PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 8 DRUG INTERACTIONS 22 DOSAGE AND ADMINISTRATION 24 OVERDOSAGE 25 ACTION AND CLINICAL PHARMACOLOGY 26 STORAGE AND STABILITY 29 DOSAGE FORMS, COMPOSITION AND PACKAGING 30

PART II: SCIENTIFIC INFORMATION 31

PHARMACEUTICAL INFORMATION 31 CLINICAL TRIALS 32 DETAILED PHARMACOLOGY 38 TOXICOLOGY 40 REFERENCES 46

PART III: CONSUMER INFORMATION. 51

PrREQUIP(r) ropinirole hydrochloride tablets

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

REQUIP(r) is contraindicated in patients with a known hypersensitivity to ropinirole hydrochloride or the excipients of the drug product. For a complete listing of excipients, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

WARNINGS AND PRECAUTIONS

Sudden Onset of Sleep

Serious Warnings and Precautions

Patients receiving treatment with REQUIP(r) and other dopaminergic agents have reported suddenly falling asleep while engaged in activities of daily living, including operating a motor vehicle, which has sometimes resulted in accidents. Although some of the patients reported somnolence while on REQUIP(r), others perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.

Physicians should alert patients of the reported cases of sudden onset of sleep, bearing in mind that these events are NOT limited to initiation of therapy. Patients should also be advised that sudden onset of sleep has occurred without warning signs. If drowsiness or sudden onset of sleep should occur, patients should immediately contact their physician.

Until further information is available on the management of this unpredictable and serious adverse event, patients should be warned not to drive or engage in other activities where impaired alertness could put themselves and others at risk of serious injury or death (e.g., operating machines). Episodes of falling asleep while engaged in activities of daily living have also been reported in patients taking other dopaminergic agents, therefore, symptoms may not be alleviated by substituting these products.

Presently, the precise cause of this event is unknown. It is known that many Parkinson's disease patients experience alterations in sleep architecture, which results in excessive daytime sleepiness or spontaneous dozing, and that dopaminergic agents can also induce sleepiness. There is insufficient information to determine whether this event is associated with REQUIP(r), all dopaminergic agents or Parkinson's disease itself. The following Warnings and Precautions are listed in alphabetical order.

Carcinogenesis and Mutagenesis

See PART II: TOXICOLOGY, Carcinogenicity and Mutagenicity for discussion on animal data.

Cardiovascular

Patients with pre-existing cardiovascular conditions

Since REQUIP(r) 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(r) in patients treated with antihypertensive and antiarrhythmic agents. Consequently, in such patients, the dose of REQUIP(r) should be titrated with caution.

Orthostatic hypotension

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(r) 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 (see PART III: CONSUMER INFORMATION).

Connective tissue

Fibrotic Complications

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(r). While the evidence is not sufficient to establish a causal relationship between REQUIP(r) and these fibrotic complications, a contribution of REQUIP(r) cannot be completely ruled out in rare cases.

Neurologic

Neuroleptic Malignant Syndrome

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(r) treatment. The patient also experienced acute bronchitis, which did not respond to antibiotic treatment. REQUIP(r) was discontinued three days before the patient died. The reporting physician considered these events to be possibly related to REQUIP(r) 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(r) treatment.

Dyskinesia with Adjunctive Levodopa

REQUIP(r) 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.

Ophthalmologic

Retinal Pathology in Rats

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 (Cmax ) 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.

Psychiatric

Compulsive Behaviours

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

Early Therapy: In placebo-controlled trials, REQUIP(r) 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(r) with levodopa in early Parkinson's patients, the overall incidence of hallucinations was 17.3% (31/179) for patients treated with REQUIP(r) and 5.6% (5/89) for levodopa patients. Hallucinations led to discontinuation of the study treatment in 5.0% of REQUIP(r) and 2.2% of levodopa patients. In a 3-year study comparing REQUIP(r) with another dopamine agonist, the overall incidence of hallucinations was 9.5% (16/168) for patients treated with REQUIP(r) and 9.0% (15/167) for patients receiving active comparator. Hallucinations led to discontinuation of the study treatment in 2.4% of REQUIP(r) patients and 3.0% of comparator patients. Concomitant Selegiline: In a 5-year study, REQUIP(r) 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%). Adjunct Therapy: Hallucinations were experienced by 10.1% of patients receiving REQUIP(r) 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.

Skin

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(r) is one of the drugs used to treat Parkinson's disease. Although REQUIP(r) 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(r) should be made aware of these results and should undergo periodic dermatologic screening.

Special Populations

Pregnant Women: The use of REQUIP(r) during pregnancy is not recommended. REQUIP(r) 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(r) (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. Nursing Women: Since REQUIP(r) suppresses lactation, it should not be administered to mothers who wish to breast-feed infants. Studies in rats have shown that REQUIP(r) 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.

Use in Women receiving Oestrogen Replacement Therapy:

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(r) may be titrated in the recommended manner according to clinical response. However, if oestrogen replacement therapy is stopped or introduced during treatment with REQUIP(r), adjustment of the REQUIP(r) dosage may be required.

Paediatrics:

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

Renal and Hepatic Impairment:

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(r) in patients with severe renal impairment or hepatic impairment has not been studied, administration of REQUIP(r) to such patients is not recommended.

DRUG INTERACTIONS

Overview

CYP1A2 Interaction: 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(r), adjustment of the dose of REQUIP(r) may be required.

Drug-Drug Interactions

Psychotropic Drugs: Neuroleptics and other centrally active dopamine antagonists may diminish the effectiveness of REQUIP(r). Therefore, concomitant use of these products is not recommended. Based on population pharmacokinetic assessment, no interaction was seen between REQUIP(r) and tricyclic antidepressants or benzodiazepines. Anti-Parkinson Drugs: Based on population pharmacokinetic assessment, there were no interactions between REQUIP(r) and drugs commonly used to treat Parkinson's disease, i.e., selegiline, amantadine, and anticholinergics.

Levodopa:

The potential pharmacokinetic interaction of levodopa/carbidopa

(100 mg/10 mg b.i.d.) and REQUIP(r) (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(r) 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(r).

Inhibitors of CYP1A2: Ciprofloxacin

The effect of ciprofloxacin (500 mg b.i.d.) on the pharmacokinetics of REQUIP(r) (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(r) was significantly increased when coadministered with ciprofloxacin (AUC increased by 1.84 fold). Thus, in patients already receiving CYP1A2 inhibitors such as ciprofloxacin, REQUIP(r) 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(r), adjustment of the REQUIP(r) dosage will be required.

Substrates of CYP1A2: Theophylline

The effect of oral theophylline (300 mg bid) on the pharmacokinetics of REQUIP(r) (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(r) when coadministered with theophylline. Similarly, coadministration of REQUIP(r) 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(r), and vice-versa. Digoxin: The effect of REQUIP(r) (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(r) 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(r) on the pharmacokinetics of digoxin is not known. Alcohol: No information is available on the potential for interaction between REQUIP(r) and alcohol. As with other centrally active medications, patients should be cautioned against taking REQUIP(r) with alcohol.

