Ropinirole (Requip, Requip XL): Drug Monograph
- Treatment of Parkinson's disease
- Treatment of moderate to severe primary restless legs syndrome (RLS) (tablet)
- General Dosing & Administration Notes:
- Take with or without food and swallow whole; do not chew, crush or divide.
- If a significant interruption in use has occurred, re-titration may be warranted.
- Parkinson's disease:
- Immediate Release (IR) Tablet:
- Week 1: 0.25 mg by mouth three times a day
- Week 2: 0.5 mg by mouth three times a day
- Week 3: 0.75 mg by mouth three times a day
- Week 4: 1 mg by mouth three times a day
- After week 4: May increase by 1.5 mg/day on a weekly basis up to a 9 mg/day, and then by up to 3 mg/day weekly
- Max Dose: 24 mg per day (or 8 mg by mouth three times a day)
- Discontinuation: Discontinue gradually over a 7-day period; reduce frequency of administration from three times a day to twice daily for 4 days, then to once daily for the remaining 3 days
- Extended Release (ER) Tablet:
- 2 mg by mouth once daily for 1-2 weeks
- May increase by 2 mg/day at ≥1-week intervals
- Max Dose: 24 mg/day
- Discontinuation: Discontinue gradually over a 7-day period
- Restless legs syndrome, tablet:
- Immediate Release (IR) Tablets:
- Days 1 and 2: 0.25 mg by mouth daily 1-3 hours before bedtime
- Days 3-7: 0.5 mg by mouth daily 1-3 hours before bedtime
- Week 2: 1 mg by mouth daily 1-3 hours before bedtime
- Week 3: 1.5 mg by mouth daily 1-3 hours before bedtime
- Week 4: 2 mg by mouth daily 1-3 hours before bedtime
- Week 5: 2.5 mg by mouth daily 1-3 hours before bedtime
- Week 6: 3 mg by mouth daily 1-3 hours before bedtime
- Week 7: 4 mg by mouth daily 1-3 hours before bedtime
- Max Dose: 4 mg per day
- Conversions, switching from immediate-release (IR) to ER tablets:
- 0.75-2.25 mg/day IR = 2 mg/day ER
- 3-4.5 mg/day IR = 4 mg/day ER
- 6 mg/day IR = 6 mg/day ER
- 7.5-9 mg/day IR = 8 mg/day ER
- 12 mg/day IR = 12 mg/day ER
- 15 mg/day IR = 12 mg/day ER
- 18 mg/day IR = 18 mg/day ER
- 21 mg/day IR = 20 mg/day ER
- 24 mg/day IR = 24 mg/day ER
- Tablets, Parkinson's disease, ESRD on hemodialysis:
- 0.25 mg three times a day
- Patients receiving regular dialysis: Maximum is 18 mg/day; supplemental doses after dialysis are not required
- Tablets, Restless legs syndrome, ESRD on hemodialysis:
- O.25 mg daily
- Patients receiving regular dialysis: Maximum is 3 mg/day; supplemental doses after dialysis are not required
- ER Tablets, ESRD on hemodialysis:
- 2 mg daily
- Patients receiving regular dialysis: Maximum is 18 mg/day; supplemental doses after dialysis are not required
- Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg 4 mg, 5 mg
- Extended-release (XL): 2 mg, 4 mg, 6 mg, 8 mg, 12 mg
- History of hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients
- Sudden onset of sleep and somnolence may occur
- Syncope may occur
- Hypotension, including orthostatic hypotension may occur
- May cause hallucinations and psychotic-like behaviors
- May cause or exacerbate dyskinesia
- May cause problems with impulse control or compulsive behaviors
- Withdrawal-emergent hyperpyrexia and confusion - may accompany rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. Taper off dose
- Melanoma - may be due to medication; monitor for melanomas frequently and on a regular basis during treatment
- Early Parkinson's disease:
- Asthenic condition
- Viral infection
- Leg edema
- Advanced Parkinson's disease:
- Restless legs syndrome:
- Asthenic condition
- The symptoms are generally related to its dopaminergic activity, as well as visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, nightmares, vomiting, increased coughing, fatigue, syncope. vasovagal syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusional state.
- General supportive measure are recommended; maintain vital signs
- Inhibitors or inducers of CYP1A2 - may alter the clearance of ropinirole; dose adjustment may be required
- Hormone replacement therapy (HRT) - starting or stopping HRT may require dose adjustment of ropinirole
- Dopamine antagonists (e.g., neuroleptics, metoclopramide) - may reduce efficacy of ropinirole
- Pregnancy: Pregnancy Category C
- Labor and Delivery: None
- Nursing Mothers: It is not known whether this drug is excreted in human milk. Caution should be exercised when administered to a nursing woman
- Renal Impairment: No dose adjustment is necessary in patients with moderate impairment; patients with end-stage renal disease on hemodialysis need a reduced maximum dose
- Hepatic Impairment: Pharmacokinetics have not been studied
- Pediatric Patients: Safety and effectiveness have not been established
- Geriatric Patients: Dose adjustment is not necessary in elderly (65 years and older)
- It is not known whether this drug is excreted in human milk. Caution should be exercised when administered to a nursing woman
- Scientific Name: 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one
- Empirical Formula: C16H24N2O•HCl
- Molecular Weight: 296.84 (260.38 as the free base)
- 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 D2 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.
- Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired ability to regulate blood pressure with resulting 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.
- 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 waveform 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.
- 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 Tmax is increased by 2.5 hours and its Cmax is 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%).
- Specific Populations: Because therapy with ropinirole 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 Cmax 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 should be lower in these patients. 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.
- Drug Interactions
- Digoxin: Coadministration of ropinirole (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 (2 mg three times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg IV) in 12 patients with Parkinson's disease.
- Ciprofloxacin: Coadministration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with ropinirole (2 mg three times daily) increased ropinirole AUC by 84% on average and Cmax 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 (2 mg three times daily) had no effect on the steady-state pharmacokinetics of ropinirole(n = 28 patients). Oral administration of ropinirole 2 mg three times daily increased mean steady- state Cmax 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-gp. 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.
- Instruct patients to take the medication only as prescribed. If a dose is missed, advise patients not to double their next dose.
- Ask patients if they are taking another medication containing ropinirole.
- 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.
- Alert patients to the potential sedating effects caused by ropinirole, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Patients should not drive a car, operate machinery, or engage in other potentially dangerous activities until they have gained sufficient experience with the medicine to gauge whether or not it affects their mental and/or motor performance adversely. If these symptoms occur, advise patients not to 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 CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with ropinirole or when taking a concomitant medication (e.g., ciprofloxacin) that increases plasma levels of ropinirole.
- Advise patients that they experience syncope and may develop hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating during treatment, especially if they are elderly. May occur more frequently during initial therapy or with an increase in dose at any time. 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.
- Inform patients that they may experience hallucinations and that other psychotic-like behavior can occur while on treatment. The elderly are at greater risk than younger patients with Parkinson's disease. Risk is greater in patients who are taking ropinirole with L-dopa or taking higher doses of ropinirole; may also be further increased in patients taking any other drugs that increase dopaminergic tone. Report hallucinations or psychotic-like behavior to their healthcare provider promptly.
- Inform patients that ropinirole may cause and/or exacerbate pre-existing dyskinesias.
- Advise patients that they may experience impulse control and/or compulsive behaviors during treatment. Advise patients to inform their physician or healthcare provider if they develop new or increase gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated.
- 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.
- Inform patients with RLS that augmentation and/or rebound may occur after starting treatment.
- Advise patients that ropinirole could inhibit lactation; therefore, a decision should be made whether to discontinue nursing or to discontinue the drug.
- Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy.
- Alert patients to the possibility of increases in blood pressure and that significant increases/decreases in heart rate may be experienced during treatment.
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