Consumer medicine information

Appese

Ropinirole

BRAND INFORMATION

Brand name

Appese

Active ingredient

Ropinirole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Appese.

What is in this leaflet

This leaflet answers some common questions about APPESE.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking APPESE against the benefits they expect it will have for you.

Talk to your doctor or pharmacist if you have any concerns about taking this medicine.

Keep this leaflet with your medicine. You may need to read it again.

What APPESE is used for

APPESE is used to treat restless legs syndrome.

Restless legs syndrome is a condition in which a sense of uneasiness, restlessness, and itching often accompanied by twitching and pain is felt in the legs and sometimes arms when sitting or lying down, especially in bed at night. The only relief is walking or moving the affected limbs, which often leads to problems sleeping at night time.

Restless legs syndrome is thought to be due to a deficiency in the body of dopamine, a naturally occurring body chemical.

APPESE belongs to a group of medicines called non-ergoline, dopamine agonists. APPESE works by having a similar effect on the body as dopamine, therefore it makes up for the dopamine shortage in restless legs syndrome. This in turn relieves the discomfort and reduces the involuntary limb movements that disrupt night time sleep.

APPESE is not recommended for use in children or adolescents (under the age of 18), as there have been no studies of its effects in this age group).

This medicine is available only with a doctor's prescription.

There is no evidence that it is addictive.

Before you take it

When you must not take it

Do not take APPESE if you are allergic to medicines containing ropinirole or any of the ingredients listed at the end of this leaflet.

Do not take it if you are pregnant or intend to become pregnant. It may affect your developing baby if you take it during pregnancy.

Do not take it if you are breastfeeding. APPESE passes into breast milk and may affect your baby.

Do not take it if the expiry date (Exp.) printed on the pack has passed.

Do not take it if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

  • liver problems
  • kidney problems
  • heart problems
  • blood pressure problems
  • a history of mental disorders
  • Neuroleptic-induced Akathisia (restlessness or difficulty keeping still, caused by medicines to treat mental disorders. This is a separate condition to restless legs syndrome).

If you have not told your doctor about any of the above, tell them before you start taking APPESE.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may be affected by APPESE, or may affect how well it works. These include:

  • Central Nervous System depressants, e.g. Benzodiazepines, antipsychotics, or antidepressants
  • fluvoxamine, a medicine to treat depression.
  • neuroleptics, medicines to treat mental disorders, for example sulpiride.
  • metoclopramide, a medicine used to treat nausea or vomiting.
  • theophylline, a medicine used to treat breathing difficulties.
  • ciprofloxacin, an antibiotic
  • hormone replacement therapy (HRT).

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking APPESE.

If you start smoking or give up smoking while taking APPESE, your doctor may also need to adjust your dosage.

If your symptoms get worse

In some people APPESE can make their symptoms of restless legs syndrome get worse. See “If your symptoms get worse” under “While you are taking it” and the information under “Side effects”.

How to take it

How much to take

The starting dose is 0.25 mg once daily. After two days your doctor may increase your dose to 0.5 mg once daily for the remainder of your first week of treatment. After the first week, your doctor may continue to increase your dose gradually.

Your doctor may increase or decrease the amount that you are taking to give you the maximum benefit from the medicine. People generally experience benefit from taking 2mg of APPESE a day. However, some people need to take more or less than this amount.

Follow all directions given to you by your doctor and pharmacist carefully.

How to take it

Take APPESE once a day. It is usually taken just before bedtime, but can be taken up to 3 hours before going to bed.

Swallow tablet(s) whole with a glass of water. You can take this medicine with or without food. Taking it with food may decrease the occurrence of nausea (feeling sick) which is a possible side effects.

Use in children and elderly patients

APPESE is not recommended in children under the age of 18 years.

Elderly patients should follow the dosing instructions from your doctor or pharmacist.

If you forget to take it

Do not take an extra dose. Wait until the next day and take your normal dose then.

Do not try to make up for the dose that you missed by taking more than one dose at a time.

If you have missed a dose for more than a few days, consult your doctor for advice on restarting APPESE.

How long to take it for

Keep taking your medicine for as long as your doctor tells you to. It may take a number of weeks for it to work.

Do not stop taking it even if you begin to feel better. For best effect it must be taken regularly.

Do not stop taking it, or change the dose without first checking with your doctor.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much APPESE. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking it

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking APPESE.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking this medicine.