Drug-Lifestyle Interactions

Psycho-Motor Performance

(See WARNINGS AND PRECAUTIONS - Sudden Onset of Sleep).

DOSAGE AND ADMINISTRATION

Dosing Considerations

Renal and Hepatic Impairment: In patients with mild to moderate renal impairment, REQUIP(r) 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(r) to such patients is not recommended. Patients with hepatic impairment have not been studied and administration of REQUIP(r) to such patients is not recommended. Oestrogen Replacement Therapy: In patients already receiving oestrogen replacement therapy, REQUIP(r) may be titrated in the recommended manner according to clinical response. However, if oestrogen replacement therapy is stopped or started during treatment with REQUIP(r), adjustment of the REQUIP(r) dosage may be required.

Recommended Dose and Dosage Adjustment

REQUIP(r) should be taken three times daily and may be taken with or without food (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). The recommended starting dosage is 0.25 mg three times daily. Based on individual patient response, dosage should then be titrated by weekly increments of 0.25 mg per dose as described in the table below. After week 4, daily dosage may be increased by 0.5 to 1.0 mg per dose on a weekly basis until an optimal therapeutic response is established. Smaller dose increments are recommended for patients who may be at risk for orthostatic symptoms.

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

Missed Dose

Patients should be instructed that, if they miss a dose of REQUIP(r), 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).

OVERDOSAGE

Symptoms and Signs

There were no reports of intentional overdose of REQUIP(r) in the premarketing clinical trials. A total of 27 patients accidentally took more than their prescribed dose of REQUIP(r), 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.

Recommended Management

It is anticipated that the symptoms of REQUIP(r) 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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

REQUIP(r) 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, GABAA, 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.

Pharmacodynamics

In healthy normotensive subjects, single oral doses of REQUIP(r), 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(r) 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(r) was not studied in healthy volunteers. The mechanism of REQUIP(r)-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(r) had no dose-related effect on ECG wave form and rhythm in young healthy male volunteers. At doses >= 0.8 mg REQUIP(r) suppressed serum prolactin concentrations in healthy male volunteers.

Pharmacokinetics

Absorption, Bioavailability and Distribution

Ropinirole is rapidly absorbed with median peak concentrations occurring within 1.5 hours after oral dosing. Despite complete absorption, absolute bioavailability of ropinirole is reduced to approximately 50% as a result of first-pass metabolism. Relative bioavailability from a tablet compared to an oral solution is 85%. Over the therapeutic dose range, Cmax and AUC values increase in proportion to the increase in dose (see Table 4). The average oral clearance is approximately 47 L/h (range 17-113 L/h) and is constant over the entire dosage range. The terminal elimination half-life is approximately 6 h (range 2-27 h) and the volume of distribution at steady state is approximately 480 L (range 216-891 L) or 7.0 L/kg (range 3.1-12.9 L/kg).

Table 4 Steady state pharmacokinetic parameters (mean and range) of ropinirole in patients with Parkinson's disease administered ropinirole in a t.i.d. regimen

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 Tmax was increased by 2.6 hours and Cmax 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 co-administered 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. Metabolism: 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).

Excretion: 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.

Special Populations and Conditions

Geriatrics: Population pharmacokinetic analysis revealed that the oral clearance of REQUIP(r), 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(r) is to be individually titrated to clinical response, dosage adjustment is not necessary in the elderly (above 65 years). Gender: Population pharmacokinetic analysis indicated that the oral clearance and volume of distribution of REQUIP(r) 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). Oestrogen Replacement Therapy: In women, on long-term treatment with conjugated estrogens (n=16, mean age 63 years), the oral clearance of REQUIP(r) 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). Renal/Hepatic Insufficiency: Based on population pharmacokinetics, no clinically significant differences were observed in the pharmacokinetics of REQUIP(r) 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(r) in patients with severe renal impairment or hepatic impairment has not been studied. Administration of REQUIP(r) to such patients is not recommended (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

STORAGE AND STABILITY

REQUIP(r) tablets should be stored between 15-30o C. Protect from light and moisture. Close container tightly after each use.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Form

REQUIP(r) is supplied as a pentagonal film-coated Tiltab(r) tablet with beveled edges containing ropinirole (as ropinirole hydrochloride) as follows: 0.25 mg - white imprinted with SB and 4890; 0.5 mg * - pale yellow imprinted with SB and 4891; 1.0 mg - green imprinted with SB and 4892; 2.0 mg - pale pink imprinted with SB and 4893; 3.0 mg * - pale purple tablets imprinted with SB and 4895, 4.0 mg * - light brown tablets imprinted with SB and 4896, 5.0 mg - blue tablets imprinted with SB and 4894. REQUIP(r) is available in bottles in the pack size of 100 tablets. It is also available as a single unit blister pack of 21 tablets.

Composition

Ropinirole hydrochloride is the active ingredient. Non-medicinal ingredients include: Hydrous lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, iron oxide yellow (0.5 *, 1.0 and 2.0 mg tablets), iron oxide red (0.5 * and 2.0 mg tablets), carmine (3.0 mg *), FD & C Blue No. 2 aluminum lake (0.5 *, 1.0, 3.0 *, 4.0 * and 5.0 mg tablets), FD & C Yellow No. 6 aluminum lake (3.0 * and 4.0 * mg), polysorbate 80 (0.25 and 5 mg tablets). They do not contain sucrose, tartrazine or any other azo dyes.

* 0.5 mg, 3.0 mg, and 4.0 mg tablets are not available in Canada.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: ropinirole hydrochloride Chemical name: 4-[2-(Dipropylamino)ethyl]-2-indolinone monohydrochloride Molecular formula and molecular mass: C16H25N2OCl 296.84 (260.38 as the free base) Structural formula: Description: Ropinirole hydrochloride is a white to pale greenish-yellow powder. Physicochemical Properties: Ropinirole hydrochloride has a melting range of 243o to 250oC and a solubility of 133 mg/mL in water. The pKa of the protonated tertiary amino group was found to be 9.68 at 25oC and that of the indol-2-one group was found to be 12.43 at 37oC. The distribution coefficients between n- octanol/water and cyclohexane/water at pH 8.4 and 37oC are given by log D values of +2.33 and -0.07 respectively.

