Ropinirole and pramipexole: first dopamine agonists for RLS

Transcription

1 Ropinirole and pramipexole: first dopamine agonists for RLS Ropinirole (Adartrel) and pramipexole (Mirapexin) are two dopamine agonists recently licensed for the treatment of moderate to severe idiopathic restless legs syndrome. In our New products review Steve Chaplin presents the clinical data relating to their efficacy and Dr Ray Chaudhuri comments on their place in treatment. Restless legs syndrome (RLS) is characterised by an urge to move the legs, accompanied by a range of unpleasant symptoms within the legs. Walking, stretching or bending the legs brings at least partial and temporary relief. At night, these sensations and the urge to move disrupt sleep and cause insomnia; involuntary movements (periodic limb movements) may occur during sleep or when awake. The pathophysiology of the syndrome remains uncertain but dysfunction of dopaminergic A11 cells that deliver dopamine to the spinal cord appears a likely cause. 1 RLS may be idiopathic or associated with iron deficiency, pregnancy or end-stage renal disease. The syndrome is approximately twice as common among women as men and is increasingly common with age. 2-4 It is usually progressive, but can be remitting or nonprogressive. 1 Diagnostic criteria for RLS agreed by the International RLS Study Group (IRLSSG) are listed in Table 1. 5 Estimates of the prevalence of RLS range from 3 6 to 24 7 per cent but the larger studies (n = ) utilising the IRLSSG criteria suggest the figure is 7-11 per cent. 2-4 About half of patients experience symptoms at least once or twice weekly; 3,4 about two-thirds report moderate or severe symptoms. 3,8 RLS is associated with significantly impaired quality of life 2,3 and sufferers report functional impairment at work and socially. 9 Management The management of RLS begins with sleep hygiene (see Table 2), and iron supplementation is indicated in patients with a low serum ferritin concentration. The treatment of first choice is a dopamine agonist, followed if unsuccessful or poorly tolerated by a modifiedrelease opioid, an anticonvulsant 44 Prescriber 19 April

2 PRODUCT PROFILE Proprietary name: Adartrel Constituents: ropinirole Indication: moderate to severe idiopathic restless legs syndrome Dosage and method of administration: adults: individual dose titration against efficacy and tolerability is recommended; recommended initial dose is 0.25mg once daily; dose may be increased to 1mg once a day at week 2, then to 2mg once a day; maximum recommended dose 4mg once a day; should be taken just before bedtime (may be taken up to 3 hours before retiring); children: not recommended; elderly: increase in dosage should be gradual and titrated against the symptomatic response in patients over 65 Contraindications: hypersensitivity to ropinirole or to any of the excipients; severe renal or hepatic impairment Precautions: should not be used to treat neuroleptic akathisia, tasikinesia, or secondary restless legs syndrome, eg caused by renal failure, iron-deficiency anaemia or pregnancy; treatment should be adjusted or discontinued if augmentation and/or early morning rebound is observed; patients must be informed of possible episodes of sudden sleep onset and advised to exercise caution while driving or operating machines during treatment; patients with major psychotic disorders should not be treated with dopamine agonists unless the potential benefits outweigh the risks; administer with caution to patients with moderate hepatic impairment; not recommended in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption; patients with severe cardiovascular disease (in particular coronary insufficiency) should be treated with caution Pregnancy and lactation: not recommended during pregnancy or breast-feeding Interactions: ciprofloxacin, enoxacin, fluvoxamine; HRT; neuroleptics, sulpiride, metoclopramide; smoking dose adjustment may be required if smoking stopped or started during treatment Side-effects: very common: vomiting, nausea; common: nervousness, syncope, somnolence, dizziness (including vertigo); abdominal pain; fatigue Presentation/cost: 0.25mg, 0.5mg, 2mg tablets; 0.25mg 12, 3.94; 0.5mg 28, 15.75; 2mg 28, gabapentin is the drug of choice (unlicensed indication) and a benzodiazepine such as clonazepam (unlicensed indication). 1 Dopamine agonists may actually worsen symptoms or cause them to affect other limbs (augmentation); this may be seen in approximately half of patients during long-term treatment, particularly those with familial or non-neuropathic disease. 