Requip Tablets 1mg
REQUIP
(ropinirole hydrochloride)
Prescription Medicine
Therapeutic indications
REQUIP is indicated for the treatment of Parkinson's disease.
REQUIP
(ropinirole hydrochloride)
Presentation
REQUIP Tablets: Film coated, pentagonal shaped tablets containing ropinirole hydrochloride equivalent to 0.25, 0.5, 1.0, 2.0 or 5.0mg ropinirole free base.
REQUIP tablets contain lactose, cellulose microcrystalline, croscarmellose sodium, magnesium stearate, hypromellose, macrogol and titanium dioxide as excipients. The 0.25mg and 5.0mg tablets also contain polysorbate.
Colouring agents are also contained in the film coating as follows:
0.5mg tablets (yellow) contains iron oxide yellow, iron oxide red, indigo carmine aluminium.
1.0mg tablets (green) contains iron oxide yellow, and indigo carmine aluminium.
2.0mg tablets (pink) contains iron oxide yellow, and iron oxide red.
5.0mg tablets (blue) contains indigo carmine aluminium.
REQUIP tablets do not contain gluten, sucrose, tartrazine, or any other azo dyes.
Therapeutic indications
REQUIP is indicated for the treatment of Parkinson's disease.
Ropinirole is effective as early therapy in patients requiring dopaminergic therapy.
In a comparative study, ropinirole was superior to bromocriptine. When these two drugs were administered concomitantly with selegiline there was no difference between them.
REQUIP delays the need for initiation of l-dopa therapy.
As adjunctive treatment of l-dopa, REQUIP enhances the efficacy of l-dopa, including control of 'on-off' fluctuations and 'end of dose' effects associated with chronic l-dopa therapy and permits reduction in daily l-dopa dose.
Posology and method of administration
Individual dose titration against efficacy and tolerability is recommended.
REQUIP should be taken three times a day, preferably with meals to improve gastrointestinal tolerance.
Treatment Initiation
The initial dose of REQUIP should be 0.25mg three times daily. The daily dose is increased by 0.75mg each week for the first four weeks of treatment.
Therapeutic Regimen
After the initial titration, weekly increments of 0.5 to 1mg tid (1.5 to 3mg/day) may be given.
A therapeutic response can be expected between 3-9mg/day. If sufficient symptomatic control is not achieved, or maintained, the dose of REQUIP may be increased until an acceptable therapeutic response is established. Doses above 24mg/day have not been investigated in clinical trials.
When REQUIP is administered as adjunct therapy to l-dopa, the concurrent dose of l-dopa may be reduced gradually by around 20% in total.
When switching treatment from another dopamine agonist to REQUIP, the manufacturer's guidance on discontinuation should be followed before initiating REQUIP.
As with other dopamine agonists, REQUIP should be discontinued gradually by reducing the number of daily doses over the period of one week.
CHILDREN: The use of REQUIP in children is not recommended as safety and efficacy have not been established in this population.
RENAL IMPAIRMENT: No dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance 30-50mL/min).
The use of REQUIP in patients with severe renal (creatinine clearance <30mL/min) or hepatic impairment has not been studied. Administration of REQUIP to such patients is not recommended.
Contraindications
Hypersensitivity to ropinirole and excipients.
Special warnings and special precautions for use
Due to the pharmacological action of ropinirole, patients with severe cardiovascular disease should be treated with caution.
Patients with major psychotic disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks (see also Interactions).
Patients should be warned about the possibility of somnolence.
Interactions
Neuroleptics and other centrally active dopamine antagonists, such as sulpiride or metoclopramide, may diminish the effectiveness of ropinirole and, therefore, concomitant use of these drugs 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.
In a study in Parkinsonian patients receiving concurrent digoxin, no interaction was seen which would require dosage adjustment.
Ropinirole is principally metabolised by the cytochrome P450 enzyme CYP1A2. A pharmacokinetic study in Parkinson's patients revealed that ciprofloxacin increased the Cmax and AUC of ropinirole. Hence, in patients already receiving ropinirole, the dose of ropinirole may need to be adjusted when drugs known to inhibit CYP1A2, e.g. ciprofloxacin, enoxacin or fluvoxamine, are introduced or withdrawn.
A pharmacokinetic interaction study in Parkinson's patients between ropinirole and theophylline, as representative of substrates of CYP1A2, revealed no change in the pharmacokinetics of either ropinirole or theophylline. Hence, changes in ropinirole pharmacokinetics following coadministration with other substrates of CYP1A2 are not expected.
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 maybe 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.
Pregnancy and lactation
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, increased foetal death at 90 mg/kg and digit malformations at 150 mg/kg. There was no teratogenic effect in the rat at 120 mg/kg and no indication of an effect on development in the rabbit. There have been no studies of ropinirole in human pregnancy.
Ropinirole should not be used in nursing mothers as it may inhibit lactation.
Effects on ability to drive and use machines
Patients should be informed about very rare cases of sudden onset of sleep without any prior warning or apparent daytime somnolence and should be cautioned that their safety and that of others is at risk if this happens whilst driving or operating dangerous machinery. If patients develop significant daytime sleepiness or episodes of falling asleep during activities that require active participation, patients should be told not to drive and to avoid other potentially dangerous activities.
Undesirable effects
The most common adverse experiences reported by early therapy patients receiving ropinirole in clinical trials, and not seen at an equivalent or greater incidence on placebo, were; nausea, somnolence, leg oedema, abdominal pain, vomiting, syncope, dyspepsia and hallucinations.
Similarly, the most common adverse experiences reported in adjunct therapy clinical trials were; dyskinesia, nausea, hallucinations and confusion.
The incidence of postural hypotension, an event commonly associated with the initiation of treatment with dopamine agonists, was not markedly different from placebo in clinical trials with ropinirole. However, decreases in systolic blood pressure have been noted.
Dopamine agonists, such as bromocriptine and pergolide, which have an ergoline chemical structure have been associated with adverse experiences such as retroperitoneal fibrosis, erythromelalgia and pulmonary reactions.
As with other dopaminergic therapies, extreme somnolence and/or sudden onset of sleep have been reported rarely during post-marketing experience, occasionally when the patient was driving. Patients experiencing this phenomenon cannot resist the urge to sleep, and on waking may be unaware of any tiredness prior to the sleep. Most patients were taking other medication with potentially sedating properties or alcohol in combination with ropinirole. There is no clear relationship between treatment dose or duration and the onset of symptoms.
Overdose
There have been no incidences of intentional overdose with ropinirole in clinical trials. It is anticipated that the symptoms of ropinirole overdose will be related to its dopaminergic activity. These symptoms maybe alleviated by appropriate treatment with dopamine antagonists such as neuroleptics or metoclopramide.
Pharmacological Properties
Pharmacodynamic properties
Ropinirole is a potent, 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.
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 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. Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approx. 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 (10-40%). Ropinirole is primarily cleared by metabolism 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, 2-fold higher steady-state plasma concentrations of ropinirole following the recommended t.i.d. regimen compared to those observed following a single oral dose.
Preclinical safety data
General Toxicology: Ropinirole is well tolerated in laboratory animals in the dose range of 15 to 50 mg/kg. 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.
Pharmaceutical Particulars
Incompatibilities
None known.
Shelf life
24 months.
Special precautions for storage
Store in a dry place at or below 25°C, and protected from light. When stored under these conditions the shelf-life of the tablets is 2 years.
Medicine Classification
Prescription Only Medicine
Package Quantities
The tablet strengths are distinguished by colour; 0.25mg (white), 0.5mg (yellow), 1.0mg (green), 2.0mg (pink) and 5.0mg (blue).
The 0.25mg tablet strength is provided in blister packs of 4, 21 and 210 tablets, or bottles of 84 tablets.
Tablet strengths 0.5mg, 1.0mg, 2.0mg and 5.0mg are provided in blister packs of 4 or 21 tablets, or bottles of 84 tablets.
Name and Address of Company
GlaxoSmithKline NZ Ltd
Quay Tower
Cnr Albert & Customs Streets
Private Bag 106600
Downtown
Auckland
NEW ZEALAND