CLINICAL TRIALS

In pre-marketing clinical trials, 1599 patients have been exposed to REQUIP(r), with 481 patients being exposed for over one year and 241 patients being exposed for over two years. Evidence to support the efficacy of REQUIP(r) in treating the signs and symptoms of Parkinson's disease was obtained in multicentre, double-blind, studies. These studies included either patients who had minimal or no prior dopaminergic therapy, or patients who were not optimally controlled with current levodopa-decarboxylase inhibitor therapy. In patients with early disease, REQUIP(r) improved motor function (assessed by the motor component of the UPDRS [Unified Parkinson's Disease Rating Scale]) and delayed the need to initiate treatment with levodopa. In patients with more advanced disease, REQUIP(r) reduced "off" time (based upon patient diaries recording time "on" and "off") and permitted a reduction in levodopa dose. The subsequent section describes some of the studies in which REQUIP(r) was titrated (see DOSAGE AND ADMINISTRATION) to the maximal dose of 8 mg t.i.d.. In clinical trials where dosing was titrated to optimal clinical effect, the mean daily dose of REQUIP(r) at 24 weeks was 9.5 mg in early therapy (n=282) and was 13.5 mg in adjunct therapy (n=303). In the pivotal clinical trials, including studies where the dose was titrated to the target maximum of 24 mg per day, the mean daily dose of REQUIP(r) at a 6 month study endpoint was 10.7 mg in early therapy (n=458) and 12.5 mg in adjunct therapy (n=456). At the end of a 3-year double-blind study in early Parkinson's patients, the average dose of ropinirole for those patients remaining in the trial (n=102) was 11.9 mg/day, regardless of levodopa supplementation; at the 3-year point of a similar 5-year study, the corresponding mean dose (n = 103) was 14.4 mg. At the completion of the 5-year study, the corresponding mean dose (n = 85) of ropinirole was 16.6 mg/day. In the premarketing clinical trial patient database (n=1599) over 50% of patients were dosed between 6 and 15 mg of REQUIP(r) per day in both early and adjunct therapy. Less than 22% of patients exceeded a total daily dose of 15 mg. During the clinical trials, the dose of REQUIP(r) was titrated to optimal clinical response and tolerance. Retrospective analysis showed that female patients required lower doses than male patients but were exposed to REQUIP(r) for similar periods of time.

Early Therapy

Placebo-Controlled Studies

In a double-blind, randomized, placebo-controlled, 6-month study, REQUIP(r)-treated patients (n=116) demonstrated a 24% improvement in UPDRS motor scores from baseline, compared to placebo-treated patients (n=125), who demonstrated a 3% worsening in motor scores. On the Clinical Global Impression (CGI) scale, 33% of REQUIP(r)-treated patients and 12% of placebo-treated patients were rated as "very much improved" and "much improved". "Rescue levodopa" was needed by 11% of REQUIP(r) -treated and 29% of placebo-treated patients. All differences were statistically significant.

Comparator-Controlled Studies

Five-Year Study

In a 5-year multi-centre, double-blind, flexible dose study, 268 patients were randomized to either REQUIP(r) (n=179) or levodopa-benserazide (n=89), with open-label L-dopa available as supplementary medication. Patients were classified between Hoehn and Yahr (H&Y) stage I and stage III, and had a mean disease duration of approximately 2.5 years and a mean age of approximately 63 years.

Six Month Interim Findings

The decrease in UPDRS motor scores vs baseline was greater with L-dopa than with REQUIP(r). However, the proportion of "responders" (UPDRS improvement of at least 30%) did not differ between L-dopa and REQUIP(r). Results on the CGI indicated that there was no difference between REQUIP(r) and L-dopa for the less severely afflicted patients (Hoehn and Yahr stage I to II) but L-dopa was more efficacious in patients with more severe disease.

Five Year Endpoint Findings

It should be noted that the interpretability of these data is limited with regard to the relative clinical efficacy of the two drugs beyond the six month point considering the progressive degenerative nature of the disease, the lack of a placebo control arm and that the minimal change associated with clinical relevance for efficacy was not defined in this study for the five year endpoint analysis.

Safety

Dyskinesia: In this 5-year study, the risk of patients developing involuntary movemements (i.e. dyskinesias) was shown to be reduced with initial treatment with REQUIP(r) (without concomitant L-dopa) compared to that associated with the administration of levodopa as initial therapy. The primary endpoint of the 5-year study was dyskinesia, defined as UPDRS Part IV Item 32 (duration of abnormal movement), plus related adverse event reports. A significantly smaller proportion of patients developed dyskinesias in the REQUIP(r) arm (20%, 36/177) compared to the L-dopa arm (45%, 40/88). This treatment difference becomes larger if the factor of supplementary L-dopa is taken into account; due to methodological issues, this comparison is most appropriately done through survival analysis. Figure 1, (below) displays the survival curves for time to dyskinesia regardless of supplementary L-dopa for both treatment groups. The vertical axis represents the proportion of individuals who remained free from dyskinesia at various times following the initiation of treatment, with the horizontal axis indicating time. The two survival curves were demonstrated to be statistically different by Cox regression analysis, such that the overall risk of dyskinesia onset was 2.82 times higher in the L-dopa arm than in the REQUIP(r) arm (hazard ratio of 2.82). Figure 2 (below) displays the survival curves for time to dyskinesia onset before receipt of supplementary L-dopa (thus, any dyskinesia-free patients who received supplementary L-dopa were removed from the analysis at the time the supplementary medication was initiated). The treatment difference between these subgroup survival curves was larger than that between the overall survival curves, such that the risk of dyskinesia onset prior to the initiation of any supplemental L-dopa was seven times higher in the L-dopa treatment arm than in the REQUIP(r) arm (hazard ratio of 7.00).

Figure 1 Kaplan-Meier survival plot for the time to onset of dyskinesias in those patients remaining in the study over time

*Mean duration of completers

Figure 2 Kaplan-Meier survival plot for the time to onset of dyskinesias (prior to supplementary L-dopa) in those patients remaining in the study over time

*Mean duration of completers

Dystonias: Dystonias were identified using Item 34 (painful dyskinesias) plus any adverse events coding to dystonia (including blepharospasm and torticollis). Dystonia was experienced by 48 (27%) REQUIP(r) patients and 42 (49%) L-dopa patients. Of the patients in the study that remained dyskinesia-free, dystonia was experienced by 12/140 patients on REQUIP(r) and 2/46 patients on L-dopa. General: The proportion of patients who completed the study was not different between treatment arms (47% REQUIP(r) vs 51% L-dopa), nor did the overall rate of withdrawal due to adverse events differ between the two treatments (27% for REQUIP(r) vs 33% for L-dopa). REQUIP(r) patients receiving concomitant selegiline reported a higher incidence of hallucination (23.5%) than did those without (12.2%); this subpopulation effect was not seen in the L-dopa arm (hallucincation with concomitant selegiline = 2.0% vs hallucination without selegiline = 8.0%).

