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Ropinirole, also known as ReQuip, is a non-ergoline dopamine agonist used in Parkinson's disease and restless legs syndrome Label, 3.

It is

In 2005, it was the first drug approved in the US for the management of primary moderate to severe restless legs syndrome 3.

In 2008, the extended-release capsules of ropinirole were approved, allowing for less frequent dosing, therefore increased compliance, and offering a similar side effect profile and efficacy to previous formulations of ropinirole 4.

For the treatment of the signs and symptoms of Parkinson's disease and for the treatment of primary moderate-severe restless legs syndrome Label.

Effects on

Parkinson's and restless leg syndrome This drug promotes the relief or improvement of symptoms of Parkinson's or restless leg syndrome by stimulatory actions on dopamine receptors, which regulate movement.

Effects on blood pressure

Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired abilities in regulating blood pressure with resulting orthostatic hypotension, especially with patients undergoing dose escalation.

In some patients in clinical studies, blood pressure changes were associated with orthostatic symptoms, bradycardia, and, in one case in a healthy volunteer, transient sinus arrest accompanied by syncope Label.

The mechanism of orthostatic hypotension caused by ropinirole is assumed to be due to a D2-mediated blunting of noradrenergic response to a standing position, followed by a decrease in peripheral vascular resistance.

Nausea is also a frequent symptom which accompanies orthostatic signs and symptoms Label.

Effects on prolactin

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 wave form and rhythm in young, healthy, male volunteers in the range of 0.01-2.5 mg Label.

Effects on QT interval

Ropinirole had no dose.

• or exposure-related effect on average QT intervals in healthy male and female volunteers at doses up to 4 mg/day.

The effect of ropinirole on QTc intervals at higher exposures reached either due to drug interactions, hepatic dysfunction, or at higher doses has not been adequately evaluated Label.

Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1-2 hours Label, 5.

Absolute bioavailability was 45% to 55%, suggesting approximately 50% hepatic first-pass effect Label.

The bioavailability of ropinirole prolonged release compared to the immediate release tablets is about 100% 2.

Ingestion of food does not affect the absorption of ropinirole, although its Tmax was increased by 2.5 hours and its Cmax was reduced by approximately 25% when the drug is taken with a high-fat meal Label.

Ropinirole is found to be widely distributed throughout the body, with an apparent volume of distribution of 7.5 L/kg Label.

Ropinirole is heavily metabolized by the liver.

The most important metabolic pathways are

N­ despropylation and hydroxylation to form the N-despropyl metabolite and hydroxy metabolites Label, both of which are inactive 4.

N-despropyl metabolite is then converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy metabolites.

Following this process, the hydroxy metabolite of ropinirole is glucuronidated at a rapid rate Label.

In vitro studies show that the major cytochrome P450 enzyme involved in the metabolism of ropinirole is CYP1A2 Label, 5.

Hover over products below to view reaction partners Ropinirole N-despropyl hydroxy metabolites + N-despropyl ropinirole + carboxylic acid.

The majority of the absorbed dose is cleared by the liver 4.

In clinical trials, more than 88% of a radiolabeled dose was recovered in urine Label.

Less than 10% of the administered dose is excreted as unchanged drug in urine.

N-despropyl ropinirole is the major metabolite found in the urine (40%), followed by the carboxylic acid metabolite (10%), and the glucuronide of the hydroxy metabolite (10%) Label.

Approximately 6 hours Label, 5.

The clearance of ropinirole after oral administration is 47 L/h Label.

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Symptoms of overdose include agitation, chest pain, confusion, drowsiness, facial muscle movements, grogginess, increased jerkiness of movement, symptoms of low blood pressure (dizziness, light-headedness)upon standing, nausea, and vomiting Label.

Two-year carcinogenicity studies of ropinirole were performed on animal models at oral doses of 5, 15, and 50 mg/kg/day and in rats at oral doses of 1.5, 15, and 50 mg/kg/day.

