4.1. Therapeutic indications

For the 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)

- for the symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome (see section 5.1)

4.2. Posology and method of administration

Oral use. Adults Individual dose titration against efficacy and tolerability is recommended. Parkinson's disease Ropinirole should be taken three times daily, preferably with meals to improve gastrointestinal tolerance. Treatment initiation The initial dose of ropinirole should be 0.25 mg three times daily for one week. Thereafter, the dose of ropinirole can be increased in 0.25 mg increments three times daily according to the following regimen: Week 1 2 3 4 Unit dose (mg) of ropinirole Total daily dose (mg) of ropinirole 0.25 0.75 0.5 1.5 0.75 2.25 1.0 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 is 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 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 holders guidance on discontinuation should be followed before initiating ropinirole therapy. 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). Restless Legs Syndrome Ropinirole should be taken just before bedtime, however the dose can be taken up to 3 hours before retiring. Ropinirole may be taken with food to improve gastrointestinal tolerance. Treatment initiation (week 1) The recommended initial dose is 0.25mg once daily (administered as above) for 2 days. If this dose is well tolerated the dose should be increased to 0.5 mg once daily for the remainder of week 1. Therapeutic regimen (week 2 onwards) Following treatment initiation, the daily dose should be increased until optimal therapeutic response is achieved. The average dose in clinical trials, in patients with moderate to severe Restless Legs Syndrome, was 2 mg once a day. The dose may be increased to 1 mg once a day at week 2. The dose may then be increased by 0.5 mg per week over the next two weeks to a dose of 2 mg once a day. In some patients, to achieve optimal improvement, the dose may be increased gradually up to a maximum of 4 mg once a day. In clinical trials the dose was increased by 0.5 mg each week to 3 mg once a day and then by 1 mg up to the maximum recommended dose of 4 mg once a day as shown in Table 1. Doses above 4 mg once daily have not been investigated in Restless Legs Syndrome patients. Table 1 Dose titration Week 2 3 4 5* 6* 7* Dose (mg)/once daily 1 1.5 2 2.5 3 4 * To achieve optimal improvement in some patients. The efficacy of ropinirole treatment has not been shown beyond 12 weeks (see Section 5.1). Patient response should be evaluated after 12 weeks treatment and the need for treatment continuation reconsidered. If treatment is interrupted for more than a few days it should be re-initiated by dose titration carried out as above. General information for the indications Parkinson's disease and Restless Legs Syndrome Children and adolescents Ropinirole is not recommended for the use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. Elderly patients 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. 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. The use of ropinirole in patients with severe renal impairment (creatinine clearance less than 30 ml/min) without regular haemodialysis has not been studied. Parkinson's disease 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). Restless Legs Syndrome 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 once daily. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose of Ropinirole is 3 mg/day in patients receiving regular haemodialysis. Supplemental doses after haemodialysis are not required (see section 5.2). <summary id="CONTRAINDICATIONS" data-evt="smpcSectionOpen"

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. <summary id="CLINICAL_PRECAUTIONS" data-evt="smpcSectionOpen"

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 onset sleep 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 the treatment, in patients with severe cardiovascular disease (in particular coronary insufficiency). Neuroleptic akathisia, tasikinesia, secondary Restless Legs Syndrome Ropinirole should not be used to treat neuroleptic akathisia, tasikinesia (neuroleptic-induced compulsive tendency to walk), or secondary Restless Legs Syndrome (e.g. caused by renal failure, iron deficiency anaemia or pregnancy). During treatment with ropinirole, paradoxical worsening of Restless Legs Syndrome symptoms occurring with earlier onset (augmentation), and reoccurrence of symptoms in the early morning hours (early morning rebound), may be observed. If this occurs, treatment should be reviewed and dosage adjustment or discontinuation of treatment may be considered. 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, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Sodium This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium free”. <summary id="INTERACTIONS" data-evt="smpcSectionOpen"

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. Increased plasma concentrations of ropinirole have been observed in patients treated with high doses 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 C max and AUC of r ropinirole increased by 60% and 84% respectively,with a potential risk of adverse events. Hence, in patients already receiving ropinirole, the dose of ropinirole may have to be adjusted when medicinal products known to inhibit CYP1A2 (such as 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 CYP1A2 substrate) – revealed no change in the pharmacokinetics of either ropinirole or theophylline. 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. <summary id="PREGNANCY" data-evt="smpcSectionOpen"

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. 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: frequency cannot be estimated from the available data. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Use of ropinirole in Restless Legs Syndrome In Restless Legs Syndrome clinical trials the most common adverse drug reaction was nausea (approximately 30% of patients). Undesirable effects were normally mild to moderate and experienced at the start of therapy or on increase of dose and few patients withdrew from the clinical studies due to undesirable effects. Table 2 lists the adverse drug reactions reported for ropinirole in the 12‑week clinical trials at ≥1.0% above the placebo rate or those reported uncommonly but known to be associated with ropinirole. Table 2 Adverse drug reactions reported in 12‑week Restless Legs Syndrome clinical trials (ropinirole n=309, placebo n=307) Psychiatric disorders Common Nervousness Uncommon Confusion Not known Dopamine dysregulation syndrome Nervous system disorders Common Syncope, somnolence, dizziness (including vertigo) Vascular disorders Uncommon Postural hypotension, hypotension Gastrointestinal disorders Very common Vomiting, nausea Common Abdominal pain General disorders and administration site conditions Common Fatigue Table 3 Adverse drug reactions reported in other Restless Legs Syndrome clinical trials Psychiatric disorders Uncommon Hallucinations Not known Dopamine dysregulation syndrome Nervous system disorders Common Augmentation, Early morning rebound (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. Hallucinations were reported uncommonly in the open label long‑term studies. Paradoxical worsening of Restless Legs Syndrome symptoms occurring with earlier onset (augmentation), and reoccurrence of symptoms in the early morning hours (early morning rebound), may be observed during treatment with ropinirole. Use of ropinirole in Parkinson's disease Ropinirole is also indicated for the treatment of Parkinson's disease. 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). 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. <summary id="OVERDOSE" data-evt="smpcSectionOpen"

4.9. Overdose

The symptoms of ropinirole overdose are related to its dopaminergic activity.

These symptoms can be alleviated by appropriate treatment with dopamine antagonists, such as neuroleptics or metoclopramide.