Efficacy

Overall, in both the REQUIP(r) and L-dopa arms, improvements in efficacy outcomes were seen for the fist six months, with gradual deterioration back towards baseline over the remainder of the trial. For the observed-cases data set, mean change from baseline scores for Activities of Daily Living (ADL, UPDRS part II) indicated that L-dopa patients showed consistently better improvement than did REQUIP(r) patients, by a margin of approximately 0.5 to 1.5 points. At completion, REQUIP(r) patients showed a mean deterioration of 1.6 +- 5.4 points from baseline, compared to 0.0 +- 4.7 points for L-dopa patients. This difference is not statistically significant. Within the REQUIP(r) arm there was a subpopulation effect in the ADL scores, in that REQUIP(r) patients with less severe status at baseline (H&Y stages I-II) showed a significantly better response than did patients with more severe status at baseline (H&Y stages II.5 - III); in contrast, the L-dopa arm showed no subpopulation effect in the ADL scores. (Mean change from baseline in ADL scores at completion, for REQUIP(r): less severe patients = 0.18 vs more severe patients = 3.61; for L-dopa: less severe patients = -0.18 vs more severe patients = -0.61). For the observed-cases data set, the mean change from baseline motor scores (UPDRS part III) show a consistent difference throughout the study of approximately 2 to 4 points in favour of L-dopa. At completion, was a statistically significant difference between the treatment arms in favour of L-dopa (mean change from baseline: REQUIP(r) = -0.8 +- 10.1 vs. L-dopa = +- -4.8 +- 8.3). Of the Intent-to-Treat patient set, supplemental L-dopa was given to 51% of REQUIP(r)- treated and 35% of levodopa-treated patients. Of the subset of patients who completed the study, 66% in the REQUIP(r) arm received supplemental L-dopa, compared to 36% in the L-dopa arm.

Three-year Study

In a 3-year multi-centre, double-blind study, 355 patients were randomized to receive either REQUIP(r) (n=168) or another dopamine agonist (n=167), with open-label L-dopa available as supplementary medication. Patients were classified between Hoehn and Yahr (H&Y) stage I and stage III, had a mean disease duration of approximately 2 years and a mean age of approximately 63 years. It should be noted that the interpretability of these data is limited with regard to the relative clinical efficacy of the two drugs considering the progressive degenerative nature of the disease, the lack of a placebo control arm and that the minimal change associated with clinical relevance for efficacy was not defined in this study for the three year end point analysis.

Safety

Dyskinesias were defined by UPDRS Part IV Items 32 (duration of abnormal movement), 33 (disability), and 34 (painful dyskinesia), plus all related adverse events. A total of 8% of REQUIP(r)-treated patients and 7% of comparator-treated patients had developed dyskinesias by the 3 years end point. The proportion of patients who completed the study did not differ between treatment arms (61% REQUIP(r) vs 67% active comparator), nor did the overall rate of withdrawal due to adverse events (20.2% for REQUIP(r) vs 19.8% for the active control).

Efficacy

Overall, in both the REQUIP(r) and dopamine agonist comparator arms, improvements in efficacy outcomes were seen for the first six months, with gradual deterioration back towards baseline over the remainder of the trial. For the observed-cases data set, mean change from baseline scores for Activities of Daily Living (ADL, UPDRS part II) for both treatment groups were within 0 to 0.5 points of each other until Week 120 (2.5 years). During the final six months, the REQUIP(r) scores remained relatively stable in contrast to those of the treatment group, such that at study endpoint, REQUIP(r) patients showed statistically more improvement than did the patients receiving the comparator agonist (mean change from baseline 1.9 +- 0.6 vs 0.4 +- 0.6 , respectively). For the observed-cases dataset, the mean change from baseline motor scores (UPDRS part III) show a consistent difference throughout the study of approximately 1 to 3 points in favour of ropinirole. At completion, REQUIP(r) patients showed a mean improvement of -6.5 +- 10.0 points from baseline, compared to -4.1 +- 10.6 for comparator patients. This difference is not statistically significant. The proportion of 'responders' (UPDRS improvement of at least 30%) did not differ statistically between the two treatment arms (REQUIP(r) = 53%; comparator = 42.5%). Supplemental levodopa was given to 34% of REQUIP(r)-treated and 42% of active comparator-treated patients.

Adjunct Therapy

In a double-blind, randomized, clinical trial of 6-month duration, REQUIP(r) (n=94) was compared to placebo (n=54) as adjunct therapy to levodopa. The primary efficacy parameter, defined as both a 20% or greater reduction in levodopa dose and a 20% or greater reduction in "off" time, was achieved by 28% of REQUIP(r)-treated patients and 11% of placebo-treated patients. This difference was statistically significant. The daily dose of levodopa was reduced by 19% and 2.8% in the REQUIP(r) and placebo-treated patients, respectively.

TOXICOLOGY

Single Dose Studies

Swiss Mice:

the approximate median lethal dose was 657 mg/kg po and 46 mg/kg iv

Wistar Rats:

the approximate median lethal dose was 862 mg/kg po and 66 mg/kg iv

Clinical signs: The clinical signs, that were similar in both species, were characteristic of central D2 stimulatory activity and at higher doses of general CNS stimulation. They were clearly dose-related and included hyperactivity, abnormal locomotion, stereotypy, tremors, convulsions and finally death.

Repeat Dose Studies

The studies were carried out in mice, rats, and cynomolgous monkeys. The dog could not be used since dopamine agonists act as potent emetics in this species.

Mice

The studies included a 7-day, 60-day and 90-day study. The clinical observations, which were clearly dose-related, included ptosis, hyperactivity, vocalization, aggression, tremors, convulsions, rapid/laboured respiration and in a few animals death. In all three studies, the maximal no effect dose was 25 mg/kg.

Rats

30-day study:

the maximal no effect dose was <10 mg/kg. BUN, ALT and AP were increased in a few mid- and high-dose animals. At necropsy, the relative weights of the liver, adrenals and ovaries were increased in mid- and high-dose females. In the adrenals, the zona fasciculata and the zona reticularis were somewhat increased. In the ovaries, the number of corpora lutea was increased. In the liver, 'ground glass' appearance of the centrilobular hepatocytes, due to moderate proliferation of the smooth endoplasmic reticulum, were noted in both sexes at the high dose (250 mg/kg).

6-month study:

the maximal no effect dose was 10 mg/kg. ALT and AP were increased in a few mid- and high-dose animals. Ropinirole reduced serum prolactin levels in both sexes at all doses. In most of the animals, the levels were below the limit of detection; however, following a 6-week recovery period, they returned to control values. There were a number of histological abnormalities that could be related to reduced prolactin levels, namely changes in the ovaries, vagina, and mammary glands, in the hypophysis of male rats and adrenocortical hypertrophy in females. Except for the ovarian changes, the abnormalities were not present after the 6-week recovery period. In addition, the following changes were observed: centrilobular hepatocyte hypertrophy in some of the high-dose animals (200 mg/kg reduced to 125 mg/kg/day on day 57), and epithelial hyperplasia of the urinary bladder in 3 high-dose animals. Leydig cell hyperplasia, observed in the 1-year toxicology and 2-year carcinogenicity studies, was not observed in this study.

