ROPINIROLE- ropinirole tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
ROPINIROLE HYDROCHLORIDE (UNII: D7ZD41RZI9) (ROPINIROLE - UNII:030PYR8953)
Available from:
Bryant Ranch Prepack
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Ropinirole tablets are indicated for the treatment of Parkinson’s disease. Ropinirole tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS). Ropinirole tablets are contraindicated in patients known to have a hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients. Risk Summary There are no adequate data on the developmental risk associated with the use of ropinirole hydrochloride in pregnant women. In animal studies, ropinirole had adverse effects on development when administered to pregnant rats at doses similar to (neurobehavioral impairment) or greater than (teratogenicity and embryolethality at >36 times) the maximum recommended human dose (MRHD) for Parkinson’s disease. Ropinirole doses associated with teratogenicity and embryolethality in pregnant rats were associated with maternal toxicity. In pregnant rabbits, ropinirole potentiated the teratogenic effects of L-dopa when these drugs were
Product summary:
Product: 63629-8123 NDC: 63629-8123-1 30 TABLET, FILM COATED in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
63629-8123-1

ROPINIROLE- ropinirole tablet, film coated

Bryant Ranch Prepack

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ROPINIROLE TABLETS safely and

effectively. See full prescribing information for ROPINIROLE TABLETS.

ROPINIROLE tablets, for oral use

Initial U.S. Approval: 1997

RECENT MAJOR CHANGES

Dosage and Administration ( 2.3) 9/2016

Warnings and Precautions ( 5.7, 5.9) 9/2016

INDICATIONS AND USAGE

Ropinirole tablets are a non-ergoline dopamine agonist indicated for the treatment of Parkinson’s disease (PD) and

moderate-to-severe primary Restless Legs Syndrome (RLS). ( 1.1, 1.2)

DOSAGE AND ADMINISTRATION

Ropinirole tablets can be taken with or without food. ( 2.1)

Retitration of ropinirole hydrochloride may be warranted if therapy is interrupted. ( 2.1)

Parkinson’s Disease:

The recommended starting dose is 0.25 mg taken three times daily; titrate to a maximum daily dose of 24 mg. (2.2)

Renal Impairment: The maximum recommended dose is 18 mg/day in patients with end-stage renal disease on

hemodialysis. (2.2)

Restless Legs Syndrome:

The recommended starting dose is 0.25 mg once daily, 1 to 3 hours before bedtime, titrate to a maximum

recommended dose of 4 mg daily. (2.3)

Renal Impairment: The maximum recommended dose is 3 mg/day in patients with end-stage renal disease on

hemodialysis. (2.3)

DOSAGE FORMS AND STRENGTHS

Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, and 5 mg (3)

CONTRAINDICATIONS

History of hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the

excipients. (4)

WARNINGS AND PRECAUTIONS

Sudden onset of sleep and somnolence may occur (5.1)

Syncope may occur (5.2)

Hypotension, including orthostatic hypotension may occur (5.3)

May cause hallucinations and psychotic-like behaviors (5.4)

May cause or exacerbate dyskinesia (5.5)

May cause problems with impulse control or compulsive behaviors (5.6)

ADVERSE REACTIONS

Most common adverse reactions (incidence with ropinirole hydrochloride at least 5% greater than placebo) in the

respective indications were:

Early PD: Nausea, somnolence, dizziness, syncope, asthenic condition, viral infection, leg edema, vomiting, and

dyspepsia. (6.1)

Advanced PD: Dyskinesia, somnolence, nausea, dizziness, confusion, hallucinations, sweating, and headache. (6.1)

RLS: Nausea, vomiting, somnolence, dizziness, and asthenic condition. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or

www.accordhealthcare.us or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Inhibitors or inducers of CYP1A2: May alter the clearance of ropinirole hydrochloride; dose adjustment of ropinirole

hydrochloride may be required. ( 7.1, 12.3)

Hormone replacement therapy (HRT): Starting or stopping HRT may require dose adjustment of ropinirole

hydrochloride. ( 7.2, 12.3)

Dopamine antagonists (e.g., neuroleptics, metoclopramide): May reduce efficacy of ropinirole hydrochloride. ( 7.3)

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: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Parkinson’s Disease

1.2 Restless Legs Syndrome

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Recommendations

2.2 Dosing for Parkinson’s Disease

2.3 Dosing for Restless Legs Syndrome

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Falling Asleep during Activities of Daily Living and Somnolence

5.2 Syncope

5.3 Hypotension/Orthostatic Hypotension

5.4 Hallucinations/Psychotic-like Behavior

5.5 Dyskinesia

5.6 Impulse Control/Compulsive Behaviors

5.7 Withdrawal-Emergent Hyperpyrexia and Confusion

5.8 Melanoma

5.9 Augmentation and Early-Morning Rebound in Restless Legs Syndrome

5.10 Fibrotic Complications

5.11 Retinal Pathology

5.12 Binding to Melanin

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

7 DRUG INTERACTIONS

7.1 CYP1A2 Inhibitors and Inducers

7.2 Estrogens

7.3 Dopamine Antagonists

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

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

14.1 Parkinson’s Disease

14.2 Restless Legs Syndrome

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Parkinson’s Disease

Ropinirole tablets are indicated for the treatment of Parkinson’s disease.

1.2 Restless Legs Syndrome

Ropinirole tablets are indicated for the treatment of moderate-to-severe primary Restless Legs

Syndrome (RLS).

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Recommendations

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

If a significant interruption in therapy with ropinirole hydrochloride has occurred, retitration of therapy

may be warranted.

2.2 Dosing for Parkinson’s Disease

The recommended starting dose of ropinirole hydrochloride for Parkinson’s disease is 0.25 mg three

times daily. Based on individual patient therapeutic response and tolerability, if necessary, the dose

should then be titrated with weekly increments as described in Table 1. After Week 4, if necessary, the

daily dose may be increased by 1.5 mg/day on a weekly basis up to a dose of 9 mg/day, and then by up to

3 mg/day weekly up to a maximum recommended total daily dose of 24 mg/day (8 mg three times daily).

Doses greater than 24 mg/day have not been tested in clinical trials.

Table 1. Ascending-Dose Schedule of Ropinirole Hydrochloride for Parkinson’s

Dis eas e

Week

Dos age

Total Daily Dose

0.25 mg 3 times daily

0.75 mg

0.5 mg 3 times daily

1.5 mg

0.75 mg 3 times daily

2.25 mg

1 mg 3 times daily

3 mg

Sections or subsections omitted from the full prescribing information are not listed.

Ropinirole tablets should be discontinued gradually over a 7-day period in patients with Parkinson’s

disease. The frequency of administration should be reduced from three times daily to twice daily for

4 days. For the remaining 3 days, the frequency should be reduced to once daily prior to complete

withdrawal of ropinirole tablets.

Renal Impairment

No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30

to 50 mL/min). The recommended initial dose of ropinirole for patients with end-stage renal disease on

hemodialysis is 0.25 mg three times a day. Further dose escalations should be based on tolerability and

need for efficacy. The recommended maximum total daily dose is 18 mg/day in patients receiving

regular dialysis. Supplemental doses after dialysis are not required. The use of ropinirole

hydrochloride in patients with severe renal impairment without regular dialysis has not been studied.

2.3 Dosing for Restless Legs Syndrome

The recommended adult starting dose for RLS is 0.25 mg once daily 1 to 3 hours before bedtime. After

2 days, if necessary, the dose can be increased to 0.5 mg once daily, and to 1 mg once daily at the end of

the first week of dosing, then as shown in Table 2 as needed to achieve efficacy. Titration should be

based on individual patient therapeutic response and tolerability, up to a maximum recommended dose of

4 mg daily. For RLS, the safety and effectiveness of doses greater than 4 mg once daily have not been

established.

Table 2. Dose Titration Schedule of Ropinirole Hydrochloride for Restless

Legs Syndrome

Day/Week

Dose to be taken once daily

1 to 3 hours before bedtime

Days 1 and 2

0.25 mg

Days 3 to 7

0.5 mg

Week 2

1 mg

Week 3

1.5 mg

Week 4

2 mg

Week 5

2.5 mg

Week 6

3 mg

Week 7

4 mg

When discontinuing ropinirole hydrochloride in patients with RLS, gradual reduction of the daily dose

is recommended [see Warnings and Precautions (5.9)] .

Renal Impairment

No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30

to 50 mL/min). The recommended initial dose of ropinirole for patients with end-stage renal disease on

hemodialysis is 0.25 mg once daily. Further dose escalations should be based on tolerability and need

for efficacy. The recommended maximum total daily dose is 3 mg/day in patients receiving regular

dialysis. Supplemental doses after dialysis are not required. The use of ropinirole hydrochloride in

patients with severe renal impairment without regular dialysis has not been studied.

3 DOSAGE FORMS AND STRENGTHS

0.25 mg: White to off white, round, biconvex, film coated tablets debossed with "R6" on one side

and plain on other side.

0.5 mg: Yellow, round, biconvex, film coated tablets debossed with "R7" on one side and plain on

other side.

1 mg: Green, round, biconvex, film coated tablets debossed with "R1" on one side and plain on other

side.

2 mg: Pink, round, biconvex, film coated tablets debossed with "R2" on one side and plain on other

side.

3 mg: Purple to light purple, round, biconvex, film coated tablets debossed with "R3" on one side

and plain on other side.

4 mg: Brown to pale brown, round, biconvex, film coated tablets debossed with "R4" on one side

and plain on other side.

5 mg: Blue, round, biconvex, film coated tablets debossed with "R5" on one side and plain on other

side.

4 CONTRAINDICATIONS

Ropinirole tablets are contraindicated in patients known to have a hypersensitivity/allergic reaction

(including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients.

5 WARNINGS AND PRECAUTIONS

5.1 Falling Asleep during Activities of Daily Living and Somnolence

Patients treated with ropinirole hydrochloride have reported falling asleep while engaged in activities

of daily living, including driving or operating machinery, which sometimes resulted in accidents.

