Ropinirole Hydrochloride (Page 3 of 9)

5.5 Dyskinesia

Ropinirole hydrochloride may potentiate the dopaminergic side effects of L-dopa and may cause and/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 the dopaminergic drug may ameliorate this adverse reaction.

5.6 Impulse Control/Compulsive Behaviors

Case 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, withdrawal of, or changes in dopaminergic therapy. Therefore, it is recommended that the dose be tapered at the end of treatment with ropinirole hydrochloride for Parkinson’s disease as a prophylactic measure [see Dosage and Administration ( 2.2)] .

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

Reports in the literature indicate treatment of RLS with dopaminergic medications can result in recurrence of symptoms in the early morning hours, referred to as rebound. Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. 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. 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.

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 (equivalent to 0.6 to 20 times the maximum recommended human dose [MRHD] for Parkinson’s disease [24 mg/day] on a mg/m 2 basis), but was statistically significant at the highest dose (50 mg/kg/day). 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 (i.e., 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)]

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) *
*
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).

Body System/Adverse Reaction

Ropinirole Hydrochloride (n = 157) (%)

Placebo (n = 147) (%)

Autonomic nervous system

Flushing

3

1

Dry mouth

5

3

Increased sweating

6

4

Body as a whole

Asthenic condition

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

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

Body System/Adverse Reaction

Ropinirole Hydrochloride (n = 208) (%)

Placebo (n = 120) (%)

Autonomic nervous system

Dry mouth

5

1

Increased sweating

7

2

Body as a whole

Increased drug level

7

3

Pain

5

3

Cardiovascular general

Hypotension

2

1

Syncope

3

2

Central/peripheral nervous system

Dizziness

26

16

Dyskinesia

34

13

Falls

10

7

Headache

17

12

Hypokinesia

5

4

Paresis

3

0

Paresthesia

5

3

Tremor

6

3

Gastrointestinal

Abdominal pain

9

8

Constipation

6

3

Diarrhea

5

3

Dysphagia

2

1

Flatulence

2

1

Nausea

30

18

Increased saliva

2

1

Vomiting

7

4

Metabolic/nutritional

Weight decrease

2

1

Musculoskeletal

Arthralgia

7

5

Arthritis

3

1

Psychiatric

Amnesia

5

1

Anxiety

6

3

Confusion

9

2

Abnormal dreaming

3

2

Hallucination

10

4

Nervousness

5

3

Somnolence

20

8

Red blood cell

Anemia

2

0

Resistance mechanism

Upper respiratory tract infection

9

8

Respiratory

Dyspnea

3

2

Urinary

Pyuria

2

1

Urinary incontinence

2

1

Urinary tract infection

6

3

Vision Diplopia

2

1

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) *
*
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).

Body System/Adverse Reaction

Ropinirole Hydrochloride (n = 496) (%)

Placebo (n = 500) (%)

Ear and labyrinth

Vertigo

2

1

Gastrointestinal

Nausea

40

8

Vomiting

11

2

Diarrhea

5

3

Dyspepsia

4

3

Dry mouth

3

2

Abdominal pain upper

3

1

General disorders and administration site conditions

Asthenic condition

9

4

Edema peripheral

2

1

Infections and infestations

Nasopharyngitis

9

8

Influenza

3

2

Musculoskeletal and connective tissue

Arthralgia

4

3

Muscle cramps

3

2

Pain in extremity

3

2

Nervous system

Somnolence

12

6

Dizziness

11

5

Paresthesia

3

1

Respiratory, thoracic, and mediastinal

Cough

3

2

Nasal congestion

2

1

Skin and subcutaneous tissue

Hyperhidrosis

3

1

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