1-year study:

mortality was higher in the high dose group (100 mg/kg) than at the lower doses (5 and 50 mg/kg), and it was often preceded by convulsions. Weight gain was decreased in both sexes at the mid- and high-doses, although in females the decreased weight gain was preceded by an actual weight gain during the first month of the study. In contrast to the observed decreased weight gain, food intake was increased in both sexes, although it was more marked in female rats. Prolactin levels were markedly decreased in male but not in female rats. Both plasma estrogen and progesterone levels were increased, but the former to a greater extent, thus, there was an absolute increase in the ratio of estrogen to progesterone. There was also a slight increase in BUN. Absolute adrenal weights were increased in mid- and high-dose males and females and absolute liver weights in females. Histopathology revealed the following changes - with most of the changes affecting animals in the mid- and high-dose groups: erosion or ulceration of the glandular mucosa of the stomach; hepatocellular alterations and centrilobular hypertrophy of the liver; a decrease in proliferative pituitary lesions at the high dose of both sexes; an increase in the incidence of Leydig cell hyperplasia in the testes. Other changes included increased incidence of endometrial hyperplasia of the uterus, and changes in the ovaries and vagina.

Cynomolgous monkeys

30-day study:

the maximal no effect dose was 5 mg/kg (high dose: 15 mg/kg). At lower doses, the animals showed slight nervousness, lip smacking and piloerection, while at higher doses they showed ptosis, salivation, hyperactivity and self-inflicted wounds. Pathological examination revealed no drug-related lesions either macroscopically or microscopically.

34-week study:

the maximal no effect dose was 15 mg/kg. Originally, the highest dose was 15 mg/kg. Since no behavioral changes were noted, the dose was increased after

8 weeks to 30 mg/kg and treatment was continued for an additional 26 weeks. Decreased weight gain was noted in some high-dose males but not in females. Plasma ALT was increased and plasma sodium decreased in some high-dose males. Serum prolactin was decreased. No ocular changes were seen by ophthalmoscopy. Adrenal weights were increased in mid- and high-dose males and liver weights in high-dose females. No drug- related changes were observed in macroscopic or microscopic examinations. Toxicokinetic analysis indicated that the levels of the N-despropyl metabolite were considerably higher than those of the parent drug or the hydroxy metabolite. Accumulation of the N-despropyl metabolite was noted.

1-year study:

the maximal no effect dose was 5 mg/kg (high dose: 15 mg/kg). Clinical signs included stereotyped locomotion and excessive grooming in some high-dose monkeys. Decreased weight gain was noted in some high-dose males but not in females. No ocular changes were seen by ophthalmoscopic exams. Adrenal weights were increased in high-dose animals of both sexes; increased weights were also noted for testes and ovaries. No drug-related changes were observed in macroscopic or microscopic examinations. Toxicokinetic analysis showed that systemic exposure to ropinirole and the N-despropyl metabolite increased non-proportionally with increasing doses, indicating saturable first pass metabolism. The concentration of the N-despropyl metabolite was considerably higher than that of ropinirole.

Carcinogenicity

Mice

Charles River mice received ropinirole by gavage at doses of 5, 15 and 50 mg/kg/day for 104 weeks. There were two control groups. Mortality was similar in all groups. Mean weight gain was less in mid- and high-dose males than among controls; the weight of females was not affected. Dose-dependent alopecia and/or thinning of fur was noted in ropinirole-treated females. WBC was lower at the end of the study in high-dose males. Histopathological examination revealed an increased incidence of benign uterine endometrial stromal polyps in high dose females.

Rats

Sprague-Dawley rats received ropinirole by gavage at doses of 1.5, 15 and 50 mg/kg/day for approximately 23 months. There were two control groups. Mortality was similar in all groups. Increased incidences of aggression, foot pad lesions and alopecia were noted in animals of both sexes at the mid- and high-doses. At necropsy, urinary bladder distention was noted more frequently among high-dose animals than controls. Enlargement of the pituitary was less frequent in treated animals than in controls. Histology: increased incidence of testicular Leydig cell adenomas at doses > 1.5 mg/kg; pituitary gland: increased incidence of hyperplasia in females and increased cytoplasmic vacuolation in males; ovary: decreased incidence of ovarian quiescence and sertoliform hyperplasia with increased incidence of abnormal corpora lutea; mammary glands: decreased incidence of fibroadenomas and adenocarcinomas at the high dose; liver: increased incidence of centrilobular hepatocellular hypertrophy in mid- and high-dose animals, but decreased incidence of vacuolation and biliary hyperplasia. Retinal atrophy was seen only in ropinirole but not in control rats. The incidence was 1.4%, 1.4% and 10% in male rats and 1.4%, 2.9% and 12.9% in female rats.

Mutagenicity

REQUIP(r) did not cause gene mutation or chromosome damage in a battery of genotoxicity assays, including the bacterial mutagenicity tests (Salmonella typhimurium and Escherichia coli), in vitro chromosome aberration test in human lymphocytes, in vitro mouse lymphoma (L5178Y cells) assay and in vivo mouse micronucleus test.

Reproductive Studies

Pregnant Rats

C-ropinirole was given to pregnant rats from day 11 to day 16 of pregnancy. Radioactivity was detectable in maternal plasma, amniotic fluid and foetuses.

Lactating Rats

C-ropinirole was given to lactating Wistar rats. Radioactivity was detectable in the milk, albeit at lower concentrations that in plasma.

Fertility Study in Male Rats

Animals were treated for 107 days, the maximal dose being 125 mg/kg/day. At this dose, clinical signs, including tremors, stereotypy, convulsions, and deaths have occurred, and the incidence of pregnancy was slightly decreased (72% versus 86% in the control group). At lower doses there was no effect on mating or fertility.

Fertility Study in Female Rats

Reproduction in the rat is prolactin-dependent during early pregnancy and throughout lactation. In studies, in which sub- or low-pharmacological doses were administered (pregnancy days 0 to 8 [5 mg/kg] and lactation [5, 10, or 20 mg/kg]), ropinirole did not affect mating performance, fertility rate or pregnancy outcome. If doses were not lowered, a dose-related decrease in fertility was seen at doses > 10 mg/kg. Ropinirole, when given at 50 mg/kg, markedly decreased serum levels of prolactin and progesterone, and prevented the establishment of pregnancy or caused abortion.

Teratology Study in Rats

Ropinirole was given to mated Wistar female rats at 20 mg/kg, from day 7 to day 8 of pregnancy. From days 9 to 16, the daily dose either remained 20 mg/kg, or was increased to 60, 90, 120, or 150 mg/kg. There were no maternal deaths or abortions. A dose- related increase in post-implantation loss (up to 43%) and a decrease in mean fetal weight were noted in groups which received ropinirole at 20/120 and 20/150 mg/kg/day. Retarded ossification of hindlimb metatarsals was seen in the 20/150 mg/kg group. Malformations, including abnormal digits, neural tube defects and cardiovascular abnormalities were observed in the fetuses of dams dosed with 20/120 and 20/150 mg/kg/day.

