ROPINIROLE HYDROCHLORIDE (Page 3 of 9)

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 tablets. If augmentation or early-morning rebound occurs, the use of ropinirole tablets should be reviewed and dosage adjustment or discontinuation of treatment should be considered. When discontinuing ropinirole tablets 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 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)]
Withdrawal Symptoms[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 tablets, patients received ropinirole tablets 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 tablets (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 tablets 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 tablets (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 tablets 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 tablets 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 tablets and Numerically More Frequent than the Placebo Group)a

Body System/ Adverse Reaction

Ropinirole Tablets (n = 157) (%)

Placebo (n = 147) (%)

Autonomic nervous system

Flushing

3

1

Dry mouth

5

3

Increased sweating

6

4

Body as a whole

Asthenic conditionb

16

5

Chest pain

4

2

Dependent edema

6

3

Leg edema

7

1

Pain

8

4

Cardiovascular general

Hypertension

5

3

Hypotension

2

0

Orthostatic symptoms

6

5

Syncope

12

1

Central/peripheral nervous system

Dizziness

40

22

Hyperkinesia

2

1

Hypesthesia

4

2

Vertigo

2

0

Gastrointestinal Abdominal pain

6

3

Anorexia

4

1

Dyspepsia

10

5

Flatulence

3

1

Nausea

60

22

Vomiting

12

7

Heart rate/rhythm

Extrasystoles

2

1

Atrial fibrillation

2

0

Palpitation

3

2

Tachycardia

2

0

Metabolic/nutritional Increased alkaline phosphatase

3

1

Psychiatric

Amnesia

3

1

Impaired concentration

2

0

Confusion

5

1

Hallucination

5

1

Somnolence

40

6

Yawning

3

0

Reproductive male Impotence

3

1

Resistance mechanism Viral infection

11

3

Respiratory

Bronchitis

3

1

Dyspnea

3

0

Pharyngitis

6

4

Rhinitis

4

3

Sinusitis

4

3

Urinary Urinary tract infection

5

4

Vascular extracardiac Peripheral ischemia

3

0

Vision

Eye abnormality

3

1

Abnormal vision

6

3

Xerophthalmia

2

0

a Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category.

b 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 tablets (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 tablets 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 tablets (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 tablets 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 tablets 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 tablets and Numerically More Frequent than the Placebo Group)a

Body System/Adverse Reaction

Ropinirole Tablets (n = 208) (%)

Placebo (n = 120) (%)

Autonomic nervous system Dry mouth Increased sweating

57

12

Body as a whole Increased drug level Pain

75

33

Cardiovascular general Hypotension Syncope

23

12

Central/peripheral nervous system Dizziness Dyskinesia Falls Headache Hypokinesia Paresis Paresthesia Tremor

2634 10175356

1613 7124033

Gastrointestinal Abdominal pain Constipation Diarrhea Dysphagia Flatulence Nausea Increased saliva Vomiting

9 6 5 2 2 30 2 7

8 3 3 1 1 18 1 4

Metabolic/nutritional Weight decrease

2

1

Musculoskeletal Arthralgia Arthritis

7 3

5 1

Psychiatric Amnesia Anxiety Confusion Abnormal dreaming Hallucination Nervousness Somnolence

5 6 9 3 10 5 20

1 3 2 2 4 3 8

Red blood cell Anemia

2

0

Resistance mechanism Upper respiratory tract infection

9

8

Respiratory Dyspnea

3

2

Urinary Pyuria Urinary incontinence Urinary tract infection

226

113

Vision Diplopia

2

1

a 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 tablets (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 tablets 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 tablets (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 tablets 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 tablets and Numerically More Frequent than the Placebo Group)a

Body System/Adverse Reaction

Ropinirole Tablets (n = 496) (%)

Placebo (n =500) (%)

Ear and labyrinth Vertigo

2

1

Gastrointestinal Nausea Vomiting Diarrhea Dyspepsia Dry mouth Abdominal pain upper

40115433

823321

General disorders and administration site conditions Asthenic conditionb Edema peripheral

9 2

4 1

Infections and infestations Nasopharyngitis Influenza

93

82

Musculoskeletal and connective tissue Arthralgia Muscle cramps Pain in extremity

433

322

Nervous system Somnolence Dizziness Paresthesia

12113

651

Respiratory, thoracic, and mediastinal Cough Nasal congestion

32

21

Skin and subcutaneous tissue Hyperhidrosis

3

1

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

thus, patients may be included in more than one category.

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

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