Although many of these patients reported somnolence while on ropinirole hydrochloride, some

perceived that they had no warning signs, such as excessive drowsiness, and believed that they were

alert immediately prior to the event. Some have reported these events more than 1 year after initiation of

treatment.

In controlled clinical trials, somnolence was commonly reported in patients receiving ropinirole

hydrochloride and was more frequent in Parkinson's disease (up to 40% ropinirole hydrochloride, 6%

placebo) than in Restless Legs Syndrome (12% ropinirole hydrochloride, 6% placebo) [see Adverse

Reactions (6.1)] .

It has been reported that falling asleep while engaged in activities of daily living usually occurs in a

setting of pre-existing somnolence, although patients may not give such a history. For this reason,

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 ropinirole hydrochloride, patients should be advised of the potential to

develop drowsiness and specifically asked about factors that may increase the risk with ropinirole

hydrochloride such as concomitant sedating medications or alcohol, the presence of sleep disorders

(other than RLS), and concomitant medications that increase ropinirole plasma levels (e.g.,

ciprofloxacin) [see Drug Interactions (7.1)] . If a patient develops significant daytime sleepiness or

episodes of falling asleep during activities that require active participation (e.g., driving a motor

vehicle, conversations, eating), ropinirole hydrochloride should ordinarily be discontinued [see Dosage

and Administration (2.2, 2.3)] . If a decision is made to continue ropinirole hydrochloride, patients

should be advised to not 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.

5.2 Syncope

Syncope, sometimes associated with bradycardia, was observed in association with treatment with

ropinirole hydrochloride in both patients with Parkinson’s disease and patients with RLS. In controlled

clinical trials in patients with Parkinson’s disease, syncope was observed more frequently in patients

receiving ropinirole hydrochloride than in patients receiving placebo (early Parkinson’s disease

without levodopa [L-dopa]: ropinirole hydrochloride 12%, placebo 1%; advanced Parkinson’s disease:

ropinirole hydrochloride 3%, placebo 2%). Syncope was reported in 1% of patients treated with

ropinirole hydrochloride for RLS in 12-week, placebo-controlled clinical trials compared with 0.2%

of patients treated with placebo [see Adverse Reactions (6.1)] . Most cases occurred more than 4 weeks

after initiation of therapy with ropinirole hydrochloride, and were usually associated with a recent

increase in dose.

Because the trials conducted with ropinirole hydrochloride excluded patients with significant

cardiovascular disease, patients with significant cardiovascular disease should be treated with caution.

Approximately 4% of patients with Parkinson’s disease enrolled in Phase 1 trials had syncope

following a 1-mg dose of ropinirole hydrochloride. In two trials in patients with RLS that used a

forced-titration regimen and orthostatic challenge with intensive blood pressure monitoring, 2% of RLS

patients treated with ropinirole hydrochloride compared with 0% of patients receiving placebo

reported syncope.

In Phase 1 trials including healthy volunteers, the incidence of syncope was 2%. Of note, 1 subject with

syncope developed hypotension, bradycardia, and sinus arrest; the subject recovered spontaneously

without intervention.

5.3 Hypotension/Orthostatic Hypotension

Patients with Parkinson’s disease may have impaired ability to respond normally to a fall in blood

pressure after standing from lying down or seated position. Patients on ropinirole hydrochloride should

be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and

should be informed of the risk for syncope and hypotension [see Patient Counseling Information (17)] .

Although the clinical trials were not designed to systematically monitor blood pressure, there were

individual reported cases of orthostatic hypotension in early Parkinson’s disease (without L-dopa) in

patients treated with ropinirole hydrochloride. Most of these cases occurred more than 4 weeks after

initiation of therapy with ropinirole hydrochloride and were usually associated with a recent increase in

dose.

In 12-week, placebo-controlled trials of patients with RLS, the adverse event orthostatic hypotension

was reported by 4 of 496 patients (0.8%) treated with ropinirole hydrochloride compared with 2 of 500

patients (0.4%) receiving placebo.

In two Phase 2 studies in patients with RLS, 14 of 55 patients (25%) receiving ropinirole hydrochloride

experienced an adverse event of hypotension or orthostatic hypotension compared with none of the 27

patients receiving placebo. In these studies, 11 of the 55 patients (20%) receiving ropinirole

hydrochloride and 3 of the 26 patients (12%) who had post-dose blood pressure assessments following

placebo, experienced an orthostatic blood pressure decrease of at least 40 mm Hg systolic and/or at

least 20 mm Hg diastolic.

In Phase 1 trials of ropinirole hydrochloride with healthy volunteers who received single doses on

more than one occasion without titration, 7% had documented symptomatic orthostatic hypotension.

These episodes appeared mainly at doses above 0.8 mg and these doses are higher than the starting

doses recommended for patients with either Parkinson’s disease or with RLS. In most of these

individuals, the hypotension was accompanied by bradycardia but did not develop into syncope [see

Warnings and Precautions (5.2)] .

Although dizziness is not a specific manifestation of hypotension or orthostatic hypotension, patients

with hypotension or orthostatic hypotension frequently reported dizziness. In controlled clinical trials,

dizziness was a common adverse reaction in patients receiving ropinirole hydrochloride and was more

frequent in patients with Parkinson’s disease or with RLS receiving ropinirole hydrochloride than in

patients receiving placebo (early Parkinson’s disease without L-dopa: ropinirole hydrochloride 40%,

placebo 22%; advanced Parkinson’s disease: ropinirole hydrochloride 26%, placebo 16%; RLS:

ropinirole hydrochloride 11%, placebo 5%). Dizziness of sufficient severity to cause trial

discontinuation of ropinirole hydrochloride was 4% in patients with early Parkinson’s disease without

L-dopa, 3% in patients with advanced Parkinson’s disease, and 1% in patients with RLS. [See Adverse

Reactions (6.1)]

5.4 Hallucinations/Psychotic-like Behavior

In double-blind, placebo-controlled, early-therapy trials in patients with Parkinson’s disease who were

not treated with L-dopa, 5.2% (8 of 157) of patients treated with ropinirole hydrochloride reported

hallucinations, compared with 1.4% of patients on placebo (2 of 147). Among those patients receiving

both ropinirole hydrochloride and L-dopa in advanced Parkinson’s disease studies, 10.1% (21 of 208)

were reported to experience hallucinations, compared with 4.2% (5 of 120) of patients treated with

placebo and L-dopa.

The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with

extended-release ropinirole hydrochloride [see Use in Specific Populations (8.5)] .

Postmarketing reports indicate that patients may experience new or worsening mental status and

behavioral changes, which may be severe, including psychotic-like behavior during treatment with

ropinirole hydrochloride or after starting or increasing the dose of ropinirole hydrochloride. 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, psychotic-like

behavior, disorientation, aggressive behavior, agitation, and delirium.

Patients with a major psychotic disorder should ordinarily not be treated with ropinirole hydrochloride

because of the risk of exacerbating the psychosis. In addition, certain medications used to treat

psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of

ropinirole hydrochloride [see Drug Interactions (7.3)].

5.5 Dyskinesia

Ropinirole hydrochloride may cause or exacerbate pre-existing dyskinesia in patients treated with L-

dopa for Parkinson’s disease.

In double-blind, placebo-controlled trials in advanced Parkinson’s disease, dyskinesia was much more

common in patients treated with ropinirole hydrochloride than in those treated with placebo. Among

those patients receiving both ropinirole hydrochloride and L-dopa in advanced Parkinson’s disease

trials, 34% were reported to experience dyskinesia, compared with 13% of patients treated with

placebo [see Adverse Reactions (6.1)].

Decreasing the dose of dopaminergic medications may ameliorate this adverse reaction.

5.6 Impulse Control/Compulsive Behaviors

Reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense

urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to

control these urges while taking one or more of the medications, including ropinirole hydrochloride,

that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s

disease and RLS. 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, binge

or compulsive eating, or other urges while being treated with ropinirole hydrochloride. Physicians

should consider dose reduction or stopping the medication if a patient develops such urges while taking

ropinirole hydrochloride.

5.7 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 of, withdrawal of, or changes in,

dopaminergic therapy. It is recommended that the dose be tapered at the end of treatment with ropinirole

hydrochloride as a prophylactic measure [see Dosage and Administration (2.2, 2.3)] .

5.8 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 ropinirole hydrochloride for any indication. Ideally, periodic skin

examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

5.9 Augmentation and Early-Morning Rebound in Restless Legs Syndrome

Augmentation is a phenomenon in which dopaminergic medication causes a worsening of symptom

severity above and beyond the level at the time the medication was started. The symptoms of

augmentation may include the earlier onset of symptoms in the evening (or even the afternoon), increase

in symptoms, and spread of symptoms to involve other extremities. Augmentation has been described

during therapy for RLS. Rebound refers to new onset of symptoms in the early morning hours.

Augmentation and/or early-morning rebound have been observed in a postmarketing trial of ropinirole

hydrochloride. If augmentation or early-morning rebound occurs, the use of ropinirole hydrochloride

should be reviewed and dosage adjustment or discontinuation of treatment should be considered. When

discontinuing ropinirole hydrochloride in patients with RLS, gradual reduction of the daily dose is

recommended whenever possible [see Dosage and Administration ( 2.3)] .

5.10 Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening,

pericarditis, 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

compounds, whether other, non-ergot derived dopamine agonists such as ropinirole can cause them is

unknown.

Cases of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung

disease, and cardiac valvulopathy have been reported in the development program and postmarketing

experience for ropinirole. While the evidence is not sufficient to establish a causal relationship

between ropinirole and these fibrotic complications, a contribution of ropinirole cannot be excluded.

5.11 Retinal Pathology

Retinal degeneration was observed in albino rats in the 2-year carcinogenicity study at all doses tested.

The lowest dose tested (1.5 mg/kg/day) is less than the maximum recommended human dose (MRHD) for

Parkinson’s disease (24 mg/day) on a mg/m2 basis. Retinal degeneration was not observed in a 3-month

study in pigmented rats, in a 2-year carcinogenicity study in albino mice, or in 1-year studies in monkeys

or albino rats. The significance of this effect for humans has not been established, but involves

disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding).