Teratology Study in Rabbits

Ropinirole was given to mated New Zealand White female rabbits at doses of 1, 5, and 20 mg/kg from day 6 to day 18 of pregnancy. At the high dose, two females died after receiving 2-3 doses. Of three females who had vaginal bleeding, one rabbit had no fetuses. Thus, although there was maternal toxicity, development of the fetuses (weight, sex ratio, skeletal and visceral development) was not affected.

Peri-/Post-Natal Study in Rats

Ropinirole was given at 0.1, 1.0 and 10 mg/kg/day to pregnant Sprague-Dawley rats from day 15 of pregnancy to weaning. No maternal deaths or abortions were observed. While the weights of the high-dose pups was higher than that of the controls at age 1-2 days, their weight subsequently decreased and by day 14, they weighed 18% less than controls. The retardation of the growth of the offsprings was due to maternal hypoprolactinemia and reduced lactation. The startle response to auditory and tactile stimulation was reduced in female, but not male offsprings, by age 29 days at the 1 and l0 mg/kg doses and at sexual maturity at the high dose.

Table 5 Comparative pharmacokinetic data at steady-state for ropinirole and its metabolites following oral administration of ropinirole to mice, rats, cynomolgus monkeys and Parkinson's disease patients

Compound Dose (mg/kg/day)

Cmax (ng/mL) Tmax (h) AUC (ng.h/mL)B

SK&F 104557

(N-despropyl ropinirole)

Data presented are for male and female animals.

A Data for man are at a maximal daily dose of 24 mg given as 8 mg t.i.d. (equivalent to 0.48 mg/kg/day assuming a body weight of 50 kg). Cmax and AUC values for man were derived by extrapolation from dose normalised data obtained in male and female patients (Cmax and AUC per mg multiplied by 24).

B AUC0- t where t is the time of the last data point (6, 8 and up to 24 h in mouse, rat and monkey,

respectively, and 24 h in man). A dose of 50 mg/kg/day was the highest dose tested in the 2-year oral

carcinogenicity studies in the mouse and in the rat. A dose of 15 mg/kg/day was the highest dose tested in the 1-year oral toxicity study in the monkey.

ND - SK&F 89124 was not detected in monkey plasma. Pharmacokinetic data for SK&F 89124 and SK&F 104557 have not been determined in the mouse.

* Numbers in parentheses represent ratios of exposure in animals to those in Parkinsonian patients at

0.48 mg/kg/day.

REFERENCES

Preclinical References

1. Freedman SB, Patel S, Marwood R, Emms F, Seabrook GR, Knowles MR et al.

Expression and pharmacological characterization of the human D3 dopamine receptor. J Pharmacol Exp Ther 1994; 268(1):417-426. Griffith RW, Grauwiler J, Hodel C, Leist KH and Matter. Toxicologic Considerations. Ergot Alkaloids and Related Compounds. Handbook of Experimental Pharmacology 1978; 49:805-851. Haseman JK, Arnold JaES. Tumour incidences in Fischer 344 rats: NTP historical data. Pathology of the Fischer rat Boorman GA et al (eds), Academic Press, Inc, San Diego, CA 1990; 555-564. Hernandez DE, Adcock JW, Orlando RC, Patrick KS, Nemeroff CB, Prange AJ, Jr. Prevention of stress-induced gastric ulcers by dopamine agonists in the rat. Life Sci 1984; 35(24):2453-2458. Huhtaniemi IT, Catt KJ. Induction and maintenance of gonadotropin and lactogen receptors in hypoprolactinemic rats. Endocrinology 1981; 109(2):483-490. Huhtaniemi IT, Stewart JM, Channabasavaiah K, Fraser HM, Clayton RN. Effect of treatment with GnRH antagonist, GnRH antiserum and bromocriptine on pituitary-testicular function of adult rats. Mol Cell Endocrinol 1984; 34(2):127- 135. MacKenzie RG, VanLeeuwen D, Pugsley TA, Shih YH, Demattos S, Tang L et al. Characterization of the human dopamine D3 receptor expressed in transfected cell lines. Eur J Pharmacol 1994; 266(1):79-85. McMartin DN, Sahota PS, Gunson DE, Hsu HH, Spaet RH. Neoplasms and related proliferative lesions in control Sprague-Dawley rats from carcinogenicity studies. Historical data and diagnostic considerations. Toxicol Pathol 1992; 20(2):212-225. McNeilly AS, Glasier A, Jonassen J, Howie PW. Evidence for direct inhibition of ovarian function by prolactin. J Reprod Fertil 1982; 65(2):559-569. Prentice D, Siegel RA, Donatsch P, Qureshi S and Ettlin RA. Mesulergine induced leydig cell tumors, a syndrome involving the pituitary-testicular axis of the rat. Medical Toxicology Proceeding of the 1991 EUROTOX Congress 1992; 197-204. Purvis K, Clausen O-PF, Hansson V. Regulation of Leydig cell sensitivity and responsiveness to LH/hCG. International Journal of Andrology {INT J ANDROL} 1978; 1(SUPP. 2):247-263. Purvis K, Clausen OP, Olsen A, Haug E, Hansson V. Prolactin and Leydig cell responsiveness to LH/hCG in the rat. Arch Androl 1979; 3(3):219-230. Roberts SA, Nett TM, Hartman HA, Adams TE, Stoll RE. SDZ 200-110 induces Leydig cell tumors by increasing gonadotropins in rats. Journal of the American College of Toxicology 1989; 8(3):487-505. Seeman P, Van Tol HH. Dopamine receptor pharmacology. Trends Pharmacol Sci 1994; 15(7):264-270. Sharpe RM, McNeilly AS. The effect of induced hyperprolactinaemia on Leydig cell function and LH-induced loss of LH-receptors in the rat testis. Mol Cell Endocrinol 1979; 16(1):19-27. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 1990; 347(6289):146-151. Stahle L. Do autoreceptors mediate dopamine agonist--induced yawning and suppression of exploration? A critical review. Psychopharmacology (Berl) 1992; 106(1):1-13. Waeber C, Reymond O, Reymond M, Lemarchand-Beraud T. Effects of hyper- and hypoprolactinemia on gonadotropin secretion, rat testicular luteinizing hormone/human chorionic gonadotropin receptors and testosterone production by isolated Leydig cells. Biol Reprod 1983; 28(1):167-177. Wahlstrom T, Huhtaniemi I, Hovatta O, Seppala M. Localization of luteinizing hormone, follicle-stimulating hormone, prolactin, and their receptors in human and rat testis using immunohistochemistry and radioreceptor assay. J Clin Endocrinol Metab 1983; 57(4):825-830. Watts VJ, Lawler CP, Knoerzer T, Mayleben MA, Neve KA, Nichols DE et al. Hexahydrobenzo[a]phenanthridines: novel dopamine D3 receptor ligands. Eur J Pharmacol 1993; 239(1-3):271-273.

