AND GETTING OUT BETWEEN GETTING UP DAYTIMECOVERAGE NIGHTTIMEDOSING GOCOVRI COULD MEAN THE DIFFERENCE

NIGHTTIME DOSING DAYTIME COVERAGE

NIGHTTIME DOSING DAYTIME COVERAGE

GOCOVRI ^® is ready when your Parkinson’s disease (PD) patients

with dyskinesia or OFF episodes need it

With a single bedtime dose, high levels of GOCOVRI ^® are reached

by morning before the first levodopa dose, providing all-day

coverage with levels slowly decreasing in the hours before

bedtime. ¹

In clinical trials, GOCOVRI ^® reduced PD dyskinesia (primary endpoint)

and OFF time and increased GOOD ON time (secondary endpoints). ²

INDICATION

GOCOVRI® is indicated:

• For the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-

based therapy, with or without concomitant dopaminergic medications

• As adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease

experiencing “off” episodes

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

GOCOVRI is contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m ² .

GOOD ON time = ON time without troublesome dyskinesia.

Not an actual patient.

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

For Parkinson’s disease patients with motor complications, ^1,2

GOCOVRI ^® COULD MEAN THE DIFFERENCE

BETWEEN GETTING UP

AND GETTING OUT

SELECT IMPORTANT SAFETY INFORMATION

2

THE EFFICACY AND SAFETY OF GOCOVRI® 274 mg QHS WERE EVALUATED IN 2 PHASE 3, RANDOMIZED, PLACEBO-CONTROLLED TRIALS ^2,3 :

Efficacy and safety profile demonstrated by a robust clinical program

Study 1

24-week study

PD patients* 121

with dyskinesia

GOCOVRI ^® (n = 63),

placebo (n = 58)

The Unified Dyskinesia Rating Scale

(UDysRS):

The UDysRS is a standardized clinical

research tool which uses both patient

historical and objective measurements

to assess presence of dyskinesia and

its impact on daily activities. Total

scores range from 0 to 104 points, with

higher scores indicating more severe

dyskinesia.

POOLED BASELINE CHARACTERISTICS 68%

INSTRUMENTS USED FOR ASSESSING EFFICACY

• Primary efficacy endpoint:

Change in UDysRS total score from

baseline through Week 12

• Secondary endpoints:

Changes from baseline to

Week 12 in ON time with

troublesome dyskinesia, OFF time,

and in GOOD ON time, based on

patient home diary data

EFFICACY ENDPOINTS

STUDY DESIGN

Patient Diary Data:

Using diaries, patients categorize their

predominant motor states divided into

30-minute intervals throughout the day.

Motor state categories are “OFF,”

“ON with no dyskinesia,” “ON with

nontroublesome dyskinesia,” “ON with

troublesome dyskinesia,” and “asleep.”

Study 2

12-week study

PD patients 75

with dyskinesia

GOCOVRI ^® (n = 37),

placebo (n = 38)

Levodopa and other

PD medication dose

adjustments were not

allowed during the

course of either study

of patients

received levodopa received concomitant

dopaminergic

medications with

levodopa

2.8 ^{OFF TIME:} 100%

HOURS (MEAN)

4.9

ON TIME WITH

TROUBLESOME DYSKINESIA:

HOURS (MEAN)

40.1

UDysRS

TOTAL SCORE:

POINTS (MEAN) GOOD ON TIME 8.4

HOURS (MEAN)

A single GOCOVRI ^® dose at bedtime reduced both dyskinesia and OFF time as an adjunct to levodopa ³

IMPORTANT SAFETY INFORMATION (CONT.)

WARNINGS AND PRECAUTIONS

Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease

medications have reported falling asleep during activities of daily living. If a patient develops daytime sleepiness

during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should

ordinarily be discontinued or the patient should be advised to avoid potentially dangerous activities.

*Patients who had at least 1 hour of troublesome dyskinesia time during the day and at least mild functional impact because of dyskinesia. ²

Dyskinesia = ON time with troublesome dyskinesia.

GOOD ON time = ON time without troublesome dyskinesia

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

3

-25

-20

-15

-10

-5

0

WEEKS

0 2 4 6 8 10 12

27% IMPROVEMENT*

(PLACEBO-ADJUSTED)

14% IMPROVEMENT

LS MEAN (SE) CHANGE IN UD ys RS

GOCOVRI ^®

PLACEBO

-17.7

-7.6

41% IMPROVEMENT

GOCOVRI ^® reduced dyskinesia without adjustments

to existing levodopa or other dopaminergic therapies ^2,3

POOLED RESULTS: MEAN IMPROVEMENT IN UDysRS TOTAL SCORE AT WEEK 12 (MEAN BASELINE, 40.1) ^3,4

PRIMARY ENDPOINT ³

GOCOVRI® achieved a 10.1-point reduction in UDysRS (placebo-adjusted) ³

*Percent improvement from baseline calculated using MMRM statistics model. ³

LS, least squares; MMRM, mixed model repeated measure; SE, standard error.

Adapted from Elmer, et al.

IMPORTANT SAFETY INFORMATION (CONT.)

WARNINGS AND PRECAUTIONS (CONT.)

Suicidality and Depression: Monitor patients for depression, including suicidal ideation or behavior. Prescribers

should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of

suicidality or depression.

DYSKINESIA: CHANGE IN UDysRS

TOTAL SCORE ^2,3

Study 1

(P = 0.0009)

Study 2

(P < 0.0001)

GOCOVRI ^® -15.9

(baseline: 40.9) -20.7

(baseline: 40.2)

Placebo -8.0

(baseline: 38.5) -6.3

(baseline: 41.2)

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

4

GOCOVRI ^® reduced OFF time without adjustments to

existing levodopa or other dopaminergic therapies ^2,3

POOLED RESULTS: MEAN REDUCTION IN OFF TIME AT WEEK 12 (MEAN BASELINE OF ALL PATIENTS: 2.8 HOURS) ^3,4

Derived from patient diary data.

SECONDARY ENDPOINT ³

IMPORTANT SAFETY INFORMATION (CONT.)

WARNINGS AND PRECAUTIONS (CONT.)

Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be

treated with GOCOVRI because of the risk of exacerbating psychosis. Observe patients for the occurrence of

hallucinations throughout treatment, especially at initiation and after dose increases.

