Requip PD 24 Hour

Requip PD 24 Hour

ropinirole

Manufacturer:

GlaxoSmithKline

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Ropinirole hydrochloride.
Description
Each prolonged release tablet contains ropinirole hydrochloride equivalent to 2 mg or 4 mg ropinirole free base.
Excipients/Inactive Ingredients: PR tab 2 mg: Lactose Monohydrate, Silica colloidal anhydrous, Hypromellose 2208, Yellow ferric oxide (E 172, CI 77492), Mannitol, Glycerol Dibehenate, Povidone K29-32, MALTODEXTRIN, Opadryl Pink OY-S-24900, Castor oil (hydrogenated), Magnesium Stearate, Carmellose Sodium.
PR tab 4 mg: Lactose Monohydrate, Silica colloidal anhydrous, Hypromellose 2208, Yellow ferric oxide (E 172, CI 77492), Mannitol, Glycerol Dibehenate, Povidone K29-32, MALTODEXTRIN, Opadry Tan OY-27207, Castor oil (hydrogenated), Magnesium Stearate, Carmellose Sodium.
Action
ATC Code: N04BC04.
Pharmacology: Pharmacodynamics: Mechanism of Action: Ropinirole is a potent, non-ergoline D2/D3 dopamine agonist.
Parkinson's disease is characterised by a marked dopamine deficiency in the nigral striatal system. Ropinirole alleviates this deficiency by stimulating striatal dopamine receptors.
Pharmacodynamic Effects: Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin.
Clinical Studies: A 36-week, double-blind, three-period crossover study conducted in 161 patients compared the efficacy and safety of ropinirole prolonged release tablets and ropinirole immediate release tablets as monotherapy in subjects with early phase Parkinson's disease. The primary endpoint of this non-inferiority study was the treatment difference in change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score (a 3-point non-inferiority margin was defined). Ropinirole prolonged release was demonstrated to be non-inferior to ropinirole immediate release on the primary endpoint, the adjusted mean difference between ropinirole prolonged release and ropinirole immediate release at study endpoint was -0.7 points (95% CI: [-1.51, 0.10], p=0.0842).
Following the overnight switch to a similar dose of the alternative tablet formulation, there was no indication of worsened adverse event profile and less than 3% of patients required a dose adjustment (by increasing one dose level).
A 24-week double-blind, placebo-controlled, parallel group study evaluated the efficacy and safety of ropinirole PR as adjunctive therapy in patients with Parkinson's disease who were not optimally controlled on L-dopa. Ropinirole PR demonstrated a clinically relevant and statistically significant superiority over placebo on the primary endpoint, change from baseline in awake time "off" (adjusted mean treatment difference -1.7 hours (95% CI: [-2.34, -1.09], p<0.0001).
The odds of ropinirole PR patients being a responder on the CGI global improvement scale were more than 4 times the odds of a placebo patient (PR 42%: IR 14%) (odds ratio 4.4 (95% CI: [2.63, 7.20], p<0.001). The odds of a ropinirole PR patient being a responder on the composite endpoint of 20% reduction from baseline in both L-dopa dose and "off" time were also more than 4 times that of a placebo patient (PR 54%: IR 20%) (odds ratio 4.3 (95% CI: [2.73, 6.78]), p<0.001) while the odds of a ropinirole PR patient requiring reinstatement of L-dopa following a dose reduction were 5 times lower than a placebo patient (PR 7%: IR 28%) (odds ratio 0.2 (95% CI: [0.09, 0.34]), p<0.001).
The results on the primary endpoint were supported by clinically meaningful and statistically significant superiority over placebo on secondary efficacy parameters of total awake time "on" (1.7 hours (95% CI: [1.06, 2.33]), p<0.0001) and total awake time "on" without troublesome dyskinesias (1.5 hours (95% CI: [0.85, 2.13]), p<0.0001).
Importantly, there was no indication of an increase from baseline in awake time "on" with troublesome dyskinesias, either from diary card data or from the UPDRS items.