Clinical References

Calne DB, Teychenne PF, Claveria LE, Eastman R, Greenacre JK, Petrie A. Bromocriptine in Parkinsonism. Br Med J 1974; 4(5942):442-444. Comella CL, Stebbins GT, Brown-Toms N, Goetz CG. Physical therapy and Parkinson's disease: a controlled clinical trial. Neurology 1994; 44(3 Pt 1):376- 378. De Jong GJ, Meerwaldt JD, Schmitz PI. Factors that influence the occurrence of response variations in Parkinson's disease. Ann Neurol 1987; 22(1):4-7. Fabbrini G, Mouradian MM, Juncos JL, Schlegel J, Mohr E, Chase TN. Motor fluctuations in Parkinson's disease: central pathophysiological mechanisms, Part I. Ann Neurol 1988; 24(3):366-371. Fahn S, Elton RL UPDRS Development Committee. Unified Parkinson`s Disease Rating Scale. Recent Developments in Parkinson`s Disease MacMillan Healthcare Information, Florham park NJ USA 1987; 2:153-163. Fahn S. Is levodopa toxic? Neurology 1996; 47(6 Suppl 3):S184-S195. Gasser T, Schwarz J, Arnold G, Trenkwalder C, Oertel WH. Apomorphine test for dopaminergic responsiveness in patients with previously untreated Parkinson's disease. Arch Neurol 1992; 49(11):1131-1134. Hefti F, Melamed E, Bhawan J, Wurtman RJ. Long-term adminisration of L DOPA does not damage Dopaminergic Neurons in the mouse. Neurology, 1981; 31(0028-3878):1194-1195. Hely MA, Morris JG, Reid WG, O'Sullivan DJ, Williamson PM, Rail D et al. The Sydney Multicentre Study of Parkinson's disease: a randomised, prospective five year study comparing low dose bromocriptine with low dose levodopa-carbidopa. J Neurol Neurosurg Psychiatry 1994; 57(8):903-910. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967; 17(5):427-442. Hubble JP, Pahwa R, Michalek DK, Thomas C, Koller WC. Interactive video conferencing: a means of providing interim care to Parkinson's disease patients. Mov Disord 1993; 8(3):380-382. Hughes AJ, Ben Shlomo Y, Daniel SE, Lees AJ. What features improve the accuracy of clinical diagnosis in Parkinson's disease: a clinicopathologic study. Neurology 1992; 42(6):1142-1146. Jankovic J. Long-term study of pergolide in Parkinson's disease. Neurology 1985; 35(3):296-299. Korczyn AD, Rascol O, Adler CH. Dosing with Ropinirole in a clinical Setting. Poster Presentation from the XIII International Congress on Parkinson`s Disease, Vancouver, Canada 1999. Lees AJ. L-dopa treatment and Parkinson's disease. Q J Med 1986; 59(230):535- 547. Lieberman A, Imke S, Muenter M, Wheeler K, Ahlskog JE, Matsumoto JY et al. Multicenter study of cabergoline, a long-acting dopamine receptor agonist, in Parkinson's disease patients with fluctuating responses to levodopa/carbidopa. Neurology 1993; 43(10):1981-1984. Martinez-Martin P, Gil-Nagel A, Gracia LM, Gomez JB, Martinez-Sarries J, Bermejo F. Unified Parkinson's Disease Rating Scale characteristics and structure. The Cooperative Multicentric Group. Mov Disord 1994; 9(1):76-83. Marttila RJ, Rinne UK. Changing epidemiology of Parkinson's disease: predicted effects of levodopa treatment. Acta Neurol Scand 1979; 59(2-3):80-87. Montastruc JL, Rascol O, Senard JM, Rascol A. A randomised controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson's disease: a five year follow up. J Neurol Neurosurg Psychiatry 1994; 57(9):1034-1038. Mouradian MM, Juncos JL, Fabbrini G, Schlegel J, Bartko JJ, Chase TN. Motor fluctuations in Parkinson's disease: central pathophysiological mechanisms, Part II. Ann Neurol 1988; 24(3):372-378. Ogawa N. Levodopa and dopamine agonists in the treatment of Parkinson's disease: advantages and disadvantages. Eur Neurol 1994; 34 Suppl 3:20-28. Olanow CW. An introduction to the free radical hypothesis in Parkinson's disease. Ann Neurol 1992; 32 Suppl:S2-S9. Olanow CW, Fahn S, Muenter M, Klawans H, Hurtig H, Stern M et al. A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson's disease. Mov Disord 1994; 9(1):40-47. Pallis CA. Parkinsonism--Natural history and clinical features. British medical journal 1971; 18:683-690. Peppe A, Dambrosia JM, Chase TN. Risk factors for motor response complications in L-dopa-treated parkinsonian patients. Adv Neurol 1993; 60:698- 702. Rascol O, Brooks DJ, Korczyn AD. Ropinirole reduces the risk of dyskinesia compared to L-dopa when used in early PD. Poster. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five- year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000; 342(20):1484-1491. Rasmussen C, Brownell J, Bergh T. Clinical response and prolactin concentration in hyperprolactinemic women during and after treatment for 24 months with the new dopamine agonist, CV 205-502. Acta Endocrinol (Copenh) 1991; 125(2):170-176. Richards M, Marder K, Cote L, Mayeux R. Interrater reliability of the Unified Parkinson's Disease Rating Scale motor examination. Mov Disord 1994; 9(1):89- 91. Richardson BP, Turkalj I, Flueckinger E. Bromocriptine. Safety Testing of New Drugs 1984; 19-63. Rinne UK. Dopamine agonists in the treatment of Parkinson`s Disease. Controversies in treatment of Parkinson`s Disease Rinne UK & Yanagisawa eds PMSI Japan, Tokyo 1992; 49-60. Schapira AH. Advances in the understanding of the cause of Parkinson's disease. J R Soc Med 1994; 87(7):373-375. Shaw KM, Lees AJ, Stern GM. The impact of treatment with levodopa on Parkinson's disease. Q J Med 1980; 49(195):283-293. The Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1989; 321(20):1364-1371. The Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1993; 328(3):176-183. Uitti RJ, Ahlskog JE. Comparative review of dopamine receptor agonists in Parkinson's disease. CNS 1996; 5(1172-7047):369-388. Yahr MD, Wolf A, Antunes JL, MiyoshiI K, Duffy P. Autopsy findings in Parkinsonism following treatment with Levo Dopa. Neurology, 1972; 22(0028- 3878):56-71. IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

PrREQUIP(r)

ropinirole hydrochloride tablets

This leaflet is part III of a three-part "Product Monograph" published when REQUIP(r) was approved for sale in Canada and is designed specifically for Consumers.

Please read this information before you start to take your medicine. Keep this leaflet until you have finished all your tablets as you may need to read it again. If you are helping someone else to take REQUIP(r), read this leaflet before you give the first tablet.