OFF TIME: CHANGE IN HOURS ^2,3

Study 1

(P = 0.0171)

Study 2

(P = 0.0199)

GOCOVRI ^® -0.6

(baseline: 3.2) -0.5

(baseline: 2.6)

Placebo +0.3

(baseline: 3.0) +0.6

(baseline: 2.0)

GOCOVRI ^® decreased OFF time by 1 hour (placebo-adjusted) ³

36%

0

-1

-2

1

WEEKS

15% MORE OFF

21% LESS OFF

LS MEAN (SE) CHANGE (HR/DAY)

-0.6

0.4

GOCOVRI ^®

PLACEBO

0 2 4 6 8 10 12

2

IMPROVEMENT

(PLACEBO-ADJUSTED)

Adapted from Elmer, et al.

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

5

GOCOVRI ^® increased GOOD ON time without adjustments

to existing levodopa or other dopaminergic therapies ^2,3

POOLED RESULTS: MEAN INCREASE IN GOOD ON TIME AT WEEK 12 (MEAN BASELINE OF ALL PATIENTS: 8.4 HOURS) ^3,4

Derived from patient diary data.

SECONDARY ENDPOINT ³

IMPORTANT SAFETY INFORMATION (CONT.)

WARNINGS AND PRECAUTIONS (CONT.)

Dizziness and Orthostatic Hypotension: Monitor patients for dizziness and orthostatic hypotension, especially

after starting GOCOVRI or increasing the dose.

GOOD ON TIME: CHANGE IN HOURS ^2,3

Study 1

(P < 0.0001)

Study 2

(P = 0.0168)

GOCOVRI ^® +3.6

(baseline: 8.3) +4.0

(baseline: 8.8)

Placebo +0.8

(baseline: 8.5) +2.1

(baseline: 7.8)

GOCOVRI ^® increased GOOD ON time by 2.4 hours (placebo- adjusted) ³

WEEKS

45% MORE ‘GOOD ON’

16% MORE ‘GOOD ON’

LS MEAN (SE) CHANGE (HR/DAY)

0

1

2

3

4

5

0 2 4 6 8 10 12

IMPROVEMENT

(PLACEBO-ADJUSTED)

29%

GOCOVRI ^®

PLACEBO

3.8

1.4

Adapted from Elmer, et al.

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

6

Less dyskinesia and OFF time means more GOOD ON time throughout

the waking day ⁴

GOCOVRI® PATIENTS ⁴

PLACEBO PATIENTS ⁴

12.2 ^HRS

2.4 ^HRS

1.4 ^HRS

OFF TIME

DYSKINESIA*

GOOD ON TIME

9.6 ^HRS

3.1 ^HRS

3.1 ^HRS

OFF TIME

DYSKINESIA*

GOOD ON TIME

INCREASED GOOD ON TIME: RESULTS FROM POOLED PATIENT DIARY DATA AT WEEK 12 ^3,4

A CLOSER LOOK AT THE SECONDARY EFFICACY ENDPOINTS BASED

ON PATIENT DIARY DATA ⁴

Results for dyskinesia, OFF time, and GOOD ON time, respectively;

GOCOVRI ^® (vs placebo)

GOCOVRI ^® provided control of motor complications throughout the day ⁴

Pooled baseline values (hours) for dyskinesia, OFF time, and GOOD ON time, respectively:

Placebo: 5.2, 2.6, and 8.1 GOCOVRI®: 4.7, 3.1, and 8.5 ⁴

*Dyskinesia defined as ON time with troublesome dyskinesia.

GOOD ON time = ON time without troublesome dyskinesia

The most common adverse reactions (>10%) were hallucination,

dizziness, dry mouth, peripheral edema, constipation, fall, and

orthostatic hypotension. Please see Prescribing Information for a full

list of adverse reactions.

STUDY 1:

• Baseline hours: 4.7 (vs 4.5),

3.2 (vs 3.0), and 8.3 (vs 8.5)

• Week 12 hours: 1.5 (vs 3.0),

2.6 (vs 3.4), and 12.0 (vs 9.2)

STUDY 2:

• Baseline hours: 4.7 (vs 6.0),

2.6 (vs 2.0), and 8.8 (vs 7.8)

• Week 12 hours: 1.4 (vs 3.2),

2.0 (vs 2.7), and 12.5 (vs 10.0)

IMPORTANT SAFETY INFORMATION (CONT.)

WARNINGS AND PRECAUTIONS (CONT.)

Withdrawal-Emergent Hyperpyrexia and Confusion: Rapid dose reduction or abrupt discontinuation of

GOCOVRI, may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions,

hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. Avoid sudden discontinuation

of GOCOVRI.

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

7

A post hoc, retrospective, subgroup analysis of patients with baseline and

Week 12 diaries (n = 162/196) evaluated the frequency, prevalence, and duration

of episodes of troublesome dyskinesia and OFF time, as well as the effect of

GOCOVRI ^® on these episodes. Patients were asked to update their home diaries

at 30-minute intervals. ⁵

Episodes are defined as time spent in a PD diary motor state (dyskinesia, or

OFF time) before entering another state. These episodes occur unpredictably

throughout the day. ⁵

Limitations of this subgroup analysis include that it is an analysis of preexisting

data derived from a population with at least mild dyskinesia at baseline and that

it did not include patients who withdrew from the study prematurely or did not

have evaluable diaries at baseline or Week 12. As a result, this analysis may not be

applicable to a more generalized PD population, and no formal conclusions can

be drawn. ⁵

0 2 4 6 8 10 12 14 16

SLEEP AWAKE

POST WAKE-UP TIME (Hours)

SAMPLE DIARY PLOT FOR A SINGLE PATIENT THROUGHOUT THE WAKING DAY ⁵

Results from a post-hoc analysis of diary data

Exploring whether reductions in daily episodes

increased continuous GOOD ON time ⁵

Adapted from Hauser, et al.

IMPORTANT SAFETY INFORMATION (CONT.)

WARNINGS AND PRECAUTIONS (CONT.)

Impulse Control/Compulsive Behaviors: Patients may experience urges (e.g. gambling, sexual, money spending,

binge eating) and the inability to control them. It is important for prescribers to ask patients or their caregivers

about the development of new or increased urges. Consider dose reduction or stopping medications.

