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ROPINIRole

Pronunciation

Pronunciation

(roe PIN i role)

Index Terms

  • Ropinirole HCl
  • Ropinirole Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Requip: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #6 aluminum lake, polysorbate 80]

Generic: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg

Tablet Extended Release 24 Hour, Oral:

Requip XL: 2 mg, 4 mg, 6 mg, 8 mg, 12 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #6 aluminum lake]

Generic: 2 mg, 4 mg, 6 mg, 8 mg, 12 mg

Brand Names: U.S.

  • Requip
  • Requip XL

Pharmacologic Category

  • Anti-Parkinson Agent, Dopamine Agonist

Pharmacology

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 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 D2-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance.

Absorption

Immediate release: Rapid

Distribution

Vd: 7.5 L/kg

Metabolism

Extensively hepatic via CYP1A2 to inactive metabolites; first-pass effect

Excretion

Urine (<10% as unchanged drug, 60% as metabolites)

Time to Peak

Immediate release: ~1-2 hours; Extended release: 6-10 hours; Tmax increased by 2.5-3 hours when taken with a high-fat meal

Half-Life Elimination

~6 hours

Protein Binding

40%

Special Populations: Renal Function Impairment

Clearance of ropinirole was reduced by ~30% in patients with ESRD on dialysis

Special Populations: Hepatic Function Impairment

Patients with hepatic impairment may have higher plasma levels and lower clearance of ropinirole

Special Populations: Elderly

Oral clearance is reduced ~15% in patients >65 years

Special Populations Note

Cigarette smoking: Clearance is expected to increase because CYP1A2 is known to be induced by smoking. Cmax was 30% and AUC was 38% lower in smokers compared with nonsmokers.

Use: Labeled Indications

Parkinson disease: Treatment of Parkinson disease

Restless legs syndrome (immediate release only): Treatment of moderate to severe primary restless legs syndrome (RLS)

Contraindications

Hypersensitivity to ropinirole or any component of the formulation

Dosing: Adult

Parkinson disease: Oral:

Immediate-release tablet: The dosage should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of nausea, dizziness, somnolence and dyskinesia. Recommended starting dose is 0.25 mg 3 times/day; based on individual patient response, the dosage should be titrated with weekly increments as described below:

• 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

Note: After week 4, if necessary, daily dosage 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 to a total of 24 mg/day. If a significant interruption in therapy with ropinirole occurs, retitration may be warranted.

Parkinson disease discontinuation taper: Gradually taper over 7 days as follows: reduce frequency of administration from 3 times daily to twice daily for 4 days, then reduce to once daily for remaining 3 days.

Extended release tablet: Initial: 2 mg once daily for 1 to 2 weeks, followed by increases of 2 mg/day at weekly or longer intervals based on therapeutic response and tolerability (maximum: 24 mg/day); Note: If a significant interruption in therapy with ropinirole occurs, retitration may be warranted. When discontinuing gradually taper over 7 days.

Restless legs syndrome (RLS): Oral: Immediate release tablets: Initial: 0.25 mg once daily 1 to 3 hours before bedtime. Dose may be increased after 2 days to 0.5 mg daily, and after 7 days to 1 mg daily. Dose may be further titrated upward in 0.5 mg increments every week until reaching a daily dose of 3 mg during week 6. Daily dose may be increased to a maximum of 4 mg beginning week 7.

Note: If a significant interruption in therapy with ropinirole occurs, retitration may be warranted. Gradually taper dose if discontinuation is warranted.

Converting from ropinirole immediate release tablets to ropinirole extended-release tablets: Choose a once daily extended-release dose that most closely matches current immediate-release daily dose.

Dosing: Geriatric

Titrate dose to clinical response. Refer to adult dosing.

Dosing: Renal Impairment

Moderate renal impairment (CrCl 30 to 50 mL/minute): No dosage adjustment necessary.

Severe renal impairment (CrCl <30 mL/minute): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Use with caution.

ESRD requiring hemodialysis:

Immediate release:

Parkinson disease: Initial: 0.25 mg 3 times daily; may titrate dose upward based on tolerability and efficacy (maximum dose: 18 mg daily); postdialysis supplemental doses are not required

Restless legs syndrome: Initial: 0.25 mg once daily; may titrate dose upward based on tolerability and efficacy (maximum dose: 3 mg daily); postdialysis supplemental doses are not required

Extended release: Initial: 2 mg once daily; may titrate dose upward based on tolerability and efficacy (maximum dose: 18 mg daily); postdialysis supplemental doses are not required

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Titrate with caution.

Administration

Administer without regard to meals. Swallow extended-release tablet whole; do not crush, split, or chew.

