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Ropinirole (Systemic )


VA CLASSIFICATION
Primary: CN500

Commonly used brand name(s): Requip.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antidyskinetic (dopamine agonist){01}

Indications

Accepted

Parkinson's disease, idiopathic (treatment)—Ropinirole is used to treat the symptoms of idiopathic Parkinson's disease {01}. Its efficacy has been demonstrated in patients with early Parkinson's disease, as well as in patients with advanced disease receiving concomitant levodopa therapy {01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—


• Ropinirole: 260.38 {01}.Ropinirole hydrochloride: 296.84 {01}.

Mechanism of action/Effect:

Ropinirole is a non-ergoline dopamine agonist with a high relative in vitro specificity and full intrinsic activity at the D 2 and D 3 dopamine receptor subtypes; it binds with higher affinity to D 3 than to D 2 or D 4 receptor subtypes {01}. The relevance of this binding specificity in Parkinson's disease is not known {01}. Ropinirole's mechanism of action in the treatment of Parkinson's disease is not precisely known {01}, but is believed to be due to the stimulation of post-synaptic dopamine D 2–type receptors within the caudate-putamen in the brain {01}. This conclusion is supported by studies in various animal models of Parkinson's disease that show that ropinirole improves motor function {01}. In particular, ropinirole attenuates the motor deficits induced by lesioning the ascending striatonigral dopaminergic pathway with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates {01}.


Other actions/effects:

Ropinirole has moderate in vitro affinity for opioid receptors {01}. Ropinirole and its metabolites have negligible in vitro affinity for dopamine D 1, 5-HT 1, 5-HT 2, benzodiazepine, GABA, muscarinic, alpha 1, alpha 2, and beta adrenoreceptors {01}.

Absorption:

Ropinirole is rapidly and fully absorbed {01}. Absolute bioavailability is 55%, indicating a first pass effect. Relative bioavailability from a tablet compared with an oral solution is 85% {01}. Food does not affect the extent of absorption {01}.

Distribution:

Ropinirole is widely distributed throughout the body, with an apparent volume of distribution (Vol D) of 7.5 L per kg {01}. Studies in rats have shown that ropinirole and/or its metabolites cross the placenta and are distributed into breast milk {01}.

Protein binding:

Up to 40% {01}. Ropinirole has a blood-to-plasma ratio of 1:1 {01}.

Biotransformation:

Hepatic {01}. Ropinirole is extensively metabolized to inactive metabolites via N-despropylation and hydroxylation pathways {01}. In vitro studies indicate that the major cytochrome P450 isoenzyme involved in the metabolism of ropinirole is CYP1A2 {01}.

Half-life:

Elimination—Approximately 6 hours {01}.

Time to peak concentration:

Median time to peak concentration (T max) is approximately 1.5 hours {02}. T max is increased by 2.5 hours when ropinirole is taken with a meal {01}.

Peak serum concentration:

Approximate dose-normalized mean peak serum concentration (C max) is 2 nanograms per mL per mg ([nanograms/mL]/mg) {02}. The C max of ropinirole is decreased by an average of 25% when the medication is taken with a meal {02}.

Time to steady-state concentration

Steady-state concentrations are expected to be achieved within 2 days of dosing {01}. Single dosing predicts that accumulation will occur with multiple dosing {01}. Ropinirole displays linear kinetics over the therapeutic dosing range of 1 to 8 mg three times a day {01}.

Elimination:
    Renal {01}. Over 88% of a radiolabeled dose is recovered in urine; less than 10% of an administered dose is excreted as unchanged drug {01}.


In dialysis—
        Although the effect of hemodialysis on ropinirole removal is not known, removal is unlikely because of the relatively high apparent volume of distribution of the medication {01}.



Precautions to Consider

Carcinogenicity/Tumorigenicity

Two-year carcinogenicity studies were conducted in Charles River CD-1 mice at doses of 5, 15, and 50 mg per kg of body weight (mg/kg) per day and in Sprague-Dawley rats at doses of 1.5, 15, and 50 mg/kg per day (top doses equivalent to 10 times and 20 times, respectively, the maximum recommended human dose [MRHD] of 24 mg per day on a mg per square meter of body surface area [mg/m 2] basis) {01}. In the male rat, there was a significant increase in testicular Leydig cell adenomas at all doses tested, i.e., ³ 1.5 mg/kg (0.6 times the MRHD on a mg/m 2 basis) {01}. This finding is of questionable significance because the endocrine mechanisms believed to be involved in the production of Leydig cell hyperplasia and adenomas in rats are not relevant to humans {01}. In the female mouse, there was an increase in benign uterine endometrial polyps at a dose of 50 mg/kg per day (10 times the MRHD on a mg/m 2 basis) {01}.

