK Concentration Analysis ............................................................................................... 25 
 
PK Parameter Analysis ..................................................................................................... 25 
 
SAFETY ......................................................................................................... 27 
 
Study Drug Exposure ........................................................................................................ 27 
 
Adverse Events .................................................................................................................. 27 
 
Adverse Event with Missing or Incomplete Start/End Date ........................................ 28 
 
Laboratory Evaluations ..................................................................................................... 29 
 
Vital Signs ........................................................................................................................... 29 
 
ECG ..................................................................................................................................... 29 
 
Physical Examination ........................................................................................................ 30 


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Other Safety Variables....................................................................................................... 30 
  INTERIM ANALYSES .................................................................................... 31 
  CHANGES FROM ANALYSIS PLANNED IN PROTOCOL ........................... 32 
REFERENCE LIST ............................................................................................... 33 
  PROGRAMMING CONSIDERATIONS .......................................................... 34 
 
General Considerations .................................................................................................... 34 
 
Table, Listing, and Figure Format .................................................................................... 34 
 
General ........................................................................................................................ 34 
 
Headers ....................................................................................................................... 35 
 
Display Titles ............................................................................................................... 35 
 
Column Headers ......................................................................................................... 35 
 
Body of the Data Display ............................................................................................. 36 
 
Footnotes .................................................................................................................... 38 
  QUALITY CONTROL ..................................................................................... 39 
  INDEX OF TABLES ....................................................................................... 40 
  INDEX OF FIGURES ..................................................................................... 41 
  INDEX OF LISTINGS ..................................................................................... 42 
  APPENDICES ................................................................................................ 43 
 
 
 
 


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GLOSSARY OF ABBREVIATIONS 
 
Abbreviation 
Description 
λz 
Terminal Elimination Rate Constant 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
AUClast 
Area Under the Concentration-time Curve From Time Zero to 
the Last Measurable Plasma Concentration Using the Linear-Up 
Log-Down Trapezoidal Rule 
AUCinf 
Area Under the Concentration-time Curve From Time Zero 
Extrapolated to Infinity Using the Linear-Up Log-Down 
Trapezoidal Rule 
BMI 
Body Mass index 
BP  
Blood Pressure 
CI 
Confidence Interval 
CL/F 
Apparent Total Clearance of the Drug From Plasma After Oral 
or Subcutaneous Administration 
Cmax 
Maximum Observed Plasma Concentration 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
EOS 
End of Study 
FDA 
Food and Drug Administration 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IWRS 
Interactive Web Response System 
L-Dopa 
Levodopa 
Max 
Maximum 


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Abbreviation 
Description 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
MMSE 
Mini–Mental State Examination 
MRT 
Mean Residence Time 
P1 
Period 1 
P2 
Period 2 
P3 
Period 3 
PD 
Parkinson’s Disease 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
QTc 
Corrected QT Interval 
QTcB 
QT Corrected with Bazett’s Formula 
QTcF 
QT Corrected with Fridericia’s Formula 
RR 
Respiration Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
s.c. 
Subcutaneous 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SV 
Screening Visit 
t½ 
Terminal Phase Half-Life 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Table, Listing and Figure 
Tmax 
Time at which the highest drug concentration occurs after 
administration of an extravascular dose 
V/F 
Apparent 
Volume 
of 
Distribution 
after 
extravascular 
Administration 
WHO 
World Health Organization 
 


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PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives.   
 
RESPONSIBILITIES 
INC Research will perform the statistical analyses and are responsible for the production 
and quality control of all tables, figures and listings. Pharmacokinetic parameters will be 
derived by Nuventra Pharma Sciences (Nuventra) and will be provided to INC Research. 
 
TIMINGS OF ANALYSES 
All final planned analyses identified in this SAP will be performed by INC Research 
Biostatistics following Sunovion’s authorization of this Statistical Analysis Plan, and after 
the database lock.  


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STUDY OBJECTIVES 
 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate the pharmacokinetics (PK) and 
comparative bioavailability of apomorphine and its metabolites (apomorphine sulfate 
and norapomorphine) following single doses of APL-130277 sublingual thin film with 
subcutaneous (s.c.) APO-go® and s.c. APOKYN® in subjects with Parkinson’s disease (PD) 
complicated by motor fluctuations (“OFF” Episodes). 
 
SECONDARY OBJECTIVE 
The secondary objective of this study is to evaluate the safety and tolerability of the 
study drugs. 
 
BRIEF DESCRIPTION 
This is a multi-center, Phase 2, open-label, randomized, three-way crossover study 
designed to evaluate the PK and comparative bioavailability of a single dose of APL-
130277 sublingual thin film with s.c. APO-go® and s.c. APOKYN® in subjects with PD.  
 
This study will commence with an initial Screening Visit, followed by an open-label, 
randomized, three-way crossover (Period 1, Period 2, Period 3). Subjects will receive all 
three treatment arms with a minimum 1-day wash-out period between each visit 
(excluding the screening visit). 
 
Screening Visit 
Before any study procedures are performed on any person, informed consent must be 
obtained. Subjects who have provided full consent to participate, will arrive at the 
clinic having taken their usual morning dose of PD medications; but before taking their 
next dose of medication. Their normally scheduled second dose of L-Dopa (without 
adjunctive PD medication) will be administered in the clinic following confirmation of 
an “OFF” episode by the Investigator, to ensure the subject experiences an “ON” 
response. Eligibility criteria will be assessed by the Investigator. Subjects who are 
considered eligible, will be scheduled for the Period 1 Visit. 
 
Wash-Out Period 
One (1) day prior to the Period 1 Visit, at a minimum, subjects will be required to 
discontinue use of subcutaneous APOKYN®; this is referred to as the wash-out period. L-
Dopa and any other adjunctive PD medication will be permitted during this time. A one 
(1) day wash-out period will be required prior to each subsequent visit (Period 2, Period 
3, End of Study Visit). 
 