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed. Otherwise, your doctor may think that it was not working as it should and change your treatment unnecessarily.

If you become pregnant while taking it, tell your doctor immediately.

Things you must not do

Do not use it to treat any other conditions unless your doctor tells you to.

Do not give APPESE to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how this medicine affects you. It may cause drowsiness in some people, especially at the start of treatment. If this occurs, do not drive, operate machinery or do anything else that could be dangerous.

In addition, some people may very rarely fall asleep suddenly without any apparent warning of sleepiness.

If you feel excessive daytime sleepiness (somnolence) or fall asleep suddenly without feeling sleepy, you must not drive or operate machinery until your doctor says you can. Make sure you know how this medicine affects you before you drive a car or operate machinery.

As with other drugs of this type, it is best to avoid alcohol while you are taking APPESE.

Tell your doctor if you experience symptoms such as depression, apathy, anxiety, fatigue, sweating or pain after stopping or reducing your APPESE treatment (called dopamine agonist withdrawal syndrome or DAWS). If the problems persist more than a few weeks, your doctor may need to adjust your dose.

Tell your doctor if you or your family/carer notices that you are developing urges or cravings to behave in ways that are unusual for you, and you cannot resist the impulse, drive or temptation to carry out certain activities that could harm yourself or others. These are called impulse control disorders and can include behaviours such as addictive gambling, excessive eating or spending, an abnormally high sex drive or an increase in sexual thoughts or feelings. Your doctor may need to adjust or stop your dose.

Tell your doctor if you or your family/carer notices that you are developing episodes of overactivity, elation or irritability (symptoms of mania). These may occur with or without the symptoms of impulse control disorders (see above). Your doctor may need to adjust or stop your dose.

If your symptoms get worse

Some people taking APPESE find that their restless legs syndrome symptoms get worse, for example they may:

  • Start earlier than usual or be more intense
  • Affect other parts of the body, such as the arms
  • Return in the early morning

Tell your doctor as soon as possible if you get any of these symptoms.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking APPESE.

Like all other medicines, it may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • dizziness
  • feeling drowsy
  • nausea
  • vomiting
  • fatigue, either mental or physical
  • abdominal pain
  • fainting
  • nervousness
  • apathy
  • anxiety
  • depression
  • sweating
  • heartburn
  • worsening of restless legs syndrome (symptoms may: start earlier than usual, be more intense, affect other parts of the body - such as the arms, or return in the early morning).
  • Hiccups
  • Spontaneous penile erection

APPESE can reduce blood pressure which may make you feel dizzy or faint especially when standing up from a sitting or lying position.

This medicine can very rarely cause excessive daytime somnolence (drowsiness) and sudden sleep onset episodes where patients fall asleep suddenly without apparently feeling sleepy. If you feel extremely tired during the day or fall asleep suddenly without warning you should see your doctor as soon as possible.

The following rare mental side effects have been reported in patients:

  • Compulsive behaviour such as gambling, increase in sex drive, shopping, eating.
  • Hallucinations, delusions, paranoia, delirium, impulse control symptoms and aggression.

Tell your doctor immediately if you notice any of the following:

  • swelling of your lower legs or hands
  • wheezing, swelling of the lips/mouth, difficulty breathing, hayfever, lumpy rash (hives) or fainting. These could be symptoms of an allergic reaction.

Tell your doctor if you notice anything that is making you feel unwell. Other side effects not listed above may also occur in some patients.

After using it

Storage

Keep your medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store APPESE or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking APPESE, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

APPESE comes in 2 strengths of tablets:

  • APPESE 0.5 - Yellow, pentagon shaped tablet with ‘RI’ over ‘50’ on one side and plain on the other side
  • APPESE 2 - Pink, pentagon shaped tablet with ‘RI’ over ‘2’ on one side and plain on the other side

Each pack contains 28 tablets.

Ingredients

The active ingredient in APPESE is ropinirole (as ropinirole hydrochloride).

  • each APPESE 0.5 tablet contains 0.5 mg of ropinirole
  • each APPESE 2 tablet contains 2 mg of ropinirole.

The tablets also contain:

  • lactose monohydrate
  • microcrystalline cellulose
  • croscarmellose sodium
  • magnesium stearate
  • Opadry II 85F62505 Yellow (0.5 mg)
  • Opadry II 85F64712 Pink (2 mg only).

The tablets do not contain gluten, sucrose, tartrazine or any other azo dyes.