Mutagenicity

Ropinirole was not mutagenic or clastogenic in the in vitro Ames test, the in vitro chromosome aberration test in human lymphocytes, the in vitro mouse lymphoma (L1578Y cells) assay, and the in vivo mouse micronucleus test {01}.

Pregnancy/Reproduction
Fertility—
When administered to female rats prior to and during mating and throughout pregnancy, ropinirole caused disruption of implantation at doses of 20 mg/kg per day (8 times the MRHD on a mg/m 2 basis) or greater {01}. This effect is thought to be due to the prolactin-lowering effect of ropinirole {01}. In humans, chorionic gonadotropin, not prolactin, is essential for implantation {01}. In rat studies, low doses of ropinirole (5 mg/kg) given during the prolactin-dependent phase of early pregnancy (gestation days 0 to 8) did not affect female fertility at dosages of up to 100 mg/kg per day (40 times the MRHD on a mg/m 2 basis) {01}. No effect on male fertility was observed in rats at dosages of up to 125 mg/kg per day (50 times the MRHD on a mg/m 2 basis) {01}.

Pregnancy—
Adequate and well-controlled studies have not been done in humans {01}. Ropinirole should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus {01}.

In animal reproduction studies, ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects {01}. Ropinirole given to pregnant rats during organogenesis (20 mg/kg on gestation days 6 and 7, followed by 20, 60, 90, 120, or 150 mg/kg on gestation days 8 through 15) resulted in decreased fetal body weight at 60 mg/kg per day, increased fetal death at 90 mg/kg per day, and digital malformations at 150 mg/kg per day (24, 36, and 60 times the maximum recommended clinical dose on a mg/m 2 basis, respectively) {01}. The combined administration of ropinirole (10 mg/kg per day [8 times the MRHD on a mg/m 2 basis]) and levodopa (250 mg/kg per day) to pregnant rabbits during organogenesis produced a greater incidence and severity of fetal malformations (primarily digit defects) than were seen in the offspring of rabbits treated with levodopa alone {01}. No indication of an effect on development of the conceptus was observed in rabbits when a maternally toxic dose of ropinirole was administered alone (20 mg/kg per day [16 times the MRHD on a mg/m 2 basis]) {01}. In a perinatal-postnatal study in rats, 10 mg/kg per day (4 times the MRHD on a mg/m 2 basis) of ropinirole impaired growth and development of nursing offspring and altered neurological development of female offspring {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

Studies in rats have shown that ropinirole and/or its metabolites are distributed into breast milk {01}. Dopamine agonist activity is a possibility in the nursing infant {01}.

Pediatrics

Appropriate studies on the relationship of age to the effects of ropinirole have not been performed in the pediatric population. Safety and efficacy have not been established {01}.


Geriatrics


Ropinirole clearance is reduced by 30% in patients older than 65 years of age as compared with that in younger patients {01}. Dosage adjustments are not necessary because dose titration is based on individual clinical response {01}.

The incidence of hallucinations appears to be greater in the elderly {01}.


Pharmacogenetics

The influence of race on the pharmacokinetics of ropinirole has not been evaluated {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Since in vitro metabolism studies have shown that CYP1A2 is the major enzyme responsible for the metabolism of ropinirole, substrates or inhibitors of this enzyme, when coadministered with ropinirole, have the potential to alter its clearance {01}. Therefore, if a potent inhibitor of CYP1A2 is initiated or discontinued during ropinirole therapy, dosage adjustments may be necessary {01}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Carbidopa and levodopa combination {01} and
» Levodopa {01}    (administration of 2 mg of ropinirole three times a day increased the mean steady-state concentration of levodopa by 20%; however, the area under the plasma concentration–time curve [AUC] was unaffected {01}; when ropinirole is administered concomitantly, the dose of levodopa may be gradually reduced as needed and tolerated {01})

    (ropinirole may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia {01}; reducing the dosage of levodopa may ameliorate this effect {01})


Ciprofloxacin {01}    (coadministration of ciprofloxacin with ropinirole increased the AUC of ropinirole by 84% on average, and the peak plasma concentration by 60% {01} through inhibition of the metabolism of ropinirole via the hepatic isoenzyme CYP1A2 {01})