Ocular electroretinogram (ERG) assessments were conducted during a 2-year, double-blind,

multicenter, flexible dose, L-dopa-controlled clinical trial of ropinirole in patients with Parkinson’s

disease; 156 patients (78 on ropinirole, mean dose: 11.9 mg/day, and 78 on L-dopa, mean dose: 555.2

mg/day) were evaluated for evidence of retinal dysfunction through electroretinograms. There was no

clinically meaningful difference between the treatment groups in retinal function over the duration of the

trial.

5.12 Binding to Melanin

Ropinirole binds to melanin-containing tissues (e.g., eyes, skin) in pigmented rats. After a single dose,

long-term retention of drug was demonstrated, with a half-life in the eye of 20 days.

6 ADVERSE REACTIONS

The following adverse reactions are described in more detail in other sections of the label:

Hypersensitivity [see Contraindications (4)]

Falling Asleep during Activities of Daily Living and Somnolence [see Warnings and Precautions

(5.1)]

Syncope [see Warnings and Precautions (5.2)]

Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.3)]

Hallucinations/Psychotic-like Behavior [see Warnings and Precautions (5.4)]

Dyskinesia [see Warnings and Precautions (5.5)]

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

Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.7)]

Melanoma [see Warnings and Precautions (5.8)]

Augmentation and Early-Morning Rebound in RLS [see Warnings and Precautions (5.9)]

Fibrotic Complications [see Warnings and Precautions (5.10)]

Retinal Pathology [see Warnings and Precautions (5.11)]

6.1 Clinical Trials 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 with rates in the clinical trials of another

drug (or of another development program of a different formulation of the same drug) and may not

reflect the rates observed in practice.

Parkinson’s Disease

During the premarketing development of ropinirole hydrochloride, patients received ropinirole

hydrochloride either without L-dopa (early Parkinson’s disease trials) or as concomitant therapy with

L-dopa (advanced Parkinson’s disease trials). Because these two populations may have differential risks

for various adverse reactions, this section will in general present adverse reaction data for these

two populations separately.

Early Parkinson’s Disease (without L-dopa)

In the double-blind, placebo-controlled trials in patients with early-stage Parkinson’s disease, the most

commonly observed adverse reactions in patients treated with ropinirole hydrochloride (incidence at

least 5% greater than placebo) were nausea, somnolence, dizziness, syncope, asthenic condition (i.e.,

asthenia, fatigue, and/or malaise), viral infection, leg edema, vomiting, and dyspepsia.

Approximately 24% of patients treated with ropinirole hydrochloride who participated in the double-

blind, placebo-controlled early Parkinson’s disease (without L-dopa) trials discontinued treatment due

to adverse reactions compared with 13% of patients who received placebo. The most common adverse

reactions in patients treated with ropinirole hydrochloride (incidence at least 2% greater than placebo)

of sufficient severity to cause discontinuation were nausea and dizziness.

Table 3 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with early

Parkinson’s disease (without L-dopa) treated with ropinirole hydrochloride participating in the double-

blind, placebo-controlled trials and were numerically more common than the incidence for placebo-

treated patients. In these trials, either ropinirole hydrochloride or placebo was used as early therapy

(i.e., without L-dopa).

Table 3. Treatment-Emergent Adverse Reaction Incidence in Double-blind,

Placebo-Controlled Early Parkinson’s Disease (without L-dopa) Trials

(Events ≥2% of Patients Treated with Ropinirole Hydrochloride and

Numerically More Frequent than the Placebo Group)

Body System/Adverse

Reaction

Ropinirole

Hydrochloride

(n = 157)

(%)

Placebo

(n = 147)

(%)

Autonomic nervous system

Flushing

Dry mouth

Increased sweating

Body as a whole

Asthenic condition

Chest pain

Dependent edema

Leg edema

Pain

Cardiovascular general

Hypertension

Hypotension

Orthostatic symptoms

Syncope

Central/peripheral nervous

system

Dizziness

Hyperkinesia

Hypesthesia

Vertigo

Gastrointestinal

Abdominal pain

Anorexia

Dyspepsia

Flatulence

Nausea

Vomiting

Heart rate/rhythm

Extrasystoles

Atrial fibrillation

Palpitation

Tachycardia

Metabolic/nutritional

Increased alkaline phosphatase

Psychiatric

a

Amnesia

Impaired concentration

Confusion

Hallucination

Somnolence

Yawning

Reproductive male

Impotence

Resistance mechanism

Viral infection

Respiratory

Bronchitis

Dyspnea

Pharyngitis

Rhinitis

Sinusitis

Urinary

Urinary tract infection

Vascular extracardiac

Peripheral ischemia

Vision

Eye abnormality

Abnormal vision

Xerophthalmia

Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus,

patients may be included in more than one category.

Asthenic condition (i.e., asthenia, fatigue, and/or malaise).

Advanced Parkinson’s Disease (with L-dopa)

In the double-blind, placebo-controlled trials in patients with advanced-stage Parkinson’s disease, the

most commonly observed adverse reactions in patients treated with ropinirole hydrochloride (incidence

at least 5 % greater than placebo) were dyskinesia, somnolence, nausea, dizziness, confusion,

hallucinations, increased sweating, and headache.

Approximately 24% of patients who received ropinirole hydrochloride in the double-blind, placebo-

controlled advanced Parkinson’s disease (with L-dopa) trials discontinued treatment due to adverse

reactions compared with 18% of patients who received placebo. The most common adverse reaction in

patients treated with ropinirole hydrochloride (incidence at least 2% greater than placebo) of sufficient

severity to cause discontinuation was dizziness.

Table 4 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with advanced

Parkinson’s disease (with L-dopa) treated with ropinirole hydrochloride who participated in the double-

blind, placebo-controlled trials and were numerically more common than the incidence for placebo-

treated patients. In these trials, either ropinirole hydrochloride or placebo was used as an adjunct to L-

dopa.

Table 4. Treatment-Emergent Adverse Reaction Incidence in Double-

blind, Placebo-Controlled Advanced Parkinson’s Disease (with L-dopa)

Trials (Events ≥2% of Patients Treated with Ropinirole Hydrochloride

and Numerically More Frequent than the Placebo Group)

a

Body System/Adverse

Reaction

Ropinirole

Hydrochloride

(n = 208)

(%)

Placebo

(n = 120)

(%)

Autonomic nervous

system

Dry mouth

Increased sweating

Body as a whole

Increased drug level

Pain

Cardiovascular general

Hypotension

Syncope

Central/peripheral nervous

system

Dizziness

Dyskinesia

Falls

Headache

Hypokinesia

Paresis

Paresthesia

Tremor

Gastrointestinal

Abdominal pain

Constipation

Diarrhea

Dysphagia

Flatulence

Nausea

Increased saliva

Vomiting

Metabolic/nutritional

Weight decrease

Musculoskeletal

Arthralgia

Arthritis

Psychiatric

Amnesia

Anxiety

Confusion

Abnormal dreaming

Hallucination

Nervousness

Somnolence

Red blood cell

Anemia

Resistance mechanism

Upper respiratory tract

infection

Respiratory

Dyspnea

Urinary

Pyuria

Urinary incontinence

Urinary tract infection

Vision

Diplopia

Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus,

patients may be included in more than one category.

Restless Legs Syndrome

In the double-blind, placebo-controlled trials in patients with RLS, the most commonly observed

adverse reactions in patients treated with ropinirole hydrochloride (incidence at least 5% greater than

placebo) were nausea, vomiting, somnolence, dizziness, and asthenic condition (i.e., asthenia, fatigue,

and/or malaise).

Approximately 5% of patients treated with ropinirole hydrochloride who participated in the double-

blind, placebo-controlled trials in the treatment of RLS discontinued treatment due to adverse reactions

compared with 4% of patients who received placebo. The most common adverse reaction in patients

treated with ropinirole hydrochloride (incidence at least 2% greater than placebo) of sufficient severity

to cause discontinuation was nausea.

Table 5 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with RLS

treated with ropinirole hydrochloride participating in the 12-week, double-blind, placebo-controlled

trials and were numerically more common than the incidence for placebo-treated patients.

Table 5. Treatment-Emergent Adverse Reaction Incidence in Double-blind,

Placebo-Controlled RLS Trials (Events ≥2% of Patients Treated with

Ropinirole Hydrochloride and Numerically More Frequent than the Placebo

Group)

Body System/Adverse

Reaction

Ropinirole

Hydrochloride

(n = 496)

(%)

Placebo

(n =500)

(%)

Ear and labyrinth

Vertigo

Gastrointestinal

Nausea

Vomiting

Diarrhea

Dyspepsia

Dry mouth

Abdominal pain upper

General disorders and

administration site conditions

Asthenic condition

a

Edema peripheral

Infections and infestations

Nasopharyngitis

Influenza

Musculoskeletal and

connective tissue

Arthralgia

Muscle cramps

Pain in extremity

Nervous system

Somnolence

Dizziness

Paresthesia

Respiratory, thoracic, and

mediastinal

Cough

Nasal congestion

Skin and subcutaneous tissue

Hyperhidrosis

Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus,

patients may be included in more than one category.

Asthenic condition (i.e., asthenia, fatigue, and/or malaise).

7 DRUG INTERACTIONS

7.1 CYP1A2 Inhibitors and Inducers

In vitro metabolism studies showed that CYP1A2 is the major enzyme responsible for the metabolism of

ropinirole. There is thus the potential for inducers or inhibitors of this enzyme to alter the clearance of

ropinirole. Therefore, if therapy with a drug known to be a potent inducer or inhibitor of CYP1A2 is

stopped or started during treatment with ropinirole hydrochloride, adjustment of the dose of ropinirole

hydrochloride may be required. Coadministration of ciprofloxacin, an inhibitor of CYP1A2, increases

the AUC and C

of ropinirole [see Clinical Pharmacology (12.3)] . Cigarette smoking is expected to

increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking [see Clinical

Pharmacology (12.3)] .

7.2 Estrogens

Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with

hormone replacement therapy [HRT]) reduced the clearance of ropinirole. Starting or stopping HRT

may require adjustment of dosage of ropinirole hydrochloride [see Clinical Pharmacology (12.3)] .