Contains sugars as lactose (0.5 mg tablet).

Supplier

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
Australia

Australian registration numbers:
APPESE 0.5 - AUST R 140833
APPESE 2 - AUST R 140835

This leaflet was revised in October 2023.

Published by MIMS December 2023

BRAND INFORMATION

Brand name

Appese

Active ingredient

Ropinirole

Schedule

S4

 

1 Name of Medicine

Ropinirole hydrochloride.

2 Qualitative and Quantitative Composition

Appese tablets come in four strengths and contain either 0.25 mg, 0.5 mg, 1 mg or 2 mg of ropinirole (as hydrochloride).

Excipients of known effect.

Contains sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Appese 0.25*.

White to off-white, pentagon shaped tablet with 'RI' over '25' on one side and plain on the other side. Each tablet contains 0.25 mg ropinirole (as hydrochloride).

Appese 0.5.

Yellow, pentagon shaped tablet with 'RI' over '50' on one side and plain on the other side. Each tablet contains 0.5 mg ropinirole (as hydrochloride).

Appese 1*.

Green, pentagon shaped tablet with 'RI' over '1' on one side and plain on the other side. Each tablet contains 1 mg ropinirole (as hydrochloride).

Appese 2.

Pink, pentagon shaped tablet with 'RI' over '2' on one side and plain on the other side. Each tablet contains 2 mg ropinirole (as hydrochloride).
* Not currently marketed.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of primary restless legs syndrome, including the reduction of associated periodic limb movement and episodes of nocturnal arousal.

4.2 Dose and Method of Administration

Individual dose titration against efficacy and tolerability is recommended. Ropinirole should be taken once daily before bedtime, however the dose can be taken up to three hours before retiring.

Treatment initiation (week 1).

The recommended initial dose is 0.25 mg once daily for two days. If this dose is well tolerated the dose may 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 can be increased according to the regimen shown in Table 1 until optimal therapeutic response is achieved.
First signs of a response can be anticipated after one week of treatment in some patients, although further titration to achieve optimal effect is likely to be required. The mean daily dose in clinical trials was 2 mg/day. Doses above 4 mg/day have not been investigated in patients with restless legs syndrome.
If treatment is interrupted for more than a few days it should be reinitiated by dose titration carried out as above.

Renal insufficiency.

No dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance 30 to 50 mL/minute).
In patients with end stage renal disease receiving regular dialysis, exposure to ropinirole as measured by the AUC is increased by approximately 27%. The recommended maximum dose is limited to 3 mg/day in patients with 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 is 3 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required.
The use of ropinirole in patients with severe renal impairment (creatinine clearance < 30 mL/minute) without regular dialysis has not been studied. Administration of Appese to such patients is not recommended.
There was no change observed in the pharmacokinetics of ropinirole in Parkinson's disease patients with mild to moderate renal impairment.

Hepatic insufficiency.

The use of ropinirole in patients with hepatic impairment has not been studied. Administration of Appese to such patients is not recommended.

Elderly.

Oral clearance of ropinirole is reduced by approximately 15% in elderly patients (65 years or above) compared to younger patients. Dosing adjustment is not necessary in the elderly.

4.3 Contraindications

Hypersensitivity to ropinirole hydrochloride or any of the listed excipients.
Pregnancy and lactation.
Severe renal impairment (creatinine clearance < 30 mL/min) without regular haemodialysis.
Severe hepatic impairment.

4.4 Special Warnings and Precautions for Use

Ropinirole should not be used in the treatment of patients with 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, treatment review may be required in some cases. The latter could be in the form of drug discontinuation, dose increment, change in dose regimen or changing to alternative treatment modality.

Fibrotic complications.

Ropinirole is a non-ergot derived dopaminergic agent. Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, non-ergot derived dopamine agonists can cause them is unknown.

Psychotic disorders.

Patients with a history or presence of major psychotic disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Impulse control disorders.

Impulsive control symptoms, including compulsive behaviours (including pathological gambling, increased libido, hypersexuality, compulsive shopping, binge eating and compulsive eating) have been reported in patients treated with dopaminergic agents, including ropinirole (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing). These were generally reversible upon dose reduction or treatment discontinuation. In some ropinirole cases, other factors were present such as a history of compulsive behaviours or concurrent dopaminergic treatment.

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.

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).

Orthostatic hypotension.

