Requip

The effect of ciprofloxacin (500 mg b.i.d.) on the pharmacokinetics of REQUIP (2 mg t.i.d.) was studied in male and female patients with Parkinson's disease (n=12, mean age 55 years). The extent of systemic availability of REQUIP was significantly increased when coadministered with ciprofloxacin (AUC increased by 1.84 fold). Thus, in patients already receiving CYP1A2 inhibitors such as ciprofloxacin, REQUIP therapy may be instituted in the recommended manner and the dose titrated according to clinical response. However, if therapy with a drug known to be an inhibitor of CYP1A2 is stopped or introduced during treatment with REQUIP, adjustment of the REQUIP dosage will be required.

Based on population pharmacokinetic assessment, there were no interactions between REQUIP and drugs commonly used to treat Parkinson's disease, i.e., selegiline, amantadine, and anticholinergics.

(See Warnings and Precautions, Sudden Onset of Sleep).

No information is available on the potential for interaction between REQUIP and alcohol. As with other centrally active medications, patients should be cautioned against taking REQUIP with alcohol.

The potential pharmacokinetic interaction of levodopa/carbidopa (100 mg/10 mg b.i.d.) and REQUIP (2 mg t.i.d.) was assessed in levodopa naive (de novo) male and female patients with Parkinson's disease (n=30, mean age 64 years). The rate and extent of availability of REQUIP at steady state were essentially the same with or without levodopa. Similarly, the rate and extent of availability of levodopa, as well as its elimination half-life, were essentially the same in the presence and absence of REQUIP.

The effect of oral theophylline (300 mg bid) on the pharmacokinetics of REQUIP (2 mg t.i.d.) was studied in male and female patients with Parkinson's disease (n=12, mean age 59 years). There was no marked change in the rate or extent of availability of REQUIP when coadministered with theophylline. Similarly, coadministration of REQUIP with intravenous theophylline (5 mg/kg) did not result in any marked change in the pharmacokinetics of theophylline. It is therefore unlikely that substrates of CYP1A2 would significantly alter the pharmacokinetics of REQUIP, and vice-versa.

Neuroleptics and other centrally active dopamine antagonists may diminish the effectiveness of REQUIP. Therefore, concomitant use of these products is not recommended.

Based on population pharmacokinetic assessment, no interaction was seen between REQUIP and tricyclic antidepressants or benzodiazepines.

In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of ropinirole. Inhibitors or inducers of this enzyme have been shown to alter its clearance when coadministered with ropinirole. Therefore, if therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or started during treatment with REQUIP, adjustment of the dose of REQUIP may be required.

The effect of REQUIP (2 mg t.i.d.) on the pharmacokinetics of digoxin (0.125-0.25 mg o.d.) was studied in male and female patients with Parkinson's disease (n=10, mean age 72 years). Coadministration at steady state with REQUIP resulted in a 10% decrease in digoxin AUC although mean trough digoxin plasma concentrations were unaltered. However, the effect of higher recommended doses of REQUIP on the pharmacokinetics of digoxin is not known.

In patients already receiving oestrogen replacement therapy, REQUIP may be titrated in the recommended manner according to clinical response. However, if oestrogen replacement therapy is stopped or started during treatment with REQUIP, adjustment of the REQUIP dosage may be required.

In patients with mild to moderate renal impairment, REQUIP may be titrated in the recommended manner according to clinical response. Patients with severe renal impairment or on hemodialysis have not been studied and administration of REQUIP to such patients is not recommended.

Patients with hepatic impairment have not been studied and administration of REQUIP to such patients is not recommended.

Patients should be instructed that, if they miss a dose of REQUIP, they should wait and take the next dose as scheduled. There is no need to make up for the missed dose. Patients should not take two doses at once. If treatment is interrupted for one day or more, re-initiation by dose titration should be considered (see Dosage and Administration).

In clinical trials, initial benefits were observed with 3 mg/day and higher doses. Doses greater than 24 mg/day have not been included in clinical trials.