10 Levodopa (unlicensed indication) may be suitable when symptoms are mild or intermittent, but more severe disease or daytime symptoms indicate the need for a longer-acting dopamine agonist. Anecdotal evidence suggests that the combination of a dopamine agonist and an opioid may be effective in severe cases. 1 Two dopamine agonists have recently been licensed for the treatment of moderate to severe idiopathic RLS ropinirole (Adartrel) and pramipexole (Mirapexin) and are currently the only drugs licensed for this condition. The main primary end-point in published randomised trials of these agents is the change in International Restless Legs Scale (IRLS) between baseline and after 12 weeks treatment. Secondary end-points included the response rate, defined as patients rated as much or very much improved on the Clinical Global Improvement (CGI) scale, and effects on sleep. Ropinirole Three large double-blind, placebocontrolled, randomised trials of 12 weeks treatment have been published to date A total of 932 patients (mean ages 52-56) had 46 Prescriber 19 April

3 PRODUCT PROFILE Proprietary name: Mirapexin Constituents: pramipexole Indications: symptomatic treatment of moderate to severe idiopathic restless legs syndrome in dosages up to 0.54mg of base (0.75mg of salt); also treatment of the signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa Dosage and method of administration: RLS recommended starting dose is 0.088mg of base (0.125mg of salt) taken once daily 2-3 hours before bedtime; for patients requiring additional symptomatic relief, the dose may be increased every 4-7 days to a maximum of 0.54mg of base (0.75mg of salt) per day; as long-term efficacy in the treatment of RLS has not been sufficiently tested, patient s response should be evaluated after 3 months treatment and the need for treatment continuation should be reconsidered; can be discontinued without tapering off; the tablets should be taken orally, swallowed with water, and either with or without food Contraindications: hypersensitivity to pramipexole or to any of the excipients Precautions: has been associated with somnolence and episodes of sudden sleep onset; patients must be informed of this and advised to exercise caution while driving or operating machines during treatment; because of possible additive effects, caution should be advised when patients are taking other sedating medication or alcohol in combination with pramipexole; patients and caregivers should be aware of the fact that behavioural changes can occur, eg pathological gambling, increased libido, binge eating; ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur; monitor blood pressure, especially at the beginning of treatment; patients with psychotic disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks Pregnancy and lactation: not recommended during pregnancy; should not be used during breast-feeding Interactions: cimetidine and amantadine may interact with pramipexole resulting in reduced clearance of either or both drugs; co-administration with antipsychotic drugs should be avoided Side-effects: very common: nausea; dyskinesia; common: constipation; fatigue, peripheral oedema; somnolence, headache; confusional state, hallucination, insomnia Presentation/cost: 0.125mg, 0.25mg tablets; 0.125mg 30, 9.55; 0.25mg 30, 19.10, 100, 63.67; 1mg 30, 76.40, 100, moderate to severe RLS (IRLS score at least 15, means 21-25). Ropinirole was administered at a dosage of 250µg-4mg per day (means mg per day) one to three hours before bedtime. The proportion of patients completing 12 weeks treatment was similar for ropinirole and placebo (77-88 vs per cent respectively). After 12 weeks, mean IRLS scores improved by points with ropinirole and by 8-9 points with placebo, a statistically and clinically 14 significant difference (see Figure 1). Responder rates defined by the CGI score were per cent with ropinirole and per cent with placebo. Patients taking ropinirole improved more quickly, with a significant difference in CGI response rates evident after three days. 13 These changes were associated with significantly greater improvements compared with placebo in quality of life scores, sleep adequacy and quantity, and reductions in daytime somnolence. In an earlier 12-week trial in 65 patients, ropinirole reduced periodic limb movements in sleep and during waking significantly more than placebo; although sleep adequacy was improved, the increases in sleep duration reported were not statistically significant. 15 Essential an urge to move the legs, usually accompanied by uncomfortable or unpleasant sensations in the legs unpleasant sensations or the urge to move begin or worsen during periods of rest or inactivity such as lying or sitting unpleasant sensations or the urge to move are partly or totally relieved by movement such as walking, bending, stretching, etc, at least for as long as the activity continues unpleasant sensations or the urge to move are worse in the evening or at night than during the day, or only occur during the evening or night Supportive positive response to dopaminergic treatment periodic limb movements (during wakefulness or sleep) positive family history of RLS suggestive of an autosomal dominant mode of inheritance Table 1. International RLS Study Group (IRLSSG) diagnostic criteria for RLS 5 During treatment lasting up to 36 weeks, relapse with ropinirole occurred less frequently than with placebo (33 vs 58 per cent); however, a rebound phenomenon of worsening symptoms on discontinuing treatment cannot be excluded. 16 About 40 per cent of patients experienced nausea with ropinirole (compared with up to 8 per cent with placebo); other common adverse events included headache, somnolence, dizziness and vomiting. Withdrawals due to adverse events were similar in two trials 12,13 but more frequent with ropinirole in the third (11 vs 4 per cent). 11 Augmentation was reported in only one trial (1.6 vs 0.5 per cent with placebo). 13 Sudden-onset sleep was not reported in these trials; the manufacturer states this phenomenon is 48 Prescriber 19 April

4 The patient should try these simple measures for a few weeks while keeping a diary: consistent bedtime routine (same time going to bed and waking up) no daytime napping exposure to daylight (morning is best) regular daytime (but not evening) exercise avoid stimulants, alcohol and cigarettes establish bedtime routine: wind down beforehand and put light out straight away solve problems before retiring; record worries, plan and write out strategies in the early evening, not at bed time, keep bedroom dark, quiet and for sleeping only; no television or books bed should be comfortable, and not too warm or too cold think pleasant thoughts and learn techniques to slow racing thoughts The patient should avoid: getting overexcited before going to bed exercising just before going to bed tea and coffee in the evening excessive smoking excessive use of alcohol excessive daytime sleeping large meals late in the evening lying in bed awake for too long Table 2. Sleep hygiene measures Mean IRLS total score very rare (<1 in ) in patients with RLS 16 (for which lower doses are used compared with the treatment of Parkinson s disease). Pramipexole One large randomised trial of pramipexole has been published; 17 a summary of a pooled analysis of trials involving a total of 1000 patients is available from the manufacturer. 18 The large trial randomised 344 patients (mean age 51, mean IRLS score 23.5) to treatment with pramipexole 250, 500 or 750µg per day or placebo. After 12 weeks, there was no significant difference in efficacy between the doses, with a mean treatment difference in IRLS score of about four points compared with placebo (see Figure 2). Responder rates (by CGI score) were 79 per cent for pramipexole overall and 56 per cent with placebo. These figures are similar to the findings of the pooled analysis. 18 Pramipexole did not reduce daytime somnolence, but improved quality-of-life scores and, from week 1, patients ratings of improvement; effects on sleep were not reported. ropinirole placebo Baseline Day Week Figure 1. Change in mean International Restless legs Scale (IRLS) total scores with ropinirole and placebo over 12 weeks (after reference 13) More patients taking the two higher doses of pramipexole discontinued treatment compared with placebo (23 per cent each vs 12 per cent with placebo); this difference was due to more discontinuations due to adverse events (14-15 per cent vs 6 per cent). Nausea was the most frequently reported adverse event with pramipexole (19 per cent overall vs 5 per cent with placebo); 17 this is more common among women than men. 18 Other common adverse events included headache and somnolence; sudden-onset sleep occurred in three patients taking pramipexole and two taking placebo. 17 Follow-up of patients treated with pramipexole for at least six months showed no loss of efficacy. 19,20 After treatment for 30 months the frequency of adverse effects decreased, with none occurring in more than 5 per cent of patients, and 81 per cent of patients reporting no adverse effects. In this series of 195 unselected patients, 43 (22 per cent) had discontinued treatment within one year, in 26 due to adverse effects (13 per cent). A second long-term follow-up (mean 27 months) of 49 patients found that augmentation occurred in 33 per cent, usually within the first year, but was not associated with previous occurrence during treatment with a dopamine agonist. 21 The mean dosage increased from 380 to 630µg per day. A retrospective review of 59 patients treated with pramipexole for at least six months found that 32 per cent experienced augmentation and 46 per cent developed tolerance. Patients who had developed similar problems with levodopa were most likely to experience them again with pramipexole. 22 By Steve Chaplin, a pharmacist who specialises in writing on therapeutics 50 Prescriber 19 April

5 Place in therapy Ray Chaudhuri DSc, MD, FRCP In 2006, two nonergot dopamine agonists, pramipexole (at doses between 125 and 750µg per day of the salt) and subsequently ropinirole (marketed as Adartrel, 250µg- 4mg per day) became licensed for the treatment of moderate to severe idiopathic RLS. The licensed indications underpinned more than a decade of successful use of dopaminergic therapy for the widely underdiagnosed, occasionally trivialised and socially disabling condition of RLS. Further work is currently underway and the future will see the licensing of other dopamine agonists with novel delivery methods such as the rotigotine transdermal patch or controlledrelease formulations of ropinirole and nondopaminergic agents The recent publication of the risk of cardiac valvulopathy and fibrosis linked to ergot dopamine agonists such as pergolide and cabergoline is also likely to increase the use of nonergot agonists such as pramipexole and ropinirole. There is little doubt about the efficacy, which can be dramatic, of pramipexole and ropinirole in confirmed cases of RLS and periodic limb movements. The drugs lead to virtual cessation of painful and Adjusted mean change in IRLS total score Placebo -9.3 Figure 2. Adjusted mean change in total IRLS score from baseline after 12 weeks treatment with placebo and different doses of pramipexole (after reference 17) Pramipexole 250µg 500µg 750µg -12.8* -13.8* -14.0* *p<0.05 distressing leg movements and sensory symptoms of RLS and produce peaceful night sleep, at least in the short term. Both drugs are effective and easy to use, although there have been no head-to-head trials. The available clinical trial data suggest that ropinirole is likely to be effective in patients with an RLS severity score of 24 or above (out of 40), while pramipexole may be effective in those above 15 points. One year s treatment with pramipexole may cost ( µg per day) while with ropinirole the costs may be (250µg-4mg per day). Comparative health economic data would suggest that pramipexole emerges as a somewhat more cost-effective treatment at one year. 23 However, limited follow-up data would suggest that augmentation rates may be in fact slightly lower with ropinirole ( per cent based on two 52-week continuation studies) compared to pramipexole. Augmentation and rebound are the main therapeutic challenges that face the physician treating RLS and long-term reallife independent observational studies are required to address the issues of augmentation, rebound and tolerability of these agents in RLS. Dr K Ray Chaudhuri is consultant neurologist and co-medical director of Forum If you have any issues you would like to air with your colleagues or comments on articles published in Prescriber, the Editor would be pleased to receive them and, if appropriate, publish them on our Forum page. Please send your comments to: The Editor, Prescriber, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, or to prescriber@wiley.co.uk Prescriber 19 April

6 the National Parkinson Foundation Centre of Excellence and the National RLS Clinic at King s College Hospital, and clinical lead in the Department of Neurology, University Hospital Lewisham, London References 1. Trenkwalder C, Paulus W, Walters AS. The restless legs syndrome. Lancet Neurology 2005;4: Berger K, Luedemann J, Trenkwalder C, et al. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med 2004; 164: Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact. REST general population study. Arch Intern Med 2005; 165: Tison F, Crochard A, Leger D, et al. Epidemiology of restless legs syndrome in French adults. A nationwide survey: the INSTANT study. Neurology 2005; 65: Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003; 4: Phillips B, Young T, Finn L, et al. Epidemiology of restless legs symptoms in adults. Arch Intern Med 2000;160: Nichols DA, Allen RP, Grauke JH, et al. Restless legs syndrome symptoms in primary care. Arch Intern Med 2003; 163: Hogl B, Kiechl S, Willeit J, et al. Restless legs syndrome. A community based study of prevalence, severity and risk factors. Neurology 2005;64: Phillips B, Hening W, Britz P, et al. Prevalence and correlates of restless legs syndrome. Results from the 2005 National Sleep Foundation Poll. Chest 2006;129: Ondo W, Romanyshyn J, Vuong KD, et al. Long-term treatment of restless legs syndrome with dopamine agonists. Arch Neurol 2004; 61: Trenkwalder C, Garcia-Borreguero D, Montagna P, 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: Walters AS, Ondo WG. Dreykluft T, et al. Ropinirole is effective in the treatment of restless legs syndrome. TREAT RLS 2: a 12-week, doubleblind, randomised, parallel-group, placebo-controlled study. Mov Dis 2004;23: Bogan RK, Fry JM, Schmidt MH, et al. Ropinirole in the treatment of patients with restless legs syndrome: a US-based randomised, double-blind, placebo-controlled clinical trial. Mayo 52 Prescriber 19 April

7 Clin Proc 2006;81: Abetz L, Arbuckle R, Allen RP, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2006;4: Allen R, Becker PM, Bogan R, et al. Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome. Sleep 2004;27: GlaxoSmithKline. Adartrel Summary of Product Characteristics. May Winkelman JW, Sethi KD, Kushida CA, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology 2006;67: Boehringer Ingelheim. Mirapexin Summary of Product Characteristics. November Montplaisir J, Denesie R, Petit D. Pramipexole in the treatment of restless legs syndrome: a follow up study. Eur J Neurol 2000;7 (suppl 1): Montplaisir J, Fantini ML, Desautels A, et al. Long-term treatment with pramipexole in restless legs syndrome. Eur J Neurol 2006;13: Silver MH, Girish M, Izurieta R. Pramipexole in the management of restless legs syndrome: an extended study. Sleep 2003;26: Winkelman JW, Johnston L. Augmentation and tolerance with longterm pramipexole treatment of restless legs syndrome (RLS). Sleep Med 2004; 5: Scottish Medicines Consortium. Pramipexole 0.125mg, 0.250mg, 1.0mg tablets (Mirapexin). Drug advice No. 247/06. medicines.org.uk. InfoPOEMs Small but prolonged weight loss maintenance with orlistat Bottom Line: In highly motivated obese people who lost at least 5 per cent of their body weight on a very-low-calorie diet, continuous orlistat (Xenical) treatment for three years allowed them to keep off more weight than those treated with placebo. The numbers were not striking; treated patients regained an average 2.2kg less than placebo-treated patients after three years. There was also less incidence of new diabetes diagnoses in the treated patients, which echoes results found in other studies. (LOE = 1b) Reference: Richelsen B, Tonstad S, Rossner S, et al. Effect of orlistat on weight regain and cardiovascular risk factors following a very-low-energy diet in abdominally obese patients. Diabetes Care 2007;30: Study Design: Randomised controlled trial (double-blinded) Funding: Industry Setting: Outpatient (any) Allocation: Concealed Synopsis: The Scandanavian researchers conducting this study started by enrolling obese patients (50 per cent female) with a mean body mass index of 37.5kg per m 2 to be treated with an eight-week very-low-calorie diet ( kcal per day). The patients weighed between 75kg and 162kg and also had one or more cardiac risk factors. The 309 patients who lost at least 5 per cent of their body weight, an average 14.4kg, were randomized, using concealed allocation, to receive either placebo or orlistat 120mg three times daily for the following three years. All patients also received continuous lifestyle counseling and were asked to follow a diet consisting of approximately 30 per cent fat. The mean weight regain over the three years was an average 4.6kg in the treated group as compared with 7.0kg in the patients receiving placebo (p=<0.02). In other words, orlistat patients weighed an average 9.4kg less and placebo patients weighed an average 7.2kg less after three years. The maintenance of weight loss was better in women than in men. New cases of diabetes occurred in 8 of 154 orlistat-treated patients over the three years compared with 17 of 156 patients treated with placebo (p=0.041; number needed to treat = 18). Prevention of diabetes has been shown with orlistat in other studies (Gillies CL. BMJ 2007;334: ). POEM (Patient Orientated Evidence that Matters) editors review more than 1200 studies monthly from over 100 medical journals, presenting only the best as InfoPOEMs. The POEMs process applies specific criteria for validity and relevance to clinical practice. About 1 in 40 studies qualifies. For more information visit: Prescriber 19 April