Dopamine antagonists {01} , including:
Haloperidol {01}
Metoclopramide {01}
Phenothiazines {01}
Thioxanthenes {01}    (since ropinirole is a dopamine agonist, its actions may be diminished by dopamine antagonists {01})


Estrogens {01}    (population pharmacokinetic analysis revealed that estrogens [mainly ethinyl estradiol, with an intake of 0.6 to 3 mg over a 4-month to 23-year period] reduced the oral clearance of ropinirole by 36% in 16 patients; with careful clinical titration, dosage adjustments of ropinirole may not be needed unless estrogen therapy is initiated or discontinued during ropinirole treatment {01})


Tobacco, smoking {01}    (increased clearance of ropinirole is expected, since smoking induces the CYP1A2 isoenzyme {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alkaline phosphatase {01}    (values may be increased)


Prolactin concentrations    (prolactin secretion in healthy male volunteers is suppressed by ropinirole at doses as low as 0.2 mg)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Fibrotic complications from ergot-derived dopaminergic agents, history of {01}    (condition may recur)


» Hallucinations {01}    (condition may be exacerbated {01})


Hepatic function impairment {01}    (the pharmacokinetics of ropinirole have not been studied in patients with impaired hepatic function; however, these patients may have higher plasma concentrations and lower clearance than do patients with normal hepatic function; doses should be titrated with caution in this patient population {01})


» Hypotension {01} or
» Orthostatic hypotension {01}    (condition may be exacerbated {01})


Retinal degeneration, or retinal problems {01}    (studies in albino rats have shown retinal degeneration; the potential significance of this effect in humans has not been established; however, disruption of disk shedding [a mechanism universally present in vertebrates] may be involved )


Sensitivity to ropinirole {01}
Somnolence, history of    (many increase the chance of falling asleep without warning during activities of daily living, including driving{03})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Monitoring for symptoms of orthostatic hypotension {01}    (particularly important during dose escalation)




Side/Adverse Effects

Note: Dopamine agonists appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation {01}. In addition, patients with Parkinson's disease appear to have an impaired capacity to respond to an orthostatic challenge {01}.
Retinal degeneration was observed in albino rats that received ropinirole in the premarketing carcinogenicity study {01}. This effect was not noted in albino mice, pigmented rats, or monkeys {01}. The potential significance for humans has not been established {01}; however, this effect cannot be disregarded because it may involve disruption of disk shedding, a mechanism that is universally present in vertebrates {01}.
A symptom complex (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability) that resembles neuroleptic malignant syndrome and has no other obvious etiology has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy {01}. This effect was not observed during premarketing trials of ropinirole, but potentially could occur with the use of this dopaminergic agent {01}.
Fibrotic complications, including retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening, have been reported in some patients treated with ergot-derived dopaminergic agents {01}. These complications may resolve upon discontinuation of the medication, but complete resolution does not always occur {01}. Although these effects are believed to be associated with the ergoline structure of these compounds, it is not known if non–ergot-derived dopamine agonists such as ropinirole may produce similar adverse effects {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Asthenia{01} (unusual tiredness or weakness)
    
confusion{01}
    
dependent edema{01} (swelling of legs)
    
dizziness{01}
    
dyskinesia{01} (twisting, twitching, or other unusual body movements)—may be dose-related
    
falling{01}
    
hallucinations{01} (seeing, hearing, or feeling things that are not there)—may be dose-related
    
nausea{01}
    
orthostatic hypotension{01} (dizziness, lightheadedness, or fainting, especially when standing up)
    
somnolence{01} (drowsiness)
    
syncope{01} (fainting)
    
viral infection{01}
    
worsening of parkinsonism{01}

Note: In placebo-controlled premarketing trials conducted in patients with early Parkinson's disease, hallucinations were observed in 5.2% of patients receiving ropinirole, as compared with 1.4% of patients receiving placebo {01}. Among those patients with advanced Parkinson's disease who were concomitantly receiving levodopa, 10.1% of patients receiving ropinirole experienced hallucinations, as compared with 4.2% of patients receiving placebo {01}. The incidence of hallucinations appears to be higher in elderly patients {01}.
Syncope, sometimes associated with bradycardia, was observed in placebo-controlled trials in patients receiving ropinirole alone or in combination with levodopa {01}. In patients with early Parkinson's disease who were receiving ropinirole, 11.5% experienced syncope, as compared with 1.4% of patients who were receiving placebo {01}. In patients with advanced Parkinson's disease, 2.9% of those receiving ropinirole plus levodopa reported syncope, as compared with 1.7% of those receiving placebo plus levodopa {01}.