7.3 Dopamine Antagonists

Because ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics

(e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may reduce the efficacy of

ropinirole hydrochloride.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of ropinirole

hydrochloride in pregnant women. In animal studies, ropinirole had adverse effects on development

when administered to pregnant rats at doses similar to (neurobehavioral impairment) or greater than

(teratogenicity and embryolethality at >36 times) the maximum recommended human dose (MRHD) for

Parkinson’s disease. Ropinirole doses associated with teratogenicity and embryolethality in pregnant

rats were associated with maternal toxicity. In pregnant rabbits, ropinirole potentiated the teratogenic

effects of L-dopa when these drugs were administered in combination [see Data].

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage

in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of

major birth defects and miscarriage in the indicated populations is unknown.

Data

Animal Data:

Oral administration of ropinirole (0, 20, 60, 90, 120, or 150 mg/kg/day) to pregnant rats during

organogenesis resulted in embryolethality, increased incidence of fetal malformations (digit,

cardiovascular, and neural tube defects) and variations, and decreased fetal weight at the two highest

doses. These doses were also associated with maternal toxicity. The highest no-effect dose for

adverse effects on embryofetal development (90 mg/kg/day) is approximately 36 times the MRHD for

Parkinson’s disease (24 mg/day) on a body surface area mg/m

basis.

No effect on embryofetal development was observed in rabbits when ropinirole was administered alone

during organogenesis at oral doses of 0, 1, 5, or 20 mg/kg/day (up to 16 times the MRHD on a mg/m

basis). In pregnant rabbits, there was a greater incidence and severity of fetal malformations (primarily

digit defects) when ropinirole (10 mg/kg/day) was administered orally during gestation in combination

with L-dopa (250 mg/kg/day) than when L-dopa was administered alone. This drug combination was also

associated with maternal toxicity.

Oral administration of ropinirole (0, 0.1, 1, or 10 mg/kg/day) to rats during late gestation and continuing

throughout lactation resulted in neurobehavioral impairment (decreased startle response) and decreased

body weight in offspring at the highest dose. The no-effect dose of 1 mg/kg/day is less than the MRHD

on a mg/m

basis.

8.2 Lactation

Risk Summary

There are no data on the presence of ropinirole in human milk, the effects of ropinirole on the breastfed

infant, or the effects of ropinirole on milk production. However, inhibition of lactation is expected

because ropinirole inhibits secretion of prolactin in humans. Ropinirole or metabolites, or both, are

present in rat milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s

clinical need for ropinirole hydrochloride and any potential adverse effects on the breastfed infant from

ropinirole or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of ropinirole

hydrochloride is individually titrated to clinical therapeutic response and tolerability. Pharmacokinetic

trials conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients

older than 65 years compared with younger patients [see Clinical Pharmacology (12.3)] .

In flexible-dose clinical trials of extended-release ropinirole for Parkinson’s disease, 387 patients

were 65 years and older and 107 patients were 75 years and older. Among patients receiving extended-

release ropinirole, hallucination was more common in elderly patients (10%) compared with non-elderly

patients (2%). In these trials, the incidence of overall adverse reactions increased with increasing age

for both patients receiving extended-release ropinirole and placebo.

In the fixed-dose clinical trials of extended-release ropinirole, 176 patients were 65 years and older

and 73 were 75 and older. Among patients with advanced Parkinson’s disease receiving extended-

release ropinirole, vomiting and nausea were more common in patients greater than 65 years (5% and

9%, respectively) compared with patients less than 65 (1% and 7%, respectively).

8.6 Renal Impairment

No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30

to 50 mL/min). For patients with end-stage renal disease on hemodialysis, a reduced maximum dose is

recommended [see Dosage and Administration ( 2.2, 2.3), Clinical Pharmacology (12.3)] .

The use of ropinirole hydrochloride in patients with severe renal impairment (creatinine clearance less

than 30 mL/min) without regular dialysis has not been studied.

8.7 Hepatic Impairment

The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment.

10 OVERDOSAGE

The symptoms of overdose with ropinirole hydrochloride are related to its dopaminergic activity.

General supportive measures are recommended. Vital signs should be maintained, if necessary.

In clinical trials, there have been patients who accidentally or intentionally took more than their

prescribed dose of ropinirole. The largest overdose reported with ropinirole in clinical trials was

435 mg taken over a 7-day period (62.1 mg/day). Of patients who received a dose greater than

24 mg/day, reported symptoms included adverse events commonly reported during dopaminergic

therapy (nausea, dizziness), as well as visual hallucinations, hyperhidrosis, claustrophobia, chorea,

palpitations, asthenia, and nightmares. Additional symptoms reported in cases of overdose included

vomiting, increased coughing, fatigue, syncope, vasovagal syncope, dyskinesia, agitation, chest pain,

orthostatic hypotension, somnolence, and confusional state.

11 DESCRIPTION

Ropinirole tablets, USP contains ropinirole, a non-ergoline dopamine agonist, as the hydrochloride salt.

The chemical name of ropinirole hydrochloride is 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-

one and the molecular formula is C

OHCl. The molecular weight is 296.84 (260.38 as the

free base).

The structural formula is:

Ropinirole hydrochloride is a white to yellow solid with a melting range of 243° to 250°C and a

solubility of 133 mg/mL in water.

Each film-coated tablet contains ropinirole hydrochloride equivalent to ropinirole, 0.25 mg, 0.5 mg, 1

mg, 2 mg, 3 mg, 4 mg, or 5 mg. Inactive ingredients consist of: croscarmellose sodium, lactose

monohydrate, and magnesium stearate, microcrystalline cellulose.

The film coating of the tablet consists of following inactive ingredients:

0.25 mg: hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide.

0.5 mg: FD&C Blue #2/Indigo carmine aluminum lake, hypromellose, iron oxide red, iron oxide

yellow, polyethylene glycol and titanium dioxide.

1 mg: FD&C Blue #2/Indigo carmine aluminum lake, hypromellose, iron oxide yellow, polyethylene

glycol and titanium dioxide.

2 mg: hypromellose, iron oxide red, iron oxide yellow, polyethylene glycol and titanium dioxide.

3 mg: carmine, FD&C Blue #2/Indigo carmine aluminum lake, FD&C Yellow No. 6/Sunset yellow

FCF aluminum lake, hypromellose, polyethylene glycol and titanium dioxide.

4 mg: hypromellose, iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol and

titanium dioxide.

5 mg: FD&C Blue #2/Indigo carmine aluminum lake, hypromellose, polyethylene glycol, polysorbate

80 and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ropinirole is a non-ergoline dopamine agonist. The precise mechanism of action of ropinirole as a

treatment for Parkinson’s disease is unknown, although it is thought to be related to its ability to

stimulate dopamine D

receptors within the caudate-putamen in the brain. The precise mechanism of

action of ropinirole as a treatment for Restless Legs Syndrome is unknown, although it is thought to be

related to its ability to stimulate dopamine receptors.

12.2 Pharmacodynamics

Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired

ability to regulate blood pressure resulting in orthostatic hypotension, especially during dose

escalation. In some patients in clinical trials, blood pressure changes were associated with the

emergence of orthostatic symptoms, bradycardia, and, in one case in a healthy volunteer, transient sinus

arrest with syncope [see Warnings and Precautions ( 5.2, 5.3)] .

The mechanism of orthostatic hypotension induced by ropinirole is presumed to be due to a D2-

mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral

vascular resistance. Nausea is a common concomitant symptom of orthostatic signs and symptoms.

At oral doses as low as 0.2 mg, ropinirole suppressed serum prolactin concentrations in healthy male

volunteers.

Ropinirole had no dose-related effect on ECG wave form and rhythm in young, healthy, male volunteers

in the range of 0.01 to 2.5 mg.

Ropinirole had no dose- or exposure-related effect on mean QT intervals in healthy male and female

volunteers titrated to doses up to 4 mg/day. The effect of ropinirole on QTc intervals at higher

exposures achieved either due to drug interactions, hepatic impairment, or at higher doses has not been

systematically evaluated.

12.3 Pharmacokinetics

Ropinirole displayed linear kinetics over the dosing range of 1 to 8 mg three times daily. Steady-state

concentrations are expected to be achieved within 2 days of dosing. Accumulation upon multiple dosing

is predictive from single dosing.

Absorption

Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1

to 2 hours. In clinical trials, more than 88% of a radiolabeled dose was recovered in urine and the

absolute bioavailability was 45% to 55%, indicating approximately 50% first-pass effect.

Relative bioavailability from a tablet compared with an oral solution is 85%. Food does not affect the

extent of absorption of ropinirole, although its T

is increased by 2.5 hours and its C

decreased by approximately 25% when the drug is taken with a high-fat meal.

Distribution

Ropinirole is widely distributed throughout the body, with an apparent volume of distribution of

7.5 L/kg. It is up to 40% bound to plasma proteins and has a blood-to-plasma ratio of 1:1.

Metabolism

Ropinirole is extensively metabolized by the liver. The major metabolic pathways are N-despropylation

and hydroxylation to form the inactive N-despropyl metabolite and hydroxy metabolites. The N-

despropyl metabolite is converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy

metabolites. The hydroxy metabolite of ropinirole is rapidly glucuronidated.

In vitro studies indicate that the major cytochrome P450 enzyme involved in the metabolism of

ropinirole is CYP1A2, an enzyme known to be induced by smoking and omeprazole and inhibited by, for

example, fluvoxamine, mexiletine, and the older fluoroquinolones such as ciprofloxacin and

norfloxacin.

Elimination

The clearance of ropinirole after oral administration is 47 L/h and its elimination half-life is

approximately 6 hours. Less than 10% of the administered dose is excreted as unchanged drug in urine.

N-despropyl ropinirole is the predominant metabolite found in urine (40%), followed by the carboxylic

acid metabolite (10%) and the glucuronide of the hydroxy metabolite (10%).

Drug Interactions

Digoxin: Coadministration of ropinirole hydrochloride (2 mg three times daily) with digoxin (0.125 to

0.25 mg once daily) did not alter the steady-state pharmacokinetics of digoxin in 10 patients.

