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, 4 mg, or 8 mg ropinirole free base.
Excipients/Inactive Ingredients: Tablet Cores: Hypromellose 2208, hydrogenated castor oil, carboxymethylcellulose sodium, povidone, maltodextrin, magnesium stearate, lactose monohydrate, colloidal silicon dioxide, mannitol (E421), yellow ferric oxide (E172), glyceryl behenate. Film Coat: See Table 1.

Click on icon to see table/diagram/image
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 (PR) 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, 0.1), 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 prolonged release 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 hrs [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 hrs (95% CI: (1.06, 2.33); p<0.0001)] and total awake time "on" without troublesome dyskinesias [1.5 hrs (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 is 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% (36-57%).
Absorption: Following oral administration of ropinirole PR, plasma concentrations increase slowly, with a median time to Cmax of 6 hrs. 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 ropinirole 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).
Toxicology: Preclinical 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. There was no teratogenic effect in the rat at 120 mg/kg and no indication of an effect on development in the rabbit. There have been no studies of ropinirole in human pregnancy.
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). The toxicology profile is principally determined by the pharmacological activity of ropinirole (behavioural changes, hypoprolactinaemia, decrease in blood pressure and heart rate, ptosis and salivation).
Indications/Uses
REQUIP PD 24 HOUR is indicated for the treatment of Parkinson's disease.
REQUIP PD 24 HOUR is effective as early therapy in patients requiring dopaminergic therapy.
As adjunctive treatment to L-dopa (ropinirole enhances the efficacy of L-dopa, including control of "on-off" fluctuations and "end of dose" effects associated with chronic L-dopa therapy and permits reduction in daily L-dopa dose).
Dosage/Direction for Use
When switching treatment from another dopamine agonist to REQUIP PD 24 HOUR, the manufacturer's guidance on discontinuation should be followed before initiating REQUIP PD 24 HOUR.
Individual dose titration against efficacy and tolerability is recommended.
Patients should be down-titrated if they experience disabling somnolence at any dose level. For other adverse events, down-titration followed by more gradual up-titration has been shown to be beneficial.
Adults: REQUIP PD 24 HOUR should be taken as a single daily dose and should be taken at a similar time each day.
Treatment Initiation: The dose should be titrated according to the individual clinical response.
Recommended initial dose is 2 mg once daily for one week. A guide for titration regimen for the first four weeks of treatment is given in Table 2. (See Table 2.)

Click on icon to see table/diagram/image

Therapeutic Regimen: If sufficient symptomatic control is not achieved or maintained after the initial titration period as described previously, the daily dose may then be increased by increments of up to 4 mg once every one to two weeks, as necessary. The dose may be adjusted depending on the therapeutic response. The dose may be increased up to a maximum of 24 mg once daily.
The safety and efficacy of doses above 24 mg/day have not been established.
When REQUIP PD 24 HOUR is given as an adjunct therapy to L-dopa, it may be possible to reduce gradually the L-dopa dose, depending on the clinical response. In clinical trials, the L-dopa dose was reduced gradually by approximately 30% in patients receiving REQUIP PD 24 HOUR concurrently. In patients with advanced Parkinson's disease receiving REQUIP PD 24 HOUR in combination with L-dopa, dyskinesias can occur during the initial titration of REQUIP PD 24 HOUR. In clinical trials, it was shown that a reduction of the L-dopa dose may ameliorate dyskinesia (see Adverse Reactions).
As with other dopamine agonists, REQUIP PD 24 HOUR should be discontinued gradually by reducing the daily dose over the period of one week.
If treatment is interrupted for one day or more, re-initiation by dose titration should be considered (see previous text).
Switching from ropinirole immediate release tablets to ropinirole prolonged release tablets: Patients may be switched overnight from REQUIP immediate release (IR) tablets to REQUIP PD 24 HOUR PR tablets. The dose of REQUIP PD 24 HOUR PR tablets should be based on the total daily dose of REQUIP IR tablets that the patient was taking.
Table 3 shows the recommended dose of REQUIP PD 24 HOUR PR tablets for patients switching from REQUIP IR tablets. (See Table 3.)

Click on icon to see table/diagram/image

After switching to REQUIP PD 24 HOUR PR tablets, the dose may be adjusted depending on the therapeutic response (see Treatment Initiation and Therapeutic Regimen previously mentioned).
Children and Adolescents: The safety and efficacy of ropinirole have not been established in patients under 18 years of age; therefore, REQUIP PD 24 HOUR is not recommended for use in patients within this age group.
Elderly: The clearance of ropinirole is decreased in patients aged 65 years or above, but the dose of REQUIP PD 24 HOUR for elderly patients can be titrated in the normal manner.
Renal impairment: In patients with mild to moderate renal impairment (creatinine clearance 30-50 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 24 HOUR 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 dialysis has not been studied.
Hepatic Impairment: The use of ropinirole in patients with hepatic impairment has not been studied. Administration of REQUIP PD 24 HOUR to such patients is not recommended.
Administration: REQUIP PD 24 HOUR must be swallowed whole and must not be chewed, crushed or divided. It may be taken with or without food (see Pharmacology: Pharmacokinetics under Actions).
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 symptoms including compulsive behaviours (including pathological gambling, hypersexuality, compulsive shopping and binge eating have been reported in patients treated with dopaminergic agents, including ropinirole (see Adverse Reactions). These 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.
Ropinirole prolonged release tablets are designed to release medication over 24 hour period. If rapid gastrointestinal transit occurs, there may be risk of incomplete release of medication, and medication residue being passed in the stool.
Effects on the Ability to Drive or Operate Machinery: 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 dizziness (including vertigo).
Patients should be informed about very rare cases of sudden onset of sleep without any prior warning or apparent daytime somnolence (see Adverse Reactions), which have 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
Use in Pregnancy: 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 (see Pharmacology: Toxicology under Actions).
Use in Lactation: 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 in Table 4 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 follow 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 4.)

Click on icon to see table/diagram/image

Adverse drug reactions reported during clinical trials in patients with restless legs syndrome: (See Table 5.)

Click on icon to see table/diagram/image

Post Marketing Data: (See Table 6.)

Click on icon to see table/diagram/image
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 co-administration 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
Store below 25°C.
ATC Classification
N04BC04 - ropinirole ; Belongs to the class of dopamine agonist. Used in the management of Parkinson's disease.
Presentation/Packing
PR-FC tab 2 mg (pink, capsule-shaped, marked with "GS" on one side and "3V2" on the other) x 28's. 4 mg (light brown, capsule-shaped, marked with "GS" on one side and "WXG" on the other) x 28's. 8 mg (red, capsule-shaped, marked with "GS" on one side and "5CC" on the other) x 28's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in