In a 5-year, double-blind study of early therapy in Parkinson's disease patients, the average daily dose of REQUIP (based on the observed data set) was 10.1 mg at 6 months (median dose=9.0 mg), 14.4 mg at 3 years (median dose=15.0 mg), and 16.6 mg at 5 years (median dose=18.0 mg), regardless of levodopa supplementation.

When REQUIP is administered as adjunct therapy to levodopa, the dose of levodopa may be decreased gradually as tolerated once a therapeutic effect with REQUIP has been observed. A decrease in levodopa dosage may be necessary in order to avoid excessive dopamine stimulation.

REQUIP 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 REQUIP.

fever, hot flushes, injury, rigors, ataxia, dyskinesia, dystonia, hyperkinesia, involuntary muscle contractions, paresthesia, aggravated Parkinsonism, tremor, diarrhea, gingivitis, increased saliva, bradycardia, gout, hyperglycemia, decreased weight, arthralgia, arthritis, back pain, myalgia, basal cell carcinoma, anxiety, depression, abnormal dreaming, insomnia, nervousness, prostatic disorder, upper respiratory tract infection, coughing, rash, hematuria and leg cramps.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The following section enumerates potentially important adverse drug reactions that have been reported spontaneously to various surveillance systems and have also occurred in post-launch clinical trials. The events enumerated represent reports arising from both domestic and nondomestic use of ropinirole. These events do not include those already listed in Adverse Reactions above.

Patients treated with REQUIP have rarely reported suddenly falling asleep while engaged in activities of daily living, including operation of motor vehicles which has sometimes resulted in accidents (see Warnings and Precautions).

Pathological (compulsive) gambling has been reported in post-market data, including those in the literature, for antiparkinson drugs. Sporatic cases of pathological (compulsive) gambling have been reported in patients treated with REQUIP. Dosage adjustment should be considered in the management of this behaviour.

Impulse control symptoms and increased libido including hypersexuality have been reported (see Warnings and Precautions).

Psychotic reactions (other than hallucinations) including delusion, paranoia, and delirium have been reported.

Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus) have been very rarely reported.

In two long-term, comparator-controlled studies of early therapy (durations of three and five years), patients with mild to moderate Parkinson's Disease initiated treatment on REQUIP alone, with open L-dopa available as supplementary medication.

The overall rates of withdrawal due to adverse events were 27% for the five year study and 20% for the three year one.

Table 3 lists the adverse events that occurred at an incidence of 5% or more in these two studies.

Of 1599 patients who received REQUIP during the premarketing clinical trials, 17.1% in early-therapy studies and 17.3% in adjunct-therapy studies discontinued treatment due to adverse reactions. The events resulting in discontinuation of REQUIP in 1% or more of patients were as follows: Early therapy: nausea (6.4%), dizziness (3.8%), aggravated Parkinson's disease (1.3%), hallucination (1.3%), headache (1.3%), somnolence (1.3%) and vomiting (1.3%). Adjunct therapy: dizziness (2.9%), dyskinesia (2.4%), confusion (2.4%), vomiting (2.4%), hallucination (1.9%), nausea (1.9%), anxiety (1.9%), and increased sweating (1.4%). Patients over 75 years of age (n=130) showed slightly higher incidences of withdrawal due to hallucination, confusion and dizziness than patients less than 75 years of age.

In addition to the events listed in Table 1, the following adverse events were recorded with rates equal to, or more common in, placebo-treated patients:

Adverse Events with Incidence of >5% from 2 Long-term Comparator-controlled Early Therapy Studies (regardless of the presence or absence of concomitant L-dopa)

asthenia, chest pain, fatigue, hot flushes, postural hypotension, abnormal gait, hyperkinesia, aggravated Parkinsonism, vertigo, abdominal pain, constipation, back pain, myalgia, depression, insomnia, paroniria (WHO dictionary term for nightmares), viral infection, upper respiratory tract infection, pharyngitis, rhinitis, rash, rash erythematous, taste perversion, hematuria, leg cramps and diplopia, myocardial infarction, extrasystoles supraventricular.

Adverse events occurring with an incidence of greater than, or equal to, 10% were as follows: Early therapy: nausea, dizziness, somnolence, headache, peripheral oedema, vomiting, syncope, fatigue and viral infection. Adjunct therapy: dyskinesia, nausea, dizziness, somnolence and headache.