GOOD ON TIME

OFF TIME

DYSKINESIA

ASLEEP

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

8

Post-hoc analysis evaluated the impact of decreased dyskinesia

and OFF time on continuous GOOD ON time ⁵

ANALYSIS OF PATIENT DIARY PLOTS (n = 162) REPRESENTING 1 DAY AT BASELINE AND WEEK 12 ⁵ *

*Patients are organized in descending order of number of episodes reported at Week 12 (with baseline reordered to match, so that patient order is the same at baseline and Week 12). ⁵

GOOD ON TIME

OFF TIME

DYSKINESIA

ASLEEP

Adapted from Hauser, et al.

AT WEEK 12

• 57.1% of patients receiving

GOCOVRI ^® reported no episodes of

dyskinesia (vs 24.7% with placebo) ⁵

• 27.3% reported no OFF time

(vs 20.0% with placebo)

• 19.5% reported no dyskinesia nor

OFF time (vs 3.5% with placebo) ⁵

This analysis may not be applicable to a

more generalized PD population and no

formal conclusions can be drawn.

IMPORTANT SAFETY INFORMATION (CONT.)

ADVERSE REACTIONS

The most common adverse reactions (>10%) were hallucination, dizziness, dry mouth, peripheral edema,

constipation, fall, and orthostatic hypotension.

0 2 4 6 8 10 12 14 16

–2

SLEEP AWAKE

Baseline

A SINGLE DAY

0 2 4 6 8 10 12 14 16

–2

SLEEP AWAKE

WEEK 12

A SINGLE DAY

POST WAKE-UP

TIME (HOURS)

GOCOVRI ® (n = 77) PLACEBO (n = 85)

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

9

In the EASE-LID 2 open-label extension (OLE) study

GOCOVRI ^® long-term efficacy and safety were

studied through 2 years ⁶

STUDY DESIGN: Results from a 2-year,

open-label trial evaluating long-term

safety, tolerability, and efficacy of

GOCOVRI ^® (N=223). Patients enrolled in

this trial had completed double-blind

GOCOVRI ^® clinical trials or had been

excluded from prior trials because they

had received DBS treatment. The MDS-

UPDRS was used to assess efficacy:

Part IV of the score captured changes

in dyskinesia and OFF symptoms with a

higher score indicating an increase in

severity (maximum score of 24). ⁶

(n = 60) (n = 78)

223 SUBJECTS ENROLLED AND INITIATED ON OPEN-LABEL GOCOVRI ^{® 6}

Directly enrolled at completion of

GOCOVRI ^® Phase III Trials Patients enrolled from a broader population

that represents real-world clinical settings

CONTINUING GOCOVRI ^® PREVIOUS PLACEBO PATIENTS WITH DBS OR TREATMENT GAP AMANTADINE IR

(n = 32)

(8 gap, 24 DBS)

(n = 85)

All groups started at a daily dose of

137 mg during Week 1, then increased to

a maintenance dosage of 274 mg from

Week 2 to Week 100, and tapered back

down to 137 mg for the final week. ⁶

PATIENTS WERE CLASSIFIED INTO GROUPS BASED ON THEIR PREVIOUS TREATMENT HISTORY ⁶

DBS, deep brain stimulation; IR, immediate release; MDS-UPDRS, Movement Disorders Society-Unified Parkinson’s Disease Rating Scale.

Adapted from Tanner, et al.

IMPORTANT SAFETY INFORMATION (CONT.)

CONTRAINDICATIONS

GOCOVRI is contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m ² .

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

10

Reductions in dyskinesia and OFF time were achieved by all

treatment groups, regardless of previous therapy ⁶

10

6

4

8

14

12

GOCOVRI®

CLINICAL

TRIALS

OPEN-LABEL

GOCOVRI®

16

8 12/24 8

2

BL

- - BL

- - - - - - - - - -

OPEN-LABEL

DOUBLE-BLIND

28 40 52 64 76 88 100

WEEKS

MDS-UPDRS, PART IV SCORE, OBSERVED MEAN (±SE)

GOCOVRI® FROM INITIATION: 44% FROM PLACEBO: 36%

FROM DBS: 38%

FROM AMANTADINE IR: 35%

IMPROVEMENT AT 8 WEEKS

GOCOVRI® FROM INITIATION: 36% FROM PLACEBO: 26%

FROM DBS: 34%

FROM AMANTADINE IR: 36%

IMPROVEMENT AT 100 WEEKS

Durable responses were observed for all groups for the full 2 years of the open-label extension ⁶

This study’s “real-world” design

permitted treatment with and

adjustment of concomitant PD

treatments.

The lack of a blinded control group

reduced the certainty that study

findings were due to GOCOVRI ^® .

No formal comparisons can be

made between GOCOVRI ^® and

other treatment regimens. ⁶

IMPORTANT SAFETY INFORMATION (CONT.)

WARNINGS AND PRECAUTIONS

Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease

medications have reported falling asleep during activities of daily living. If a patient develops daytime sleepiness

during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should

ordinarily be discontinued or the patient should be advised to avoid potentially dangerous activities.

AMANTADINE IR

PLACEBO

DBS ONLY

GOCOVRI®

Adapted from Tanner, et al.

BL, baseline.

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

11

The safety profile of GOCOVRI ^® in this open-label extension study

remained consistent with the pivotal trials ⁶

• Discontinuations due to AEs occurred

more frequently among patients

initiating GOCOVRI ^® in this OLE study,

compared to those who continued on

GOCOVRI ^® from phase 3 trials ⁶

• Discontinuations tended to occur in the

first weeks of treatment around dose

initiation and titration ⁶

• No new safety signals were observed in

this open-label extension ⁶

ADVERSE EVENTS AND DISCONTINUATIONS DUE TO ADVERSE EVENTS (SAFETY POPULATION) ⁶ *

ADVERSE EVENTS Continuing GOCOVRI ^® (n = 60) Previous Placebo (n = 78) All Patients (N = 223)

Summary

Any AE 57 (95.0%) 70 (89.7%) 205 (91.9%)

Study-drug related 31 (51.7%) 45 (57.7%) 124 (55.6%)