At week 24 the mean dose of investigational product was 18.8 mg/day for ropinirole PR and 20.0 mg/day of placebo equivalent.
Pharmacokinetics: The pharmacokinetics of ropinirole are consistent between healthy volunteers, Parkinson's disease patients and patients with Restless Legs Syndrome.
Wide inter-individual variability in the pharmacokinetic parameters has been seen. Bioavailability of ropinirole is approximately 50% (36 to 57%).
Absorption: Following oral administration of ropinirole PR, plasma concentrations increase slowly, with a median time to Cmax of 6 hours. In a steady-state study in Parkinson's disease patients receiving 12 mg of ropinirole PR once daily, a high fat meal increased the systemic exposure to ropinirole as shown by an average 20% increase in AUC and an average 44% increase in Cmax. Tmax was delayed by 3.0 hours. However, in the studies that established the safety and efficacy of ropinirole PR, patients were instructed to take study medication without regard to food intake.
Distribution: Plasma protein binding of the drug is low (10 to 40%). Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approx. 7 L/kg).
Metabolism: Ropinirole is primarily cleared by CYP1A2 metabolism and its metabolites are mainly excreted in the urine. The major metabolite is at least 100 times less potent than ropinirole in animal models of dopaminergic function.
Elimination: Ropinirole is cleared from the systemic circulation with an average elimination half-life of about 6 hours.
The increase in systemic exposure (Cmax and AUC) to ropinirole is approximately proportional over the therapeutic dose range. No change in the oral clearance of ropinirole is observed following single and repeated oral administration.
Special Patient Populations: Elderly: Oral clearance of ropinirole is reduced by approximately 15% in elderly patients (65 years or above) compared to younger patients. Dosing adjustment is not necessary in the elderly.
Renal Impairment: There was no change observed in the pharmacokinetics of ropinirole in Parkinson's disease patients with mild to moderate renal impairment.
In patients with end stage renal disease receiving regular dialysis, oral clearance of ropinirole is reduced by approximately 30%. The recommended maximum dose is limited to 18 mg/day in patients with Parkinson's disease (see Renal impairment under Dosage & Administration).
Pregnancy: Physiological changes in pregnancy (including decreased CYP1A2 activity) are predicted to gradually lead to an increased maternal systemic exposure of ropinirole (reaching an approximate 2-fold increase by the third trimester based on physiologically based pharmacokinetic modelling).
Toxicology: Pre-clinical Safety Data: Carcinogenesis, mutagenesis: Two-year studies have been conducted in the mouse and rat at dosages up to 50 mg/kg. The mouse study did not reveal any carcinogenic effect. In the rat, the only drug-related lesions were Leydig cell hyperplasia/adenoma in the testis resulting from the hypoprolactinaemic effect of ropinirole. These lesions are considered to be a species specific phenomenon and do not constitute a hazard with regard to the clinical use of ropinirole.
Genotoxicity was not observed in a battery of in vitro and in vivo tests.
Reproductive toxicology: In fertility studies in rats, effects were seen on implantation due to the prolactin-lowering effect of ropinirole. In humans, chorionic gonadotropin, not prolactin, is essential for implantation in females. No effects were seen on male fertility.
Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg, increased foetal death at 90 mg/kg and digit malformations at 150 mg/kg (3.4, 5.1 and 8.5 times the mean human AUC at the Maximum Recommended Human Dose (MRHD)). There was no teratogenic effect in the rat at 120 mg/kg (6.8 times the mean human AUC at the MRHD) and no indication of an effect during organogenesis in the rabbit when given alone at 20 mg/kg (9.5 times the mean human Cmax at the MRHD). However, ropinirole at 10 mg/kg (4.8 times the mean human Cmax at the MRHD) administered to rabbits in combination with oral L-dopa produced a higher incidence and severity of digit malformations than L-dopa alone.
Ropinirole-related material was shown to transfer into the milk of lactating rats in small amounts (approximately 0.01% of the dose per pup).