This leaflet is a summary and will not tell you everything about REQUIP(r). Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

REQUIP(r), also known as ropinirole, is used to treat the signs and symptoms of Parkinson's disease.

You may receive REQUIP(r) on its own but it may also be given with another drug used to treat Parkinson's disease.

What it does:

REQUIP(r) belongs to the family of medicines called dopamine agonists. REQUIP(r) improves some of the chemical

imbalance in the part of the brain affected by Parkinson's disease.

When it should not be used:

Do not use REQUIP(r) if you are allergic to it or any of the components of its formulation (see list below). REQUIP(r) is

not recommended for children under 18 years of age.

What the medicinal ingredient is:

ropinirole hydrochloride

What the nonmedicinal ingredients are:

Non-medicinal ingredients include: Hydrous lactose, microcrystalline cellulose, croscarcellose sodium, magnesium

stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, iron oxide yellow (0.5, 1.0 and 2.0 mg

tablets), iron oxide red (0.5 and 2.0 mg tablets), carmine

(3.0 mg) FD & C Blue No. 2 aluminum lake (0.5, 1.0, 3.0, 4.0 and 5.0 mg tablets), FD & C Yellow No. 6 aluminum lake (3.0 and 4.0 mg), polysorbate 80 (0.25 and 5 mg tablets).

What dosage forms it comes in:

REQUIP(r) is available as 0.25 mg (white), 0.5 mg * (pale yellow), 1.0 mg (green), 2.0 mg (pale pink), 3.0 mg * (pale purple), 4.0 mg * (light brown) and 5.0 mg (blue) tablets.

• 0.5 mg, 3.0 mg, and 4.0 mg tablets are not available in Canada.

WARNINGS AND PRECAUTIONS

You are warned of a sudden onset of sleep condition which may occur without warning, while taking REQUIP(r). You should not operate machinery or engage in activities that require alertness, as you may put yourself and others at risk of serious injury or death. This sudden onset of sleep condition has also been reported in patients taking other similar anti-Parkinson drugs.

What should I know before taking REQUIP(r):

Studies of people with Parkinson's disease show that they may be at an increased risk of developing melanoma, a form of skin

cancer, when compared to people without Parkinson's disease. It is not known if this problem is associated with Parkinson's

disease or the drugs used to treat Parkinson's disease. REQUIP(r) is one of the drugs used to treat Parkinson's disease, therefore, patients treated with REQUIP(r) should have periodic skin examinations.

BEFORE you use REQUIP(r) talk to your doctor or pharmacist:

• if you have any health problem, especially any heart, liver or kidney condition.

• if you have previously taken REQUIP(r) and became unwell.

• if you have any allergies or reactions to foods or drugs.

• if you are pregnant or think you may be pregnant, or if you are breast feeding. You should not be taking REQUIP(r) if you are pregnant or breast feeding.

• if you are taking any other medications, including any drugs you can buy without a prescription.

• if you have experienced any unusual urges and/or behaviours (such as excessive gambling or excessive sexual behaviour).

INTERACTIONS WITH THIS MEDICATION

Other medications may be affected by REQUIP(r) or may affect how REQUIP(r) works. Do not take any other medication, including any drugs or herbal products you can buy without a prescription. Tell any other doctor, dentist or pharmacist that you talk to that you are taking REQUIP(r). IMPORTANT: PLEASE READ

Drugs that may interact with REQUIP(r) include:

a drug used to help with breathing difficulties called theophylline

an antibiotic called ciprofloxacin

any hormone replacement therapy (HRT)

other dopamine agonists

certain medicines called neuroleptics used to treat schizophrenia and other serious mental illnesses

digoxin, a heart medicine that is used to treat congestive heart failure or certain heartbeat irregularities

Before making any change to other medications you are taking, or stopping them, talk to your doctor first.

PROPER USE OF THIS MEDICATION

Usual dose:

Follow the doctor's instructions about how and when you

should take your tablets. Your doctor will decide how many tablets you need to take each day and you should always follow his/her instructions. When you first start taking REQUIP(r), the amount you take will be increased gradually.

Your doctor may adjust the amount that you are taking. You will usually be told to take REQUIP(r) three times a day. You should not change the dose or discontinue treatment with REQUIP(r) without the recommendation of your doctor.

If you are taking other medicines for Parkinson's disease, the doctor may adjust the dose of these medicines while you are taking REQUIP(r).

You should swallow the tablets whole with water. Do not chew. REQUIP(r) can be taken with or without food.

You should continue to take your medicine even if you do not feel better, as it may take a number of weeks for the medicine to work.

REMEMBER: THIS MEDICINE IS FOR THE PERSON NAMED BY THE DOCTOR. DO NOT GIVE IT TO ANYBODY ELSE.

Overdose:

If you or someone you know have taken too many tablets all at once, you should get medical help immediately, either by

calling your doctor, the Regional Poison Control Centre, or the nearest hospital (do not drive yourself). Always take the

labelled medicine container with you even if there are no

tablets left.

Missed Dose:

If you have forgotten to take REQUIP(r), do not take extra doses to make up for forgotten individual doses. When you

do remember to take REQUIP(r), take your next dose of REQUIP(r) at the usual time. If you have missed taking REQUIP(r) for more than a few days consult your doctor for advice on restarting REQUIP(r).

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like all medications, REQUIP(r) tablets can cause some side effects. You may not experience any of them. For most patients these side effects are likely to be minor and temporary. However, some may be serious. Consult your doctor if you experience these or other side effects.

Some of the most commonly reported side effects of REQUIP(r) tablets are:

Feeling or being sick

Stomach ache

Dizziness or lightheadedness

Sleepiness

Headache

Some leg swelling

Tiredness

Viral infection

Other side effects include:

Some patients taking REQUIP(r) have shown urges to behave in a way unusual for them. Examples of this are an unusual urge

to gamble or increased sexual urges and/or behaviours. If you or your family notices that you are developing any unusual

behaviours, talk to your doctor.

IMPORTANT: PLEASE READ

HOW TO STORE IT

The expiry date of this medicine is printed on the label. Do not use the medicine after this date.

Keep your tablets in their original pack in a dry place away from light and moisture. They should be kept at room temperature (between 15-30oC). Close container tightly after each use.

Keep out of reach of children.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs . If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office

Marketed Health Products Safety and Effectiveness Information Bureau

Marketed Health Products Directorate Health Products and Food Branch

Health Canada

Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

This is not a complete list of side effects. For any unexpected effects while taking REQUIP(r), contact your doctor or pharmacist. IMPORTANT: PLEASE READ

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.gsk.ca or by contacting the sponsor, GlaxoSmithKline Inc.

7333 Mississauga Road Mississauga, Ontario

Canada L5N 6L4 1-800-387-7374

This leaflet was prepared by GlaxoSmithKline Inc. Last revised: November 4, 2008

(c)

2008 GlaxoSmithKline Inc., All Rights Reserved.

(r) REQUIP is a registered trademark, used under license by GlaxoSmithKline Inc.