Theophylline: Administration of theophylline (300 mg twice daily, a substrate of CYP1A2) did not alter

the steady-state pharmacokinetics of ropinirole (2 mg three times daily) in 12 patients with Parkinson’s

disease. Ropinirole hydrochloride (2 mg three times daily) did not alter the pharmacokinetics of

theophylline (5 mg/kg intravenously) in 12 patients with Parkinson’s disease.

Ciprofloxacin: Coadministration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with

ropinirole hydrochloride (2 mg three times daily) increased ropinirole AUC by 84% on average and C

by 60% (n = 12 patients).

Estrogens: Population pharmacokinetic analysis revealed that estrogens (mainly ethinylestradiol: intake

0.6 to 3 mg over 4-month to 23-year period) reduced the oral clearance of ropinirole by 36% in 16

patients.

L-dopa: Coadministration of carbidopa + L-dopa (10/100 mg twice daily) with ropinirole hydrochloride

(2 mg three times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28

patients). Oral administration of ropinirole hydrochloride 2 mg three times daily increased mean steady-

state C

of L-dopa by 20%, but its AUC was unaffected (n = 23 patients).

Commonly Administered Drugs: Population analysis showed that commonly administered drugs, e.g.,

selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides, antihistamines,

and anticholinergics, did not affect the clearance of ropinirole. An in vitro study indicates that

ropinirole is not a substrate for P-glycoprotein. Ropinirole and its circulating metabolites do not inhibit

or induce P450 enzymes; therefore, ropinirole is unlikely to affect the pharmacokinetics of other drugs

by a P450 mechanism.

Specific Populations

Because therapy with ropinirole hydrochloride is initiated at a low dose and gradually titrated upward

according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose

based on gender, weight, or age is not necessary.

Age: Oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with

younger patients. Dosage adjustment is not necessary in the elderly (older than 65 years), as the dose of

ropinirole is to be individually titrated to clinical response.

Gender: Female and male patients showed similar clearance.

Race: The influence of race on the pharmacokinetics of ropinirole has not been evaluated.

Cigarette Smoking: Smoking is expected to increase the clearance of ropinirole since CYP1A2 is known

to be induced by smoking. In a trial in patients with RLS, smokers (n = 7) had an approximately 30%

lower C

and a 38% lower AUC than did nonsmokers (n = 11) when those parameters were

normalized for dose.

Renal Impairment: Based on population pharmacokinetic analysis, no difference was observed in the

pharmacokinetics of ropinirole in subjects with moderate renal impairment (creatinine clearance

between 30 to 50 mL/min) compared with an age-matched population with creatinine clearance above

50 mL/min. Therefore, no dosage adjustment is necessary in patients with moderate renal impairment.

A trial of ropinirole in subjects with end-stage renal disease on hemodialysis has shown that clearance

of ropinirole was reduced by approximately 30%. The recommended maximum dose is lower in these

patients [see Dosage and Administration ( 2.2, 2.3)] .

The use of ropinirole in subjects with severe renal impairment (creatinine clearance less than

30 mL/min) without regular dialysis has not been studied.

Hepatic Impairment: The pharmacokinetics of ropinirole have not been studied in patients with hepatic

impairment. Because ropinirole is extensively metabolized by the liver, these patients may have higher

plasma levels and lower clearance of ropinirole than patients with normal hepatic function.

Other Diseases: Population pharmacokinetic analysis revealed no change in the clearance of ropinirole

in patients with concomitant diseases such as hypertension, depression, osteoporosis/arthritis, and

insomnia compared with patients with Parkinson’s disease only.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies of ropinirole were conducted in mice at oral doses of 0, 5, 15, and

50 mg/kg/day and in rats at oral doses of 0, 1.5, 15, and 50 mg/kg/day.

In rats, there was an increase in testicular Leydig cell adenomas at all doses tested. The lowest dose

tested (1.5 mg/kg/day) is less than the MRHD for Parkinson’s disease (24 mg/day) on a mg/m2 basis. The

endocrine mechanisms believed to be involved in the production of these tumors in rats are not

considered relevant to humans.

In mice, there was an increase in benign uterine endometrial polyps at a dose of 50 mg/kg/day. The

highest dose not associated with this finding (15 mg/kg/day) is 3 times the MRHD on a mg/m2 basis.

Mutagenesis

Ropinirole was not mutagenic or clastogenic in in vitro (Ames, chromosomal aberration in human

lymphocytes, mouse lymphoma tk) assays, or in the in vivo mouse micronucleus test.

Impairment of Fertility

When administered to female rats prior to and during mating and throughout pregnancy, ropinirole

caused disruption of implantation at oral doses of 20 mg/kg/day (8 times the MRHD on a mg/m

basis)

or greater. This effect in rats is thought to be due to the prolactin-lowering effect of ropinirole. In rat

studies using a low oral dose (5 mg/kg) during the prolactin-dependent phase of early pregnancy

(gestation days 0 to 8), ropinirole did not affect female fertility at oral doses up to 100 mg/kg/day

(40 times the MRHD on a mg/m

basis). No effect on male fertility was observed in rats at oral doses

up to 125 mg/kg/day (50 times the MRHD on a mg/m

basis).

14 CLINICAL STUDIES

14.1 Parkinson’s Disease

The effectiveness of ropinirole hydrochloride in the treatment of Parkinson’s disease was evaluated in

a multinational drug development program consisting of 11 randomized, controlled trials. Four trials

were conducted in patients with early Parkinson’s disease and no concomitant L-dopa and seven trials

were conducted in patients with advanced Parkinson’s disease with concomitant L-dopa.

Three placebo-controlled trials provide evidence of effectiveness of ropinirole hydrochloride in the

management of patients with Parkinson’s disease who were and were not receiving concomitant L-dopa.

Two of these three trials enrolled patients with early Parkinson’s disease (without L-dopa) and one

enrolled patients receiving L-dopa.

In these trials a variety of measures were used to assess the effects of treatment (e.g., the Unified

Parkinson’s Disease Rating Scale [UPDRS], Clinical Global Impression [CGI] scores, patient diaries

recording time “on” and “off,” tolerability of L-dopa dose reductions).

In both trials of patients with early Parkinson’s disease (without L-dopa), the motor component (Part III)

of the UPDRS was the primary outcome assessment. The UPDRS is a multi-item rating scale intended to

evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and

complications of therapy (Part IV). Part III of the UPDRS contains 14 items designed to assess the

severity of the cardinal motor findings in patients with Parkinson’s disease (e.g., tremor, rigidity,

bradykinesia, postural instability) scored for different body regions and has a maximum (worst) score of

108. In the trial of patients with advanced Parkinson’s disease (with L-dopa), both reduction in percent

awake time spent “off” and the ability to reduce the daily use of L-dopa were assessed as a combined

endpoint and individually.

Trials in Patients with Early Parkinson’s Disease (without L-dopa)

Trial 1 was a 12-week multicenter trial in which 63 patients with idiopathic Parkinson’s disease

receiving concomitant anti-Parkinson medication (but not L-dopa) were enrolled and 41 were

randomized to ropinirole hydrochloride and 22 to placebo. Patients had a mean disease duration of

approximately 2 years. Patients were eligible for enrollment if they presented with bradykinesia and at

least tremor, rigidity, or postural instability. In addition, they must have been classified as Hoehn &

Yahr Stage I-IV. This scale, ranging from I = unilateral involvement with minimal impairment to

V = confined to wheelchair or bed, is a standard instrument used for staging patients with Parkinson’s

disease. The primary outcome measure in this trial was the proportion of patients experiencing a

decrease (compared with baseline) of at least 30% in the UPDRS motor score.

Patients were titrated for up to 10 weeks, starting at 0.5 mg twice daily, with weekly increments of

0.5 mg twice daily to a maximum of 5 mg twice daily. Once patients reached their maximally tolerated

0.5 mg twice daily to a maximum of 5 mg twice daily. Once patients reached their maximally tolerated

dose (or 5 mg twice daily), they were maintained on that dose through 12 weeks. The mean dose

achieved by patients at trial endpoint was 7.4 mg/day. Mean baseline UPDRS motor score was 18.6 for

patients treated with ropinirole hydrochloride and 19.9 for patients treated with placebo. At the end of

12 weeks, the percentage of responders was greater on ropinirole hydrochloride than on placebo and

the difference was statistically significant (Table 6).

Table 6. Percent Responders for UPDRS Motor Score in Trial 1 (Intent-

to-Treat Population)

% Responders

Difference from

Placebo

Placebo

Ropinirole

hydrochloride

Trial 2 in patients with early Parkinson’s disease (without L-dopa) was a double-blind, randomized,

placebo-controlled, 6-month trial. In this trial, 241 patients were enrolled and 116 were randomized to

ropinirole hydrochloride and 125 to placebo. Patients were essentially similar to those in the trial

described above; concomitant use of selegiline was allowed, but patients were not permitted to use

anticholinergics or amantadine during the trial. Patients had a mean disease duration of 2 years and

limited (not more than a 6-week period) or no prior exposure to L-dopa. The starting dosage of

ropinirole hydrochloride in this trial was 0.25 mg three times daily. The dosage was titrated at weekly

intervals by increments of 0.25 mg three times daily to a dosage of 1 mg three times daily. Further

titrations at weekly intervals were at increments of 0.5 mg three times daily up to a dosage of 3 mg

three times daily, and then weekly at increments of 1 mg three times daily. Patients were to be titrated to

a dosage of at least 1.5 mg three times daily and then to their maximally tolerated dosage, up to a

maximum of 8 mg three times daily. The mean dose attained in patients at trial endpoint was 15.7 mg/day.

The primary measure of effectiveness was the mean percent reduction (improvement) from baseline in

the UPDRS motor score. At the end of the 6-month trial, patients treated with ropinirole hydrochloride

showed improvement in motor score compared with placebo and the difference was statistically

significant (Table 7).