Animal toxicology and/or pharmacology: Ropinirole caused no serious or irreversible toxicity in laboratory animals at 15 mg/kg (monkey), 20 mg/kg (mouse) or 50 mg/kg (rat); 0.9, 0.4 and 2.8 times the mean human AUC at the MRHD. The toxicology profile is principally determined by the pharmacological activity of the drug (behavioural changes, hypoprolactinaemia, and decrease in blood pressure and heart rate, ptosis and salivation).
Indications/Uses
REQUIP PD 24 HOUR is indicated for the treatment of idiopathic Parkinson's disease.
REQUIP PD 24 HOUR may be used alone (without levodopa [L-dopa]) in the treatment of idiopathic Parkinson's disease.
Addition of REQUIP PD 24 HOUR to levodopa may be used to control 'on-off' fluctuations and permit a reduction in the total daily dose of L-Dopa.
Dosage/Direction for Use
Oral use.
Individual dose titration against efficacy and tolerability is recommended. REQUIP PD 24 HOUR prolonged-release tablets should be taken once a day and at a similar time each day. The tablets must be swallowed whole and must not be chewed, crushed or divided. The tablets may be taken with or without food (see Pharmacology: Pharmacokinetics under Actions).
Adults: Initial titration: The starting dose of REQUIP PD 24 HOUR prolonged-release tablets is 2 mg once daily for the first week; this should be increased to 4 mg once daily from the second week of treatment. A therapeutic response may be seen at a dose of 4 mg once daily of REQUIP PD 24 HOUR prolonged-release tablets.
Patients who initiate treatment with a dose of 2 mg/day of ropinirole prolonged-release tablets and who experience side effects that they cannot tolerate, may benefit from switching to treatment with REQUIP IR (immediate release) tablets at a lower daily dose, divided into three equal doses.
Therapeutic regimen: Patients should be maintained on the lowest dose of REQUIP PD 24 HOUR prolonged-release tablets that achieve symptomatic control.
If sufficient symptomatic control is not achieved or maintained at a dose of 4 mg once daily of REQUIP PD 24 HOUR prolonged-release tablets, the daily dose may be increased by 2 mg at weekly or longer intervals up to a dose of 8 mg once daily of REQUIP PD 24 HOUR prolonged-release tablets.
If sufficient symptomatic control is still not achieved or maintained at a dose of 8 mg once daily of REQUIP PD 24 HOUR prolonged-release tablets, the daily dose may be increased by 2 mg to 4 mg at two weekly or longer intervals. The maximum daily dose of REQUIP PD 24 HOUR prolonged-release tablets is 24 mg.
It is recommended that patients are prescribed the minimum number of REQUIP PD 24 HOUR prolonged-release tablets that are necessary to achieve the required dose by utilising the highest available strengths of REQUIP PD 24 HOUR prolonged-release tablets.
When REQUIP PD 24 HOUR prolonged-release tablets are administered as adjunct therapy to levodopa, it may be possible to gradually reduce the levodopa dose, depending on the clinical response. In clinical trials, the levodopa dose was reduced gradually by approximately 30% in patients receiving REQUIP PD 24 HOUR prolonged-release tablets concurrently. In patients with advanced Parkinson's disease receiving REQUIP PD 24 HOUR prolonged-release tablets in combination with L-dopa, dyskinesias can occur during the initial titration of REQUIP PD 24 HOUR prolonged-release tablets. In clinical trials it was shown that a reduction of the L-dopa dose may ameliorate dyskinesia (see Adverse Reactions).
When switching treatment from another dopamine agonist to ropinirole, the marketing authorisation holder's guidance on discontinuation should be followed before initiating ropinirole.
As with other dopamine agonists, it is necessary to discontinue ropinirole treatment gradually by reducing the daily dose over the period of one week.
Switching from REQUIP immediate release (IR) tablets to REQUIP PD 24 HOUR prolonged-release tablets: Patients may be switched overnight from REQUIP IR tablets to REQUIP PD 24 HOUR prolonged-release tablets.