 
 
 


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Three-Way Open-Label Randomized Crossover (Period 1, Period 2, Period 3) 
Subjects will be asked to return to the clinic the morning of Period 1 (P1) after their 
usual morning dose of PD medications; but before taking their next dose of medication 
and will be randomized to one of the 6 treatment sequences. 
 
Subjects will be required to wait to take their normally scheduled second dose of PD 
medications until after confirmation by the Investigator that the subject is in the “OFF” 
state and will be dosed according to the randomized treatment sequence with either 
APL-130277, APO-go®, or APOKYN®. All PD medications should be held until 60 minutes 
after dosing. 
 
Following the same procedures described above, subjects will return to clinic within 3-5 
days after Period 1 and will be dosed for Period 2 (P2) with one of the other two 
treatments. Subjects will return to clinic within 3-5 days after Period 2 and will be 
dosed for Period 3 (P3) with the third and last treatment. 
 
Subjects will be randomly assigned to one of the following sequences, according to a 
William’s design: 
 
 
Treatment Arms: 
1. APL-130277 sublingual thin film 
2. Subcutaneous APO-go® 
3. Subcutaneous APOKYN® 
APL-130277 and APO-go® dosing in the Three-Way Crossover will be based on the 
subjects’ current prescribed dose of APOKYN®. 
 
 
 
Period 1 
Period 2
Period 3 
Sequence 1 
APL-130277
APOKYN®
APO-go® 
Sequence 2 
APL-130277
APO-go®
APOKYN® 
Sequence 3 
APOKYN®
APL-130277
APO-go® 
Sequence 4 
APOKYN®
APO-go®
APL-130277 
Sequence 5 
APO-go® 
APL-130277
APOKYN® 
Sequence 6 
APO-go® 
APOKYN®
APL-130277 


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Dose 
Group 
APOKYN® 
Current Prescribed 
Dose 
APO-go®
Study Dose 
APL-130277 
Study Dose* 
1 
2 mg 
2 mg
15 mg 
2 
3 mg 
3 mg
20 mg 
3 
4 mg 
4 mg
25 mg 
4 
5 mg 
5 mg
30 mg 
*These are approximate equivalent doses based on PK. 
 
 
SUBJECT SELECTION 
A screening log of potential study candidates and an enrollment log of enrolled subjects 
must be maintained at each study site. 
The study will require approximately 12 subjects to complete the Three-Way Crossover 
phase. Recruitment will continue until the required number of subjects complete the 
study. Inclusion criteria and exclusion criteria are described in detail in protocol Section 
11.1.1 and 11.1.2.  
 
DETERMINATION OF SAMPLE SIZE 
With a sample size of 12 subjects, a two-sided 90% confidence interval for the 
difference in paired PK parameter means on the log scale will have an interval that 
extends no more than 0.221 units from the observed difference with 90% coverage 
probability. This calculation assumes a coefficient of variation of 35% for the difference 
on the original scale. If the observed mean difference on the log scale were zero, this 
would correspond to a 90% confidence interval for the ratio of geometric means of 
(80.2%, 124.7%) on the original scale. 
 
TREATMENT ASSIGNMENT & BLINDING 
At Screening, the Interactive Web Response System (IWRS) will assign a unique subject 
identification number to the subject known as the Screening Number. This number will 
be associated with the subject throughout the study. Every subject that signs an 
informed consent form (ICF) must be entered into the IWRS regardless of eligibility in 
order to obtain a Screening Number. This 7-digit number will consist of a 4-digit site ID 
followed by a 3-digit number assigned sequentially within each site starting at 001. 


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Following Sponsor approval, subjects will be randomized centrally at a study level after 
the Screening Visit has been completed to one of the six randomization sequences using 
the Williams design (See Section 3.3). 
No stratification factors will be used. The randomization scheme will be designed by the 
study statistician. Once designed, an independent randomization expert will execute 
the randomization in the IWRS. The randomization number is used to identify the 
treatment sequence (APL-130277, APO-go®, APOKYN®) of the treatment that will be 
administered to the subject during the Three-Way Open-Label Randomized Crossover 
Phase (Period 1, Period 2, Period 3). 
A randomization number can only be assigned to one subject and cannot be reused once 
assigned. 
 
STUDY PROCEDURES 
All assessments will be performed at each visit according to the schedule of events 
(Section 17). 


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ENDPOINTS 
 
PHARMACOKINETIC ENDPOINTS 
The primary endpoint of this study is the PK profile (plasma) for apomorphine and its 
metabolites (apomorphine sulfate and norapomorphine). Apomorphine PK parameters 
will include: Cmax, Tmax, λz, t½, AUClast, AUCinf, AUC0-24, MRT, CL/F and V/F. Comparative 
bioavailability (FT/R) of apomorphine between the Test (APL-130277) and Reference 
(APO-go and APOKYN) products will be evaluated and calculated using Cmax, AUClast, and 
AUCinf. In addition, the comparative bioavailability between APOKYN (Reference) and 
APO-go (Test) will be determined using Cmax, AUClast and AUCinf (FT/R_APO-
go/APOKYN). Apomorphine metabolites (norapomorphine and apomorphine sulphate) PK 
parameters will consist of determination of Cmax, Tmax, λz, t½, AUClast, AUCinf, AUC0-24, 
and metabolite-to-parent (M/P) ratios of Cmax, AUCinf and AUClast. 
 
SAFETY ENDPOINTS  
The secondary endpoints are safety and tolerability: evaluation of clinical laboratory 
tests, 12-lead ECGs, physical examinations, vital signs (including blood pressure [BP], 
heart rate [HR], respiration rate [RR], body temperature and weight), and adverse events 
(AEs). 


