1. 1 門 診 處 方 討 論 Ropinirole 用於 Restless legs syndrome (RLS) 治療 98.9.24 黃怡君藥師

2. 2 處方 :

3. 3 Outline Ropinirole 的角色 ? 何謂 RLS (Restless legs syndrome) ? 如何治療 ? Ropinirole 使用在 RLS 時用法是否合理 ? Ropinirole 使用在 RLS 上健保是否給付 ? 其它治療 RLS 的藥物健保是否有核準 ?

4. 4 Restless legs syndrome (RLS) Introduction Restless legs syndrome (RLS) refers to symptoms of spontaneous, continuous leg movements associated with unpleasant paresthesias. These sensations occur only at rest and are relieved by movement. The symptoms of this syndrome worsen in the evening and at night, leading to difficulty in sleeping. The abnormal feeling are typically deep seated and localized below the knees. Distribution is usually bilateral, but some asymmetry may occur and the arms can be affected in more severe cases.

5. 5 Pathogenesis  In most cases RLS is a primary idiopathic disorder, but it also can be associated with a variety of underlying medical disorders.  Primary RLS — The cause of primary (or idiopathic) RLS is unknown.

6. 6 Pathogenesis  Secondary RLS — RLS can occur secondary to a number of disorders including ： Iron deficiency End-stage renal disease (Uremic polyneuropathy)- RLS is common among dialysis patients, with a reported incidence of 6 -60 ％ Diabetes mellitus Rheumatic disease Venous insufficiency Others - Multiple sclerosis, Parkinson disease, Pregnancy

7. 7 Epidemiology Mild symptoms of RLS occur in 5-15 % of the population RLS symptoms occurred at least twice a week and were reported as moderately or severely distressing by 2.7 % RLS occurs among people of all ages, and the prevalence generally increases with age. RLS also occurs in children. A biologic parent with RLS symptoms was noted for >70% of children with RLS.

8. 8 Prevalence of restless legs syndrome (RLS) by age and sex

9. 9 Treatment – Nonpharmacologic therapy Iron replacement therapy Serum ferritin level ＜ 45-50 mcg/mL 給予 ferrous sulfate 325 mg tid/ day+ vitamin-C 100-200 mg. Ferritin levels should be checked after three to four months of therapy and then every three to six months until the serum ferritin level is greater than 50 mcg/mL and iron saturation is greater than 20 ％. Mental alerting activities such as video games or crossword puzzles Avoidance of aggravating factors ex: Caffeine, nicotine and alcohol may aggravate RLS symptoms. Antidepressants, dopamine-blocking antiemetics (ex:metoclopramide), antihistamines may contribute to RLS symptoms. 適度的運動、熱水澡、腿部按摩、熱敷 或冰敷

10. 10 Drugs used to treat restless legs syndrome Agent Initial dose Recommended max. daily dose Half-life in serumCommon side effects Dopaminergic agents Levodopa (with carbidopa or benserazide) 50 mg200 mg hs1.5-2 hrNausea or vomiting, orthostatic hypotension, hallucination, augmentation of symptoms, insomnia Pergolide* 0.025 mg0.5 mg bid-tid12-16 hrSame as for levodopa, plus nasal congestion and fluid retention, Cardiac valve disease Pramipexole* (Mirapex ® ) 0.125 mg1.5 mg bid-tid8-10 hr (possibly longer with renal dysfunction) Same as for levodopa, plus nasal congestion and fluid retention Ropinirole* (Requip®) 0.25 mg4 mg bid-tid6-8 hr (possibly longer with hepatic dysfunction) Same as for levodopa, plus nasal congestion and fluid retention

11. 11 Drugs used to treat restless legs syndrome Agent Initial dose Recommended maximal daily doseHalf-life in serumCommon side effects Sedative-hypnotic agents Clonazepam0.25 mg2 mg hs30-40 hr Tolerance, sedation Oxazepam10 mg40 mg hs5-10 hr Zaleplon5 mg20 mg hs1 hr (possibly longer with hepatic dysfunction) Zolpidem5 mg20 mg hs1.6 hr (possibly longer in elderly patients or with hepatic dysfunction) Triazolam0.1250.5 mg hs2-4 hr Antiepileptic agents Gabapentin300 mg3600 mg, tid or 1500 mg, hs 5-7 hr (possibly longer with renal dysfunction) Sedation, dizziness, fatigue, somnolence, ataxia

