4.1. Therapeutic indications

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).

4.2. Posology and method of administration

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 levodopa, the concurrent dose of levodopa may be reduced gradually according to the symptomatic response. In clinical trials, the levodopa dose 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 levodopa, 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 4.8).

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 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 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 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 of ropinirole 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 of age due to a lack of data on safety and efficacy.

4.3. Contraindications

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

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

Hepatic impairment.

4.4. Special warnings and precautions for use

Somnolence and episodes of sudden sleep onset

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. A reduction of dosage or termination of therapy may be considered.

Psychiatric or psychotic disorders

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.

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, aggressive behaviours, 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 considered if such symptoms develop.

Mania

Patients should be regularly monitored for the development of mania. Patients and carers should be made aware that symptoms of mania can occur with or without the symptoms of impulse control disorders in patients treated with ropinirole. Dose reduction/tapered discontinuation should be considered if such symptoms develop.

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).

Hypotension

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).

Dopamine agonist withdrawal syndrome (DAWS)

DAWS has been reported with dopamine agonists, including ropinirole (see section 4.8). To discontinue treatment in patients with Parkinson's disease, ropinirole should be tapered off (see section 4.2). Limited data suggests that patients with impulse control disorders and those receiving high daily dose and/or high cumulative doses of dopamine agonists may be at higher risk for developing DAWS. Withdrawal symptoms may include apathy, anxiety, depression, fatigue, sweating and pain and do not respond to levodopa. Prior to tapering off and discontinuing ropinirole, patients should be informed about potential withdrawal symptoms. Patients should be closely monitored during tapering and discontinuation. In case of severe and/or persistent withdrawal symptoms, temporary re-administration of ropinirole at the lowest effective dose may be considered.

Hallucinations

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

Excipients

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.

Sodium

Each Ropinirole contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium free'.

4.5. Interaction with other medicinal products and other forms of interaction

There is no pharmacokinetic interaction has been seen between ropinirole and levodopa 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.

Neuroleptics and other centrally active dopamine antagonists, such as sulpiride or metoclopramide, may diminish the effectiveness of ropinirole and therefore, concomitant use of these medicinal products should be avoided.

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, it may be necessary to adjust the ropinirole dose, in accordance with clinical response, if HRT is stopped or introduced during treatment with ropinirole.

Ropinirole is principally metabolised by the cytochrome P450 isoenzyme 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.

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

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of ropinirole in pregnant women. Ropinirole concentrations may gradually increase during pregnancy (see section 5.2).

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-related material was shown to transfer into the milk of lactating rats. It is unknown whether ropinirole and its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Ropinirole should not be used in nursing mothers as it may inhibit 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 but no effects were seen on male fertility (see Section 5.3).

4.7. Effects on ability to drive and use machines

Patients being treated with ropinirole and presenting with hallucinations, 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 section 4.4).

4.8. Undesirable effects

Undesirable effects reported are listed below by system organ class and frequency. It is noted if these undesirable effects were reported in clinical trials as monotherapy or adjunct therapy to levodopa.

Frequencies are defined as 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).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Immune system disorders

Not known: Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus).

Psychiatric disorders

Common: hallucinations.

Uncommon: psychotic reactions (other than hallucinations) including delirium, delusion and paranoia.

Not known: aggression*, dopamine dysregulation syndrome, mania (see section 4.4.), impulse control disorders** (see section 4.4.).

* Aggression has been associated with psychotic reactions as well as compulsive symptoms.

** Impulse control disorders: pathological gambling, increased libido, hypersexuality, aggression, compulsive spending or buying, binge eating, and compulsive eating can occur in patients treated with dopamine agonists including Ropinirole (see section 4.4).

Use in adjunct therapy studies:

Common: confusion.

Nervous system disorders

Very common: somnolence

Common: dizziness (including vertigo).

Uncommon: sudden onset of sleep, excessive daytime somnolence.

Ropinirole is associated with somnolence and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes.

Use in monotherapy studies:

Very common: syncope.

Use in adjunct therapy studies:

Very common: dyskinesia. 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).

Vascular disorders

Uncommon: postural hypotension, hypotension. postural hypotension or hypotension is rarely severe.

Respiratory, thoracic and mediastinal disorders

Uncommon: hiccups

Gastrointestinal disorders

Very common: nausea.

Common: heartburn.

Use in monotherapy studies:

Common: vomiting, abdominal pain.

Hepatobiliary disorders

Not known: hepatic reactions, mainly increased liver enzymes.

Reproductive system and breast disorders

Not known: spontaneous penile erection

General disorders

Use in monotherapy studies:

Common: Oedema peripheral (including leg oedema)

Not known: Dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, sweating and pain).

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.

4.9. Overdose

The symptoms of ropinirole overdose are related to its dopaminergic activity. These symptoms may be alleviated by appropriate treatment with dopamine antagonists such as neuroleptics or metoclopramide.