Any SAE 16 (26.7%) 21 (26.9%) 60 (26.9%)

Study-drug related 1 (1.7%) 3 (3.8%) 5 (2.2%)

Any leading to study-drug discontinuation or death 12 (20.0%) 21 (26.9%) 49 (22.0%)

Study-drug related 4 (6.7%) 15 (19.2%) 31 (13.9%)

By preferred term*

Fall 13 (21.7%) 29 (37.2%) 73 (32.7%)

Hallucination 15 (25.0%) 24 (30.8%) 54 (24.2%)

Visual 14 (23.3%) 24 (30.8%) 52 (23.3%)

Auditory 1 (1.7%) 1 (1.3%) 5 (2.2%)

Peripheral edema 10 (16.7%) 12 (15.4%) 36 (16.1%)

Constipation 9 (15.0%) 12 (15.4%) 30 (13.5%)

Urinary tract infection 7 (11.7%) 8 (10.3%) 23 (10.3%)

Dizziness 4 (6.7%) 10 (12.8%) 22 (9.9%)

Nausea 7 (11.7%) 8 (10.3%) 22 (9.9%)

Insomnia 8 (13.3%) 5 (6.4%) 21 (9.4%)

Livedo reticularis 6 (10.0%) 5 (6.4%) 20 (9.0%)

ON and OFF phenomenon 7 (11.7%) 4 (5.1%) 18 (8.1%)

Dry mouth 4 (6.7%) 6 (7.7%) 17 (7.6%)

* Includes all preferred terms with an incidence ≥7.5%

among all patients.

AE, adverse event; SAE, serious adverse event.

IMPORTANT SAFETY INFORMATION (CONT.)

WARNINGS AND PRECAUTIONS (CONT.)

Suicidality and Depression: Monitor patients for depression, including suicidal ideation or behavior. Prescribers

should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of

suicidality or depression.

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

12

A single bedtime dose delivers high morning levels before the

first levodopa dose ¹

SLEEP AWAKE

2000

1500

500

0

10PM 2AM 6AM 10AM 2PM 6PM 10PM

1000

AMANTADINE PLASMA CONCENTRATIONS, NG/ML

TIME

AMANTADINE IR

81 mg QAM DOSE

AMANTADINE IR

81 mg QPM DOSE

GOCOVRI®

274 mg

QHS DOSE

1

2

3

4

There are no head-to-head studies in

patients with PD comparing the safety

and efficacy of GOCOVRI® to that of

amantadine IR.

PK data do not provide evidence of

clinical safety or efficacy.

These simulated data are derived from a

steady-state PK study using the 137 mg

QHS dose of GOCOVRI ^® and amantadine

IR 81 mg BID. ¹

1 An initial lag in drug release

2 Gradual increase in plasma

concentrations during the night

3 High levels reached in the morning,

providing all-day coverage that

slowly tapers

4 Plasma concentrations decrease in

the hours before bedtime

BID, twice daily; PK, pharmacokinetic; QAM, once in the morning; QHS, once at bedtime; QPM, once in the afternoon.

GOCOVRI® is not interchangeable with other amantadine immediate- or extended-release products

Adapted from Hauser, et al.

IMPORTANT SAFETY INFORMATION (CONT.)

WARNINGS AND PRECAUTIONS (CONT.)

Dizziness and Orthostatic Hypotension: Monitor patients for dizziness and orthostatic hypotension, especially

after starting GOCOVRI or increasing the dose.

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

13

IMPORTANT SAFETY INFORMATION (CONT.)

WARNINGS AND PRECAUTIONS (CONT.)

Withdrawal-Emergent Hyperpyrexia and Confusion: Rapid dose reduction or abrupt discontinuation of

GOCOVRI, may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions,

hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. Avoid sudden discontinuation

of GOCOVRI.

STARTING DOSE - WEEK 1 TREATMENT DOSE - AFTER WEEK 1

68.5 mg QHS ² (CrCl = 15-59 ML/MIN/1.73M ² )

137 mg QHS ² (CrCl = 30-59 ML/MIN/1.73M ² )

68.5 mg QHS ² (CrCl = 15-29 ML/MIN/1.73M ² )

Because rapid dose reduction or withdrawal may cause adverse reactions,

it is recommended to avoid sudden discontinuation of GOCOVRI ^® . To avoid

sudden discontinuation, patients who have taken GOCOVRI ^® for more than 4

weeks should reduce their dose by half during their final week of dosing ²

A single bedtime dose gives patients all-day coverage

that decreases in the hours before bedtime ²

If a dose is missed, the next dose should be taken as scheduled ²

GOCOVRI ^® can be taken with or without food. GOCOVRI ^® may be administered

by carefully opening and sprinkling the entire contents in 1 teaspoon of soft

food, such as applesauce. Concomitant use of GOCOVRI ^® with alcohol is not

recommended ²

STARTING DOSE - WEEK 1 TREATMENT DOSE - AFTER WEEK 1

*Please see full Prescribing Information for additional dosing information for patients with renal impairment.

137 mg QHS ²

(CrCl ≥ 60 ML/MIN/1.73M ² ) 274 mg QHS ²

(CrCl ≥ 60 ML/MIN/1.73M ² )

A lower dose is recommended for patients with moderate to severe renal impairment*

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

14

Hallucinations (pooled safety data from pivotal trials) ^2,4

INVESTIGATOR

RATING:

• 13 (62%) as mild

• 6 (29%) as moderate

• 2 (10%) as severe

RESOLUTION OF

HALLUCINATIONS:

• 18 (86%) fully resolved

• 12 (57%) resolved in ≤ 2 weeks

• 0 (0%) required

hospitalization or treatment

with antipsychotics

HALLUCINATIONS (21/100, 21%)

<65 YEARS OLD

5/48 (10%) ≥65 YEARS OLD

16/52 (31%)

DISCONTINUED 3 5

DISCONTINUED

REDUCED OR 1

INTERRUPTED

REDUCED OR 3

INTERRUPTED

CONTINUED 1

TREATMENT

CONTINUED 8

TREATMENT

RESOLVED: 3 RESOLVED: 1 RESOLVED: 1 RESOLVED: 5 RESOLVED: 3 RESOLVED: 5

• Majority of patients with PD are elderly and therefore more likely to have decreased renal function, which may put

these patients at greater risk of adverse events ²

• Care should be taken in dose selection; observe patients for the occurrence of hallucinations throughout

treatment, especially at initiation and after dose increases ²

IMPORTANT SAFETY INFORMATION (CONT.)