The dose of REQUIP PD 24 HOUR prolonged-release tablets should be based on the total daily dose of REQUIP IR tablets that the patient was receiving. The recommended dose for switching from REQUIP IR tablets to REQUIP PD 24 HOUR prolonged-release tablets are provided in the following table. If patients are taking a different total daily dose of REQUIP IR tablets to those typically prescribed doses as shown in the table, they should be switched to the nearest available dose of REQUIP PD 24 HOUR prolonged-release tablets as stated in the table: see Table 1.

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After switching to REQUIP PD 24 HOUR prolonged-release tablets, the dose may be adjusted depending on the therapeutic response (see Initial titration and Therapeutic regimen as previously mentioned).
Dose interruption or discontinuation: If treatment is interrupted for one day or more, re-initiation by dose titration on REQUIP IR tablets should be considered.
If it is necessary to discontinue ropinirole treatment, this should be done gradually by reducing the daily dose over the period of one week.
Renal impairment: In parkinsonian patients with mild to moderate renal impairment (creatinine clearance between 30 and 50 ml/min) no change in the clearance of ropinirole was observed, indicating that no dosage adjustment is necessary in this population.
A study into the use of ropinirole in patients with end stage renal disease (patients on haemodialysis) has shown that a dose adjustment in these patients is required as follows: The recommended initial dose of REQUIP PD prolonged-release tablets is 2 mg once daily. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required.
The use of ropinirole in patients with severe renal impairment (creatinine clearance less than 30 ml/min) without regular haemodialysis has not been studied.
Hepatic impairment: The use of ropinirole in patients with hepatic impairment has not been studied. Administration of ropinirole to such patients is not recommended.
Elderly: The clearance of ropinirole is decreased by approximately 15% in patients aged 65 years or above. Although a dose adjustment is not required, ropinirole dose should be individually titrated, with careful monitoring of tolerability, to the optimal clinical response. In patients aged 75 years and above, slower titration during treatment initiation may be considered.
Children and adolescents: REQUIP PD 24 HOUR prolonged-release tablets are not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.
Overdosage
The symptoms of ropinirole overdose are generally related to its dopaminergic activity. These symptoms may be alleviated by appropriate treatment with dopamine antagonists such as neuroleptics or metoclopramide.
Contraindications
Hypersensitivity to ropinirole or to any of the excipients.
Special Precautions
Due to the pharmacological action of ropinirole, patients with severe cardiovascular disease should be treated with caution.
Patients with a history or presence of major psychotic disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks.
Impulse control disorders: Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists, including REQUIP PD 24 HOUR prolonged-release tablets. Dose reduction/tapered discontinuation should be considered if such symptoms develop. Impulse control disorders were reported especially at high doses and were generally reversible upon reduction of the dose or treatment discontinuation. Risk factors such as a history of compulsive behaviours were present in some cases. Ropinirole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported uncommonly. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with ropinirole. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dosage or termination of therapy may be considered.
REQUIP PD 24 HOUR prolonged-release tablets are designed to release medication over a 24 hour period. If rapid gastrointestinal transit occurs, there may be risk of incomplete release of medication, and of medication residue being passed in the stool.
This medicinal product also contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The 4 mg tablets contain the azo colouring agent sunset yellow (E110), which may cause allergic reactions.
Effects on Ability to Drive and Use Machines: No data are available on the effect of ropinirole on the ability to drive or use machinery. Patients should be cautioned about their ability to drive or operate machinery whilst taking REQUIP PD 24 HOUR because of the possibility of somnolence and of dizziness (including vertigo).
Patients should be informed about the possibility of sudden onset of sleep without any prior warning or apparent daytime somnolence (see Adverse Reactions), which has primarily been observed in patients with Parkinson's disease, and should be cautioned that their safety and that of others is at risk should this happen when driving or operating machinery. If patients develop significant daytime sleepiness or episodes of falling asleep during activities that require active participation, patients should be told not to drive and to avoid other potentially dangerous activities.