Oral clearance of REQUIP is reduced in patients older than 65 years of age, however the dosing of ropinirole for elderly patients can be titrated in the normal manner. (See Action and Clinical Pharmacology, Special Populations and Conditions, Geriatrics.)

The safety and efficacy of REQUIP have not been established in children under 18 years of age, therefore REQUIP is not recommended in this patient population.

REQUIP (ropinirole hydrochloride) is indicated in the treatment of the signs and symptoms of idiopathic Parkinson's disease.

REQUIP can be used both as early therapy without concomitant levodopa and as an adjunct to levodopa.

It is anticipated that the symptoms of REQUIP overdose will be related to its dopaminergic activity. General supportive measures are recommended. Vital signs should be maintained, if necessary. Removal of any unabsorbed material (e.g. by gastric lavage) should be considered.

There were no reports of intentional overdose of REQUIP in the premarketing clinical trials. A total of 27 patients accidentally took more than their prescribed dose of REQUIP, with 10 patients ingesting more than 24 mg/day. The largest overdose reported in premarketing clinical trials was 435 mg taken over a 7-day period (62.1 mg/day). Of patients who received a dose greater than 24 mg/day, one experienced mild oro-facial dyskinesia, another patient experienced intermittent nausea. Other symptoms reported with accidental overdoses were: agitation, increased dyskinesia, grogginess, sedation, orthostatic hypotension, chest pain, confusion, vomiting and nausea.

Each green, pentagonal, film-coated, beveled-edged Tiltab tablet, imprinted with SB and 4892, contains: ropinirole 1 mg (as ropinirole HCl). Nonmedicinal ingredients: croscarmellose sodium, FD&C Blue No. 2 aluminum lake, hydrous lactose, hydroxypropyl methylcellulose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide. Sucrose-, tartrazine- or any other azo dyes-free. Bottles of 100. Single unit blister packs of 21.

Each blue, pentagonal, film-coated, beveled-edged Tiltab tablet, imprinted with SB and 4894, contains: ropinirole 5 mg (as ropinirole HCl). Nonmedicinal ingredients: croscarmellose sodium, FD&C Blue No. 2 aluminum lake, hydrous lactose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide. Sucrose-, tartrazine- or any other azo dyes-free. Bottles of 100. Single unit blister packs of 21.

Each white, pentagonal, film-coated, beveled-edged Tiltab tablet, imprinted with SB and 4890, contains: ropinirole 0.25 mg (as ropinirole HCl). Nonmedicinal ingredients: croscarmellose sodium, hydrous lactose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide. Sucrose-, tartrazine- or any other azo dyes-free. Bottles of 100. Single unit blister packs of 21.

Each pale pink, pentagonal, film-coated, beveled-edged Tiltab tablet, imprinted with SB and 4893, contains: ropinirole 2 mg (as ropinirole HCl). Nonmedicinal ingredients: croscarmellose sodium, hydrous lactose, hydroxypropyl methylcellulose, iron oxide red, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide. Sucrose-, tartrazine- or any other azo dyes-free. Bottles of 100. Single unit blister packs of 21.

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot-derived dopamine agonists can cause them is unknown.

A small number of reports have been received of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung diseases, and cardiac valvulopathy, in the development program and postmarketing experience for REQUIP. While the evidence is not sufficient to establish a causal relationship between REQUIP and these fibrotic complications, a contribution of REQUIP cannot be completely ruled out in rare cases.

Dopamine agonists appear to impair the systemic regulation of blood pressure with resulting orthostatic symptoms of dizziness or lightheadedness, with or without documented hypotension. These symptoms appear to occur especially during dose initiation and escalation. Therefore, patients treated with REQUIP and other dopamine agonists should be carefully monitored for signs and symptoms of orthostatic hypotension, especially during dose initiation and escalation (see Dosage and Administration) and should be informed of this risk.