Storage

Store at room temperature. Protect from light and moisture.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Alcohol (Ethyl): May enhance the sedative effect of ROPINIRole. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amisulpride: Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Amisulpride. Amisulpride may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Avoid combination

Antipsychotic Agents (First Generation [Typical]): Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible and monitor for decreased effects of both agents when these combinations cannot be avoided. Atypical antipsychotics such as clozapine and quetiapine may be less likely to reduce the effects of anti-Parkinson agents. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider using an alternative antipsychotic agent when possible in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

BuPROPion: Anti-Parkinson Agents (Dopamine Agonist) may enhance the adverse/toxic effect of BuPROPion. Monitor therapy

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Ciprofloxacin (Systemic): May increase the serum concentration of ROPINIRole. Monitor therapy

CNS Depressants: May enhance the sedative effect of ROPINIRole. Monitor therapy

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Estrogen Derivatives: May increase the serum concentration of ROPINIRole. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Methylphenidate: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

Metoclopramide: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Sulpiride: May diminish the therapeutic effect of ROPINIRole. ROPINIRole may diminish the therapeutic effect of Sulpiride. Avoid combination

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Adverse Reactions

Frequency not always defined. Data inclusive of trials in early Parkinson disease (without levodopa) and Restless Legs Syndrome.

>10%:

Cardiovascular: Hypotension (including orthostatic; 2% to 25%), syncope (1% to 12%)

Central nervous system: Drowsiness (11% to 40%), dizziness (6% to 40%), fatigue (including weakness, malaise; 9% to 16%)

Gastrointestinal: Nausea (immediate release: 40% to 60%; extended release: 19%), vomiting (11% to 12%)

Infection: Viral infection (11%)

1% to 10%:

Cardiovascular: Lower extremity edema (7%), dependent edema (6%), hypertension (5%), chest pain (4%), flushing (3%), palpitations (3%), peripheral ischemia (3%), atrial fibrillation (2%), extrasystoles (2%), peripheral edema (2%), tachycardia (2%)

Central nervous system: Pain (8%), headache (extended release: 6%), confusion (5%), hallucination (5%; dose related), hypoesthesia (4%), amnesia (3%), paresthesia (3%), yawning (3%), lack of concentration (2%), vertigo (2%), falling, insomnia

Dermatologic: Diaphoresis (6%), hyperhidrosis (3%)

Gastrointestinal: Dyspepsia (4% to 10%), abdominal pain (3% to 7%), constipation (5%), xerostomia (3% to 5%), diarrhea (5%), anorexia (4%), flatulence (3%)

Genitourinary: Urinary tract infection (5%), impotence (3%)

Hepatic: Increased serum alkaline (3%)

Infection: Influenza (3%)

Neuromuscular & skeletal: Arthralgia (4%), limb pain (3%), muscle cramps (3%), hyperkinesia (2%), muscle spasm, myalgia

Ophthalmic: Visual disturbance (6%), eye disease (3%), xerophthalmia (2%)

Respiratory: Nasopharyngitis (9%), pharyngitis (6%), rhinitis (4%), sinusitis (4%), bronchitis (3%), cough (3%), dyspnea (3%), nasal congestion (2%)

Miscellaneous: Fever

Advanced Parkinson disease (with levodopa):

>10%:

Cardiovascular: Decreased diastolic blood pressure (orthostatic; ≥10 mm Hg: 63%; ≥20 mm Hg: 10%; semi-supine; ≥20 mm Hg: 25%), systolic hypotension (orthostatic; ≥20 mm Hg: 38%; semi-supine; ≥40 mm Hg: 10%); decreased blood pressure (combined systolic and diastolic; orthostatic; mild to moderate: 23%), decreased heart rate (≥15 beats/minute: 19% to 24%), increased heart rate (≥15 beats/minute: 23%; ≥30 beats/minute: 2%)

Central nervous system: Dizziness (immediate release: 26%; extended release: 8%), drowsiness (immediate release: 20%, extended release: 7%), headache (17%)

Gastrointestinal: Nausea (immediate release: 30%; extended-release: 11%)

Neuromuscular & skeletal: Dyskinesia (immediate release: 34%; extended-release: 13%; dose related)

1% to 10%:

Cardiovascular: Systolic hypertension (≥40 mm Hg: 8% to 9%), hypotension (≤7%; including orthostatic), peripheral edema (4%), syncope (1% to 3%), hypertension (3%; dose related), bradycardia

Central nervous system: Hallucination ( 6% to 10%; dose related), falling (2% to 10%; dose related), confusion (9%), anxiety (2% to 6%), amnesia (5%), nervousness (5%), pain (5%), paresthesia (5%), vertigo (4%), abnormal dreams (3%), paresis (3%), ,

Dermatologic: Diaphoresis (5% to 7%)

Endocrine & metabolic: Weight loss (2%)

Gastrointestinal: Abdominal pain (6% to 9%), vomiting (7%), constipation (4% to 6%), diarrhea (3% to 5%), xerostomia (2% to 5%), dysphagia (2%), flatulence (2%), sialorrhea (2%)

Genitourinary: Urinary tract infection (6%), pyuria (2%), urinary incontinence (2%)

Hematologic: Anemia (2%)

Infection: Viral infection

Neuromuscular & skeletal: Arthralgia (7%), tremor (6%), hypokinesia (5%), arthritis (3%), back pain (3%)

Ophthalmic: Diplopia (2%)

Respiratory: Upper respiratory tract infection (9%), dyspnea (3%), nasopharyngitis (≥2%)

Miscellaneous: Increased drug level (7%)

Postmarketing and/or case reports (Limited to important or life-threatening): Heart valve disease, hypersensitivity reaction (angioedema, pruritus), impulse control disorder (eg, pathological gambling, hypersexuality, binge eating), interstitial pulmonary disease, mental status changes, pleural effusion

Warnings/Precautions

Concerns related to adverse effects:

• Dyskinesias: May cause and/or exacerbate dyskinesias. Use with caution in patients with preexisting dyskinesias.