WARNINGS AND PRECAUTIONS (CONT.)

Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be

treated with GOCOVRI because of the risk of exacerbating psychosis. Observe patients for the occurrence of

hallucinations throughout treatment, especially at initiation and after dose increases.

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

15

GOCOVRI Onboard ^® : Dedicated to helping your patients access GOCOVRI ^®

Once you have identified an appropriate patient, a free, 4-week trial may be available*

Your GOCOVRI ^® Care Coordinator is a dedicated, single point-of-contact for you and your patients who partners

with a specialty pharmacy to provide timely fulfillment.

In addition, GOCOVRI Onboard ^® offers the following for you and your patients:

• Benefits verification

• Electronic submission of prior authorizations through CoverMyMeds ^®

• Next-day delivery to patients each month

• Monthly follow-up from a specialty pharmacy to schedule deliveries to patients

• Answers to questions you or your patients may have

93% ^{APPROVED PAY} $25 ^{OR LESS} $20 ^CO-PAY

Regardless of formulary status, 93% of prescriptions

have been processed and approved ^† For patients receiving GOCOVRI ^® , ~75% pay $25 or less

per prescription and ~92% pay $100 or less ^† Commercially insured patients who participate in the GOCOVRI ^®

Co-pay Assistance Program pay $20 per prescription ^‡

Learn more about GOCOVRI Onboard ^® at GocovriHCP.com

*For new, eligible patients.

† Based on specialty pharmacy data 1/1/2019-6/30/2019.

‡ This offer is valid only for patients who have commercial (nongovernment-funded) insurance and must meet eligibility requirements. See full Terms & Conditions.

1-844-GOCOVRI

(1-844-462-6874)

8 am—8 pm ET M-F

IMPORTANT SAFETY INFORMATION (CONT.)

WARNINGS AND PRECAUTIONS

Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease

medications have reported falling asleep during activities of daily living. If a patient develops daytime sleepiness

during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should

ordinarily be discontinued or the patient should be advised to avoid potentially dangerous activities.

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

SELECT IMPORTANT SAFETY INFORMATION

16

Important Safety Information

CONTRAINDICATIONS

GOCOVRI is contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m ² .

WARNINGS AND PRECAUTIONS

Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported falling asleep

during activities of daily living. If a patient develops daytime sleepiness during activities that require full attention (e.g., driving a motor vehicle,

conversations, eating), GOCOVRI should ordinarily be discontinued or the patient should be advised to avoid potentially dangerous activities.

Suicidality and Depression: Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits

outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression.

Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of

exacerbating psychosis. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases.

Dizziness and Orthostatic Hypotension: Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose.

Withdrawal-Emergent Hyperpyrexia and Confusion: Rapid dose reduction or abrupt discontinuation of GOCOVRI, may cause an increase in the

symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech.

Avoid sudden discontinuation of GOCOVRI.

Impulse Control/Compulsive Behaviors: Patients may experience urges (e.g. gambling, sexual, money spending, binge eating) and the inability to control

them. It is important for prescribers to ask patients or their caregivers about the development of new or increased urges. Consider dose reduction or

stopping medications.

ADVERSE REACTIONS

The most common adverse reactions (>10%) were hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and orthostatic hypotension.

View the full Prescribing Information.

References: 1. Hauser RA, Pahwa R, Wargin WA, et al. Pharmacokinetics of ADS-5102 (amantadine) extended release capsules administered once daily at

bedtime for the treatment of dyskinesia. Clin Pharmacokinet. 2019;58(1):77-88. 2. GOCOVRI® (amantadine) [Prescribing Information]. Emeryville, CA. Adamas

Pharma LLC; 2021. 3. Elmer LW, Juncos JL, Singer C, et al. Pooled analyses of phase III studies of ADS-5102 (amantadine) extended-release capsules for dyskinesia

in Parkinson’s disease. CNS Drugs. 2018;32(4):387-398. 4. Data on file. Adamas Pharma LLC, Emeryville, CA. 5. Hauser RA, Kremens DE, Elmer LW, et al. Prevalence

of dyskinesia and OFF by 30-minute intervals through the day and assessment of daily episodes of dyskinesia and OFF: novel analyses of diary data from Gocovri

pivotal trials. J Parkinsons Dis. 2019;9(3):591-600. 6. Tanner CM, Pahwa R, Hauser RA, et al. EASE LID 2: a 2-year open-label trial of Gocovri (amantadine) extended

release for dyskinesia in Parkinson’s disease. J Parkinsons Dis. 2020;10(2):543–558. 7. Isaacson, S.H., Fahn, S., Pahwa, R., et al. Parkinson’s Patients with Dyskinesia

Switched from Immediate Release Amantadine to Open‐label ADS‐5102. Mov Disord Clin Pract, 2018;5: 183-190.

* Pooled results from 2 independently positive, pivotal, Phase 3, randomized, placebo-controlled trials (Study 1 and Study 2) in PD patients on levodopa. Study 1, a 24-week study, was conducted in 121 PD patients

with dyskinesia (GOCOVRI® [n = 63], placebo [n = 58]). Study 2, a 12-week study, was conducted in 75 PD patients with dyskinesia (GOCOVRI® [n = 37], placebo [n = 38]). ^2,3

† In Study 1, GOCOVRI® reduced the UDysRS total score by 15.9 points (vs 8.0 with placebo) (P = 0.0009), decreased OFF time by 0.6 hours (vs an increase of 0.3 hours with placebo) (P = 0.0171), and increased GOOD

ON time by 3.6 hours (vs 0.8 hours with placebo) (P < 0.0001) from baseline. In Study 2, GOCOVRI® reduced the UDysRS total score by 20.7 points (vs 6.3 with placebo) (P < 0.0001), decreased OFF time by 0.5 hours

(vs an increase of 0.6 hours with placebo) (P = 0.0199), and increased GOOD ON time by 4.0 hours (vs 2.1 hours with placebo) (P = 0.0168) from baseline. ²

‡ For new eligible patients. No purchase of GOCOVRI® or enrollment into GOCOVRI Onboard® is required. See Terms & Conditions at gocovrihcp.com/terms-and-conditions.

