Ropinirole 5 mg film-coated tablets

Each film-coated tablet contains ropinirole hydrochloride equivalent to 5.0 mg of ropinirole.

Ropinirole 5 mg film-coated tablets:

Each film-coated tablet contains ropinirole hydrochloride equivalent to 5 mg of ropinirole

Excipient with known effect: 67.55 mg lactose (as lactose monohydrate and lactose anhydrous).

For the full list of excipients, see section 6.1.

Film-coated tablet.

5.0 mg Blue, circular, bevelled edged, biconvex film coated tablets with '259' debossed on one side and 'G' on the other side.

Treatment of Parkinson's disease under the following conditions:

Initial treatment as monotherapy, in order to delay the introduction of levodopa

In combination with levodopa, over the course of the disease, when the effect of levodopa wears off or becomes inconsistent and fluctuations in the therapeutic effect occur ("end of dose" or "on-off" type fluctuations).

Oral use.

Adults

Individual dose titration against efficacy and tolerability is recommended.

Ropinirole 5mg film-coated tablets should be taken three times a day, preferably with meals to improve gastrointestinal tolerance.

Treatment initiation

The initial dose of ropinirole should be 0.25 mg three times daily for 1 week. Thereafter, the dose of ropinirole can be increased in 0.25 mg three times daily increments, according to the following regimen:

Week

1

2

3

4

Unit dose (mg) of ropinirole

0.25

0.5

0.75

1.0

Total daily dose (mg) of ropinirole

0.75

1.5

2.25

3.0

Therapeutic regimen

After the initial titration, weekly increments of 0.5 to 1 mg three times daily (1.5 to 3 mg/day) of ropinirole may be given.

A therapeutic response may be seen between 3 and 9 mg/day of ropinirole. If sufficient symptomatic control is not achieved, or maintained after the initial titration as described above, the dose of ropinirole may be increased up to 24 mg/day.

Doses of ropinirole above 24 mg/day have not been studied.

If treatment is interrupted for one day or more re-initiation by dose titration should be considered (see above).

When Ropinirole 5 mg film-coated tablets are administered as adjunct therapy to L-dopa, the concurrent dose of L-dopa may be reduced gradually according to the symptomatic response. In clinical trials, the L-dopadose was reduced gradually by around 20% in patients treated with Ropinirole 5 mg film-coated tablets as adjunct therapy. In patients with advanced Parkinson's disease receiving ropinirole in combination with L-dopa, dyskinesias can occur during the initial titration of ropinirole. In clinical trials it was shown that a reduction of the L-dopa dose may ameliorate dyskinesia (see section 4.8).

When switching treatment from another dopamine agonist to ropinirole, the manufacturer'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 number of daily doses over the period of one week (see section 4.4).

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 initial dose of ropinirole should be 0.25 mg three times a day. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose is 18 mg/day in patients receiving regular haemodialysis. Supplemental doses after haemodialysis are not required (see section 5.2).

The use of ropinirole in patients with severe renal impairment (creatinine clearance less than 30 ml/min) without regular haemodialysis has not been studied.

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.

Children and adolescents

Ropinirole 5 mg film-coated tablets are not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

Elderly

The clearance of ropinirole is decreased by approximately 15% in patients over 65 years of age. Although a dose adjustment is not required, ropinirole dose should be individually titrated, with careful monitoring of tolerability, to the optimal clinical response.

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 dose adjustment is necessary.

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 ropinirole is 0.25 mg three times a day. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose is 18 mg/day in patients receiving regular haemodialysis. Supplemental doses after haemodialysis are not required (see section 5.2).

The use of ropinirole in patients with severe renal impairment (creatinine clearance less than 30 ml/min) without regular haemodialysis has not been studied.

Hypersensitivity to ropinirole or to any of the excipients listed in section 6.1.

Severe renal impairment (creatinine clearance <30ml/min) without regular haemodialysis.

Hepatic impairment.

Patients with major psychiatric or psychotic disorders, or a history of these disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks.

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 phenomenon 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.

Dopamine agonist withdrawal syndrome

To discontinue treatment in patients with Parkinson's disease, ropinirole should be tapered off (see section 4.2). Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including ropinirole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain which may be severe. Patients should be informed about this before tapering the dopamine agonist, and monitored regularly thereafter. In case of persistent symptoms, it may be necessary to increase the ropinirole dose temporarily (see section 4.8).

Hallucinations

Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients should be informed that hallucinations can occur.

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 ropinirole. Dose reduction/tapered discontinuation should be consistent 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 (see section 4.8).

Due to the risk of hypotension, blood pressure monitoring is recommended, particularly at the start of treatment, in patients with severe cardiovascular disease (in particular coronary insufficiency).