The hormonal mechanisms thought to be involved in the development of these tumors in rats are not considered relevant to humans.

In mice, there was an increase in benign uterine endometrial polyps at a dose of 50 mg/kg/day. The highest dose not associated with this observation (15 mg/kg/day) is three times the maximum recommended human dose on a mg/m2 basis Label.

Ropinirole was not found to be mutagenic or clastogenic during in vitro assays, or in the in vivo mouse micronucleus test Label.

Effects on reproduction

When given to female rats prior to and during mating and throughout pregnancy, ropinirole led to disruption of implantation at oral doses of 20 mg/kg/day (8 times the MRHD on a mg/m2 basis) or higher.

This effect in rats is believed to be due to the prolactin-lowering effects of ropinirole.

There are no sufficient and well-controlled studies done in pregnant women.

In animal reproduction studies, ropinirole has demonstrated adverse effects on embryo-fetal development, including teratogenicity Label.

Ropinirole tablets are contraindicated in patients known to have a hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients.

History of hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients.

· Ropinirole tablets can be taken with or without food. · Retitration of ropinirole tablets may be warranted if therapy is interrupted.

Parkinson’s Disease: · The recommended starting dose is 0.25 mg taken three times daily; titrate to a maximum daily dose of 24 mg. · Renal Impairment: The maximum recommended dose is 18 mg/day in patients with end-stage renal disease on hemodialysis.

Syndrome: · The recommended starting dose is 0.25 mg once daily, 1 to 3 hours before bedtime, titrate to a maximum recommended dose of 4 mg daily. · Renal Impairment: The maximum recommended dose is 3 mg/day in patients with end-stage renal disease on hemodialysis. 2.1 General Dosing Recommendations Ropinirole tablets can be taken with or without food.

If a significant interruption in therapy with ropinirole tablets have occurred, retitration of therapy may be warranted. 2.2 Dosing for Parkinson's Disease Week Dosage Total Daily Dose 1 0.25 mg 3 times daily 0.75 mg 2 0.5 mg 3 times daily 1.5 mg 3 0.75 mg 3 times daily 2.25 mg 4 1 mg 3 times daily 3 mg Ropinirole tablets should be discontinued gradually over a 7-day period in patients with Parkinson’s disease.

The frequency of administration should be reduced from three times daily to twice daily for 4 days.

For the remaining 3 days, the frequency should be reduced to once daily prior to complete withdrawal of ropinirole tablets.

No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of to 50 mL/min).

The recommended initial dose of ropinirole for patients with end-stage renal disease on hemodialysis is 0.25 mg three times a day. Further dose escalations should be based on tolerability and need for efficacy.

The recommended maximum total daily dose is 18 mg/day in patients receiving regular dialysis.

Supplemental doses after dialysis are not required.

The use of ropinirole tablets in patients with severe renal impairment without regular dialysis has not been studied. 2.3 Dosing for Restless Legs Syndrome The recommended adult starting dose for RLS is 0.25 mg once daily to 3 hours before bedtime.

After 2 days, if necessary, the dose can be increased to 0.5 mg once daily, and to 1 mg once daily at the end of the first week of dosing, then as shown in Table as needed to achieve efficacy.

Titration should be based on individual patient therapeutic response and tolerability, up to a maximum recommended dose of 4 mg daily.

RLS, the safety and effectiveness of doses greater than 4 mg once daily have not been established.

Table 2.

Dose Titration Schedule of ropinirole tablets for Restless Legs Syndrome Day/Week Dose to be taken once daily to 3 hours before bedtime Days and 2 0.25 mg Days to 7 0.5 mg Week 2 1 mg Week 3 1.5 mg Week 4 2 mg Week 5 2.5 mg Week 6 3 mg Week 7 4 mg When discontinuing ropinirole tablets in patients with RLS, gradual reduction of the daily dose is recommended.