Adamas, Gocovri, and Gocovri Onboard are registered trademarks of Adamas Pharmaceuticals, Inc. or its related companies.

© 2021 Adamas Pharmaceuticals, Inc. or its related companies. All rights reserved. GOC-0752 V4 7/21

Learn more at GocovriHCP.com

INDICATION

GOCOVRI® is indicated:

• For the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications

• As adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

GOCOVRI is contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m ² .

POOLED RESULTS FROM PIVOTAL TRIALS*

Primary endpoint: Secondary endpoints:

DECREASE

IN DYSKINESIA DECREASE

IN OFF TIME INCREASE IN

GOOD ON TIME

27% ^{36% 29%}

10.1-point reduction in

UDysRS score (-17.7

GOCOVRI® vs -7.6 placebo) ^3,4†

1-hour decrease

(-0.6 GOCOVRI® vs

0.4 placebo) ^3,4†

2.4-hour increase

(3.8 GOCOVRI® vs

1.4 placebo) ^3,4†

GOCOVRI ^® is not interchangeable with other amantadine immediate- or extended-release products

The first and only medication approved to

treat both OFF episodes and dyskinesia in

patients taking levodopa. ²

GOCOVRI Onboard®:

dedicated to helping your

patients access GOCOVRI®

Once you have identified an

appropriate patient, a free,

4-week trial may be available ^‡

Please see Important Safety Information on page 16 and click here for full Prescribing Information.

NIGHTTIME DOSING NIGHTTIME DOSING DAYTIME COVERAGE DAYTIME COVERAGE

1 HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use GOCOVRI^® safely and effectively. See full prescribing infor mation for GOCOVRI.

GOCOVRI^® (amantadine) extended-release capsules, for oral use Initial U.S. Approval: 1968

---RECENT MAJOR CHANGES--- Indications and Usage (1) 1/2021 Dosage and Administration, Dosing Information (2.1) 3/2020

---INDICATIONS AND USAGE--- GOCOVRI^® is indicated:

• For the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications (1)

• As adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes (1)

---DOSAGE AND ADMINISTRATION---

• Administer orally once daily at bedtime (2.1, 2.3)

• The initial daily dosage is 137 mg; after 1 week, increase to the recommended daily dosage of 274 mg (2.1)

• Swallow whole; may sprinkle contents on soft food (2.2)

• May be taken with or without food; avoid use with alcohol (2.2)

• A lower dosage is recommended for patients with moderate or severe renal impairment (2.3)

---DOSAGE FORMS AND STRENGTHS--- Extended-release capsules: 68.5 mg and 137 mg (3)

---CONTRAINDICATIONS--- GOCOVRI is contraindicated in patients with end-stage renal disease (4)

---WARNINGS AND PRECAUTIONS---

• Falling Asleep During Activities of Daily Living: Advise patients prior to treatment; ordinarily discontinue if occurs (5.1)

• Suicidality and Depression: Monitor patients for depressed mood, depression, or suicidal ideation or behavior (5.2)

• Hallucinations/Psychotic Behavior: Patients with major psychotic disorder should ordinarily not be treated with GOCOVRI; observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases (5.3)

• Dizziness and Orthostatic Hypotension: Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose (5.4)

• Withdrawal-Emergent Hyperpyrexia and Confusion: Avoid sudden discontinuation (5.5)

• Impulse Control/Compulsive Behaviors: Ask patients about increased gambling urges, sexual urges, uncontrolled spending or other urges;

consider dose reduction or discontinuation if occurs (5.6)

---ADVERSE REACTIONS--- The most commonly observed adverse reactions occurring at a frequency of >10% and greater than placebo were hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and orthostatic hypotension (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Adamas Pharma, LLC at 1-833-223-2627 or FDA at 1-800-FDA- 1088 or http://www.fda.gov/medwatch.

---DRUG INTERACTIONS---

• Other Anticholinergic Drugs: Doses should be reduced if atropine-like effects occur (7.1)

• Drugs Affecting Urinary pH: Excretion increases with acidic urine;

possible accumulation with urine change towards alkaline (7.2)

• Live Attenuated Influenza Vaccines: Not recommended during use (7.3)

• Alcohol: Concomitant use not recommended (7.4)

---USE IN SPECIFIC POPULATIONS---

• Pregnancy: Based on animal data, may cause fetal harm (8.1)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 1/2021

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information 2.2 Administration Information

2.3 Dosing in Patients with Renal Impairment 2.4 Discontinuation and Missed Dose 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Falling Asleep During Activities of Daily Living and Somnolence 5.2 Suicidality and Depression

5.3 Hallucinations/Psychotic Behavior 5.4 Dizziness and Orthostatic Hypotension

5.5 Withdrawal-Emergent Hyperpyrexia and Confusion 5.6 Impulse Control/Compulsive Behaviors

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS

7.1 Other Anticholinergic Drugs 7.2 Drugs Affecting Urinary pH 7.3 Live Attenuated Influenza Vaccines 7.4 Alcohol

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy

8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 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 16.1 How Supplied

16.2 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 GOCOVRI^® is indicated:

• For the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa- based therapy, with or without concomitant dopaminergic medications

• As adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information

The initial daily dosage of GOCOVRI is 137 mg, administered orally once daily at bedtime.

After one week, increase to the recommended dosage of 274 mg (two 137 mg capsules) once daily at bedtime.GOCOVRI is not interchangeable with other amantadine immediate- or extended-release products.

2.2 Administration Information

GOCOVRI should be swallowed whole. Do not crush, chew or divide capsules. If needed, GOCOVRI may be administered by carefully opening and sprinkling the entire contents on a small amount (teaspoonful) of soft food, such as applesauce. The drug/food mixture should be swallowed immediately without chewing. Do not store mixture for future use.

GOCOVRI can be taken with or without food [see Clinical Pharmacology (12.3)].

Concomitant use of GOCOVRI with alcohol is not recommended [see Drug Interactions (7.4)].

It is recommended to avoid sudden discontinuation of GOCOVRI [see Dosage and Administration (2.4)].