Table 7. Mean Percentage Change from Baseline in UPDRS Motor Score at

End of Treatment in Trial 2 (Intent-to-Treat Population)

Treatment

Baseline UPDRS

Motor Score

Mean Change

from Baseline

Difference from

Placebo

Placebo

17.7

Ropinirole

hydrochloride

17.9

-22%

-26%

Trial in Patients with Advanced Parkinson’s Disease (with L-dopa)

Trial 3 was a double-blind, randomized, placebo-controlled, 6-month trial that randomized 149 patients

(Hoehn & Yahr II IV) who were not adequately controlled on L-dopa. Ninety-five patients were

randomized to ropinirole hydrochloride and 54 were randomized to placebo. Patients in this trial had a

mean disease duration of approximately 9 years, had been exposed to L-dopa for approximately 7 years,

and had experienced “on-off” periods with L-dopa therapy. Patients previously receiving stable doses

of selegiline, amantadine, and/or anticholinergic agents could continue on these agents during the trial.

Patients were started at a dosage of 0.25 mg three times daily of ropinirole hydrochloride and titrated

upward by weekly intervals until an optimal therapeutic response was achieved. The maximum dosage

of trial medication was 8 mg three times daily. All patients had to be titrated to at least a dosage of

2.5 mg three times daily. Patients could then be maintained on this dosage level or higher for the

remainder of the trial. Once a dosage of 2.5 mg three times daily was achieved, patients underwent a

mandatory reduction in their L-dopa dosage, to be followed by additional mandatory reductions with

continued escalation of the dosage of ropinirole hydrochloride. Reductions in the dosage of L-dopa

were also allowed if patients experienced adverse reactions that the investigator considered related to

dopaminergic therapy. The mean dose attained at trial endpoint was 16.3 mg/day. The primary outcome

was the proportion of responders, defined as patients who were able both to achieve a decrease

(compared with baseline) of at least 20% in their L-dopa dosage and a decrease of at least 20% in the

proportion of the time awake in the “off” condition (a period of time during the day when patients are

particularly immobile), as determined by subject diary. In addition, the mean change in “off” time from

baseline and the percent change from baseline in daily L-dopa dosage were examined.

At the end of 6 months, the percentage of responders was greater on ropinirole hydrochloride than on

placebo and the difference was statistically significant (Table 8).

Based on the protocol-mandated reductions in L-dopa dosage with escalating doses of ropinirole

hydrochloride, patients treated with ropinirole hydrochloride had a 19.4% mean reduction in L-dopa

dosage while patients treated with placebo had a 3% reduction. Mean daily L-dopa dosage at baseline

was 759 mg for patients treated with ropinirole hydrochloride and 843 mg for patients treated with

placebo.

The mean number of daily “off” hours at baseline was 6.4 hours for patients treated with ropinirole

hydrochloride and 7.3 hours for patients treated with placebo. At the end of the 6-month trial, there was

a mean reduction of 1.5 hours of “off” time in patients treated with ropinirole hydrochloride and a mean

reduction of 0.9 hours of “off” time in patients treated with placebo, resulting in a treatment difference

of 0.6 hours of “off” time.

Table 8. Mean Responder Percentage of Patients Reducing Daily L-

Dopa Dosage by at Least 20% and Daily Proportion of “Off” Time by at

Least 20% at End of Treatment in Trial 3 (Intent-to-Treat Population)

Treatment

% Responders

Difference from

Placebo

Placebo

Ropinirole

hydrochloride

14.2 Restless Legs Syndrome

The effectiveness of ropinirole hydrochloride in the treatment of RLS was demonstrated in randomized,

double-blind, placebo-controlled trials in adults diagnosed with RLS using the International Restless

Legs Syndrome Study Group diagnostic criteria. Patients were required to have a history of a minimum

of 15 RLS episodes/month during the previous month and a total score of ≥15 on the International RLS

Rating Scale (IRLS scale) at baseline. Patients with RLS secondary to other conditions (e.g., pregnancy,

renal failure, anemia) were excluded. All trials employed flexible dosing, with patients initiating

therapy at 0.25 mg ropinirole hydrochloride once daily. Patients were titrated based on clinical

response and tolerability over 7 weeks to a maximum of 4 mg once daily. All doses were taken between

1 and 3 hours before bedtime.

A variety of measures were used to assess the effects of treatment, including the IRLS scale and

Clinical Global Impression-Global Improvement (CGI-I) scores. The IRLS scale contains 10 items

designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence,

and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40,

with 0 being absence of RLS symptoms and 40 the most severe symptoms. Three of the controlled trials

utilized the change from baseline in the IRLS scale at the Week 12 endpoint as the primary efficacy

outcome.

Three hundred eighty patients were randomized to receive ropinirole hydrochloride (n = 187) or

placebo (n = 193) in a US trial (RLS-1); 284 were randomized to receive either ropinirole

hydrochloride (n = 146) or placebo (n = 138) in a multinational trial (excluding US) (RLS-2); and 267

patients were randomized to ropinirole hydrochloride (n = 131) or placebo (n = 136) in a multinational

trial (including US) (RLS-3). Across the three trials, the mean duration of RLS was 16 to 22 years

(range: 0 to 65 years), mean age was approximately 54 years (range: 18 to 79 years), and approximately

61% were women. The mean dose at Week 12 was approximately 2 mg/day for the three trials.

At baseline, mean total IRLS score was 22.0 for ropinirole hydrochloride and 21.6 for placebo in RLS-

1, was 24.4 for ropinirole hydrochloride and 25.2 for placebo in RLS-2, and was 23.6 for ropinirole

hydrochloride and 24.8 for placebo in RLS-3. In all three trials, a statistically significant difference

between the treatment group receiving ropinirole hydrochloride and the treatment group receiving

placebo was observed at Week 12 for both the mean change from baseline in the IRLS scale total score

and the percentage of patients rated as responders (much improved or very much improved) on the CGI-I

(see Table 9).

Table 9. Mean Change in Total IRLS Score and Percent Responders on CGI-

I

Ropinirole

Hydrochloride

Placebo

Difference

from

Placebo

Mean change in total IRLS score

at Week 12

RLS-1

-13.5

-9.8

-3.7

RLS-2

-11.0

-8.0

-3.0

RLS-3

-11.2

-8.7

-2.5

Percent responders on CGI-I at

Week 12

RLS-1

73.3%

56.5%

16.8%

RLS-2

53.4%

40.9%

12.5%

RLS-3

59.5%

39.6%

19.9%

Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36-week trial.

Following a 24-week, single-blind treatment phase (flexible dosages of ropinirole hydrochloride of

0.25 to 4 mg once daily), patients who were responders (defined as a decrease of >6 points on the IRLS

scale total score relative to baseline) were randomized in double-blind fashion to placebo or

continuation of ropinirole hydrochloride for an additional 12 weeks. Relapse was defined as an increase

of at least 6 points on the IRLS scale total score to a total score of at least 15, or withdrawal due to lack

of efficacy. For patients who were responders at Week 24, the mean dose of ropinirole hydrochloride

was 2 mg (range: 0.25 to 4 mg). Patients continued on ropinirole hydrochloride demonstrated a

significantly lower relapse rate compared with patients randomized to placebo (32.6% versus 57.8%, P

= 0.0156).

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 63629-8123

NDC: 63629-8123-1 30 TABLET, FILM COATED in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Dosing Instructions

Instruct patients to take ropinirole hydrochloride only as prescribed. If a dose is missed, advise patients

not to double their next dose. Ropinirole tablets can be taken with or without food [see Dosage and

Administration (2.1)] .

Ropinirole is the active ingredient in both ropinirole tablets (the immediate release formulation). Ask

your patients if they are taking another medication containing ropinirole.

Hypersensitivity/Allergic Reactions

Advise patients about the potential for developing a hypersensitivity/allergic reaction including

manifestations such as urticaria, angioedema, rash, and pruritus when taking any ropinirole product.

Inform patients who experience these or similar reactions to immediately contact their healthcare

professional [see Contraindications (4)] .

Falling Asleep during Activities of Daily Living and Somnolence

Alert patients to the potential sedating effects caused by ropinirole hydrochloride, including

somnolence and the possibility of falling asleep while engaged in activities of daily living. Because

somnolence is a frequent adverse reaction with potentially serious consequences, patients should not

drive a car, operate machinery, or engage in other potentially dangerous activities until they have gained

sufficient experience with ropinirole hydrochloride to gauge whether or not it adversely affects their

mental and/or motor performance. Advise patients that if increased somnolence or episodes of falling

asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle, etc.) are

experienced at any time during treatment, they should not drive or participate in potentially dangerous

activities until they have contacted their physician.

Advise patients of possible additive effects when patients are taking other sedating medications,

alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics,

antidepressants, etc.) in combination with ropinirole hydrochloride or when taking a concomitant

medication (e.g., ciprofloxacin) that increases plasma levels of ropinirole [see Warnings and

Precautions (5.1)] .

Syncope and Hypotension/Orthostatic Hypotension

Advise patients that they may experience syncope and may develop hypotension with or without

symptoms such as dizziness, nausea, syncope, and sometimes sweating while taking ropinirole

hydrochloride, especially if they are elderly. 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

weeks of treatment). Postural/orthostatic symptoms may be related to sitting up or standing.

Accordingly, caution patients against standing rapidly after sitting or lying down, especially if they have

been doing so for prolonged periods and especially at the initiation of treatment with ropinirole

hydrochloride [see Warnings and Precautions (5.2, 5.3 )] .

Hallucinations/Psychotic-like Behavior

Inform patients that they may experience hallucinations (unreal visions, sounds, or sensations), and that

other psychotic-like behavior can occur while taking ropinirole hydrochloride. The elderly are at

greater risk than younger patients with Parkinson’s disease. This risk is greater in patients who are

taking ropinirole hydrochloride with L-dopa or taking higher doses of ropinirole hydrochloride and

may also be further increased in patients taking any other drugs that increase dopaminergic tone. Tell

patients to report hallucinations or psychotic-like behavior to their healthcare provider promptly should

they develop [see Warnings and Precautions (5.4)] .

Dyskinesia

Inform patients that ropinirole hydrochloride may cause and/or exacerbate pre-existing dyskinesias [see

Warnings and Precautions (5.5)] .