• Impulse control disorders: Has been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, libido increases (hypersexuality), compulsive buying, binge or compulsive eating, and/or other intense urges. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some, but not all cases.

• Melanoma: Risk for melanoma development is increased in Parkinson disease patients; drug causation or factors contributing to risk have not been established. Patients should be monitored closely and periodic skin examinations should be performed.

• Orthostatic hypotension: May cause orthostatic hypotension; Parkinson disease patients appear to have an impaired capacity to respond to a postural challenge. Use with caution in patients at risk of hypotension (such as those receiving antihypertensive or antiarrhythmic drugs) or where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Parkinson 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. Syncope, sometimes associated with bradycardia, was observed in association with ropinirole in early Parkinson disease patients and patients with RLS.

• Pleural/retroperitoneal fibrosis: Ergot-derived dopamine agonists have been associated with fibrotic complications (eg, pericarditis, retroperitoneal fibrosis, pleural effusion, pleural thickening, pulmonary infiltrates, cardiac valvulopathy). Although ropinirole is not an ergot, there have been postmarketing reports of possible fibrotic complications (pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy) with ropinirole; monitor closely for signs and symptoms of fibrosis. Discontinuation of therapy may resolve complications, but not in all cases.

• Psychotic effects: May cause hallucinations, particularly in older patients. May also cause or exacerbate mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment or after starting or increasing the dose; manifestations may include paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Avoid use in patients with a major psychotic disorder.

• Retinal changes: Pathologic degenerative changes were observed in the retinas of albino rats during studies with this agent, but were not observed in the retinas of albino mice or in other species. The significance of these data for humans remains uncertain.

• Somnolence: Patients have reported falling asleep while engaging in activities of daily living; this has been reported to occur without significant warning signs; some of these events had been reported one year after the initiation of therapy. Ropinirole has also been associated with somnolence. Before initiating treatment, advise patients of the potential to develop drowsiness, and inquire about factors that may increase the risk (eg, concomitant sedating medications and/or alcohol, presence of sleep disorders, concomitant medications that increase pramipexole plasma levels). Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Monitor for daytime somnolence or preexisting sleep disorder; discontinue if significant daytime sleepiness or episodes of falling asleep occur; if a decision is made to continue therapy, advise patients not to drive and to avoid other potentially dangerous activities.

Disease-related concerns:

• Hepatic impairment: Use with caution.

• Renal impairment: Dosage adjustment recommended in patients with ESRD on dialysis.

• Restless legs syndrome (RLS): Augmentation (earlier onset of symptoms in the evening/afternoon, increase and/or spread of symptoms to other extremities) or rebound (shifting of symptoms to early morning hours) may occur in some RLS patients. Consider dosage adjustment or discontinuation of treatment if augmentation or rebound symptoms occur.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: May be prone to an increased risk of adverse drug reactions.

Dosage form specific issues:

• Extended release: Extended-release ropinirole is designed to release medication over a 24-hour period. If rapid gastrointestinal transit occurs, there may be risk of incomplete release of medication and medication residue being passed in the stool.

Other warnings/precautions:

• Discontinuation of therapy: Taper gradually when discontinuing therapy; dopaminergic agents have been associated with a syndrome resembling neuroleptic malignant syndrome on abrupt withdrawal or significant dosage reduction after long-term use.

Monitoring Parameters

Blood pressure (orthostatic); daytime alertness; CNS depression, fall risk, behavior changes (eg, compulsive behaviors); periodic skin examinations

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Information related to the use of ropinirole for the treatment of restless legs syndrome (RLS) in pregnant women is limited. Current guidelines note that the available information is insufficient to make a recommendation for use in pregnant women (Aurora, 2012; Dostal, 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, constipation, fatigue, sweating a lot, pharyngitis, abdominal pain, loss of strength and energy, tremors, dry mouth, or joint pain. Have patient report immediately to prescriber severe dizziness, passing out, confusion, uncontrollable urges, skin growths, mole changes, severe headache, severe anxiety, painful urination, hematuria, vision changes, angina, tachycardia, abnormal heartbeat, bradycardia, hallucinations, mood changes, behavioral changes, shortness of breath, abnormal movements, swelling of arms or legs, burning or numbness feeling, memory impairment, difficulty focusing, or narcolepsy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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