Neuroleptic malignant syndrome

Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy. Therefore it is recommended to taper treatment (see section 4.2).

Lactose

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.

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 ropinirole should be avoided.

There is no pharmacokinetic interaction has been seen between ropinirole and L-dopa or domperidone which would necessitate dosage adjustment of these medicinal products. . Domperidone antagonises the dopaminergic actions of ropinirole peripherally and does not cross the blood-brain barrier. Hence its value as an anti-emetic in patients treated with centrally acting dopamine agonists.

Ropinirole is principally metabolised by the cytochrome P450 enzyme CYP1A2. A pharmacokinetic study (with a ropinirole dose of 2 mg, three times a day in patients with Parkinson's disease) revealed that ciprofloxacin increased the Cmax and AUC of ropinirole by 60% and 84% respectively, with a potential risk of adverse events. Hence, in patients already receiving ropinirole, the dose of ropinirole may need to be adjusted when medicinal products known to inhibit CYP1A2, e.g. ciprofloxacin, enoxacin or fluvoxamine, are introduced or withdrawn.

A pharmacokinetic interaction study in patients with Parkinson's disease between ropinirole (at a dose of 2 mg, three times a day) and theophylline, a substrate of CYP1A2, revealed no change in the pharmacokinetics of either ropinirole or theophylline. Therefore, it is not expected that ropinirole will compete with the metabolism of other medicinal products which are metabolised by CYP1A2.

Increased plasma concentrations of ropinirole have been observed in patients treated with high doses of oestrogens. In patients already receiving hormone replacement therapy (HRT), ropinirole treatment may be initiated in the normal manner. However, if HRT is stopped or introduced during treatment with ropinirole, dosage adjustment may be required, in accordance with clinical response.

Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or start smoking during treatment with ropinirole, adjustment of dose maybe required.

In patients receiving the combination of vitamin K antagonists and ropinirole, cases of unbalanced INR have been reported. Increased clinical and biological surveillance (INR) is warranted.

Pregnancy

There are no adequate data from the use of ropinirole in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). As the potential risk for humans is unknown, it is recommended that ropinirole is not used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the foetus.

Breast feeding

Ropinirole should not be used in nursing mothers as it may inhibit lactation.

Patients being treated with ropinirole and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see also Section 4.4).

Adverse events are listed in the table below by system organ class and following the MedDRA frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data).

System Organ Class

Ropinirole

Parkinson's disease used

As monotherapy

Parkinson's disease used as adjunct therapy to Levodopa.

Immune system disorders

Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus).

Not known:

Not known:

Gastrointestinal disorders

Nausea

Very common

Very common

heartburn

Common

Common

Vomiting1

Common

Common

abdominal pain1

Common

Common

Hepatobiliary disorders

Hepatic reactions, increased liver enzymes (ALT, AST)

Not known

Not known

Psychiatric disorders:

Confusion1

Common

Common

hallucinations1

Common

Common

somnolence

Very common

Very common

excessive daytime somnolence

Uncommon

Uncommon

sudden sleep onset episodes

Uncommon

Uncommon

psychotic reactions (other than hallucinations) including delirium, delusion, paranoia

Not known

Not known

dizziness (including vertigo)

Common

Common

increased libido1

Uncommon

Uncommon

Aggression2

Not known

Not known

dopamine dysregulation syndrome3

Not known

Not known

impulse control disorders3

Not known

Not known

Nervous system disorders:

Dyskinesia1,4

Very Common

Very common

General disorders and administration site conditions

Oedema Peripheral (including leg oedema) 1

Common

Common

Dopamine agonist withdrawal syndrome including apathy, anxiety, depression, fatigue, sweating and pain

Not known

-

Vascular disorders

Hypotension, postural hypotension5

Uncommon

Uncommon

syncope1

Very common

Very common

1 Parkinson's disease on ropinirole monotherapy and adjunct therapy at doses up to 24 mg/day

2 has been associated with psychotic reactions as well as compulsive symptoms.

3 Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including ropinirole (see section 4.4 'Special warnings and precautions for use').

4 In patients with advanced Parkinson's disease, dyskinesias can occur during the initial titration of ropinirole. In clinical trials it was shown that a reduction of the levodopa dose may ameliorate dyskinesia (see section 4.2).

5 Postural hypotension or hypotension is rarely severe

Dopamine agonist withdrawal syndrome

Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including ropinirole (see section 4.4).

Management of undesirable effects

Dose reduction should be considered if patients experience significant undesirable effects. If the undesirable effect abates, gradual up-titration can be re-instituted. Anti-nausea medicinal products that are not centrally active dopamine antagonists, such as domperidone, may be used, if required.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google play or Apple App store.