2.3 Dosing in Patients with Renal Impairment

The initial and maximum recommended daily dosage of GOCOVRI for patients with renal impairment (creatinine clearance estimated by Modification of Diet in Renal Disease (MDRD) method) is provided below.

Creatinine Clearance Dosage

Mild renal impairment

(60 to 89 mL/min/1.73 m²)

Initial dosage: 137 mg once daily at bedtime. After one week, increase to recommended dosage of 274 mg once daily at bedtime.

Moderate renal impairment (30 to 59 mL/min/1.73 m²)

Initial dosage: 68.5 mg once daily at bedtime

Maximum recommended dosage: 137 mg once daily at bedtime¹ Severe renal impairment

(15 to 29 mL/min/1.73 m²)

68.5 mg once daily at bedtime

3

Creatinine Clearance Dosage

End Stage Renal Disease (below 15 mL/min/1.73 m²)

Contraindicated

1 Increase, if needed, after one week of the initial dosage

2.4 Discontinuation and Missed Dose

Rapid dose reduction or withdrawal of GOCOVRI may cause adverse reactions [see Warnings and Precautions (5.5)]. Therefore, to discontinue GOCOVRI in patients who have been on the drug for more than 4 weeks, GOCOVRI dosage should, if possible, be reduced by half for the final week of dosing.

If a dose of GOCOVRI is missed, the next dose should be taken as scheduled.

3 DOSAGE FORMS AND STRENGTHS

GOCOVRI is available as extended-release capsules for oral administration. Each capsule contains 68.5 mg or 137 mg of amantadine.

The 68.5 mg capsule is a white opaque size #2 capsule, with black printing of ‘ADAMAS’ on front and ‘85’ on back of the cap and three black bands printed on body of capsule.

The 137 mg capsule is a light blue opaque size #0 capsule, with black printing of ‘ADAMAS’ on front and ‘170’ on back of the cap and three black bands printed on body of capsule.

4 CONTRAINDICATIONS

GOCOVRI is contraindicated in patients with end-stage renal disease (i.e., creatinine clearance below 15 mL/min/1.73 m² ) [see Clinical Pharmacology (12.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Falling Asleep During Activities of Daily Living and Somnolence

Patients treated for Parkinson’s disease have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. In controlled clinical trials, somnolence and fatigue were reported as adverse reactions in 4% of patients treated with GOCOVRI 274 mg and 1% for placebo.

Before initiating treatment with GOCOVRI, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with GOCOVRI, such as concomitant sedating medications or the presence of a sleep disorder. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued.

4

If a decision is made to continue GOCOVRI, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living or daytime somnolence.

5.2 Suicidality and Depression

In controlled clinical trials, suicidal ideation or suicide attempt was reported in 2% of

GOCOVRI-treated patients and 0% of placebo-treated patients. Depression or depressed mood was reported in 6% of GOCOVRI-treated patients and 1% of placebo-treated patients.

Confusional state was reported in 3% of GOCOVRI-treated patients and 2% of placebo-treated patients. Apathy was reported in 2% of GOCOVRI-treated patients and 0% of placebo-treated patients.

Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression.

5.3 Hallucinations/Psychotic Behavior

Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. In controlled trials, the incidence of patients who experienced visual hallucinations, auditory hallucinations, delusions, illusions, or paranoia was 25% in patients treated with GOCOVRI 274 mg, and 3% in placebo-treated patients.

Hallucinations caused discontinuation of treatment in 8% of GOCOVRI-treated patients, and in 0% of placebo-treated patients.

Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation, and after dose increases.

5.4 Dizziness and Orthostatic Hypotension

In controlled clinical trials, 29% of GOCOVRI-treated patients and 2% of placebo-treated patients experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness or hypotension. In GOCOVRI-treated patients, 3% discontinued study treatment because of dizziness, postural dizziness, or syncope, compared to 0% of placebo-treated patients.

Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose. Concomitant use of alcohol when using GOCOVRI is not recommended [see Drug Interactions (7.4)].

5.5 Withdrawal-Emergent Hyperpyrexia and Confusion

A symptom complex resembling 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 drugs that increase central dopaminergic tone.

Abrupt discontinuation of GOCOVRI may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. It is recommended to avoid sudden discontinuation of GOCOVRI [see Dosing Information (2.4)].

5

5.6 Impulse Control/Compulsive Behaviors

Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including GOCOVRI, that increase central dopaminergic tone. In some cases, 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 GOCOVRI. Consider dose reduction or stopping the medication if a patient develops such urges while taking GOCOVRI.

6 ADVERSE REACTIONS

The following serious adverse reactions are described in more detail elsewhere in the labeling:

• Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1)]

• Suicidality and Depression [see Warnings and Precautions (5.2)]

• Hallucinations/Psychotic Behavior [see Warnings and Precautions (5.3)]

• Dizziness and Orthostatic Hypotension [see Warnings and Precautions (5.4)]

• Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.5)]

• Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.6)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Placebo-Controlled Trials

GOCOVRI was evaluated in two double-blind, placebo-controlled efficacy trials of similar design and population: Study 1 (123 patients) and Study 2 (75 patients) [see Clinical Studies (14)]. The study population was approximately 56% male and 94% white, with a mean age of 65 years (age range from 34 years to 82 years). The mean duration of levodopa-induced

dyskinesia was 4 years (range 0.1 to 14 years). Active treatment started at 137 mg once daily for one week, followed by a dose increase to 274 mg once daily. The treatment duration was 25 weeks for Study 1 and 13 weeks for Study 2. Of the 100 patients in the safety population described below, 39 patients were treated with GOCOVRI for 24 weeks. The safety data for these trials were pooled.

The most common adverse reactions reported in >10% of GOCOVRI-treated patients and more frequently than on placebo were: hallucinations, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension.

The overall rate of discontinuation because of adverse reactions for GOCOVRI-treated patients was 20%, compared to 8% for placebo-treated patients. Adverse reactions that led to treatment discontinuation in at least 2% of patients were hallucinations (8% GOCOVRI vs. 0% placebo),

6

dry mouth (3% GOCOVRI vs. 0% placebo), peripheral edema (3% GOCOVRI vs. 0% placebo), blurred vision (GOCOVRI 3% vs. 0% placebo), postural dizziness and syncope (GOCOVRI 2%

vs. 0% placebo), abnormal dreams (GOCOVRI 2% vs. 1% placebo), dysphagia (GOCOVRI 2%

vs. 0% placebo), and gait disturbance (GOCOVRI 2% vs. 0% placebo).