12. 12 AgentInitial dose Recommended maximal daily doseHalf-life in serumCommon side effects Opiates Propoxyphene100-200 mg600 mg bid-tid6-12 hr (possibly longer with hepatic dysfunction) Sedation, pruritus, constipation, nausea or vomiting, dry mouth, dependence Hydrocodone5 mg20-30 mg bid- tid 3 hr (possibly longer with hepatic dysfunction) Codeine30 mg180 mg bid-tid2.5-3 hr (possibly longer with hepatic dysfunction) Tramadol50 mg300 mg bid-tid5-8 hr (possibly longer with hepatic or renal dysfunction) Same as for propoxyphene and augmentation Oxycodone5 mg20-30 mg, bid- tid 3 hr (possibly longer with renal dysfunction) Sedation, pruritus, constipation, nausea or vomiting, dry mouth, dependence Oxycodone-XR10 mg20-30 mg, bid- tid 12 hr (possibly longer with renal dysfunction) Methadone*2.5 mg20 mg, bid-tid16-22 hr (possibly longer with hepatic dysfunction or long-term use) Morphine sulphate-XR 15 mg30-45 mg, bid- tid 4 hr (possibly longer with hepatic dysfunction) * Medication should be started at least two hours before bedtime or the anticipated onset of symptoms. Reproduced with permission from: Earley, CJ. Restless legs syndrome. N Engl J Med 2003

13. 13 Types of RLS  Intermittent RLS (Mild RLS ) — That is troublesome enough when present to require treatment but that is not sufficiently frequent to require regular daily medication use.  Daily RLS (Moderate to Severe RLS ) — That is frequent and troublesome enough to require daily treatment.  Refractory RLS — Refractory RLS is defined as daily RLS treated with a dopamine agonist but with a poor response.

14. 14 Intermittent RLS (Mild RLS ) Treatment options include: Nonpharmacologic therapy Levodopa (first) Dopamine agonists Low potency opioids or opioid agonists Benzodiazepines or benzodiazepine agonists

15. 15 Daily RLS (Moderate to severe RLS ) Nonpharmacologic therapy Dopamine agonists (first) Gabapentin Low potency opioids or opioid agonists Treatment options include:

16. 16 Refractory RLS Change to gabapentin Change to a different dopamine agonist Add a second agent such as gabapentin, a benzodiazepine, or an opioid Change to a high potency opioid or tramadol 2009 UpToDate, Inc. Treatment options include:

17. 17 Ropinirole （ Requip ® ） A non-ergot dopamine agonist ( D 3 ＞D 2 ＞D 4 ) For the treatment of moderate to severe primary RLS. Dose titration: once daily 1-3 hrs at hs 0.25 mg for days 1 and 2 0.5 mg for days 3 to 7 1 mg for week 2 1.5 mg for week 3 2 mg for week 4 2.5 mg for week 5 3 mg for week 6 4 mg for week 7 Micromedex Last Modified April 21,2009

18. 18 Ropinirole in Restless Legs Syndrome FDA Approval: Adult, yes; Pediatric, no Efficacy: Adult, Evidence favors efficacy Indicated for the treatment of moderate-to- severe primary Restless Legs Syndrome Reference: Micromedex Last Modified April 21,2009

19. 19 AASM Classification of Evidence Recommendation Grades Evidence Levels Study Design A Ｉ Large, well-designed, randomized and blinded controlled study with statistically significant conclusions on relevant variables. B Ⅱ Smaller, well-designed, randomized and blinded controlled study with statistically significant conclusions on relevant variables C Ⅲ Well-designed, non-randomized prospective study with control group C Ⅳ Well-designed, large prospective study with historical controls or careful attention to confounding effects or small prospective study with control group. C Ⅴ Small prospective study or case series without control groups. AASM: The American Academy of Sleep Medicine Sleep 2004;27(3):557-9

20. 20 AASM Levels of Recommendations TermDefinition Standard This is a generally accepted patient-care strategy, which reflects a high degree of clinical certainty. The term standard generally implies the use of Level I Evidence, which directly addresses the clinical issue, or overwhelming Level II Evidence Guideline This is a patient-care strategy, which reflects a moderate degree of clinical certainty. The term guideline implies the use of Level II Evidence or a consensus of Level III Evidence. Option This is a patient-care strategy, which reflects uncertain clinical use. The term option implies either inconclusive or conflicting evidence or conflicting expert opinion. Sleep 2004;27(3):557-9

21. 21 Recommendations for treatment of RLS Standard : Levodopa with decarboxylase inhibitor and the dopamine agonist pergolide Guideline : The dopamine agonist pramipexole Option : The dopamine agonist ropinirole Sleep 2004;27(3):557-9

22. 22 衛生署核准適應症 治療自發性帕金森氏症（ Idiopathic Parkinson’s Disease) 治療原發性腿部躁動症 (Primary Restless Legs Syndrome)

23. 23 全民健康保險藥品給付修正規定 97.7.1 生效 1.3.4 帕金森氏症治療藥品 : 5. Pramipexole 及 Ropinirole 用於治療原發 性腿部躁動症時需先排除腎衰竭、鐵缺乏 症及多發性神經病變，且不得與 dopamine agonist 及 levodopa 併用 （ 1 ） Pramipexole 每日最大劑量 0.75mg （ 2 ） Ropinirole 每日最大劑量為 4mg