Dopamine agonists appear to impair the systemic regulation of blood pressure with resulting orthostatic symptoms of dizziness or light headedness, with or without documented hypotension. These symptoms appear to occur especially during dose initiation and escalation. Therefore, patients treated with ropinirole and other dopamine agonists should be carefully monitored for signs and symptoms of orthostatic hypotension, especially during dose initiation and escalation (see Section 4.2 Dose and Method of Administration, Renal insufficiency) and should be informed of this risk.

Dopamine agonist withdrawal syndrome (DAWS).

DAWS has been reported with dopamine agonists, including ropinirole (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing). To discontinue treatment in patients with restless legs syndrome, ropinirole should be tapered off. 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.

Dyskinesia with adjunctive levodopa.

Ropinirole may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate pre-existing dyskinesia. Decreasing the dose of levodopa may ameliorate this side effect.

Somnolence and episodes of sudden sleep onset.

Patients treated with ropinirole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on ropinirole, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as 1 year after initiation of treatment.
In controlled clinical trials, somnolence was a common occurrence in patients receiving ropinirole and is more frequent in Parkinson's disease (up to 40% ropinirole, 6% placebo) than in restless legs syndrome (12% ropinirole, 6% placebo). Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
Before initiating treatment with ropinirole, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with ropinirole, such as concomitant sedating medications, the presence of sleep disorders (other than restless legs syndrome), and concomitant medications that increase ropinirole plasma levels (e.g. ciprofloxacin, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g. conversations, eating, etc.), ropinirole should ordinarily be discontinued. (See Section 4.2 Dose and Method of Administration for guidance on discontinuing ropinirole). If a decision is made to continue ropinirole, patients should be advised to not drive and to avoid other potentially dangerous activities. There is sufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Hallucinations.

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

Cardiovascular conditions.

Due to the peripheral dopaminergic action of ropinirole hydrochloride, patients with severe cardiovascular disease (in particular coronary insufficiency) should be treated with caution.
Since ropinirole has not been studied in patients with a history or evidence of significant cardiovascular disease including myocardial infarction, unstable angina, cardiac decompensation, cardiac arrhythmias, vaso-occlusive disease (including cerebral) or cardiomyopathy, it should be used with caution in such patients.
There is limited experience with ropinirole in patients treated with antihypertensive and antiarrhythmic agents. Consequently, in such patients, the dose of ropinirole should be titrated with caution.

Lactose.

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

Ophthalmologic.

Retinal pathology in rats.

While the potential significance of this effect on humans has not been established, it cannot be excluded that human albinos (or people who suffer from albinismus oculi) might have an increased susceptibility to ropinirole compared to normally pigmented people. Therefore, such patients should take ropinirole only under ophthalmological control.

Use in hepatic impairment.

Ropinirole should be administered with caution to patients with moderate hepatic impairment. Undesirable effects should be closely monitored. See Section 4.2 Dose and Method of Administration.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

There are no data available on the use of ropinirole in patients with restless legs syndrome under 18 years of age, therefore ropinirole is not recommended for use in patients within this age group.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Because of the possible additive sedative effects, caution should also be used when patients are taking CNS depressants (e.g. benzodiazepines, antipsychotics, antidepressants, etc.) in combination with ropinirole.

Dopamine antagonists.

Neuroleptics and other centrally active dopamine antagonists, such as sulpiride or metoclopramide, may diminish the effectiveness of ropinirole hydrochloride and, therefore, concomitant use of these drugs with ropinirole hydrochloride should be avoided.
Domperidone is a peripherally active dopamine antagonist and as such may be useful in managing peripheral dopaminergic adverse events. No pharmacokinetic interaction has been seen between ropinirole hydrochloride, levodopa and domperidone which would necessitate dosage adjustment of either drug.

Drugs metabolised by cytochrome P450 1A2.

It has been established from in vitro experiments that ropinirole is principally metabolised by the cytochrome P450 enzyme CYP1A2. There is therefore the potential for an interaction between ropinirole hydrochloride and substrates (such as theophylline) or inhibitors (such as ciprofloxacin, enoxacin or fluvoxamine) of this enzyme. In patients already receiving ropinirole hydrochloride, the dose of ropinirole hydrochloride may need to be adjusted when drugs known to inhibit CYP1A2 are introduced or withdrawn.

Psychotropic drugs.

Neuroleptics and other centrally active dopamine antagonists may diminish the effectiveness of ropinirole. Therefore, concomitant use of these products is not recommended.