Impulse control symptoms including compulsive behaviours such as pathological gambling and hypersexuality have been reported in patients treated with dopaminergic agents, including ropinirole. As described in the literature, such behaviours have been reported principally in Parkinson’s disease patients treated with dopaminergic agents, especially at higher doses, and were generally reversible upon dose reduction or treatment discontinuation. In some ropinirole cases, other factors were present such as a history of compulsive behaviours or concurrent dopaminergic treatment.

Hallucinations were experienced by 10.1% of patients receiving REQUIP and levodopa, compared to 4.2% receiving placebo and levodopa. Hallucinations were of sufficient severity that it led to discontinuation in 1.9% of patients. The incidence of hallucinations was dose dependent.

Safety and effectiveness in the paediatric population have not been established.

The use of REQUIP during pregnancy is not recommended. REQUIP given to pregnant rats during organogenesis (gestation days 8 through 15) resulted in decreased fetal body weight at 60 mg/kg/day (approximately 3-4 times the AUC at the maximal human dose of 8 mg t.i.d), increased fetal death at 90 mg/kg/day (approximately 5 times the AUC at the maximal human dose of 8 mg t.i.d ) and digital malformations at 150 mg/kg/day (approximately 8-9 times the AUC at the maximal human dose of 8 mg t.i.d). These effects occurred at maternally toxic doses. There was no indication of an effect on development of the conceptus at a maternally toxic dose of 20 mg/kg/day in the rabbit. In a perinatal-postnatal study in rats, 10 mg/kg/day of REQUIP (approximately 0.5-0.6 times the AUC at the maximal human dose of 8 mg t.i.d) impaired growth and development of nursing offspring and altered neurological development of female offspring.

In female patients on long-term treatment with conjugated oestrogens, oral clearance was reduced and elimination half-life prolonged compared to patients not receiving oestrogens (see Action and Clinical Pharmacology, Special Populations and Conditions). In patients, already receiving oestrogen replacement therapy, REQUIP may be titrated in the recommended manner according to clinical response. However, if oestrogen replacement therapy is stopped or introduced during treatment with REQUIP, adjustment of the REQUIP dosage may be required.

In placebo-controlled trials, REQUIP caused hallucinations in 5.1% of patients during early therapy (1.4% in the placebo group). Hallucinations were of sufficient severity to result in that it led to discontinuation in 1.3% of patients. The incidence of hallucinations was dose-dependent.

In a 5-year study comparing REQUIP with levodopa in early Parkinson's patients, the overall incidence of hallucinations was 17.3% (31/179) for patients treated with REQUIP and 5.6% (5/89) for levodopa patients. Hallucinations led to discontinuation of the study treatment in 5.0% of REQUIP and 2.2% of levodopa patients. In a 3-year study comparing REQUIP with another dopamine agonist, the overall incidence of hallucinations was 9.5% (16/168) for patients treated with REQUIP and 9.0% (15/167) for patients receiving active comparator. Hallucinations led to discontinuation of the study treatment in 2.4% of REQUIP patients and 3.0% of comparator patients.

Concomitant Selegiline: In a 5-year study, REQUIP patients receiving concomitant selegiline reported a higher incidence of hallucinations (23.5%) than did those without (12.2%); this subpopulation effect was not seen in the L-dopa arm (hallucinations with concomitant selegiline=2.0% vs hallucinations without selegiline=8.0%).

Since REQUIP has not been studied in patients with a history or evidence of significant cardiovascular disease including myocardial infarction, unstable angina, cardiac decompensation, cardiac arrhythmias, vaso-occlusive disease (including cerebral) or cardiomyopathy, it should be used with caution in such patients.

There is limited experience with REQUIP in patients treated with antihypertensive and antiarrhythmic agents. Consequently, in such patients, the dose of REQUIP should be titrated with caution.

In a two year carcinogenicity study in albino Sprague-Dawley rats, retinal atrophy was observed at incidences of 0%, 1.4%, 1.4% and 10% of male rats and 0%, 4.4%, 2.9% and 12.9% of female rats dosed at 0, 1.5, 15 and 50 mg/kg/day respectively. The incidence was significantly higher in both male and female animals dosed at 50 mg/kg/day. The 50 mg/kg/day dose represents a 2.8 fold greater exposure (AUC) and a 13.1 fold greater exposure (C_max) to ropinirole in rats than the exposure would be in humans at the maximum recommended dose of 24 mg/day. The relevance of this finding to humans is not known.

