Ropinirole 5 Mg Film-Coated Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ropinirole 5 mg Film-Coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains ropinirole hydrochloride equivalent to 5.0 mg ropinirole base.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Ropinirole 5 mg Film-Coated Tablets are blue, round (10.5mm in diameter), biconvex, and embossed with R5 on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of idiopathic Parkinson’s Disease:
Ropinirole may be used alone (without levodopa) in the treatment of idiopathic Parkinson’s disease.
Addition of ropinirole to levodopa may be used to control “on-off’ fluctuations and permit a reduction in the total daily dose of levodopa.
4.2 Posology and method of administration
Oral use.
Individual dose titration against efficacy and tolerability is recommended.
Ropinirole should be taken three times a day, preferably with meals to improve gastrointestinal tolerance.
Treatment initiation: The initial dose should be 0.25 mg three times daily. A guide for the titration regimen for the first four weeks of treatment is given in the table below:
|
Week | ||||
|
1 |
2 |
3 |
4 | |
|
Unit dose ( mg ) |
0.25 |
0.5 |
0.75 |
1.0 |
|
Unit dose presentation ( mg ) |
0.25 |
0.5 |
0.25, 0.5 |
1.0 |
|
Total daily dose ( mg ) |
0.75 |
1.5 |
2.25 |
3.0 |
Therapeutic regimen: After the initial titration, weekly increments of up to 3 mg/day may be given. Ropinirole is usually given in divided doses three times per day.
A therapeutic response may be seen between 3 and 9 mg/day, although adjunct therapy patients may require higher doses. If sufficient symptomatic control is not achieved, or maintained, the dose of ropinirole may be increased until an acceptable therapeutic response is established. Doses above 24 mg/day have not been investigated in clinical trials and this dose should not be exceeded. When ropinirole is administered as adjunct therapy to L-dopa, the concurrent dose of L-dopa may be reduced gradually by around 20% in total. In patients with advanced Parkinson's disease receiving ropinirole in combination with L-dopa, dyskinesias can occur during the initial titration of ropinirole. In clinical trials it was shown that a reduction of the L-dopa dose may ameliorate dyskinesia (see also section 4.8).
When switching treatment from another dopamine agonist to ropinirole, the manufacturer’s guidance on discontinuation should be followed before initiating ropinirole.
Ropinirole should be discontinued gradually by reducing the number of daily doses over the period of one week.
In parkinsonian patients with mild to moderate renal impairment (creatinine clearance 30-50 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 (creatinine clearance <30 ml/min) or hepatic impairment has not been studied. Administration of ropinirole to such patients is not recommended.
Elderly: The clearance of ropinirole is decreased in patients over 65 years of age, but the dose of ropinirole for elderly patients can be titrated gradually against the symptomatic response in the normal manner.
Children: Parkinson's disease does not occur in children. The use of ropinirole in this population has therefore not been studied and it should not be given to children.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In light of the results of animal studies and the lack of studies in human pregnancy, ropinirole is contra-indicated in pregnancy, lactation and in women of child-bearing potential unless adequate contraception is used.
4.4 Special warnings and precautions for use
Due to the pharmacological action of ropinirole, patients with severe cardiovascular disease should be treated with caution.
Co-administration of ropinirole with anti-hypertensive and anti-arrhythmic agents has not been studied. Caution should be exercised when these compounds are given concomitantly with ropinirole because of the unknown potential for the occurrence of hypotension, bradycardias or other arrhythmias. 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 also Section 4.5).
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. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Ropinirole has been associated with somnolence and episodes of sudden sleep onset particularly in patients with Parkinson’s Disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported uncommonly. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with ropinirole. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dosage or termination of therapy may be considered.
Ropinirole Film-Coated Tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
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.
No pharmacokinetic interaction has been seen between ropinirole and L-dopa or domperidone which would necessitate dosage adjustment of either drug. No interaction has been seen between ropinirole and other drugs commonly used to treat Parkinson’s Disease but, as is common practice, care should be taken when adding a new drug to a treatment regimen. Other dopamine agonists may be used with caution.
In a study of Parkinsonian patients receiving concurrent digoxin, no interaction was seen which would require dosage adjustment.
It has been established from in vitro experiments that ropinirole is metabolised by the cytochrome P450 enzyme CYP1A2. There is, therefore, the potential for an interaction between ropinirole and substrates (such as theophylline) or inhibitors (such as ciprofloxacin, fluvoxamine and cimetidine) of this enzyme. In patients already receiving ropinirole, the dose of ropinirole may need to be adjusted when these drugs are introduced or withdrawn.
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, if HRT is stopped or introduced during treatment with ropinirole, dosage adjustment may be required.
No information is available on the potential for interaction between ropinirole and alcohol. As with other centrally active medications, patients should be cautioned against taking ropinirole with alcohol.
Smoking is known to induce CYP1A2 metabolism. Therefore, if patients stop or start smoking during treatment with ropinirole, dose adjustment may be required.
4.6 Fertility, pregnancy and lactation
Pregnancy
Ropinirole should not be used during pregnancy. In animal studies, administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg (approximately three times the AUC of the maximum dose in man), increased foetal death at 90 mg/kg (~x5) and digit malformations at 150 mg/kg (~x9).
There was no teratogenic effect in the rat at 120 mg/kg (~x7) and no indication of an effect on development in the rabbit. There have been no studies of ropinirole in human pregnancy.
Breastfeeding
Ropinirole should not be used in nursing mothers as it may inhibit lactation.
4.7 Effects on ability to drive and use machines
Patients should be warned about the possibility of dizziness (including vertigo). Patients being treated with ropinirole and presenting with 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 also Section 4.4 ).