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ANALYSIS POPULATIONS 
 
SAFETY POPULATION 
All subjects who receive at least one dose of study drug will be included in the Safety 
population. The Safety population will be used for the analysis of the safety endpoints 
and the subjects will be grouped according to the treatment that they received. 
 
 
PHARMACOKINETIC POPULATION 
The PK population includes all subjects who receive at least one dose of study drug and 
have at least one quantifiable PK concentration. Subjects will be grouped according to 
the treatment that they received. 
 


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GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
 
GENERAL METHODS 
In general, summaries will present data by treatment group and assessment time point 
where appropriate. Unless stated otherwise, descriptive statistics for continuous 
variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. Descriptive statistics for categorical 
data will include frequency counts and percent. The total number of subjects in the 
treatment group overall (N) will be used as the denominator for percent calculations, 
unless stated otherwise. Significance testing will be 2-sided using α = 0.05, unless 
otherwise specified. 
All PK analyses will be presented using PK population, while other analyses will be 
presented using Safety population. 
Data from all patients entered into the database will be included in subject data listings.  
All statistical procedures will be performed using SAS® Version 9.3 or higher. 
Additional programming considerations are presented in Section 12. 
 
KEY DEFINITIONS 
 Baseline 
6.2.1.1. 
Study Baseline 
Study baseline is defined as the last non-missing measurement in the screening period 
(SV). 
6.2.1.2. 
Period Baseline  
The period baseline is defined as the pre-dose time point within each period. 
 Study Day 
Study day is defined as follows: 
 
The day when the dosing started is designated as Day 1. 
 
For visit days after Day 1, study day = visit date – Day 1 date + 1. 
 
For visit days prior to Day 1, study day = visit date – Day 1 date. Thus, study days 
for screening visit are negative numbers. There is no “Day 0”. 


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MISSING DATA 
Every attempt will be made to avoid missing data. All subjects will be used in the 
analyses, as per the analysis population defined in Section 5.  No imputation will be done 
for missing data, except for medication dates (as detailed in section 7.4.3) and PK 
(detailed in section 8.3). Observed data will be used for analyses. 
 


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DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
 
SUBJECT DISPOSITION AND WITHDRAWALS 
Summary tables reflecting the number of subjects for the following will be presented 
overall and by treatment group: 
- 
Screened subjects (overall only) 
- 
Failed screening subjects and reasons for screen failures (overall only) 
- 
Randomized subjects 
- 
Safety population 
- 
PK population 
- 
Subjects who complete the study 
- 
Subjects who early terminate the study and reasons for early termination 
Subject disposition and screen failures will be listed. 
In addition, the number of randomized subjects will also be summarized by treatment 
sequence. 
 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographics data, such as age, gender, race and ethnicity, and baseline characteristics, 
such as height, weight, body mass index (BMI), smoking status, MMSE score and baseline 
modified Hoehn and Yahr scale will be summarized descriptively overall, by treatment 
group. The following conventions will be implemented: 
 
Age at Study day 1 = INTCK(‘year’, Subject Birthday, Date of study day 1) 
 
Height (in cm) = height (in inches) * 2.54 
 
Weight (in kg) = weight (in lbs) * 0.4536 
 
BMI (kg/m2) = Weight(kg)/[Height(m)2] 
Demographic characteristics will also be listed.  


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MEDICAL HISTORY AND CONCOMITANT DISEASES 
Medical history collected at screening will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA®) version 19.1. Medical history data will be summarized 
by system organ class (SOC) and preferred term (PT) overall and listed.  
Subject’s PD history will also be summarized overall and listed. Time since diagnosis of 
PD (in years) is calculated as the year of screening visit – the year of diagnosis of PD + 1. 
Time since motor fluctuations started (in years) is calculated as the year of screening 
visit – the year motor fluctuations started+1. 
 
MEDICATION 
The number and percentage of subjects using each prior or concomitant medication will 
be summarized using Anatomical Therapeutic Chemical (ATC) classification codes and 
PT according to the World Health Organization-Drug Dictionary (WHO-Drug) March, 
2017.  The number and percentage of subjects using each prior medication will be 
summarized overall, while concomitant medications will be summarized overall and for 
each treatment group. 
Summaries of prior and concomitant PD treatment medications (medications which start 
with ATC code N04) will be presented in tabular form using the ATC Level 4 and PT. 
Other prior and concomitant medications will be presented in tabular form using the 
ATC Level 1, ATC Level 2, and PT. Subjects with multiple uses of a concomitant 
medication will be counted only once for a given PT in a given ATC term and only once 
within a given ATC term. 
PD medications and other medications will be summarized and listed separately.  
 
Prior Medication 
Medications with a stop date before the first date of study drug dosing will be 
considered prior medications. 
 
Concomitant Medication 
Medications with start date or stop date on or after the first date of study drug dosing 
will be considered concomitant medications. A medication that has a start or stop date 
anytime on or after Day 1 of a Treatment Period, up through and including the day prior 
to Day 1 of the next Treatment Period or start and stop dates that span this interval will 
be assigned to the treatment group associated with the former Treatment Period. A 
medication that has a start or stop date anytime on or after Day 1 of the last Treatment 
Period up to EOS in which a subject participates or start and stop dates that span this 
interval will be assigned to the treatment group associated with this last Treatment 
Period.  


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Medications with Missing or Incomplete Start/End Date 
If the medication start date is incomplete, then it will be imputed as follows for the 
purpose of determining concomitant use:  
 
If the start date is completely missing, the start date will be equal to the first 
dose date. However, if the stop date is not missing and is before the first dose 
date, then the stop date will be used instead.  
 
If the start day is missing: Check if month is same as month of first dose date of 
study treatment. If yes, impute to first dose date of study treatment; else impute 
first day of the month. However, if the stop date is not missing and is before the 
date of the first dose of study treatment or the imputed start date, then the stop 
date will be used instead. 
 