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.

Pharmacotherapeutic group: Dopaminergic agents, dopamine agonists, ATC code: N04BC04.

Mechanism of action

Ropinirole is a non-ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors.

Ropinirole alleviates the dopamine deficiency which characterises Parkinson's disease by stimulating striatal dopamine receptors.

Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin.

Study of the effect of ropinirole on cardiac repolarisation

A thorough QT study conducted in male and female healthy volunteers who received doses of 0.5, 1, 2 and 4 mg of ropinirole film-coated (immediate release) tablets once daily showed a maximum increase of the QT interval duration at the 1 mg dose of 3.46 milliseconds (point estimate) as compared to placebo. The upper bound of the one sided 95% confidence interval for the largest mean effect was less than 7.5 milliseconds. The effect of ropinirole at higher doses has not been systematically evaluated.

The available clinical data from a thorough QT study do not indicate a risk of QT prolongation at doses of ropinirole up to 4 mg/day. A risk of QT prolongation cannot be excluded as a thorough QT study doses up to 24 mg/day has not been conducted.

Absorption

The bioavailability of ropinirole is about 50% (36% to 57%). Oral absorption of ropinirole film-coated (immediate release) tablets is rapid with peak concentrations achieved at a median time of 1.5 hours post dose. A high fat meal decreases the rate of absorption of ropinirole, as shown by a delay in median Tmax by 2.6 hours and an average 25% decrease in Cmax.

Distribution

Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approx. 7 l/kg). Plasma protein binding of ropinirole is low (10 – 40%).

Biotransformation

Ropinirole is primarily cleared by the cytochrome P450 enzyme, CYP1A2, 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 approximately 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. Wide inter-individual variability in the pharmacokinetic parameters has been observed.

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 haemodialysis, oral clearance of ropinirole is reduced by approximately 30%. Oral clearance of the metabolites SKF-104557 and SKF-89124 were also reduced by approximately 80% and 60%, respectively. Therefore, the recommended maximum dose is limited to 18 mg/day in patients with Parkinson's disease.

Reproductive Toxicity

Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg/day (approximately twice the AUC at the maximum dose in humans), increased foetal death at 90 mg/kg/day (approximately 3 times the AUC at the maximum dose in humans) and digit malformations at 150 mg/kg/day (approximately 5 times the AUC at the maximum dose in humans). There were no teratogenic effects in the rat at 120 mg/kg/day (approximately 4 times the AUC at the maximum dose in humans) and no indication of an effect on development in the rabbit.

Toxicology

The toxicology profile is principally determined by the pharmacological activity of: behavioural changes, hypoprolactinaemia, decrease in blood pressure and heart rate, ptosis and salivation. In the albino rat only, retinal degeneration was observed in a long term study at the highest dose (50 mg/kg/day), and was probably associated with an increased exposure to light.

Genotoxicity

Genotoxicity was not observed in the usual battery of in vitro and in vivo tests.

Carcinogenicity

From two-year studies conducted in the mouse and rat at dosages up to 50 mg/kg/day. The mouse study did not reveal any carcinogenic effect. In the rat, the only drug-related lesions were Leydig cell hyperplasia and testicular adenoma 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.

Safety Pharmacology

In vitro studies have shown that ropinirole inhibits hERG-mediated currents. The IC50 is 5-fold higher than the expected maximum plasma concentration in patients treated at the highest recommended dose (24 mg/day), see section 5.1.

Tablet Cores

Lactose, Anhydrous

Lactose Monohydrate

Cellulose, microcrystalline (E460)

Citric acid, anhydrous (E330)

Croscarmellose sodium (E468)

Magnesium Stearate (E572)

Film Coating

5.0 mg

Hypromellose (E464), Titanium dioxide (E171), Macrogol 400, Talc, Indigo carmine aluminium lake (E132), Brilliant blue FCF Aluminium lake (E133)

None known.

2 years

Do not store above 30°C.

Blisters

Store in the original package in order to protect from moisture.

Bottles

Keep the bottle tightly closed in order to protect from moisture.

Blisters:

Plain Aluminium/Aluminium blisters; White, opaque Triplex(PVC/PE/Aclar)/Aluminium blisters.

Bottles:

White opaque HDPE bottle with polypropylene child-resistant closure.

Pack Sizes

Blister: 21 and 84

Bottle: 84

Not all pack sizes may be marketed.

No special requirements for disposal.

Glenmark Pharmaceuticals Europe, Limited Laxmi House, 2 B Draycott Avenue, Kenton, Middlesex HA3 0BU, United Kingdom

PL25258/0051

17/12/2009

11/2017