Incidence less frequent
    
Abdominal pain{01}
    
amnesia{01} (loss of memory)
    
bronchitis{01} (cough; shortness of breath; tightness in chest; wheezing)
    
cardiac arrhythmias{01} (irregular or pounding heartbeat)
    
chest pain{01}
    
difficulty in concentrating{01}
    
diplopia{01} , xeropthalmia{01} , or other eye or vision problems{01}
    
dyspnea{01} (troubled breathing)
    
hematuria{01} (blood in urine)
    
hypertension{01}
    
hypotension{01}
    
mental depression{01}
    
pain{01}
    
pain in arms or legs{01}
    
paresthesia{01} (tingling, numbness, or prickly feelings)
    
pharyngitis{01} (sore throat)
    
tachycardia{01} (fast heartbeat)
    
urinary tract infection{01} (burning, pain, or difficulty in urinating)
    
vomiting{01}

Incidence rare
    
Anxiety or nervousness{01}
    
chills{01}
    
dysphagia{01} (trouble in swallowing)
    
fever{01}
    
joint pain{01}
    
muscle cramps, pain, or spasms{01}
    
sinus infection{01} (fever; headache; nasal congestion)
    
tinnitus{01} (buzzing or ringing in ears)
    
upper respiratory infection{01} (cough; fever; runny nose; sneezing)
    
urinary incontinence{01} (loss of bladder control)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Abnormal dreams
    
anorexia{01} (loss of appetite)
    
constipation{01}
    
diarrhea{01}
    
dryness of mouth{01}
    
flushing{01}
    
headache{01}
    
heartburn or gas{01}
    
hot flashes{01}
    
impotence{01} (decrease in sexual desire or performance)
    
increased sweating{01}
    
malaise{01} (general feeling of discomfort or illness)
    
tremor{01}
    
weight loss{01}
    
yawning{01}





Overdose
For information on the management of ropinirole overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
Symptoms of ropinirole overdose will most likely be related to its dopaminergic activity {01}.

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Agitation
    
chest pain
    
confusion
    
grogginess
    
increased dyskinesia, including mild oro-facial dyskinesia
    
nausea
    
orthostatic hypotension
    
sedation
    
vomiting


Treatment of overdose
To decrease absorption—Gastric lavage may be indicated {01}.

Supportive care—General supportive measures are recommended {01}. Vital signs should be maintained {01}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to ropinirole

Pregnancy—Animal studies have shown adverse effects on embryo-fetal development, including teratogenicity





Breast-feeding—Potential for serious adverse effects in nursing infant





Use in the elderly—Age-related reductions in renal function may require dosage adjustments; also, increased risk of occurrence of hallucinations
Other medications, especially carbidopa and/or levodopa
Other medical problems, especially hallucinations, hypotension, or orthostatic hypotension

Proper use of this medication
» Compliance with therapy; not taking more or less medication than prescribed

» Proper dosing
Missed dose: Taking dose as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress of therapy

» Checking with physician before discontinuing medication; gradual dosage reduction may be needed

» Possible drowsiness, dizziness, lightheadedness, vision problems, weakness, or muscular incoordination; caution when driving or doing jobs requiring alertness, clear vision, and coordination

» Possible falling asleep without warning during daily living activities, including driving which have resulted in accidents.

» Caution when getting up suddenly from lying or sitting position

» Possible occurrence of hallucinations


Side/adverse effects
Signs of potential side effects, especially asthenia; confusion; dependent edema; dizziness; dyskinesia; falling; hallucinations; nausea; orthostatic hypotension; somnolence; syncope; viral infection; worsening of parkinsonism; abdominal pain; amnesia; bronchitis; cardiac arrhythmias; chest pain; difficulty in concentrating; diplopia, xeropthalmia, or other eye or vision problems; dyspnea; hematuria; hypertension; hypotension; mental depression; pain; pain in arms or legs; paresthesia; pharyngitis; tachycardia; urinary tract infection; vomiting; anxiety or nervousness; chills; dysphagia; fever; joint pain; muscle cramps, pain, or spasms; sinus infection; tinnitus; upper respiratory infection; and urinary incontinence


General Dosing Information
Ropinirole doses should be titrated slowly in all patients. Dosage goal should be to achieve maximum therapeutic effect balanced against the principal side effects of nausea, dizziness, somnolence, and dyskinesia {01}.