Impulse Control/Compulsive Behaviors

Advise patients that they may experience impulse control and/or compulsive behaviors while taking 1 or

more of the medications (including ropinirole hydrochloride) that increase central dopaminergic tone,

that are generally used for the treatment of Parkinson’s disease. Advise patients to inform their

physician or healthcare provider if they develop new or increased gambling urges, sexual urges,

uncontrolled spending, binge or compulsive eating, or other urges while being treated with ropinirole

hydrochloride. Physicians should consider dose reduction or stopping the medication if a patient

develops such urges while taking ropinirole hydrochloride [see Warnings and Precautions (5.6)] .

Withdrawal-Emergent Hyperpyrexia and Confusion

Advise patients to contact their healthcare provider if they wish to discontinue ropinirole

hydrochloride or decrease the dose of ropinirole hydrochloride [see Warnings and Precautions (5.7)] .

Melanoma

Advise patients with Parkinson’s disease that they have a higher risk of developing melanoma. Advise

patients to have their skin examined on a regular basis by a qualified healthcare provider (e.g.,

dermatologist) when using ropinirole hydrochloride for any indication [see Warnings and Precautions

(5.8)] .

Augmentation and Rebound

Inform patients with RLS that augmentation and/or rebound may occur after starting treatment with

ropinirole hydrochloride [see Warnings and Precautions (5.9)] .

Nursing Mothers

Because of the possibility that ropinirole may be excreted in breast milk, discuss the developmental and

health benefits of breastfeeding along with the mother’s clinical need for ropinirole and any potential

adverse effects on the breastfed child from ropinirole or from the underlying maternal condition [see

Use in Specific Populations (8.2)] . Advise patients that ropinirole could inhibit lactation because

ropinirole inhibits prolactin secretion.

Pregnancy

Because experience with ropinirole in pregnant women is limited and ropinirole has been shown to have

adverse effects on embryofetal development in animals, including teratogenic effects, advise patients of

this potential risk. Advise patients to notify their physician if they become pregnant or intend to become

pregnant during therapy [see Use in Specific Populations (8.1)] .

Manufactured For:

Accord Healthcare, Inc.,

1009, Slater Road,

Suite 210-B,

Durham, NC 27703,

USA.

Manufactured By:

Intas Pharmaceuticals Limited,

Plot No. 5 to 12, Pharmez,

Sarkhej-Bavla, National Highway No. 8-A,

Near Village Matoda, Tal Sanand,

Ahmedabad - 382 213,

Gujarat, India

51 2097 0 713364

Issued August 2017

PATIENT

INFORMATION

Ropinirole

Tablets

(roe-PIN-i-

ROLE)

If you have Parkinson’s disease, read this.

What is the most important information I should know about ropinirole tablets?

Ropinirole tablets can cause serious side effects, including:

Falling asleep during normal activities. You may fall asleep while doing normal activities such as

driving a car, doing physical tasks, or using hazardous machinery while taking ropinirole tablets.

You may suddenly fall asleep without being drowsy or without warning. This may result in having

accidents. Your chances of falling asleep while doing normal activities while taking ropinirole

tablets are greater if you take other medicines that cause drowsiness. Tell your healthcare provider

right away if this happens. Before starting ropinirole tablets, be sure to tell your healthcare

provider if you take any medicines that make you drowsy.

Fainting. Fainting can happen, and sometimes your heart rate may be decreased. This can happen

especially when you start taking ropinirole tablets or your dose is increased. Tell your healthcare

provider if you faint, feel dizzy, or feel light-headed.

Decrease in blood pressure. Ropinirole tablets can decrease your blood pressure (hypotension),

especially when you start taking ropinirole tablets or when your dose is changed. If you faint or feel

dizzy, nauseated, or sweaty when you stand up from sitting or lying down (orthostatic hypotension),

this may mean that your blood pressure is decreased. When you change position from lying down or

sitting to standing up, you should do it carefully and slowly. Call your healthcare provider if you

have any of the symptoms of decreased blood pressure listed above.

Increase in blood pressure. Ropinirole tablets may increase your blood pressure.

Changes in heart rate (decrease or increase). Ropinirole tablets can decrease or increase your

heart rate.

Hallucinations and other psychotic-like behavior. Ropinirole tablets 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. The chances of having hallucinations or these other

psychotic-like changes are higher in people with Parkinson’s disease who are taking ropinirole

tablets or taking higher doses of these drugs. If you have hallucinations or any of these other

psychotic-like changes, talk with your healthcare provider.

Uncontrolled sudden movements. Ropinirole tablets may cause uncontrolled sudden movements

or make such movements you already have worse or more frequent. Tell your healthcare provider if

this happens. The doses of your anti-Parkinson’s medicine may need to be changed.

Unusual urges. Some patients taking ropinirole tablets get urges to behave in a way unusual for

them. Examples of this are an unusual urge to gamble, increased sexual urges and behaviors, or an

uncontrollable urge to shop, spend money, or eat. If you notice or your family notices that you are

developing any unusual behaviors, talk to your healthcare provider.

Increased chance of skin cancer (melanoma). People with Parkinson’s disease may have a higher

chance of getting melanoma. It is not known if ropinirole tablets increase your chances of getting

melanoma. You and your healthcare provider should check your skin on a regular basis. Tell your

healthcare provider right away if you notice any changes in your skin such as a change in the size,

shape, or color of moles on your skin.

What are ropinirole tablets?

Ropinirole tablets are a short-acting prescription medicine containing ropinirole (usually taken 3

times a day) that is used to treat Parkinson’s disease. It is also used to treat a condition called

Restless Legs Syndrome (RLS).

Having one of these conditions does not mean you have or will develop the other condition.

You should not be taking more than 1 medicine containing ropinirole. Tell your healthcare provider

if you are taking any other medicine containing ropinirole.

It is not known if ropinirole tablets are safe and effective for use in children younger than 18 years

of age.

Do not take ropinirole tablets if you:

are allergic to ropinirole or any of the ingredients in ropinirole tablets. See the end of this page for

a complete list of the ingredients in ropinirole tablets.

Get help right away if any of the symptoms of an allergic reaction cause problems swallowing or

breathing. Call your healthcare provider if you have any of the symptoms of an allergic reaction.

Symptoms of an allergic reaction may include:

hives

ras h

swelling of the face, lips, mouth, tongue, or throat

itching

Before taking ropinirole tablets, tell your healthcare provider about all of your medical

conditions, including if you:

have daytime sleepiness from a sleep disorder or have unexpected or unpredictable sleepiness or

periods of sleep.

start or stop taking other medicines while you are taking ropinirole tablets. This may increase your

chances of getting side effects.

start or stop smoking while you are taking ropinirole tablets. Smoking may decrease the treatment

effect of ropinirole tablets.

feel dizzy, nauseated, sweaty, or faint when you stand up from sitting or lying down.

drink alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while

taking ropinirole tablets.

have high or low blood pressure.

have or have had heart problems.

are pregnant or plan to become pregnant. It is not known if ropinirole tablets can harm your unborn

baby.

are breastfeeding or plan to breastfeed. It is not known if ropinirole passes into your breast milk.

The amount of breast milk you make may be decreased while taking ropinirole tablets. Talk to your

healthcare provider to decide if you should breastfeed while taking ropinirole tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements. Some of these medicines may increase your

chances of getting side effects while taking ropinirole tablets.

How should I take ropinirole tablets?

Take ropinirole tablets exactly as directed by your healthcare provider.

Take ropinirole tablets with or without food

Do not suddenly stop taking ropinirole tablets without talking to your healthcare provider. If you

stop this medicine suddenly, you may develop fever, confusion, or severe muscle stiffness.

Before starting ropinirole tablets, you should talk to your healthcare provider about what to do if

you miss a dose. If you have missed the previous dose and it is time for your next dose, do not

double the dose.

Your healthcare provider will start you on a low dose of ropinirole tablets. Your healthcare

provider will change the dose until you are taking the right amount of medicine to control your

symptoms. It may take several weeks before you reach a dose that controls your symptoms.

Contact your healthcare provider if you stop taking ropinirole tablets for any reason. Do not restart

without talking with your healthcare provider.

Your healthcare provider may prescribe ropinirole tablets alone, or add ropinirole tablets to

medicine that you are already taking for Parkinson’s disease.

You should not substitute ropinirole tablets for ropinirole extended-release tablets or ropinirole

extended-release tablets for ropinirole tablets without talking with your healthcare provider.

If you are taking ropinirole tablets:

Ropinirole tablets are usually taken 3 times a day for Parkinson’s disease.

Your healthcare provider may prescribe ropinirole tablets alone, or add ropinirole tablets to

medicine that you are already taking for Parkinson’s disease.

You can take ropinirole tablets with or without food.

What are the possible side effects of ropinirole tablets?

Ropinirole tablets can cause serious side effects, including:

See “What is the most important information I should know about ropinirole tablets?”

The most common side effects of ropinirole tablets include:

fainting

sleepiness or drowsiness

hallucinations (seeing or hearing things that are not real)

dizziness

nausea or vomiting

uncontrolled sudden movements

upset stomach, abdominal pain or discomfort

fatigue, tiredness, or weakness

confusion

headache

leg swelling

increased sweating

constipation

suddenly falling asleep

high blood pressure (hypertension)

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all of the possible side effects with ropinirole tablets.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store ropinirole tablets?

Store ropinirole tablets at room temperature between 68°F and 77°F (20°C to 25°C).

Keep ropinirole tablets in a tightly closed container and out of direct sunlight.

Keep ropinirole tablets and all medicines out of the reach of children.

General information about the safe and effective use of ropinirole tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.

Do not use ropinirole tablets for a condition for which it was not prescribed. Do not give ropinirole

tablets to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about ropinirole tablets that is

written for health professionals.

For more information, go to www.accordhealthcare.us or call Accord Healthcare at 1-866-941-7875.

What are the ingredients in ropinirole tablets?

The following ingredients are in ropinirole tablets:

Active ingredient: ropinirole (as ropinirole hydrochloride)

Inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, and

microcrystalline cellulose.