No dosage adjustment is needed in patients with mild to moderate renal impairment (creatinine clearance of 30 to 50 mL/min; see Action and Clinical Pharmacology).

Because the use of REQUIP in patients with severe renal impairment or hepatic impairment has not been studied, administration of REQUIP to such patients is not recommended.

REQUIP may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate pre-existing dyskinesia. Decreasing the dose of levodopa may ameliorate this side effect.

A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious aetiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.

A single spontaneous report of a symptom complex resembling the neuroleptic malignant syndrome has been observed in a 66 year old diabetic male patient with Parkinson's disease, who developed fever, muscle stiffness, and drowsiness 8 days after beginning REQUIP treatment. The patient also experienced acute bronchitis, which did not respond to antibiotic treatment. REQUIP was discontinued three days before the patient died. The reporting physician considered these events to be possibly related to REQUIP treatment (see Dosage and Administration).

A single spontaneous report of severe muscle pain has been reported in a 66 year old male patient around his thigh. The reporting physician considered the event to be probably related to REQUIP treatment.

Some epidemiological studies have shown that patients with Parkinson's disease have a higher risk (perhaps 2- to 4-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, was unclear. REQUIP is one of the drugs used to treat Parkinson's disease. Although REQUIP has not been associated with an increased risk of melanoma specifically, its potential role as a risk factor has not been systematically studied. Patients treated with REQUIP should be made aware of these results and should undergo periodic dermatologic screening.

Since REQUIP suppresses lactation, it should not be administered to mothers who wish to breast-feed infants.

Studies in rats have shown that REQUIP and/or its metabolites cross the placenta and are excreted in breast milk. Consequently, the human foetus and/or neonate may be exposed to dopamine agonist activity.

Population pharmacokinetic analysis revealed that the oral clearance of REQUIP, seen in patients under the age of 65 years (n=97), was reduced from 62.1 L/h to 45.5 L/h in patients between the ages of 65 and 75 years (n=63). In patients older than 75 years (n=11), oral clearance was similar to that seen in the 65 to 75 year age group (41.7 L/h). However, since the dose of REQUIP is to be individually titrated to clinical response, dosage adjustment is not necessary in the elderly (above 65 years).

REQUIP is a non-ergoline dopamine agonist, which activates post-synaptic dopamine receptors.

In vitro studies have shown that ropinirole binds with high affinity to cloned human D₂, D₃, and D₄ receptors. The antiparkinson activity of ropinirole is believed to be due to its stimulatory effects on central post-synaptic dopamine D₂ receptors within the caudate-putamen.

Ropinirole is a potent agonist both in vitro and in vivo and restores motor function in animal models of Parkinson's disease. Ropinirole has been shown to reverse the motor deficits induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in primates.

Neither ropinirole nor its metabolites bind with high affinity to dopamine D₁ receptors. Ropinirole also has very low affinity for 5-HT₁, 5-HT₂, benzodiazepine, GABA_A, muscarinic, alpha- or beta-adrenoreceptors. Ropinirole binds to opiate receptors with low affinity, however, studies show that this weak opiate activity has no consequences at pharmacological doses in vivo.

In rats, ropinirole binds to melanin-containing tissues (e.g. the eye) to a greater degree than non-pigmented tissues, and tissue levels decline with a half-life of 16-20 days. It is unknown whether or not ropinirole accumulates in these tissues over time.

In women, on long-term treatment with conjugated estrogens (n=16, mean age 63 years), the oral clearance of REQUIP was decreased by an average of 36% compared to the oral clearance in women not receiving supplemental oestrogens (n=56, mean age 65 years). The average terminal elimination half-life was 9.0 hours in the oestrogen group and 6.5 hours in patients not taking oestrogens (see Warnings and Precautions and Dosage and Administration).