If the start day and month are missing: Check if year is same as the year of the 
first dose date of study treatment. If yes, impute to first dose date of study 
treatment; else impute to first day of the first month (January). However, if the 
stop date is not missing and is before the date of the first dose of study treatment 
or the imputed start date, then the stop date will be used instead. 
If the medication stop date is partial, then it will be imputed as follows for the purpose 
of determining concomitant use:  
 
If the stop date is completely missing and the medication is not ongoing, the stop 
date will be equal to the last dose date or date of completion/withdrawal, 
whichever is the latest.  
 
If the stop day is missing, the last day of the month will be used. If resulted 
imputed stop date is after the latest of last dose date or date of 
completion/withdrawal, then the latest of last dose date or date of 
completion/withdrawal will be used.  
 
If the stop day and month are missing, then the last day of the last month 
(December) will be used. If resulted imputed stop date is after the latest of last 
dose date or date of completion/withdrawal, then the latest of last dose date or 
date of completion/withdrawal will be used. 


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ANALYSIS OF PHARMACOKINETICS 
The primary endpoint of this study is the PK profile (plasma) for apomorphine and its 
metabolites (apomorphine sulfate and norapomorphine). Apomorphine PK parameters 
will include: Cmax, Tmax, λz, t½, AUClast, AUCinf, AUC0-24h, MRT, CL/F and V/F. Comparative 
bioavailability (FT/R) of apomorphine between the Test (APL-130277) and Reference 
(APO-go and APOKYN) products will be evaluated and calculated using dose normalized 
Cmax, AUClast, and AUCinf. In addition, the comparative bioavailability between APOKYN 
(Reference) and APO-go (Test) will be determined using Cmax, AUClast and AUCinf 
(FT/R_APO-go/APOKYN). Apomorphine metabolites (norapomorphine and apomorphine 
sulphate) PK parameters will consist of determination of Cmax, Tmax, λz, t½, AUClast, 
AUCinf, AUC0-24h, and metabolite-to-parent (M/P) ratios of Cmax, AUCinf and AUClast. 
Pharmacokinetic parameters will be derived using noncompartmental methods 
employing Phoenix WinNonlin® version 6.3 or higher (Certara, Princeton, NJ). 
Pharmacokinetic analysis will be conducted using actual time elapsed from dosing 
concentration-time data for apomorphine and metabolites (norapomorphine and 
apomorphine sulphate). 
 
PK SAMPLING SCHEDULE  
Pharmacokinetic evaluation of APL-130277, subcutaneous APO-go® and APOKYN® will be 
completed in Period 1, Period 2, and Period 3. Blood draws for PK analyses will occur at 
t = 0 (just prior to dosing), 15, 30, 45, 60 minutes after dosing and at 1.5, 3, 6 hours after 
dosing. Sampling should occur as close as possible to the target time. Actual sampling 
date and time should be recorded in the case report form (CRF). 
 
PLASMA PK ENDPOINT 
Table 1 provides the PK parameters that will be estimated by noncompartmental methods 
from plasma samples. Actual elapsed time from dosing will be used to determine all 
individual PK parameters. For APL-130277, the time the sublingual film was  placed under 
the tongue will be used as the start of dosing to calculate the actual elapsed time.  
The PK parameters in Table 1 (except M/P Cmax, M/P AUClast, M/P AUCinf) will be calculated 
and summarized for apomorphine. The same PK parameters, excluding FT/R Cmax,         
FT/R AUClast, FT/R AUCinf, MRT, CL/F and V/F, will be calculated and summarized for 
metabolites (norapomorphine and apomorphine sulphate).  
All PK parameters will be listed and summarized ( AUCext i.e. % extrapolated will  only 
be listed). 


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Table 1. 
PK Parameters 
 
Cmax (ng/mL) 
Maximum plasma concentration, observed by inspection of individual 
subject plots of plasma concentration versus time. 
Cmax/D* 
(ng/mL)/(mg) 
(Parent only) 
Dose normalized maximum observed concentration 
Tmax (h) 
Time from dosing to Cmax, observed by inspection of individual subject 
plots of plasma concentration versus time. 
AUC0-24 
(h*ng/mL) 
Area under the concentration-time curve from time zero to 24 hours 
using the linear-up log-down trapezoidal rule. 
AUC0-24/D 
(h*ng/mL)/(mg) 
(Parent only) 
Dose normalized area under the concentration-time curve from time 
zero to 24 hours using the linear-up log-down trapezoidal rule. 
AUClast (hr*ng/mL) 
Area under the plasma concentration vs. time curve from dosing to 
the last measurable concentration, calculated using the linear 
trapezoidal rule for incremental trapezoids and the log-trapezoidal 
rule for decremental trapezoids. 
AUClast/D 
(h*ng/mL)/(mg) 
(Parent only) 
Dose normalized area under the plasma concentration vs time curve 
from time zero to the last measurable concentration. 
AUCinf (h*ng/mL) 
Area under the plasma concentration vs. time curve from Hour 0.0 to 
infinity. AUCinf is calculated as the sum of AUC0-t and AUCt-∞. The 
extrapolated AUCt-∞ is estimated as the ratio of the last measurable 
plasma concentration and the apparent terminal elimination rate 
constant (Ct/kel).  
AUCinf/D 
(h*ng/mL)/(mg) 
(Parent only) 
Dose normalized area under the plasma concentration vs time curve 
from time zero extrapolated to infinity 
AUCext 
The percentage (%) of AUCinf extrapolated