4.8 Undesirable effects
Adverse drug reactions are listed below by system organ class and frequency. Frequencies are defined as: Very Common (> 1/10), Common (> 1/100, < 1/10), Uncommon (> 1/1000, < 1/100), Rare (> 1/10,000, < 1/1000), and Very Rare (<1/10,000), including isolated reports.
Common and uncommon events were generally determined from pooled safety data from clinical trial populations of ropinirole and are quoted as excess incidence over placebo.
Rare and Very Rare events were generally determined from post-marketing data and refer to reporting rate rather than the true frequency.
The most commonly reported undesirable effects are nausea, somnolence, dyskinesia and syncope.
Adverse drug reactions reported from patients taking ropinirole_
|
Immune system disorders | |
|
Very Rare: |
Hypersensitivity reactions (including urticaria, 3 angioedema, rash, pruritis) |
|
Psychiatric Disorders | |
|
Common: |
Confusion1, Hallucinations |
|
Uncommon: |
Psychotic reactions (other than hallucinations) including delusion, and paranoia, delirium. |
|
Nervous System Disorders | |
|
Very Common: |
Somnolence2, Dyskinesia1* |
|
Common: |
Dizziness (including vertigo) ’ , syncope |
|
Uncommon: |
Extreme somnolence3, Sudden onset of sleep3 |
|
Vascular Disorders | |
|
Common: |
Hypotension, Postural hypotension |
|
Gastrointestinal Disorders | |
|
Very Common: |
Nausea |
|
Common: |
Abdominal pain2, Vomiting2, Dyspepsia2 |
|
General Disorders and Administration Site Conditions | |
|
Common: |
Leg oedema2 |
|
Hepatobiliary Disorders | |
|
Very Rare: |
Hepatic enzymes increased3 |
1 Adjunct therapy studies
2 Monotherapy studies
3 Post-marketing data (see Section 4.4)
* 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 L-dopa dose may ameliorate dyskinesia (see also section 4.2)
Impulse control disorders
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’).
4.9 Overdose
The symptoms of ropinirole overdose are generally related to its dopaminergic activity. These symptoms may be alleviated by appropriate treatment with dopamine antagonists such as neuroleptics or metoclopramide.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Dopamine agonist ATC code:
N04BC04
Mechanism of action
Ropinirole is a non-ergoline dopamine agonist.
Parkinson's disease is characterised by a marked dopamine deficiency in the nigral striatal system. Ropinirole alleviates this deficiency by stimulating striatal dopamine receptors.
Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin.
5.2 Pharmacokinetic properties
Oral absorption of ropinirole is rapid and essentially complete. Bioavailability of ropinirole is approximately 50% and average peak concentrations of the drug are achieved at a median time of 1.5 hours post-dose. Wide interindividual variability in the pharmacokinetic parameters has been seen but, overall, there is a proportional increase in the systemic exposure (Cmax and AUC) to the drug with an increase in dose, over the therapeutic dose range. Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approx. 8 l/kg) and is cleared from the systemic circulation with an average elimination half-life of about six hours. Plasma protein binding of the drug is low (10-40%). Ropinirole is metabolised primarily by oxidative metabolism and ropinirole and its metabolites are mainly excreted in the urine. The major metabolite is at least 100 times less potent than ropinirole in animal models of dopaminergic function.
No change in the oral clearance of ropinirole is observed following single and repeated oral administration. As expected for a drug being administered approximately every half life, there is, on average, two-fold higher steady-state plasma concentrations of ropinirole following the recommended t.i.d. regimen compared to those observed following a single oral dose.
Paediatric population
Limited pharmacokinetic data obtained in adolescents (12-17 years, n=9) showed that the systemic exposure following single doses of 0.125 mg and 0.25 mg was similar to that observed in adults (see also section 4.2; subparagraph “Children and adolescents).
5.3 Preclinical safety data
General toxicology: Ropinirole caused no serious or irreversible toxicity in laboratory animals at 15mg/kg (monkey), 20mg/kg (mouse) or 50mg/kg (rat). The toxicology profile is principally determined by the pharmacological activity of the drug (behavioural changes, hypoprolactinaemia, decrease in blood pressure and heart rate, ptosis and salivation).
Genotoxicity: Genotoxicity was not observed in a battery of in vitro and in vivo tests.
Carcinogenicity: Two-year studies have been conducted in the mouse and rat at dosages up to 50 mg/kg. The mouse study did not reveal any carcinogenic effect. In the rat, the only drug-related lesions were Leydig cell hyperplasia/adenoma in the testis resulting from the hypoprolactinaemic effect of ropinirole. These lesions are considered to be a species specific phenomenon and do not constitute a hazard with regard to the clinical use of ropinirole.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose monohydrate Microcrystalline cellulose Pregelatinised starch Magnesium stearate
Film coating:
Opadry II 85F20521 (Polyvinyl alcohol, Titanium dioxide, Macrogol 3350, Talc, Indigo carmine aluminium lake)
6.2
Incompatibilities
Not applicable
6.3 Shelf life
24 months
6.4 Special precautions for storage
Do not store above 25°C
Store in the original package in order to protect from light HDPE tablet containers only:
Keep the container tightly closed in order to protect from moisture
6.5 Nature and contents of container
Aluminium/Aluminium blister or induction sealed HDPE tablet containers of 2, 5, 7, 10, 12, 14, 20, 21, 28, 30, 50, 56, 60, 84, 100, 126 and 210 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Actavis Group PTC ehf Reykjavikurvegi 76-78 220 Hafnarfjordur Iceland
8 MARKETING AUTHORISATION NUMBER(S)
PL 30306/0401
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
21/01/2011
10 DATE OF REVISION OF THE TEXT
27/01/2014