The film coating of the tablet consists of following inactive ingredients:

0.25 mg: hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide.

0.5 mg: FD&C Blue #2/Indigo carmine aluminum lake, hypromellose, iron oxide red, iron oxide

yellow, polyethylene glycol and titanium dioxide.

1 mg: FD&C Blue #2/Indigo carmine aluminum lake, hypromellose, iron oxide yellow, polyethylene

glycol and titanium dioxide.

2 mg: hypromellose, iron oxide red, iron oxide yellow, polyethylene glycol and titanium dioxide.

3 mg: carmine, FD&C Blue #2/Indigo carmine aluminum lake, FD&C Yellow No. 6/Sunset yellow

FCF aluminum lake, hypromellose, polyethylene glycol and titanium dioxide.

4 mg: hypromellose, iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol and

titanium dioxide.

5 mg: FD&C Blue #2/Indigo carmine aluminum lake, hypromellose, polyethylene glycol, polysorbate

80 and titanium dioxide.

Manufactured For:

Accord Healthcare, Inc.,

1009, Slater Road,

Suite 210-B,

Durham, NC 27703,

USA.

Manufactured By:

Intas Pharmaceuticals Limited,

Plot No. 5 to 12, Pharmez,

Sarkhej-Bavla, National Highway No. 8-A,

Near Village Matoda, Tal Sanand,

Ahmedabad - 382 213,

Gujarat, India

51 2097 0 713364

Issued August 2017

PATIENT

INFORMATION

Ropinirole

Tablets

(roe-PIN-i-

ROLE)

If you have Restless Legs Syndrome (RLS), read this.

People with RLS should take ropinirole tablets differently than people with Parkinson’s disease (see

“How should I take ropinirole tablets for RLS?” for the recommended dosing for RLS). A lower

dose of ropinirole tablets is generally needed for people with RLS, and is taken once daily before

bedtime.

What is the most important information I should know about ropinirole tablets?

Ropinirole tablets can cause serious side effects, including:

Falling asleep during normal activities. You may fall asleep while doing normal activities such as

driving a car, doing physical tasks, or using hazardous machinery while taking ropinirole tablets.

You may suddenly fall asleep without being drowsy or without warning. This may result in having

accidents. Your chances of falling asleep while doing normal activities while taking ropinirole

tablets are greater if you take other medicines that cause drowsiness. Tell your healthcare provider

right away if this happens. Before starting ropinirole tablets, be sure to tell your healthcare

provider if you take any medicines that make you drowsy.

Fainting. Fainting can happen, and sometimes your heart rate may be decreased. This can happen

especially when you start taking ropinirole tablets or your dose is increased. Tell your healthcare

provider if you faint, feel dizzy, or feel light-headed.

Decrease in blood pressure. Ropinirole tablets can decrease your blood pressure (hypotension),

especially when you start taking ropinirole tablets or when your dose is changed. If you faint or feel

dizzy, nauseated, or sweaty when you stand up from sitting or lying down (orthostatic hypotension),

this may mean that your blood pressure is decreased. When you change position from lying down or

sitting to standing up, you should do it carefully and slowly. Call your healthcare provider if you

have any of the symptoms of decreased blood pressure listed above.

Hallucinations and other psychotic-like behavior. Ropinirole tablets 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. If you have hallucinations or any of these other

psychotic-like changes, talk with your healthcare provider.

Unusual urges. Some patients taking ropinirole tablets get urges to behave in a way unusual for

them. Examples of this are an unusual urge to gamble, increased sexual urges and behaviors, or an

uncontrollable urge to shop, spend money, or eat. If you notice or your family notices that you are

developing any unusual behaviors, talk to your healthcare provider.

Increased chance of skin cancer (melanoma). It is not known if ropinirole tablets increases your

chance of getting melanoma. You and your healthcare provider should check your skin on a regular

basis. Tell your healthcare provider right away if you notice any changes in your skin such as a

change in the size, shape, or color of moles on your skin.

Changes in Restless Legs Syndrome symptoms. Ropinirole tablets may cause Restless Legs

symptoms to come back in the morning (rebound), happen earlier in the evening, or even happen in

the afternoon.

What is ropinirole tablets?

Ropinirole tablets is a prescription medicine containing ropinirole used to treat moderate-to-severe

primary Restless Legs Syndrome. It is also used to treat Parkinson’s disease.

Having one of these conditions does not mean you have or will develop the other condition.

You should not be taking more than 1 medicine containing ropinirole. Tell your healthcare provider if

you are taking any other medicine containing ropinirole.

It is not known if ropinirole tablets is safe and effective for use in children younger than 18 years of

age.

Do not take ropinirole tablets if you:

are allergic to ropinirole or any of the ingredients in ropinirole tablets. See the end of this page for

a complete list of the ingredients in ropinirole tablets.

Get help right away if any of the symptoms of an allergic reaction cause problems swallowing or

breathing. Call your healthcare provider if you have any of the symptoms of an allergic reaction.

Symptoms of an allergic reaction may include:

hives

ras h

swelling of the face, lips, mouth, tongue, or throat

itching

Before taking ropinirole tablets, tell your healthcare provider about all of your medical

conditions, including if you:

have daytime sleepiness from a sleep disorder or have unexpected or unpredictable sleepiness or

periods of sleep.

start or stop taking other medicines while you are taking ropinirole tablets. This may increase your

chances of getting side effects.

start or stop smoking while you are taking ropinirole tablets. Smoking may decrease the treatment

effect of ropinirole tablets.

feel dizzy, nauseated, sweaty, or faint when you stand up from sitting or lying down.

drink alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while

taking ropinirole tablets.

have high or low blood pressure.

have or have had heart problems.

are pregnant or plan to become pregnant. It is not known if ropinirole can harm your unborn baby.

are breastfeeding or plan to breastfeed. It is not known if ropinirole passes into your breast milk.

The amount of breast milk you make may be decreased while taking ropinirole tablets. Talk to your

healthcare provider to decide if you should breastfeed while taking ropinirole tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements. Some of these medicines may increase your

chances of getting side effects while taking ropinirole tablets.

How should I take ropinirole tablets?

Ropinirole tablets are usually taken once in the evening, 1 to 3 hours before bedtime.

Take ropinirole tablets with or without food.

Do not suddenly stop taking ropinirole tablets without talking to your healthcare provider. If you

stop this medicine suddenly, you may develop fever, confusion, or severe muscle stiffness.

Your healthcare provider will start you on a low dose of ropinirole tablets. Your healthcare

provider may change the dose until you are taking the right amount of medicine to control your

symptoms.

If you miss your dose, do not double your next dose. Take only your usual dose 1 to 3 hours

before your next bedtime.

Contact your healthcare provider if you stop taking ropinirole tablets for any reason. Do not restart

without talking with your healthcare provider.

What are the possible side effects of ropinirole tablets?

Ropinirole tablets can cause serious side effects, including:

See “What is the most important information I should know about ropinirole tablets?”

The most common side effects of ropinirole tablets include:

nausea or vomiting

drowsiness or sleepiness

dizziness

fatigue, tiredness, or weakness

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all of the possible side effects with ropinirole tablets.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store ropinirole tablets?

Store ropinirole tablets at room temperature between 68°F and 77°F (20°C to 25°C).

Keep ropinirole tablets in a tightly closed container and out of direct sunlight.

Keep ropinirole tablets and all medicines out of the reach of children.

General information about the safe and effective use of ropinirole tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.

Do not use ropinirole tablets for a condition for which it was not prescribed. Do not give ropinirole

tablets to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about ropinirole tablets that is

written for health professionals.

For more information, go to www.accordhealthcare.us or call Accord Healthcare at 1-866-941-7875.

What are the ingredients in ropinirole tablets?

Active ingredient: ropinirole (as ropinirole hydrochloride)

Inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, and

microcrystalline cellulose.

The film coating of the tablet consists of following inactive ingredients:

0.25 mg: hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide.

0.5 mg: FD&C Blue #2/Indigo carmine aluminum lake, hypromellose, iron oxide red, iron oxide

yellow, polyethylene glycol and titanium dioxide.

1 mg: FD&C Blue #2/Indigo carmine aluminum lake, hypromellose, iron oxide yellow, polyethylene

glycol and titanium dioxide.

2 mg: hypromellose, iron oxide red, iron oxide yellow, polyethylene glycol and titanium dioxide.

3 mg: carmine, FD&C Blue #2/Indigo carmine aluminum lake, FD&C Yellow No. 6/Sunset yellow

FCF aluminum lake, hypromellose, polyethylene glycol and titanium dioxide.

4 mg: hypromellose, iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol and

titanium dioxide.

5 mg: FD&C Blue #2/Indigo carmine aluminum lake, hypromellose, polyethylene glycol, polysorbate

80 and titanium dioxide.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured For:

Accord Healthcare, Inc.,

1009, Slater Road,

Suite 210-B,

Durham, NC 27703,

USA.

Manufactured By:

Intas Pharmaceuticals Limited,

Plot No. 5 to 12, Pharmez,

Sarkhej-Bavla, National Highway No. 8-A,

Near Village Matoda, Tal Sanand,

Ahmedabad - 382 213,

Gujarat, India

51 2097 0 713364

Issued August 2017

ROPINIROLE 2MG TABLET

ROPINIROLE

ropinirole tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 36 29 -8 123(NDC:16 729 -235)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

Bryant Ranch Prepack

RO PINIRO LE HYDRO CHLO RIDE (UNII: D7ZD41RZI9 ) (ROPINIROLE - UNII:0 30 PYR8 9 53)

ROPINIROLE

2 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

PO LYETHYLENE GLYCO L, UNSPECIFIED (UNII: 3WJQ0 SDW1A)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

pink

S core

no sco re

S hap e

ROUND (Bico nvex)

S iz e

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 29 -8 123-1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/25/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 40 22

10 /17/20 18

Labeler -

Bryant Ranch Prepack (171714327)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

171714327

REPACK(6 36 29 -8 123) , RELABEL(6 36 29 -8 123)

Revised: 8/2019

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