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

Posology

Adults

Individual dose titration against efficacy and tolerability is recommended.

Initial titration

The starting dose of ropinirole 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 ropinirole prolonged-release tablets.

Patients who initiate treatment with a dose of 2 mg/day of ropinirole prolonged-release tablets and who experience undesirable effects that they cannot tolerate, may benefit from switching to treatment with ropinirole immediate release tablets at a lower daily dose, divided into three equal doses.

Therapeutic regimen

Patients should be maintained on the lowest dose of ropinirole prolonged-release tablets that achieves symptomatic control.

If sufficient symptomatic control is not achieved or maintained at a dose of 4 mg once daily of ropinirole 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 ropinirole prolonged-release tablets.

If sufficient symptomatic control is still not achieved or maintained at a dose of 8 mg once daily of ropinirole 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 ropinirole prolonged-release tablets is 24 mg.

It is recommended that patients are prescribed the minimum number of ropinirole prolonged-release tablets that are necessary to achieve the required dose by utilising the highest available strengths of ropinirole prolonged-release tablets.

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

When Ropinirole Krka 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 Ropinirole Krka prolonged-release tablets concurrently. In patients with advanced Parkinson's disease receiving ropinirole prolonged-release tablets in combination with levodopa, dyskinesias can occur during the initial titration of ropinirole prolonged-release tablets. 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 daily dose over the period of one week (see section 4.4).

Switching from ropinirole immediate-release tablets to Ropinirole Krka prolonged-release tablets Patients may be switched overnight from ropinirole immediate-release tablets to Ropinirole Krka prolonged-release tablets. The dose of Ropinirole Krka prolonged-release tablets should be based on the total daily dose of ropinirole immediate-release tablets that the patient was taking. The table below shows the recommended dose of Ropinirole Krka prolonged-release tablets for patients switching from ropinirole immediate-release tablets:

Switching from ropinirole immediate-release tablets to Ropinirole Krka prolonged-release tablets

Ropinirole immediate-release tablets

Total daily dose (mg)

Ropinirole Krka prolonged-release tablets

Total daily dose (mg)

0,75 – 2,25

2

3 – 4,5

4

6

6

7,5 - 9

8

12

12

15 - 18

16

21

20

24

24

After switching to Ropinirole Krka prolonged-release tablets, the dose may be adjusted depending on the therapeutic response (see “Initial titration” and “Therapeutic regimen” above).

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.

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 recommended initial dose of ropinirol 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 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.

Paediatric population

Ropinirole Krka 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.

Method of administration

Oral use.

Ropinirole Krka prolonged-release tablets should be taken once a day, at a similar time each day. The prolonged-release tablets may be taken with or without food (see section 5.2).

Ropinirole Krka prolonged-release tablets must be swallowed whole and must not be chewed, crushed or divided because the coating is intended to ensure a prolonged release.

4.3. Contraindications

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

- Severe renal impairment (creatinine clearance <30 ml/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 (see section 4.8). 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 not be treated with dopamine agonists unless 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 Ropinirole Krka. 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 tablets. 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).

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.

Rapid gastrointestinal transit

Ropinirole prolonged release tablets are designed to release medication over a 24hr period. If rapid gastrointestinal transit occurs, there may be risk of incomplete release of medication, and of medication residue being passed in the stool.

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).

Ropinirole Krka prolonged-release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

There is no pharmacokinetic interaction between ropinirole and levodopa or domperidone which would necessitate dosage adjustment of these medicinal products.

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.

Ropinirole is principally metabolised by the cytochrome P450 isoenzyme CYP1A2. A pharmacokinetic study (with a ropinirole immediate-release tablet dose of 2 mg, three times a day) in Parkinson's disease patients, 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 (with a ropinirole immediate-release tablet 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.

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.

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

Ropinirole Krka has major influence on the 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.

The following adverse drug reactions have been reported in either Parkinson's disease clinical trials with ropinirole prolonged-release or immediate-release tablets at doses up to 24 mg/day, or from post-marketing reports.

As monotherapy

As add-on therapy

Immune system disorders

Not known

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

Psychiatric disorders

Common

Hallucinations

Confusion

Uncommon

Psychotic reactions (other than hallucinations) including delirium, delusion, paranoia.

Not known

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').

Not known

Mania (see section 4.4), aggression*, dopamine dysregulation syndrome

Nervous system disorders

Very common

Somnolence

Somnolence**

Syncope

Dyskinesia***

Common

Dizziness (including vertigo), sudden onset of sleep

Uncommon

Excessive daytime somnolence

Vascular disorders

Common

Postural hypotension, hypotension

Uncommon

Postural hypotension, hypotension

Gastrointestinal disorders

Very common

Nausea

Nausea****

Common

Constipation, heartburn

Vomiting, abdominal pain

Hepatobiliary disorders

Not known

Hepatic reactions, mainly increased liver enzymes

General disorders and administration site conditions

Common

Oedema peripheral

Leg oedema

Not known

Dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, sweating and pain)*****.

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

** Somnolence has been reported very commonly in the adjunct therapy immediate- release clinical trials, and commonly in the adjunct therapy prolonged-release clinical trials.

*** 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).

**** Nausea has been reported very commonly in the adjunct therapy immediate- release clinical trials, and commonly in the adjunct therapy prolonged-release clinical trials.

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

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the 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.