Table 1: Adverse Reactions Reported for ≥ 3% of Patients Treated with 274 mg GOCOVRI in Study 1 and Study 2 (Pooled Analysis)

Adverse Reactions GOCOVRI 274 mg

N=100

%

Placebo N=98

% Psychiatric disorders

Hallucinations^a Anxiety^b Insomnia

Depression/Depressed mood Abnormal dreams

Confusional state

21 7 7 6 4 3

3 3 2 1 2 2 Nervous system disorders

Dizziness Headache Dystonia

16 6 3

1 4 1 Gastrointestinal disorders

Dry mouth Constipation Nausea Vomiting

16 13 8 3

1 3 3 0 General disorders and administration site conditions

Peripheral edema Gait disturbance

16 3

1 0 Injury, poisoning and procedural complications

Fall Contusion

13 6

7 1 Infections and infestations

Urinary tract infection 10 5

Skin and subcutaneous tissue disorders Livedo reticularis

Pigmentation disorder 6

3

0 0 Metabolism and nutrition disorders

Decreased appetite 6 1

Vascular disorders

Orthostatic hypotension^c 13 1

Eye disorders Blurred vision Cataract Dry eye

4 3 3

1 1 0 Musculoskeletal and connective tissue disorders

Joint swelling Muscle spasms

3 3

0 0 Reproductive system and breast disorders

Benign prostatic hyperplasia^d 6 2

Respiratory, thoracic and mediastinal disorders

Cough 3 0

a=Includes visual hallucinations and auditory hallucinations b=Includes anxiety and generalized anxiety

c=Includes orthostatic hypotension, posturaldizziness,syncope, presyncope, and hypotension

d=The denominator is all male patients in the safety population randomized to GOCOVRI (n=54) or placebo (n=57)

7

Other clinically relevant adverse reactions observed at <3% included somnolence, fatigue, suicide ideation or attempt, apathy, delusions, illusions, and paranoia [see Warnings and Precautions (5.1, 5.2, 5.3)].

Difference in the Frequency of Adverse Reactions by Gender

Adverse reactions reported more frequently in women treated with 274 mg of GOCOVRI (n=46), compared to men (n=54), were: dry mouth (22% women, 11% men), nausea (13%

women, 4% men), livedo reticularis (13% women, 0% men), abnormal dreams (9% women, 0%

men) and cataracts (7% women, 0% men).

Men treated with 274 mg of GOCOVRI reported the following adverse reactions more

frequently than women: dizziness (20% men, 11% women), peripheral edema (19% men, 11%

women), anxiety (11% men, 2% women), orthostatic hypotension (7% men, 2% women) and gait disturbance (6% men, 0% women).

Difference in the Frequency of Adverse Reactions by Age

Hallucinations (visual or auditory) were reported in 31% of GOCOVRI-treated patients age 65 years and over (n=52), compared to 10% in patients below the age of 65 years (n=48). Falls were reported in 17% of GOCOVRI-treated patients age 65 and over, compared to 8% of patients below age 65. Orthostatic hypotension was reported in 8% of patients age 65 and over, compared to 2% of patients below age 65.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of GOCOVRI.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System Disorders: Seizure.

7 DRUG INTERACTIONS 7.1 Other Anticholinergic Drugs

Products with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. The dose of anticholinergic drugs or of GOCOVRI should be reduced if atropine- like effects appear when these drugs are used concurrently.

7.2 Drugs Affecting Urinary pH

The pH of the urine has been reported to influence the excretion rate of amantadine. Urine pH is altered by diet, drugs (e.g., carbonic anhydrase inhibitors, sodium bicarbonate), and clinical state of the patient (e.g., renal tubular acidosis or severe infections of the urinary tract).

Since the excretion rate of amantadine increases rapidly when the urine is acidic, the

administration of urine acidifying drugs may increase the elimination of the drug from the body.

Alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse reactions. Monitor for efficacy or adverse reactions under conditions that alter the urine pH to more acidic or alkaline, respectively.

8

7.3 Live Attenuated Influenza Vaccines

Because of its antiviral properties, amantadine may interfere with the efficacy of live attenuated influenza vaccines. Therefore, live vaccines are not recommended during treatment with

GOCOVRI. Inactivated influenza vaccines may be used, as appropriate.

7.4 Alcohol

Concomitant use with alcohol is not recommended, as it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension [see Warnings and Precautions (5.4)], and may result in dose-dumping [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with use of amantadine in pregnant women. Animal studies suggest a potential risk for fetal harm with amantadine. In mice and rats, adverse developmental effects (embryolethality, increased incidence of malformations, and reduced fetal body weight) were observed when amantadine was administered to pregnant animals at clinically relevant doses [see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk for major birth defects and miscarriage in patients with Parkinson’s disease is unknown.

Data

Animal Data

The effects of amantadine on development have not been tested in studies conducted in animals using currently recommended methodology; however, developmental toxicity studies of

amantadine have been reported in the published literature.

In mice, oral administration of amantadine (0, 10, or 40 mg/kg/day) to pregnant animals during organogenesis (gestation days 7-12) resulted in embryolethality and reduced fetal body weight at the highest dose tested, which was associated with maternal toxicity. The no-effect dose for developmental toxicity in mice (10 mg/kg/day) is less than the recommended human dose (RHD) of 274 mg/day, based on body surface area (mg/m²).

In rats, oral administration of amantadine (0, 40 or 120 mg/kg/day) to pregnant animals during organogenesis (gestation days 7-12) resulted in embryolethality and reduced fetal body weight at the highest dose. The no-effect dose for developmental toxicity in this study (40 mg/kg/day) is approximately equal to the RHD on a mg/m² basis.

In another study in pregnant rats, oral administration of amantadine during organogenesis (gestation days 7-14) resulted in an increase in visceral and skeletal malformations at oral doses of 50 and 100 mg/kg/day. The no-effect dose for teratogenicity in this study (37 mg/kg/day) is approximately equal to the RHD on a mg/m² basis.