ADARTREL Film-coated tablet Ref.[49681] Active ingredients: Ropinirole

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).

Paradoxical worsening of Restless Legs Syndrome symptoms described as augmentation (either earlier onset, increased intensity, or spread of symptoms to previously unaffected limbs), or early morning rebound (reoccurrence of symptoms in the early morning hours), have been observed during treatment with ropinirole. If this occurs, the adequacy of ropinirole treatment should be reviewed and dosage adjustment or discontinuation of treatment may be considered (see section 4.8).

Somnolence and episodes of sudden sleep onset

In Parkinson’s disease, ropinirole has been associated uncommonly with somnolence and episodes of sudden sleep onset (see section 4.8) however, in Restless Legs Syndrome, this phenomenon is very rare. Nevertheless, 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. A reduction of dosage or termination of therapy may be considered.

Psychotic disorders

Patients with major psychotic 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 Adartrel. 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, patients with severe cardiovascular disease (in particular coronary insufficiency) should be treated with caution.

Dopamine agonist withdrawal syndrome (DAWS)

DAWS has been reported with dopamine agonists, including ropinirole (see section 4.8). To discontinue treatment in patients with Restless Legs Syndrome, 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.

Patients with moderate hepatic impairment

Ropinirole should be administered with caution to patients with moderate hepatic impairment. Undesirable effects should be closely monitored.

Excipients

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

Each ADARTREL film coated tablet contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium free’.

Ropinirole is principally metabolised by the cytochrome P450 isoenzyme CYP1A2. A pharmacokinetic study (with a ropinirole dose of 2 mg, three times a day) revealed that ciprofloxacin increased the C_max 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 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.

Based on in-vitro data, ropinirole has little potential to inhibit cytochrome P450 at therapeutic doses. Hence, ropinirole is unlikely to affect the pharmacokinetics of other medicinal products, via a cytochrome P450 mechanism.

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

Increased plasma concentrations of ropinirole have been observed in patients treated with hormone replacement therapy. In patients already receiving hormone replacement therapy, ropinirole treatment may be initiated in the usual manner. However, it may be necessary to adjust the ropinirole dose, in accordance with clinical response, if hormone replacement therapy is stopped or introduced during treatment with ropinirole.

No pharmacokinetic interaction has been seen between ropinirole and domperidone (a medicinal product used to treat nausea and vomiting) that would necessitate dosage adjustment of either medicinal product. Domperidone antagonises the dopaminergic actions of ropinirole peripherally and does not cross the blood-brain barrier. It may therefore have 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 with ropinirole should be avoided.

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. 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.

Breastfeeding

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).

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 effects have resolved (see section 4.4).

Adverse drug reactions are listed below by system organ class and frequency. Frequencies from clinical trials are determined as excess incidence over placebo and are classed 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.

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):

Table 3. Adverse drug reactions reported in other Restless Legs Syndrome clinical trials:

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.

Other experience with ropinirole

Ropinirole is also indicated for the treatment of Parkinson’s disease. The adverse drug reactions reported in patients with Parkinson’s disease on ropinirole monotherapy and adjunct therapy at doses up to 24 mg/day at an excess incidence over placebo are described below.

Table 4. Adverse drug reactions reported in Parkinson’s disease clinical trials at doses up to 24 mg/day:

Post marketing reports

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

Psychotic reactions (other than hallucinations) including delirium, delusion and paranoia have been reported.

Aggression (frequency not known): aggression has been associated with psychotic reactions as well as compulsive symptoms.

Dopamine dysregulation syndrome (frequency not known).

Mania (frequency not known) (see section 4.4.).

Impulse control disorders (frequency 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 ADARTREL (see section 4.4).

Dopamine agonist withdrawal syndrome (frequency not known): including apathy, anxiety, depression, fatigue, sweating and pain. Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including ropinirole (see section 4.4).

In Parkinson’s disease, ropinirole is associated with somnolence and has been associated uncommonly (≥1/1,000 to <1/100) with excessive daytime somnolence and sudden sleep onset episodes, however, in Restless Legs Syndrome, this phenomenon is very rare (<1/10,000).

Following ropinirole therapy, postural hypotension or hypotension has been reported uncommonly (≥1/1,000 to <1/100), rarely severe.

Very rare cases of hepatic reactions (<1/10,000), mainly increase of liver enzymes, have been reported.

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 the Google Play or Apple App Store.

Not applicable.