The recommended initial dose of ropinirole for patients with end-stage renal disease on hemodialysis is 0.25 mg once daily.

Further dose escalations should be based on tolerability and need for efficacy.

The recommended maximum total daily dose is 3 mg/day in patients receiving regular dialysis.

The use of ropinirole tablets in patients with severe renal impairment without regular dialysis has not been studied.

Each circular, biconvex, film-coated tablet contains ropinirole as follows: 0.5 mg: yellow tablets debossed with “H” on one side and “122” on other side NDC: 71335-0727-1: 30 Tablets in a BOTTLE NDC: 71335-0727-2: 60 Tablets in a BOTTLE NDC: 71335-0727-3: 90 Tablets in a BOTTLE NDC: 71335-0727-4: 28 Tablets in a BOTTLE NDC: 71335-0727-5: 100 Tablets in a BOTTLE STORAGE: Protect from light and moisture.

Close container tightly after each use.

Store at controlled room temperature 20°-25°C (68°-77°F) .

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

There are no adequate data on the developmental risk associated with the use of ropinirole tablets in pregnant women.

In animal studies, ropinirole had adverse effects on development when administered to pregnant rats at doses similar to (neurobehavioral impairment) or greater than (teratogenicity and embryolethality at >36 times) the maximum recommended human dose (MRHD) for Parkinson’s disease.

Ropinirole doses associated with teratogenicity and embryolethality in pregnant rats were associated with maternal toxicity.

In pregnant rabbits, ropinirole potentiated the teratogenic effects of L-dopa when these drugs were administered in combination.

In the

U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

The background risk of major birth defects and miscarriage in the indicated populations is unknown.

Oral administration of ropinirole (0, 20, 60, 90, 120, or 150 mg/kg/day) to pregnant rats during organogenesis resulted in embryolethality, increased incidence of fetal malformations (digit, cardiovascular, and neural tube defects) and variations, and decreased fetal weight at the two highest doses.

These doses were also associated with maternal toxicity.

The highest no-effect dose for adverse effects on embryofetal development (90 mg/kg/day) is approximately 36 times the MRHD for Parkinson’s disease (24 mg/day) on a body surface area (mg/m 2 ) basis.

No effect on embryofetal development was observed in rabbits when ropinirole was administered alone during organogenesis at oral doses of 0, 1, 5, or 20 mg/kg/day (up to 16 times the MRHD on a mg/m 2 basis).

In pregnant rabbits, there was a greater incidence and severity of fetal malformations (primarily digit defects) when ropinirole (10 mg/kg/day) was administered orally during gestation in combination with L-dopa (250 mg/kg/day) than when L-dopa was administered alone.

This drug combination was also associated with maternal toxicity.

Oral administration of ropinirole (0, 0.1, 1, or 10 mg/kg/day) to rats during late gestation and continuing throughout lactation resulted in neurobehavioral impairment (decreased startle response) and decreased body weight in offspring at the highest dose.

The no-effect dose of 1 mg/kg/day is less than the MRHD on a mg/m 2 basis.

Safety and effectiveness in pediatric patients have not been established.

Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of ropinirole tablets are individually titrated to clinical therapeutic response and tolerability.

Pharmacokinetic trials conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients.

In flexible-dose clinical trials of extended-release ropinirole for Parkinson’s disease, 387 patients were 65 years and older and 107 patients were 75 years and older.

Among patients receiving extended-release ropinirole, hallucination was more common in elderly patients (10%) compared with non-elderly patients (2%).

In these trials the incidence of overall adverse reactions increased with increasing age for both patients receiving extended-release ropinirole and placebo.

In the fixed-dose clinical trials of extended-release ropinirole, 176 patients were 65 years and older and were 75 and older.

Among patients with advanced

Parkinson’s disease receiving extended-release ropinirole, vomiting and nausea were more common in patients greater than 65 years (5% and 9%, respectively) compared with patients less than 65 (1% and 7%, respectively).