Digoxin.

The effect of higher recommended doses of ropinirole hydrochloride on the pharmacokinetics of digoxin is not known.

Hormone replacement therapy (HRT).

Increased plasma concentrations of ropinirole hydrochloride have been observed in patients treated with high doses (0.6 to 3 mg) of oestrogens, predominantly conjugated oestrogens, with ropinirole clearance reduced by, on average, 33% (range 26 to 39%) in postmenopausal women receiving HRT. In patients already receiving hormone replacement therapy (HRT), ropinirole hydrochloride treatment may be initiated in the normal manner. However, if HRT is stopped or introduced during treatment with ropinirole hydrochloride, dosage adjustment may be required.

Alcohol.

No information is available on the potential for interaction between ropinirole hydrochloride and alcohol. As with other centrally active medications, patients should be cautioned against taking ropinirole hydrochloride with alcohol.

Smoking.

The effect of smoking on the oral clearance of ropinirole has not been systematically evaluated. Smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking. Therefore, if patients stop or start smoking during treatment with ropinirole, adjustment of dose 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

Effects on fertility.

There are no data on the effects of ropinirole on human fertility.
When administered to female rats prior to, during mating and throughout pregnancy, ropinirole caused reduced implantation at oral doses of 10 mg/kg/day or greater. This effect is thought to be due to the prolactin lowering effect of ropinirole. In humans, chorionic gonadotrophin, not prolactin, is essential for implantation. In rat studies using low doses of ropinirole (5 mg/kg) during the prolactin dependent phase of early pregnancy (gestation days 0 to 8), oral doses of ropinirole, up to 100 mg/kg/day, did not affect female fertility. There was no effect on fertility in male rats dosed at 125 mg/kg/day for ten weeks.
(Category B3)
Appese should not be used during pregnancy. In animal studies, oral administration of ropinirole to pregnant rats at maternotoxic doses resulted in abortion at 40 mg/kg/day, decreased fetal body weight at 60 mg/kg/day, increased fetal death at 90 mg/kg/day and fetal malformations (predominantly digital malformations) at 120 mg/kg/day. There was no teratogenic effect in rats at 90 mg/kg/day and no indication of an effect on fetal development in rabbits at 20 mg/kg/day. In rabbits, ropinirole in combination with levodopa (10/250 mg/kg/day) increased the incidence of malformations (predominantly digital malformations). There have been no studies of ropinirole in human pregnancy.
 Appese should not be used in breastfeeding mothers as it may inhibit lactation.
Animal studies showed that ropinirole is excreted in the milk of lactating rats.

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 or dizziness (including vertigo) 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 Special Warnings and Precautions for Use, Sudden onset of sleep).

4.8 Adverse Effects (Undesirable Effects)

In restless legs syndrome (RLS) clinical trials the most common adverse event was nausea occurring in approximately 38% of patients. Adverse events 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 adverse events. Dose reduction should be considered if patients experience significant adverse events. If the adverse event abates, gradual up-titration can be reinstituted. Table 2 lists the adverse reactions reported for ropinirole in the 12 week clinical trials at greater than or equal to 2.0% above the placebo rate.
Table 3 lists the adverse reactions reported for ropinirole in the 12 week clinical trials at greater than or equal to 1.0% above the placebo rate, for which a possible causal relationship with ropinirole has been established. Adverse reactions are listed 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) or common (> 1/100, < 1/10).

Postmarketing.

As with other dopaminergic therapies, extreme somnolence and/or sudden onset of sleep have been reported very rarely primarily in Parkinson's disease, during postmarketing experience. Patients experiencing sudden onset of sleep cannot resist the urge to sleep, and on waking may be unaware of any tiredness prior to the sleep. Where data are available, all cases have recovered after down titration or on withdrawal of the drug. In most cases the patients received concomitant medication with potential sedating properties.
As with other dopamine agonists, hypotension including postural hypotension has been observed with ropinirole treatment.
Psychiatric disorders. Uncommon: psychotic reactions (including hallucinations), delusion, paranoia, delirium, impulse control symptoms, increased libido including hypersexuality, pathological gambling, compulsive shopping, binge eating (see Section 4.4 Special Warnings and Precautions for Use).

Aggression (frequency not known).

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

Psychiatric disorders (frequency not known).

Dopamine dysregulation syndrome (frequency not known).