Recovery of radioactivity after oral and intravenous administration of ¹⁴C-ropinirole was approximately 88% and 90% of the dose, respectively. Urinary excretion of unchanged ropinirole is low and represents approximately 5 to 10% of the dose. N-despropyl ropinirole is the predominant metabolite found in the urine (40%), followed by the glucuronide of the hydroxy metabolite (10%), and the carboxylic acid metabolite (10%) formed from N-despropyl ropinirole.

Population pharmacokinetic analysis indicated that the oral clearance and volume of distribution of REQUIP at steady state were similar in male patients (n=99, mean age 60 years) and female patients who were not taking concomitant estrogens (n=56, mean age 65 years).

Ropinirole is extensively metabolized by the liver. The N-despropyl metabolite is the major metabolite circulating in the plasma. Based on AUC data, the plasma levels of the metabolite were consistently higher than those of the parent drug suggesting a nonsaturable conversion of ropinirole to the N-despropyl metabolite. The affinity of the N-despropyl metabolite for human cloned D₂ receptors is lower than the affinity of ropinirole. In addition the metabolite does not cross the blood-brain barrier; thus, it is unlikely to contribute to the therapeutic effects of ropinirole. The plasma concentrations of the hydroxylated metabolite are low and account for about 1-5% of the ropinirole concentrations. Although the hydroxylated metabolite was more active than ropinirole in in vitro D₂ receptor binding studies, at therapeutic doses it is not expected to contribute to the activity of ropinirole.

In vitro studies indicate that the major cytochrome P450 isozyme involved in the metabolism of ropinirole is CYP1A2. In patients with Parkinson's disease, ciprofloxacin, an inhibitor of CYP1A2, significantly increased the systemic availability of ropinirole, while theophylline, a substrate of CYP1A2, was devoid of such activity (see Drug Interactions).

Steady state concentrations are expected to be achieved within 2 days of dosing. There is, on average, a two-fold higher steady-state plasma concentration of ropinirole following the recommended t.i.d. regimen compared to those observed following a single oral dose.

A high fat meal delayed the rate of absorption of ropinirole (median T_max was increased by 2.6 hours and C_max was decreased by 25%) in Parkinsonian patients. However, there was no marked change in the overall systemic availability of the drug. Ropinirole may be given with or without food. While administration of the drug with food may improve gastrointestinal tolerance, in severely fluctuating patients, the morning dose may be given without food in order to avoid a delay in time to switch “ON”.

Population pharmacokinetic analyses have shown that frequently coadministered medications, such as levodopa, selegiline, amantadine, anticholinergic drugs, ibuprofen, benzodiazepines and antidepressants did not alter the pharmacokinetics of ropinirole.

Plasma protein binding is low (10 to 40%).

Ropinirole has a blood to plasma ratio of 1.2.

Based on population pharmacokinetics, no clinically significant differences were observed in the pharmacokinetics of REQUIP in Parkinsonian patients with moderate renal impairment (creatinine clearance between 30 to 50 mL/min; n=18, mean age 74 years) compared to age-matched patients with creatinine clearance above 50 mL/min (n=44, mean age 70 years). Therefore, no dosage adjustment is necessary in Parkinsonian patients with mild to moderate renal impairment (see Warnings and Precautions and Dosage and Administration).

The use of REQUIP in patients with severe renal impairment or hepatic impairment has not been studied. Administration of REQUIP to such patients is not recommended (see Warnings and Precautions and Dosage and Administration).

In healthy normotensive subjects, single oral doses of REQUIP, in the range of 0.01 to 2.5 mg, had little or no effect on supine blood pressure and pulse rate. Upon standing, REQUIP caused decreases in systolic and mainly diastolic blood pressure at doses above 0.25 mg. In some subjects, these changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case, transient sinus arrest in the context of a severe vasovagal syncope. The effect of repeat dosing and slow titration of REQUIP was not studied in healthy volunteers.

The mechanism of REQUIP-induced orthostatic symptoms probably relates to its dopamine D₂-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Orthostatic signs and symptoms were often accompanied by nausea.

REQUIP had no dose-related effect on ECG wave form and rhythm in young healthy male volunteers.

At doses ≥0.8 mg REQUIP suppressed serum prolactin concentrations in healthy male volunteers.