Use In Pregnancy & Lactation
Fertility: There are no data on the effects of ropinirole on human fertility. In female fertility studies in rats, effects were seen on implantation (see Pharmacology: Toxicology: Pre-clinical Safety Data under Actions). No effects were seen on male fertility in rats.
Pregnancy: There are no adequate and well-controlled studies of ropinirole in pregnant women. Ropinirole concentrations may gradually increase during pregnancy (see Pharmacology: Pharmacokinetics under Actions). Studies in animals have shown embryo-foetal toxicity (see Pharmacology: Toxicology: Pre-clinical Safety Data under Actions). It is recommended that REQUIP PD 24 HOUR is not used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the foetus.
Lactation: There are no data regarding the excretion of ropinirole in human milk. Ropinirole has been detected in rat milk (see Pharmacology: Toxicology: Pre-clinical Safety Data under Actions). REQUIP PD 24 HOUR should not be used in nursing mothers as it may inhibit lactation.
Adverse Reactions
Adverse reactions are tabulated as follows according to the indication. The overall safety profile of ropinirole comprises adverse reactions from all indications from clinical trial data and from post-marketing experience.
Adverse events are listed as follows by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports.
Clinical Trial Data: The tables as follows list the adverse drug reactions reported at a higher rate with ropinirole than placebo or a higher or comparable rate to comparator in clinical trials.
Adverse Drug Reactions Reported from Patients with Parkinson's Disease: Unless otherwise indicated, the data in the following table was observed with both immediate release and prolonged release formulations. (See Table 2).

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See Tables 3 and 4.

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Drug Interactions
Neuroleptics and other centrally active dopamine antagonists, such as sulpiride or metoclopramide, may diminish the effectiveness of ropinirole and, therefore, concomitant use of these drugs with REQUIP PD 24 HOUR should be avoided.
There is no pharmacokinetic interaction between ropinirole and L-dopa or domperidone which would necessitate dosage adjustment of these drugs. No interaction has been seen between ropinirole and other drugs commonly used to treat Parkinson's disease.
In a study in parkinsonian patients receiving concurrent digoxin, no interaction was seen which would require dosage adjustment.
Ropinirole is principally metabolised by the cytochrome P450 enzyme CYP1A2. A pharmacokinetic study in Parkinson's patients revealed that ciprofloxacin increased the Cmax and AUC of ropinirole by approximately 60% and 84% respectively. Hence, in patients already receiving REQUIP PD 24 HOUR, the dose of REQUIP PD 24 HOUR may need to be adjusted when drugs known to inhibit CYP1A2, e.g. ciprofloxacin, enoxacin or fluvoxamine, are introduced or withdrawn.
A pharmacokinetic interaction study in Parkinson's patients between ropinirole and theophylline, as representative of substrates of CYP1A2, revealed no change in the pharmacokinetics of either ropinirole or theophylline. Hence, changes in ropinirole pharmacokinetics following coadministration with other substrates of CYP1A2 are not expected.
Increased plasma concentrations of ropinirole have been observed in patients treated with high doses of oestrogens. In patients already receiving hormone replacement therapy (HRT), REQUIP PD 24 HOUR treatment may be initiated in the normal manner. However, if HRT is stopped or introduced during treatment with ropinirole, dosage adjustment may be required.
No information is available on the potential for interaction between ropinirole and alcohol. As with other centrally active medications, patients should be cautioned against taking REQUIP PD 24 HOUR with alcohol.
Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or start smoking during treatment with REQUIP PD 24 HOUR, adjustment of dose may be required.
Caution For Usage
Instructions for Use/Handling: No special instructions.
Incompatibilities: None known.
Storage
Requip PD Tablet 2mg, 4mg: Do not store above 30°C. Store in the original package.
ATC Classification
N04BC04 - ropinirole ; Belongs to the class of dopamine agonist. Used in the management of Parkinson's disease.
Presentation/Packing
PR tab 2 mg (pink, capsule-shaped, film-coated, marked "GS" on one side and "3V2" on the other) x 28's. 4 mg (light brown, capsule-shaped, film-coated, marked "GS" on one side and "WXG" on the other) x 28's.
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