Dopamine agonist withdrawal syndrome (frequency not known).

Adverse effects including apathy, anxiety, depression, fatigue, sweating and pain. Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including ropinirole.

Mania (frequency not known).

(See Section 4.4 Special Warnings and Precautions for Use, Mania).

Reproductive system and breast disorders (frequency not known).

Spontaneous penile erection.

Respiratory, thoracic and mediastinal disorders: (frequency not known).

Hiccups.
Very rare cases of hepatic reactions (< 1/10,000), mainly increase of liver enzymes have been reported.
Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus) have been reported very rarely.
Other reported actions adverse events include heartburn, vomiting and peripheral oedema.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

There have been no incidences of intentional overdose with ropinirole in clinical trials. 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.
Symptomatic supportive therapy and cardiovascular monitoring are recommended.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ropinirole hydrochloride is a potent, non-ergoline D2/D3-dopamine agonist.
Studies with human cloned receptors in vitro show that ropinirole binds with high affinity to cloned human D2, D3 and D4-receptors. Neither ropinirole hydrochloride nor its metabolites bind with high affinity to dopamine D1-receptors. Ropinirole hydrochloride also has very low affinity for 5HT1, 5HT2, benzodiazepine, GABA, muscarinic, α or β-adrenoceptors. Ropinirole hydrochloride is a potent dopamine agonist in vitro and in vivo. The pathophysiology of restless legs syndrome is thought to be a result of dopaminergic deficiency, such as a reduction in the synthesis of dopamine and/or D2-receptor density in the striatum. Neuropharmacological evidence suggests primary dopaminergic system involvement and possibly other neurotransmitter systems. Furthermore, evidence from positron emission tomography (PET) studies show that a mild striatal presynaptic dopaminergic dysfunction may be involved.
D2-receptors are found in the central nervous system, cardiovascular system, hypothalamic pituitary axis and gastrointestinal tract. Ropinirole hydrochloride acts in the hypothalamus and pituitary to inhibit the secretion of prolactin.
In healthy subjects, mean uric acid excretion decreased after acute dosing with ropinirole 0.2 and 0.4 mg. This was not associated with changes in serum uric acid level measured 24 hours after dosing and is not likely to be of clinical significance. There is no information available on the effect of ropinirole on uric acid excretion in healthy elderly subjects or on those with mild to moderate renal impairment.

Clinical trials.

The effectiveness of ropinirole in the treatment of primary restless legs syndrome (RLS) was demonstrated in two randomised, double blind, placebo controlled 12 week studies in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria. Patients were required to have a history of a minimum of 15 RLS episodes/month during the previous month and a total score of greater than or equal to 15 on the International RLS Rating Scale (IRLS scale) at baseline.
Patients with RLS secondary to other conditions (e.g. pregnancy, renal failure and anaemia) were excluded.
Both studies employed flexible dosing, with patients initiating therapy at 0.25 mg ropinirole once daily. Patients were titrated based on clinical response and tolerability over 7 weeks to a maximum of 4 mg once daily. All doses were taken between 1 and 3 hours before bedtime.
A variety of measures were used to assess the effects of treatment, including the IRLS Scale and Clinical Global Impression (CGI) scores. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. Both studies utilised the change from baseline in the IRLS Scale at the week 12 endpoint as the primary efficacy outcome. (See Table 4.)
Across the two studies, the mean duration of RLS was 16 to 22 years (range of 0 to 64 years), mean age was approximately 55 years (range of 28 to 79 years), and approximately 61% were women. The mean dose at week 12 was approximately 2 mg/day for both studies.
A third study (191) (12 week placebo controlled polysomnography study) in 65 patients who had periodic leg movements of sleep (PLMS) associated with their restless legs syndrome examined the effect of treatment with ropinirole on PLMS (per hour of sleep) and on PLMS associated with arousal from sleep. The mean reduction from baseline in PLMS (per hour of sleep) at week 12 was 32.9 in the ropinirole treated group, compared to a reduction of 5.7 for the placebo group. The treatment difference showed that ropinirole was statistically superior to placebo at week 12 (p < 0.0001). A significant reduction from baseline to week 12 in PLMS associated with arousal from sleep was also observed in the group treated with ropinirole (mean reduction of 3.3) compared to the group treated with placebo (mean increase of 1.1, p = 0.0096).
Long-term maintenance of efficacy (study 188) in the treatment of RLS was demonstrated in a 36 week study 188. Following a 24 week single blind treatment phase (flexible doses of 0.25 mg ropinirole to 4 mg once daily), patients who were responders (defined as a decrease of > 6 points on the IRLS scale total score relative to baseline) were randomised in double blind fashion to placebo or continuation of ropinirole for an additional 12 weeks. Relapse was defined as an increase of at least 6 points on the IRLS scale total score to a total score of at least 15, or withdrawal due to lack of efficacy. For patients who were responders at week 24 the mean dose of ropinirole was 2.0 mg (range 0.25 to 4 mg). Patients continued on ropinirole demonstrated a significantly lower relapse rate compared with patients randomised to placebo (32.6 versus 57.8%, p = 0.0156).

