No

Anti-Parkinson's Agent (Dopamine Agonist)

Treatment of idiopathic Parkinson's disease; in patients with early Parkinson's disease who were not receiving concomitant levodopa therapy as well as in patients with advanced disease on concomitant levodopa

C

Known hypersensitivity to ropinirole or any component of the formulation

Syncope, sometimes associated with bradycardia, was observed in association with ropinirole in both early Parkinson's disease (without L-dopa) patients and advanced Parkinson's disease (with L-dopa) patients. Dopamine agonists appear to impair the systemic regulation of blood pressure resulting in postural hypotension, especially during dose escalation. Parkinson's disease patients appear to have an impaired capacity to respond to a postural challenge; use with caution in patients at risk of hypotension (ie, those receiving antihypertensive drugs) or where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Parkinson's patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and should be informed of this risk. May cause hallucinations. Use with caution in patients with pre-existing dyskinesia, severe hepatic or renal dysfunction.

Although not reported for tolcapone, other dopaminergic agents have been associated with a syndrome resembling neuroleptic malignant syndrome on withdrawal or significant dosage reduction after long-term use. Dopaminergic agents from the ergot class have also been associated with fibrotic complications, such as retroperitoneum, lungs, and pleura.

Early Parkinson's disease:

Cardiovascular: Syncope, dependent/leg edema, orthostatic symptoms, flushing, chest pain, hypotension, hypertension, tachycardia, palpitations

Central nervous system: Dizziness (40%), somnolence (40%), headache, fatigue, pain, confusion, hallucinations, amnesia, malaise, hypoesthesia, vertigo, yawning

Gastrointestinal: Nausea (60%), dyspepsia, abdominal pain, xerostomia, anorexia, flatulence, vomiting

Genitourinary: Impotence

Neuromuscular & skeletal: Weakness

Ocular: Abnormal vision

Respiratory: Pharyngitis, dyspnea, rhinitis, sinusitis

Miscellaneous: Viral infection, diaphoresis (increased)

Advanced Parkinson's disease (with levodopa):

Cardiovascular: Hypotension (2%), syncope (3%)

Central nervous system: Dizziness (26%), aggravated parkinsonism, somnolence, headache (17%), insomnia, hallucinations, confusion (9%), pain (5%), paresis (3%), amnesia (5%), anxiety (6%), abnormal dreaming (3%)

Gastrointestinal: Nausea (30%), abdominal pain (9%), vomiting (7%), constipation (6%), diarrhea (5%), dysphagia (2%), flatulence (2%), increased salivation (2%), xerostomia, weight loss (2%)

Genitourinary: Urinary tract infections

Neuromuscular & skeletal: Dyskinesias (34%), falls (10%), hypokinesia (5%), paresthesia (5%), tremor (6%), arthralgia (7%), arthritis (3%)

Respiratory: Upper respiratory tract infection

Miscellaneous: Injury, increased diaphoresis (7%), viral infection, increased drug level (7%)

Endocrine & metabolic: Hypoglycemia, increased LDH, hyperphosphatemia, hyperuricemia, diabetes mellitus, hypokalemia, hypercholesterolemia, hyperkalemia, acidosis, hyponatremia, dehydration, hypochloremia

Gastrointestinal: Weight increase

Hepatic: Increased alkaline phosphatase

Neuromuscular & skeletal: Increased CPK

Renal: Elevated BUN, glycosuria

Miscellaneous: Thirst, increased lactate dehydrogenase (LDH)

No reports of intentional overdose; symptoms reported with accidental overdosage were agitation, increased dyskinesia, sedation, orthostatic hypotension, chest pain, confusion, nausea, and vomiting. It is anticipated that the symptoms of overdose will be related to its dopaminergic activity. General supportive measures are recommended. Vital signs should be maintained, if necessary. Removal of any unabsorbed material (eg, by gastric lavage) should be considered.

CYP1A2 enzyme substrate

CYP1A2 inducers or inhibitors may alter ropinirole's clearance

Estrogens reduced the oral clearance of ropinirole by 36%; dosage adjustments may be needed

Dopamine antagonists (antipsychotics, metoclopramide) may diminish the effects of ropinirole

Ropinirole has a high relative in vitro specificity and full intrinsic activity at the D₂ and D₃ dopamine receptor subtypes, binding with higher affinity to D₃ than to D₂ or D₄ receptor subtypes; relevance of D₃ receptor binding in Parkinson's disease is unknown. Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole and its metabolites have negligible in vitro affinity for dopamine D₁, 5-HT₁, 5-HT₂, benzodiazepine, GABA, muscarinic, alpha₁-, alpha₂-, and beta-adrenoreceptors. Although precise mechanism of action of ropinirole is unknown, it is believed to be due to stimulation of postsynaptic dopamine D₂-type receptors within the caudate-putamen in the brain. Ropinirole caused decreases in systolic and diastolic blood pressure at doses >0.25 mg. The mechanism of ropinirole-induced postural hypotension is believed to be due to D-₂-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance.

Absorption: Not affected by food; T_max increased by 2.5 hours when drug taken with a meal; absolute bioavailability was 55%, indicating first-pass effect

Distribution: V_d: 525 L

Metabolism: Extensively by liver to inactive metabolites; CYP1A2 was the major enzyme responsible for metabolism of ropinirole

Half-life, elimination: ~6 hours

Time to peak concentration: ~1-2 hours

Clearance: Reduced by 30% in patients >65 years of age and removal of drug by hemodialysis is unlikely

Adults: Oral: The dosage should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of nausea, dizziness, somnolence and dyskinesia

• Week 1: 0.25 mg 3 times/day; total daily dose: 0.75 mg
• Week 2: 0.5 mg 3 times/day; total daily dose: 1.5 mg
• Week 3: 0.75 mg 3 times/day; total daily dose: 2.25 mg
• Week 4: 1 mg 3 times/day; total daily dose: 3 mg

After week 4, if necessary, daily dosage may be increased by 1.5 mg per day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly to a total of 24 mg/day

Ropinirole can be taken with or without food

No information available to require special precautions

Up to 2% of patients may experience increased salivation, dry mouth

Ropinirole can be taken with or without food. Hallucinations can occur and elderly are at a higher risk than younger patients with Parkinson's disease. Postural hypotension may develop with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time. Use caution when rising rapidly after sitting or lying down, especially after having done so for prolonged periods and especially at the initiation of treatment with ropinirole. Because of additive sedative effects, caution should be used when taking CNS depressants (eg, benzodiazepines, antipsychotics, antidepressants) in combination with ropinirole.

Hallucinations can occur and elderly are at a higher risk than younger patients with Parkinson's disease. Postural hypotension may develop with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time. Use caution when rising rapidly after sitting or lying down, especially after having done so for prolonged periods and especially at the initiation of treatment with ropinirole. Because of additive sedative effects, caution should be used when taking CNS depressants (eg, benzodiazepines, antipsychotics, antidepressants) in combination with ropinirole.

Tablet: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 5 mg

Stern MB, "contemporary Approaches to the Pharmacotherapeutic Management of Parkinson's Disease: An Overview," Neurology, 1997, 49(1 Suppl 1):S2-9.

Watts RL, "The Role of Dopamine Agonists in Early Parkinson's Disease," Neurology, 1997, 49(1 Suppl 1):S34-48.