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λz (h-1) 
Apparent terminal elimination rate constant, determined by log linear 
regression of the plasma concentration versus time data that was 
judged to be in the log-linear elimination phase. At least 3 data 
points in the terminal phase will be used in the determination of the 
rate constant.   
t½ (h) 
Terminal phase half-life, as calculated by the following equation: t½ = 
ln(2)/λz. 
MRT (h) 
(parent only) 
Mean residence time during one dosing interval calculated using the 
following equation: MRT = AUMCinf/AUC inf. AUMCinf is the area under 
the first moment (time.plasma concentration vs. time) curve. 
FT/R Cmax 
(parent only) 
The comparative bioavailability calculated as the ratio of the 
Test/Reference (APOGO and APOKYN) formulation PK parameter 
(Dose normalized Cmax).  
Ratio of APO_go/APOKYN will be determined 
FT/R AUClast 
(parent only) 
The relative bioavailability calculated as the ratio of the 
Test/Reference (APOGO and APOKYN) formulation PK parameter 
(Dose normalized AUClast). 
Ratio of APO_go/APOKYN will be determined 
FT/R AUCinf 
(parent only) 
The relative bioavailability calculated as the ratio of the 
Test/Reference (APOGO and APOKYN) formulation PK parameter 
(Dose normalized AUCinf). 
Ratio of APO_go/APOKYN will be determined 
M/P Cmax 
(metabolite only) 
Metabolite to Parent exposure ratio, Cmax, corrected for molecular 
weight differences. 
M/P AUClast 
(metabolite only) 
Metabolite to Parent exposure ratio, AUClast, corrected for molecular 
weight differences. 
M/P AUCinf 
(metabolite only) 
Metabolite to Parent exposure ratio, AUCinf, corrected for molecular 
weight differences. 
CL/F (L/h) 
(parent only) 
Apparent total clearance of the drug from plasma extravascular 
administration, calculated as Dose/AUCinf. 
V/F (L) 
(parent only) 
Apparent volume of distribution after extravascular administration, 
calculated as Dose/(AUCinf * λz).  


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HANDLING OF DROPOUTS, MISSING DATA OR DATA BELOW THE LOWER 
LIMIT OF QUANTIFICATION  
For PK concentration analyses: 
For calculation of mean concentrations and generation of mean concentration time 
profiles, all BLQ values will be set to zero except when an individual BLQ falls between 
two quantifiable values, in which case it will be treated as missing data. PK 
concentration listing will list original values without any data handling adjustments.  
For APL-130277, time when sublingual film was placed under the tongue will be use as 
time zero. For APOKYN and APOGO, start of dosing time will be used as time zero. 
For PK parameter calculation: 
For the PK analysis, a concentration that is BLQ will be assigned a value of zero if it 
occurs in a profile before the first measurable concentration. If a BLQ value occurs after 
a measurable concentration in a profile and is followed by a value above the lower limit 
of quantification, then the BLQ will be treated as missing data. BLQ values occurring at 
the end of the collection interval (after the last quantifiable concentration) will be 
treated as missing data. If two BLQ values occur in succession after Cmax, the profile 
will be deemed to have terminated at the first BLQ value and any subsequent 
concentrations will be omitted from PK calculations. 
All PK parameter calculations will use actual times relative to time of dosing.  APL-
130277 apomorphine and its metabolite PK data from subjects who experience emesis 
for a given study treatment dose may be excluded from statistical analysis if vomiting 
occurs at or before two times of median Tmax. These APL-130277 PK concentration and 
parameter data may be excluded from descriptive and mixed effect model analyses but 
will be included in individual listings. 
PK analysis will be performed for individual profiles with at least 4 quantifiable results 
following BLQ imputation unless noted otherwise in the study report. 
For APL-130277, time when sublingual thin film was placed under the tongue will be 
used as time zero. For APOKYN and APOGO, start of dosing time will be used as time 
zero. 
Reporting of AUCinf and AUCinf-dependent parameters is contingent on the percent of 
the total area obtained by extrapolation as follows: 
• AUCinf values with <20% of the total area coming from Clast/λz are acceptable to 
report. 


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• Individual plasma concentration-time profiles for which the extrapolated areas are 
>20% of AUCinf will be identified in the report. 
• It is unacceptable to use AUCinf data if >40% of the AUC has been extrapolated, 
except in specific situations. 
The percentage of AUCinf obtained by extrapolation (AUC%Extrap) will be calculated as 
follows: 
AUC%Extrap (AUCext) = [(AUCinf – AUClast) / AUCinf] x 100 
 
PK CONCENTRATION ANALYSIS 
Apomorphine and metabolite concentration-time data will be summarized descriptively 
in tabular formats by dose level for each treatment group using the following summary 
statistics: n, mean, SD, coefficient of variation (CV)%, median, minimum, maximum. In 
addition, dose normalized apomorphine  concentration (PK concentration/dose level) will 
be summarized descriptively.  
Figures illustrating the time course of mean drug concentration vs. time for apomorphine 
and its metabolites separately will be presented for relevant comparisons on linear and 
semi-logarithmic scales by dose level with treatment groups overlaid, and by treatment 
group with dose levels overlaid. Plots illustrating dose normalized concentration data may 
be included as appropriate. In addition, the individual subject concentration-time data 
will be listed and displayed graphically on linear and semi-log scales by overlaid treatment 
group and dose level.  
 
PK PARAMETER ANALYSIS 
Individual PK parameters from the noncompartmental PK analysis will be tabulated, 
where calculable, and summarized descriptively by treatment group and dose level. The 
following summary statistics will be presented for PK parameters: n, arithmetic mean, 
CV%, SD of the arithmetic mean, median, minimum, maximum, geometric mean and CV% 
of the geometric mean. Tmax will be presented as n, median, minimum and maximum. 
Other analyses such as exploring the relationship between PK parameters and dose will 
be conducted, as appropriate. 
A mixed effects model with fixed effects for treatment and period, with subject nested 
within sequence as a random effect will be used to analyze the natural-log transformed 
dose normalized AUClast,AUC0-24 , AUCinf, and Cmax. The Kenward-Roger method will be used 
for the model. For each treatment comparison, a point estimate and 90% CIs will be 
provided for the geometric mean ratio upon back-transformation. Tmax will be analyzed 
by dose level for each treatment group using a non-parametric test (Wilcoxon test); two-
sided p-value will be presented. t½ will be analyzed by dose levels for each treatment 
group using a t-test; t-statistics score, two-sided p-value, mean difference and 


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corresponding 90% CIs will be presented. These tests will only be performed if there are 
more than 5 subjects at a dose level. Descriptive statistics will be presented for all PK 
parameters by dose level for each treatment group.  


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SAFETY 
Safety will be assessed on the basis of clinical laboratory tests, 12-lead ECGs, physical 
examinations, vital signs (including BP, HR, RR, body temperature and weight), and AEs. 
 
STUDY DRUG EXPOSURE 
A summary of subjects receiving any dose of study drug, subjects that had a confirmed 
“OFF” episode prior to dose, the dose administered, subjects that experienced an “ON” 
response, subjects that were rescued with L-Dopa or other PD medications will be 
presented overall for each treatment. The time from the start of dosing to an “ON” 
response (in hours) will be summarized descriptively. 
Study drug administration will be provided in subject listings. 
Note that for APL-130277, time when sublingual thin film was placed under the tongue 
will be used as start of dosing time.  
 
ADVERSE EVENTS 
Adverse events will be recorded from the time of signing of the ICF by the subject 
through to study completion or earlier, if warranted by a subject discontinuation. All 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 
19.1 and summarized by SOC and PT. 
AEs that occur on or after Day 1 of a Treatment Period, up through and including the 
day prior to Day 1 of the next Treatment Period will be assigned to the treatment group 
associated with the former Treatment Period and considered a treatment-emergent 
adverse event (TEAE). An AE that occurs on or after Day 1 of the last Treatment Period 
up to EOS in which a subject participates will be assigned to the treatment group 
associated with this last Treatment Period and considered a TEAE.  
AEs that are associated with injection site reactions reported on the injection site CRF 
will be directly assigned to the last treatment they received (APOKYN or APOGO) 
regardless of the AE onset date. 
Pre-treatment emergent AEs are defined as any AEs with a start date prior to the start 
of dosing in Period 1. 
An overall summary of the number and percentages of subjects reporting any TEAEs, 
drug-related TEAEs, severe TEAEs, serious TEAEs, non-serious TEAEs, TEAEs leading to 
study treatment discontinuation, leading to death, drug-related TEAEs leading to study 
treatment discontinuation and  drug-related serious TEAEs will be presented. 
Corresponding event counts will also be provided. 


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TEAEs will be summarized (number of events and number of subjects having 
experienced at least one event) overall and by treatment group, SOC and PT. TEAEs will 
also be summarized by maximum severity (in the order of mild, moderate and severe) 
and by relationship to study drugs (related and unrelated). Subjects with multiple TEAEs 
at the same SOC or PT within an SOC level will only be counted once at the maximum 
severity. Subjects with multiple TEAEs at the same SOC or PT within an SOC level and at 
least one is related, will only be counted once as related. An AE with missing 
relationship to study drug will be considered as related to study drug. Serious adverse 
events (SAEs) and TEAEs leading to drug discontinuation will also be summarized.  
Pre-treatment AEs will be summarized (number of events and number of subjects having 
experienced at least one event) overall and by SOC and PT. 
All AEs will be listed.  
 
Adverse Event with Missing or Incomplete Start/End Date 
Missing or incomplete AE start and stop dates will not be imputed. The treatment period 
for which the AE was treatment-emergent will be determined using the following rules:  
 
If the day of the AE start date is missing, the month is on or after the month of 
first dose in Period 1 and the end date is on or after the first dose date in Period 
1, then this AE will be considered treatment emergent. The TEAE will be 
considered a Period 1 TEAE if based on the available partial date information, 
the TEAE could have started prior to the first dose in Period 2. The TEAE will be 
considered a Period 2 TEAE if based on the available partial date information, 
the TEAE could have started on or after the first dose in Period 2 but prior to the 
first dose in Period 3. The TEAE will be considered a Period 3 TEAE if based on 
the partial date information, the TEAE could have started on or after the first 
dose in Period 3 up to the EOS. If based on the available partial date 
information, the TEAE couldn’t be assigned to any specific treatment period, 
then this TEAE will be assigned to APL-130277.  
 
If the day and month of the AE start date is missing but the year is on or after 
the year of first dose in Period 1, then this AE will be assigned as Period 1 TEAE 
or Period 2 TEAE or Period 3 TEAE, assuming any available AE end date 
information does preclude inclusion into one or more of the periods. If based on 
the available partial date information, the TEAE couldn’t be assigned to any 
specific treatment period, then this TEAE will be assigned to APL-130277.  
 
If the AE start date is completely missing, then this AE will be assigned as Period 
1 TEAE or  Period 2 TEAE or Period 3 TEAE, assuming any available AE end date 
information does preclude inclusion into one or more of the periods. If based on 
the available partial date information, the TEAE couldn’t be assigned to any 
specific treatment period, then this TEAE will be assigned to APL-130277.  


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AEs with missing time will not be imputed. 
 
LABORATORY EVALUATIONS 
All clinical laboratory parameters will be converted to consistent units according to the 
International System of Units (SI) before summarization. 
Laboratory data will be summarized by the type of laboratory test. Normal reference 
ranges and abnormal results will be used in the summary of laboratory data. Data will be 
flagged according to the reference limits (high or low) if applicable. 
Descriptive statistics will be calculated for each numeric laboratory test parameter at 
study baseline and end of study (EOS) visit overall. Changes from study baseline results 
will be presented descriptively. For chemistry and hematology lab tests, shift tables 
showing baseline and EOS visit will be performed for the following categories: low, 
normal, and high. A listing of subjects with any laboratory results outside the reference 
ranges will be provided. 
 
VITAL SIGNS  
Descriptive summaries of actual values and changes from study baseline will be 
calculated for vital signs by treatment group and time points (study baseline and EOS 
will be summarized overall), which includes blood pressure (BP), heart rate (HR), 
respiration rate (RR), and body temperature.  
Vital sign results for each parameter will then be tabulated for actual and change from 
period baseline values by treatment group and time points. The proportion of subjects 
with orthostatic hypotension will be tabulated by treatment group and time point 
(screening and EOS will be summarized overall). 
Actual values and change from study baseline for weight will be summarized separately 
by treatment group and visit (study baseline and EOS will be summarized overall). 
All vital sign data will be listed by subject and time of measurement.  
 
ECG  
A standard 12-lead ECG will be performed at all time points outlined in Table 2. A 
triplicate 12-lead ECG will be performed at the Screening Visit and the median value will 
be used for summary purposes. ECGs will be performed in a semi-recumbent position and 
after 5 minutes of rest. All ECGs should be assessed by the Investigator and deemed 
“Normal”, “Abnormal, not clinically significant” and “Abnormal, clinically significant”. A 
shift table showing period baseline to 60 minutes post-dose by treatment group and a 
shift table showing study baseline to EOS visit will be performed for the above categories. 
The ECG variables that will be analyzed are heart rate, RR interval, PR interval, QRS 
interval, QT interval, QT corrected with Bazett’s formula (QTcB), and QT corrected with 


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Fridericia’s formula (QTcF). The actual value and change from study baseline of ECG 
measurements will be summarized  by treatment group and time point (study baseline 
and EOS will be summarized overall). The same ECG results will then be summarized for 
change from period baseline by treatment group.  
All-important abnormalities from the ECG readings that, in the opinion of the Investigator 
are deemed clinically significant should be reported as AEs and will be listed in the AE 
listing.  
 
PHYSICAL EXAMINATION 
A complete physical examination including the oropharyngeal cavity examination will be 
performed at the screening and EOS visit. Findings of the oropharyngeal cavity 
examination will be tabulated by treatment group for the treatment period assessments 
and overall for the Screening and EOS Visit assessment. 
Examination for injection site reactions will be completed just prior to dosing and 2 
hours after dosing in P1, P2, and P3, as well as the EOS Visit. The findings will be 
summarized by treatment group for the treatment period assessments and overall for 
the EOS Visit assessment. All findings will be listed.   
 
All abnormal findings at baseline will be recorded on the Medical History/Concomitant 
Diagnoses page (or equivalent) of the CRF. New abnormal findings or a worsening of 
baseline conditions detected at follow-up physical examinations will be recorded as AEs 
on the CRF. 
 
All physical examination data will be listed.  
 
OTHER SAFETY VARIABLES 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a measure of suicidal ideation 
and behavior. The rating scale has 4 general categories: suicidal ideation, intensity of 
ideation, suicidal behavior, and actual attempts. All C-SSRS data will be listed.  


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INTERIM ANALYSES 
Two unplanned interim analyses were conducted for regulatory submissions. 


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CHANGES FROM ANALYSIS PLANNED IN PROTOCOL 
AUC 0-24 for apomorphine and apomorphine metabolites parameters were added 
to primary analyses. 
Analysis of raw PK concentration and parameter data will only be conducted by dose 
level as different dose levels will have different PK profiles and cannot be combined 
together for analysis without dose-normalization.  
The analysis on log-transformed AUClast, AUCinf, and Cmax has been changed to a mixed 
effect model on dose-normalized log-transformed PK parameters. 


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REFERENCE LIST 
 
 


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PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using 
SAS® for Windows, Release 9.3 or higher (SAS® Institute Inc., Cary, NC, USA). Computer-
generated table, listing and figure output will adhere to the following specifications. 
PK parameters will be derived using noncompartmental methods employing Phoenix 
WinNonlin® version 6.3 or higher (Pharsight, St Louis, MO). 
 
GENERAL CONSIDERATIONS 
 
Each output will be stored in a separate file. 
 
Output files will be delivered in Rich Text Format. 
 
Numbering of TFLs will follow ICH E3 guidance. 
 
TABLE, LISTING, AND FIGURE FORMAT 
 
General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size 8. 
• 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
• 
Headers and footers for figures will be in Courier New font, size 8. 
• 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified. 
• 
Specialized text styles, such as bolding, italics, borders, shading, and 
superscripted and subscripted text, will not be used in the TLFs, unless 
otherwise specified. On some occasions, superscripts 1, 2, or 3 may be used (see 
below). 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, 
such as non-printable control characters, printer-specific, or font-specific 
characters, will not be used. Hexadecimal-derived characters will be used, 
where possible, if they are appropriate to help display math symbols (e.g., μ). 
Certain subscripts and superscripts (e.g., cm2, Cmax) will be employed on a case-
by-case basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and 
programmer-supplied formats, as appropriate. 


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Headers 
 
All output should have the following header at the top left of each page: 
Sunovion Pharmaceuticals Inc. 
Protocol CTH-203 
 
All output should have Page n of N at the top or right corner of each page. TLFs 
should be internally paginated in relation to the total length (i.e., the page number 
should appear sequentially as page n of N, where N is the total number of pages in 
the table). 
 
The date output was generated should appear along with the program name as a 
footer on each page. 
 
Display Titles 
 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
The title is centered. The analysis population will be identified on the line 
immediately following the title. The title and table designation will be single 
spaced. A solid line spanning the margins will separate the display titles from the 
column headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
Safety Population 
 
 
Column Headers 
 
Column headings will be displayed immediately below the solid line described above 
in initial upper-case characters.  
 
When appropriate the variable (or characteristic) column will be on the far left 
followed by the treatment group or sequence columns and total column (if 
applicable). P-values may be presented under the total column or in separate p-
value column (if applicable). Within-treatment comparisons may have p-values 
presented in a row beneath the summary statistics for that treatment. 
 
For numeric variables, the “unit” in column or row heading will be included when 
appropriate. 
 
Analysis population sizes will be presented for each treatment group in the column 
heading as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ 
used for the descriptive statistics representing the number of subjects in the 
analysis population. 
 
For tables presented by treatment group, the order of treatments will be APL-
130277, APOKYN® and APO-go®, followed by an overall column. For tables presented 


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by treatment sequence, the order will following sequentially, followed by an overall 
column. 
 
Body of the Data Display 
12.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
12.2.5.2. Table Conventions 
 
Units will be included where available 
 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category will be presented in the table, even if n=0 for all 
treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating
n
severe
0
moderate
8
mild
3
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as “0” and not as “0 (0%)”. 
 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups will be included. 
 
An Unknown or Missing category will be added to any parameter for which 
information is not available for 1 or more subjects.  
 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 
n 
XX
Mean (SD)
XX.X (XX.XX)
Median
XXX.X
Min, Max
XX.X, XX.X
 
P-values will be output in the format: “0.xxx”, where xxx is the value rounded to 3 
decimal places. Any p-value less than 0.001 will be presented as “<0.001”.  


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 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Unless otherwise 
noted, for all percentages, the number of subjects in the analysis set for the 
treatment group who have an observation will be the denominator. Percentages 
after zero counts should not be displayed and percentages equating to 100% should 
be presented as “100%”, without any decimal places.  
 
Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of adverse event data should be presented by the body system, 
treatment class, or SOC with the highest occurrence in the overall column in 
decreasing order, assuming all terms are coded. Within the body system, drug class 
and SOC, medical history (by preferred term), drugs (by ATC1 code), and adverse 
events (by preferred term) should be displayed in decreasing order. If incidence for 
more than 1 term is identical, they should then be sorted alphabetically. Missing 
descriptive statistics or p-values which cannot be estimated should be reported as 
“-”. 
 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page.  The overall summary statistics for the subheading should only be 
output on the first relevant page. 
12.2.5.3. Listing Conventions 
 
Listings will be sorted for presentation in order of subject number, visit/collection 
day, and visit/collection time. 
 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 


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 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
 
Units will be included where available. 
 
12.2.5.4. Figure Conventions 
 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis. 
 
Footnotes 
 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
 
Subject specific footnotes should be avoided, where possible. 
 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page.  
 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


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QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. INC Research SOP 03.010 and 
03.013 provide an overview of the development of such SAS programs. 
INC Research SOP 03.009 describes the quality control procedures that are performed for 
all SAS programs and output. Quality control is defined here as the operational techniques 
and activities undertaken to verify that the SAS programs produce the proper clinical trial 
output by checking for their logic, efficiency and commenting and by review of the 
produced output. 


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INDEX OF TABLES 
Please see table shell attachment 1. 


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INDEX OF FIGURES 
Please see figure shell attachment 2. 
 


Statistical Analysis Plan 
Protocol # CTH-203
Version 1.0 
INC Research #1009488
 
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03.007A.03     
  INC Research © LLC 
Page 42 of 45 
 
INDEX OF LISTINGS 
Please see listing shell attachment 3


Statistical Analysis Plan 
 
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APPENDICES 
Table 2. 
Schedule of Events Tables
 


Statistical Analysis Plan 
Protocol # CTH-203
Version 1.0 
INC Research #1009488
 
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1 All screening procedures to be conducted within 21 days prior to dosing (Period 1). 
2 Telephone contact as a reminder for subject to discontinue APOKYN® a minimum of 1-day prior to each study visit for the 
wash-out period (excluding SV). 


Statistical Analysis Plan 
Protocol # CTH-203
Version 1.0 
INC Research #1009488
 
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03.007A.03     
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3 Physical examinations to include the following: head-eyes-ears-nose and throat; respiratory system; cardiovascular system; 
gastrointestinal system, including mouth – oral cavity; musculoskeletal system; central and peripheral nervous system; skin; 
and injection site. The oropharyngeal cavity examination should include a visual inspection of the inside of each cheek, the 
inside of the upper and lower lip, the surface of the tongue, and under the tongue. Examination for injection site reaction will 
be completed at the End of Study Visit (EOS). 
4 Abbreviated physical examinations to include head-eyes-ears-nose and throat; heart; lungs; abdomen; skin; mouth – oral 
cavity and injection site to be done at t= 0 (just prior to dosing) and 2 hours after dosing at Period 1, Period 2, and Period 3. 
The oropharyngeal cavity examination should include a visual inspection of the inside of each cheek, the inside of the upper 
and lower lip, the surface of the tongue, and under the tongue. 
5 Both height and weight captured at the Screening Visit to calculate BMI; only weight captured at all other indicated visits. 
6 Vital signs will be assessed at the Screening Visit and End of Study Visit; Period 1, Period 2 and Period 3 at t = 0 minutes (just 
prior to dosing), 15, 45 and 60 minutes. Blood pressure to be measured supine and standing (measured within 3 minutes of 
standing) at all time points. 
7 Suggested Sequence of Assessments: PK – ECG – Vitals. 
8 12-lead ECG: Obtain in triplicate at the Screening Visit. Period 1, Period 2 and Period 3 obtain at t = 0 (just prior to dosing) 
and 60 minutes after dosing. Obtain at the End of Study Visit. 
9 Blood and urine collection for clinical laboratory tests will occur at the Screening Visit and at the End of Study Visit. In 
addition, serum pregnancy test will be performed on all females of childbearing potential. 
10 PK will be assessed in Period 1, Period 2 and Period 3 at t = 0 (just prior to dosing), 15, 30, 45, 60 minutes and 1.5, 3, 6 
hours after dosing. 
11 The modified Hoehn and Yahr will be used during the Screening Visit in the “ON” state to determine eligibility. 
12 C-SSRS “Screening” scale to be used at the Screening Visit; “Since Last Visit” scale to be used at End of Study Visit.