5.2 Pharmacokinetic Properties

Absorption.

Oral absorption of ropinirole hydrochloride is rapid and essentially complete with first-pass metabolism by the liver. Bioavailability of ropinirole hydrochloride may be up to approximately 46% and average peak concentrations of the drug are achieved at a median time of 1.5 hours post-dose. Wide inter-individual variability in the pharmacokinetic parameters has been seen and the increase in systemic exposure (Cmax and AUC) to the drug is proportional to the increase in dose, over the therapeutic dose range. The bioavailability of a tablet formulation is 86% relative to an oral solution. Ropinirole is mainly metabolised by the liver, and it has been shown that the enzyme predominantly responsible for its clearance is CYP1A2.

Distribution.

Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approximately 7 L/kg) and is cleared from the systemic circulation with an average elimination half-life of about 6 hours. Plasma protein binding of the drug is low (10 to 40%).

Metabolism.

Ropinirole hydrochloride is primarily cleared by CYP1A2 metabolism and its metabolites are mainly excreted in urine. The major metabolite (N-despropyl derivative) is at least 100 times less potent than ropinirole in animal models of dopaminergic function. The active metabolite (SK and F 89124) represents a much smaller proportion of circulating dose derived material and would not notably contribute to the pharmacological activity of ropinirole.
Administration of ropinirole hydrochloride with food delayed the rate of absorption (prolonged median Tmax by 2.6 hours and 25% decrease in Cmax); however, there was no marked change in overall systemic availability of the drug.

Excretion.

No change in the oral clearance of ropinirole is observed following single and repeated oral administration.
In patients with mild to moderate renal impairment, no change in the clearance of ropinirole hydrochloride was observed by population kinetics.
The pharmacokinetics of ropinirole are consistent between healthy volunteers and patients with restless legs syndrome.

5.3 Preclinical Safety Data

Genotoxicity.

Ropinirole was not genotoxic in a series of assays for gene mutations and chromosomal damage.

Carcinogenicity.

Two-year carcinogenicity studies were conducted in mice and rats at oral doses up to 50 mg/kg/day (6 times (in the mouse) and 27 times (in the rat) the systemic exposure at the maximum recommended clinical dose, based on AUC). In the male rat, there was a significant increase in testicular Leydig cell adenomas at doses of 15 mg/kg and above. This finding is thought to be due to the effects of hypoprolactinaemia in rats and not relevant to humans. In the female mouse there was an increase in benign uterine endometrial polyps at a dose of 50 mg/kg/day (equivalent to the systemic exposure at the maximum recommended clinical dose, based on AUC). No drug related carcinogenic effects were seen in male mice or female rats.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets also contain the following excipients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, Opadry II complete film coating system 85F18378 White (ARTG No. 12135, 0.25 mg only), Opadry II complete film coating system 85F62505 Yellow (ARTG No. 11728, 0.5 mg), Opadry II complete film coating system 85F61303 Green (ARTG No. 11732, 1 mg only) and Opadry II complete film coating system 85F64712 Pink (ARTG No. 11730, 2 mg only). The tablets are gluten free.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Appese 0.25*.

Blister (PVC/PCTFE (Aclar/Al) packs of 12 tablets.

Appese 0.5, 1* and 2.

Blister (PVC/PCTFE (Aclar/Al)) packs of 28 tablets.
* These products are not currently marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

The chemical name for ropinirole hydrochloride is 4-[2-(dipropylamino) ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride. Its structural formula is:
Ropinirole hydrochloride is a white to pale greenish-yellow powder. It is highly soluble in water (133 mg/mL).
C16H24N2O.HCl. Molecular weight: 296.84.

CAS number.

91374-20-8.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes