Ropinirole Hydrochloride

(BANM, USAN, pINNM)
Ropinirole Hydrochloride Chemical formula
Synonyms: (BANM, USAN, pINNM) Hidrocloruro de ropinirol; Ropinirole, Chlorhydrate de; Ropiniroli Hydrochloridum; SKF-101468 (ropinirole); SKF-0101468A (ropinirole hydrochloride). 4-[2-(Dipropylamino)ethyl]-2-indolinone hydrochloride.
Cyrillic synonym: Ропинирола Гидрохлорид.

💊 Chemical information

Chemical formula: C16H24N2O,HCl = 296.8.
CAS — 91374-21-9 (ropinirole); 91374-20-8 (ropinirole hydrochloride).
ATC — N04BC04.
ATC Vet — QN04BC04.

💊 Adverse Effects and Precautions

As for Bromocriptine. Licensed product information states that the pharmacokinetics of ropinirole have not been studied in patients with hepatic or severe renal impairment and therefore it should be used with caution, if at all, in such patients. No pharmacokinetic changes were noted in those with mild to moderate renal impairment. In the treatment of restless legs syndrome, earlier onset of symptoms in the afternoon or evening (augmentation) and recurrence of symptoms in the early morning hours (rebound) have been reported with ropinirole.

Incidence of adverse effects.

References.
1. Etminan M, et al. Comparison of the risk of adverse events with pramipexole and ropinirole in patients with Parkinson’s disease: a meta-analysis. Drug Safety 2003; 26: 439–44.

Effects on mental function.

For reports of daytime somnolence occurring in patients receiving dopamine agonists including ropinirole, see under Adverse Effects of Levodopa.

💊 Interactions

Since it is a dopamine agonist, ropinirole may share some of the pharmacological interactions of bromocriptine. In addition, high doses of oestrogens can increase plasma concentrations of ropinirole and dosage adjustments may be necessary if oestrogen therapy is started or withdrawn during treatment with ropinirole. Ropinirole is metabolised by the cytochrome P450 isoenzyme CYP1A2 and there is therefore the potential for interactions between ropinirole and other drugs that are metabolised similarly or more particularly with inducers or inhibitors of this enzyme. Dosage adjustments may be necessary if therapy with such drugs is started or withdrawn during treatment with ropinirole.

💊 Pharmacokinetics

Ropinirole is rapidly absorbed from the gastrointestinal tract and mean peak plasma concentrations have been achieved 1.5 hours after oral doses; the rate of absorption, but not the extent, may be reduced if taken with food. Bioavailability is reported to be about 50%. It is widely distributed throughout the body and plasma protein binding is low (10 to 40%). Ropinirole is extensively metabolised in the liver, primarily by the cytochrome P450 isoenzyme CYP1A2, and excreted in the urine as inactive metabolites; less than 10% of an oral dose is excreted as unchanged drug. A mean elimination half-life of about 6 hours has been reported for ropinirole. It is thought to be distrib-
uted into breast milk on the basis of studies in rats.
1. Brefel C, et al. Effect of food on the pharmacokinetics of ropinirole in parkinsonian patients. Br J Clin Pharmacol 1998; 45: 412–15
2. Hubble J, et al. Linear pharmacokinetic behavior of ropinirole during multiple dosing in patients with Parkinson’s disease. J Clin Pharmacol 2000; 40: 641–6
3. Kaye CM, Nicholls B. Clinical pharmacokinetics of ropinirole. Clin Pharmacokinet 2000; 39: 243–54.

💊 Uses and Administration

Ropinirole is a non-ergot dopamine D 2 -agonist with similar actions to those of bromocriptine, but in contrast to bromocriptine it also has agonist properties at D 3 receptors. It is used similarly in the management of Parkinson’s disease, either alone or as an adjunct to reduce ‘on-off’ fluctuations in levodopa response. Ropinirole is also used for the treatment of moderate to severe idiopathic restless legs syndrome. It is given by mouth as the hydrochloride; doses are expressed in terms of the base. Ropinirole hydrochloride 1.14 mg is equivalent to about 1 mg of ropinirole. In the treatment of Parkinson’s disease, ropinirole should be introduced gradually and during this period patients already receiving levodopa can have their levodopa dosage decreased gradually until an optimal response is achieved; the concurrent dose of levodopa may be reduced by about 20 to 30%. The daily dosage of ropinirole should be given in three divided doses, preferably with food. The initial daily dose of ropinirole is 750 micrograms increased at weekly intervals in steps of 750 micrograms for the first 4 weeks. After week 4, the weekly increments may be made in steps of 1.5 mg up to a dose of 9 mg daily according to response; subsequent weekly increments may be made in steps of up to 3 mg. The daily dosage should not exceed 24 mg. Optimal response is usually achieved within the range of 3 to 9 mg daily; higher doses may be required if used with levodopa. If it is necessary to stop ropinirole therapy, it should be withdrawn gradually by reducing the number of daily doses over the period of 1 week. Once adequate symptomatic control has been established, ropinirole may be given as oncedaily modified-release tablets. Ropinirole is also given as a single daily dose, 1 to 3 hours before bedtime, in the treatment of restless legs syndrome. The initial dose of ropinirole is 250 micrograms daily for 2 days; if tolerated, the dose is then increased to 500 micrograms daily for the rest of the first week. Subsequent increases may be made in weekly steps of 500 micrograms until a dose of 3 mg daily is reached; if necessary, the dose may then be increased after 1 further week to a maximum of 4 mg daily. In the UK, it has been recommended that treatment should be re-assessed 3 months after starting therapy. For this indication, ropinirole may be withdrawn without gradual tapering of the dose. If treatment with ropinirole is interrupted for more than a few days it should be restarted at the low initial dose and increased gradually as required.
1. Tulloch IF. Pharmacologic profile of ropinirole: a nonergoline dopamine agonist. Neurology 1997; 49 (suppl 1): S58–S62.

Parkinsonism.

Dopamine agonists such as ropinirole may be used to begin treatment of parkinsonism in an attempt to delay therapy with levodopa, particularly in younger patients. They also have an adjunctive use when levodopa is no longer effective alone or cannot be tolerated, and may be useful in reducing ‘off’ periods with levodopa and in ameliorating other fluctuations of mobility in the later stage of the disease.
1. Rascol O, et al. A placebo-controlled study of ropinirole a new D agonist, in the treatment of motor fluctuations of -DOPAtreated parkinsonian patients. Adv Neurol 1996; 69: 531–4
2. Adler CH, et al. The Ropinirole Study Group. Ropinirole for the treatment of early Parkinson’s disease. Neurology 1997; 49: 393–9
3. Rascol O, et al. Ropinirole in the treatment of early Parkinson’s disease: a 6-month interim report of a 5-year levodopa-controlled study. Mov Disord 1998; 13: 39–45
4. Korczyn AD, et al. A 3-year randomized trial of ropinirole and bromocriptine in early Parkinson’s disease. Neurology 1999; 53: 364–70
5. Matheson AJ, Spencer CM. Ropinirole: a review of its use in the management of Parkinson’s disease. Drugs 2000; 60: 115–37
6. Clarke CE, Deane KHO. Ropinirole for levodopa-induced complications in Parkinson’s disease. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2001 (accessed 16/02/06)
7. Clarke CE, Deane KHO. Ropinirole versus bromocriptine for levodopa-induced complications in Parkinson’s disease. Available in The Cochrane Database of Systematic Reviews: Issu
1. Chichester: John Wiley; 2001 (accessed 16/02/06)
8. Whone AL, et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: the REAL-PET study. Ann Neurol 2003; 54: 93–101
9. Pahwa R, et al. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Neurology 2007; 68: 1108–15.

Restless legs syndrome.

The aetiology of restless legs syndrome is obscure and treatment has largely been empirical although dopaminergic therapy has emerged as a common firstline choice. Ropinirole is licensed for the treatment of moderate to severe RLS in some countries.
1. Trenkwalder C, et al. Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry 2004; 75: 92–7
2. Cheer SM, et al. Ropinirole: for the treatment of restless legs syndrome. CNS Drugs 2004; 18: 747–54
3. Walters AS, et al. Ropinirole is effective in the treatment of restless legs syndrome—TREAT RLS 2: a 12-week, double-blind, randomized, parallel-group, placebo-controlled study. Mov Disord 2004; 19: 1414–23
4. Bogan RK, et al. TREAT RLS US Study Group. Ropinirole in the treatment of patients with restless legs syndrome: a US-based randomized, double-blind, placebo-controlled clinical trial. Mayo Clin Proc 2006; 81: 17–27.

💊 Preparations

Proprietary Preparations

Arg.: Requip; Austral.: Repreve; Austria: Requip; Belg.: Requip; Canad.: Requip; Chile: Requip; Cz.: Adartrel; Requip; Denm.: Requip; Fin.: Requip; Fr.: Adartrel; Requip; Ger.: Requip; Gr.: Adartrel; Requip; Hong Kong: Requip; Hung.: Requip; Irl.: Requip; Israel: Requip; Ital.: Requip; Malaysia: Requip; Neth.: Requip; Norw.: Requip; NZ: Requip; Pol.: Requip; Port.: Requip; Zyatrol; S.Afr.: Requip; Singapore: Requip; Spain: Requip; Swed.: Requip; Switz.: Adartrel; Requip; Turk.: Requip; UK: Adartrel; Requip; USA: Requip.
Published November 24, 2018.