Ropinirole

Uses

Ropinirole is used alone or with other medicines to treat Parkinson’s disease. It helps to improve muscle control and movement difficulties. Thus, is also used to treat a condition called Restless Legs Syndrome (RLS). This condition is an overwhelming feeling of wanting to move the legs to make them comfortable from unpleasant sensations in the legs.

Ropinirole is also used to associated treatment for these conditions: Idiopathic Parkinson's Disease, Parkinson's Disease (PD), Moderate Restless Legs Syndrome, Severe Restless Legs Syndrome

How Ropinirole works

Ropinirole is a non-ergoline dopamine agonist. Ropinirole has the highest affinity at the D3 receptors, which are concentrated in the limbic areas of the brain and may be responsible for some of the neuropsychiatric effects . The exact mechanism of action of ropinirole as a treatment for Parkinson’s disease is unknown, however, it is believed to be related to its ability to selectively stimulate dopamine D2 receptors within the caudate-putamen system in the brain. This system affects body movement. Negligible affinity is seen for ropinirole at α2 adrenoreceptors in the periphery and 5HT-1 receptor. Ropinirole has no affinity at the D1-like receptors, benzodiazepine or GABA receptors .

The precise mechanism of action of ropinirole as a treatment for Restless Legs Syndrome is unknown, however, it is believed to be related to its ability to stimulate dopamine receptors .

Dosage

Ropinirole dosage

In all clinical studies, dosage was initiated at a sub therapeutic level and gradually titrated to therapeutic response. The dosage should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of nausea, dizziness, somnolence and dyskinesia.

The recommended starting dose is 0.25 mg three times daily with or without food. Based on individual patient response, dosage should then be titrated with weekly increments as described in the table below. 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 per day, and then by up to 3 mg per day weekly to a total dose of 24 mg per day.

Ascending-Dose Schedule of Ropinirole:

• First week:0.25 mg three times daily.Total Daily Dose:0.75 mg
• Second week:0.5 mg three times daily.Total Daily Dose:1.5 mg
• Third week:0.75 mg three times daily.Total Daily Dose:2.25 mg
• Fourth week:1.0 mg three times daily.Total Daily Dose:3.0 mg

Dosage greater than 24 mg/day have not been tested in clinical trials. Ropinirole should be discontinued gradually over a 7 day period. 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.

Side Effects

Some of the side effects that are known to be associated with Ropinirole are abdominal pain, swelling of the legs and ankles due to excess fluid retention (peripheral oedema), confusion, difficulty performing voluntary movements, resulting in jerky or involuntary movements or muscle twitches (dyskinesia), false perceptions of things that are not really there (hallucinations), nausea and vomiting, sleepiness (somnolence), fainting (syncope), slower than normal heart beat (bradycardia), profound drop in blood pressure (hypotension).

Toxicity

Overdose

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 .

Carcinogenicity

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. There was an increase in testicular Leydig cell adenomas at all doses tested in rats. 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 .

Mutagenesis

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

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.

Use in Pregnancy

Pregnancy Category C. 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 .

Precaution

If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g. conversations, eating, etc.), Riponirole should ordinarily be discontinued. If a decision is made to continue Ropinirole, patients should be advised to no drive and to avoid other potentially dangerous activities.

Interaction

Co-administration of Ropinirole with carbidopa or L-dopa or digoxin or theophylline did not show any interaction between them to hamper pharmacological effect. Co administration of ciprofloxacin (500 b.i.d.), an inhibitor of CYP1A2 ( enzyme responsible for Ropinirole metabolism), with Ropinirole (2 mg t.i.d.) increased Ropinirole AUC by 84%. Since ropinirole is a dopamine agonist, it is possible that dopamine antagonists, such as neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of Ropinirole.

Food Interaction

• Take with or without food. May take with food to reduce nausea.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Ropinirole Drug Interaction

Moderate: duloxetine, pregabalin, acetaminophen / hydrocodone, alprazolam, cetirizineUnknown: fluticasone / salmeterol, aspirin, aspirin, omega-3 polyunsaturated fatty acids, furosemide, atorvastatin, metoprolol, metoprolol, esomeprazole, albuterol, montelukast, levothyroxine, cyanocobalamin, ascorbic acid, cholecalciferol

Ropinirole Disease Interaction

Major: hypotension, psychosis, neuroleptic malignant syndromeModerate: cardiovascular disease, hepatic dysfunction, renal dysfunction

Volume of Distribution

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

Elimination Route

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

Absolute bioavailability was 45% to 55%, suggesting approximately 50% hepatic first-pass effect . The bioavailability of ropinirole prolonged release compared to the immediate release tablets is about 100% .

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 .

Half Life

Approximately 6 hours , .

Clearance

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

Elimination Route

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

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

Pregnancy & Breastfeeding use

Pregnancy: Pregnancy category C. There are no adequate and well-controlled studies using Ropinirole in pregnant women. Ropinirole should be used during pregnancy only if the potential benefit outweighs the potential risk of the fetus.

Nursing Mothers: Ropinirole inhibits prolactin secretion in humans and could potentially inhibit lactation. Because of the potential for serious adverse reactions in nursing infants from Ropinirole, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Contraindication

Ropinirole is contraindicated for patients known to have hypersensitivity to the product.

Special Warning

Pediatric Use: Safety and effectiveness of Ropinirole in the pediatric population have not been established.

Acute Overdose

Symptoms include nausea, vomiting, visual hallucinations, hyperhidrosis, asthenia and nightmares. General supportive measures and monitoring of vital signs are recommended. May consider gastric lavage.

Storage Condition

Store in a cool and dry place, away from light. Keep out of reach of children.

Innovators Monograph

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