When ropinirole is used in combination with levodopa, the required dosage of levodopa may be reduced {01}. In clinical trials, the levodopa dose was reduced on average by 31% from baseline {01}.

It is recommended that ropinirole be discontinued gradually over a 7-day period {01}. The frequency of administration should be reduced to two times a day for 4 days, then to once a day for the remaining 3 days before complete withdrawal of ropinirole {01}.

Diet/Nutrition
Ropinirole may be taken with or without food {01}. Taking this medication with food possibly may reduce the occurrence of nausea {01}.


Oral Dosage Forms

ROPINIROLE HYDROCHLORIDE TABLETS

Note: In clinical studies, dosage was initiated at subtherapeutic levels and gradually titrated to therapeutic response.


Usual adult dose
Parkinson"s disease, idiopathic
Oral, initially 0.25 mg three times a day {01}{04}. Based on patient response, dosage should be increased at weekly intervals {01}{04}. A suggested schedule for titration follows:

Ascending Dosage Schedule of Ropinirole 
Week  Dosage  Total Daily Dose 
0.25 mg three times a day  0.75 mg 
0.5 mg three times a day   1.5 mg 
0.75 mg three times a day  2.25 mg 
1 mg three times a day  3 mg 



Usual adult prescribing limits
24 mg a day {01}.

Usual pediatric dose
Safety and efficacy have not been established {01}.

Strength(s) usually available
U.S.—


0.25 mg (Rx) [Requip (croscarmellose sodium) (hydrous lactose) (magnesium stearate ) (microcrystalline cellulose) ( Aluminum Lake) (FD&C Blue No. 2) (hydroxypropyl methylcellulose) (iron oxides) (polyethylene glycol) ( polysorbate 80) (talc) ( titanium dioxide)]


0.5 mg (Rx) [Requip (croscarmellose sodium) (hydrous lactose) (magnesium stearate ) (microcrystalline cellulose) ( Aluminum Lake) (FD&C Blue No. 2) (hydroxypropyl methylcellulose) (iron oxides) (polyethylene glycol) ( polysorbate 80) (talc) ( titanium dioxide)]


1 mg (Rx) [Requip (croscarmellose sodium) (hydrous lactose) (magnesium stearate ) (microcrystalline cellulose) ( Aluminum Lake) (FD&C Blue No. 2) (hydroxypropyl methylcellulose) (iron oxides) (polyethylene glycol) ( polysorbate 80) (talc) ( titanium dioxide)]


2 mg (Rx) [Requip (croscarmellose sodium) (hydrous lactose) (magnesium stearate ) (microcrystalline cellulose) ( Aluminum Lake) (FD&C Blue No. 2) (hydroxypropyl methylcellulose) (iron oxides) (polyethylene glycol) ( polysorbate 80) (talc) ( titanium dioxide)]


5 mg (Rx) [Requip (croscarmellose sodium) (hydrous lactose) (magnesium stearate ) (microcrystalline cellulose) ( Aluminum Lake) (FD&C Blue No. 2) (hydroxypropyl methylcellulose) (iron oxides) (polyethylene glycol) ( polysorbate 80) (talc) ( titanium dioxide)]

Canada—


0.25 mg (Rx) [Requip (sucrose-, tartrazine-, azo dyes-free )]


1 mg (Rx) [Requip (sucrose-, tartrazine-, azo dyes-free )]


2 mg (Rx) [Requip (sucrose-, tartrazine-, azo dyes-free)]


5 mg (Rx) [Requip (sucrose-, tartrazine-, azo dyes-free )]

Packaging and storage:
Store at controlled room temperature between 20 and 25 ºC (68 and 77 ºF) {01}. Protect from light {01}.

Auxiliary labeling:
   • May cause drowsiness.
   • May cause dizziness.



Developed: 11/17/1997
Revised: 04/25/2000



References
  1. Requip package insert (SmithKline Beecham—US), Rev 9/97, Rec 10/97.
  1. Requip product information (SmithKline Beecham—US), 10/20/97.
  1. Product Information: Requip®, ropinirole hydrochloride tablets. SmithKline Beecham, Philadelphia, PA, (PI revised 12/99) reviewed 4/2000.
  1. Product Information: Requip(TM), ropinirole. In: Welbanks L (ed): Compendium of Pharmaceuticals and Specialties, 35th ed. Canadian Pharmaceutical Association, Ottawa, Ontario, Canada, 2000: p. 1360–1364..
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