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Home , Biperiden, Trihexyphenidyl

Expert peer review No.2 on application for anti‐ medicines

1. Assessment of efficacy a. Have all relevant studies on efficacy been included Yes No√ (if no, please provide reference and information) Attachment 1‐5 part 1‐2 b. Summarize the data on efficacy, in comparison to what is listed in EML where applicable (limit to 2 to 3 sentences).

(1) Levodopa/ (L/C): L/C (100/20) is more effective than L/C (100/10) in treatment of Parkinson’s disease (PD) [1]. L/C 300mg:75mg per day is effective and safe for PD [2].

(2) : A significant improvement occurred in the total Unified Parkinson’s Disease Scale (UPDRS) score with pramipexole monotherapy compared with placebo and [3‐4]. When used as adjunct therapy in parkinson’s disease (PD), it is also significant better than levodopa [5]. Pramipexole treatment of depression symptoms achieved a significant advantage in Hamilton depression scale (HAM‐D) compared with placebo, but had no difference with other anti‐depression drugs [6].

(3) : Compared with placebo, selegiline do not appear to delay disease progression in terms of improved survival, but may improve patient’s compliance and symptoms [7].

(4) : Early study indicated trihexyphenidyl could improve neural function [8]. Trihexyphenidyl was equally effective as (WHO EML medicine) [9].

(5) : There is insufficient evidence to support the use of amantadine for early Parkinson’s disease (PD) [10]. The results from our study suggested that amantadine can be used as an antidyskinesia agent [11‐12]. c. Please provide any additional relevant information with reference

See references and attachment 1‐5 part 1‐2.

2. Assessment of safety a. Have all relevant studies on safety been included Yes No√ (if no, please provide reference and information) Attachment 1‐5 part 1‐2 b. Summarize the data on safety, in comparison to what is listed in EML where applicable (limit to 2 to 3 sentences)

(1) L/C: L/C mainly causes ADRs in digestive system ( 26%, 8%, dyspepsia 6%), motor system ( 16%, freezing of gait 7%, falls 5%), nervous system (depression 8%, 6%, 6%, insomnia 5%, 5%); as well as wearing off (18%) [2].

(2) Pramipexole: The majority of adverse events associated with pramixezole are in nervous system, such as insomnia, illusion, dizziness, movement disorders, etc. Besides that, nausea, constipation, peripheral oedema and postural hypotension are also common adverse events. Most adverse events are mild, however cases of heart failure were reported.

(3) Selegiline: The most frequently reported adverse events including nervous system (such as , hallucinations, depression, dizziness, ) [13], circulating system (such as postural hypotension, palpitation), digestive system (such as nausea, dry mouth, constipation) [14], endocrine system ( such as sweat). No serious adverse events were reported based on our included studies [15].

(4) Trihexyphenidyl: Trihexyphenidyl was reported resulting in mental symptoms (7 cases), myasthenia gravis (1 case), toxicosis (4 cases), and drug dependence (2 cases)

(5) Amantadine: Most adverse events are mild, the most frequently reported adverse events included nervous system (53.23%), digestive system(35.48%), others system(total: 18.99%) [16] c. Please provide any additional relevant information with reference

See references and attachment 1‐5 part 1‐2.

3. Assessment of cost and availability a. Have all relevant data on cost provided Yes No√ (if no, please provide reference and information) b. Summarize the data on cost and cost effectiveness, in comparison to what is listed in EML where applicable (limit to 2 to 3 sentences)

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(1) L/C: In China, controlled‐release L/C (200mg:50mg)×30=¥68.4=$10.95. Therefore yearly cost (100mg:25mg three times daily) is approximately $200.00.

(2) Pramipexole: In China, pramixezole 0.25mg×30=¥218.00. Therefore yearly cost (0.5mg three times daily) is approximately $2514.49.

(3) Selegiline: In China, selegiline hydrochloride tablets: 5mg×10=¥ 34.3= $ 5.49. Therefore 1 year treatment of 10mgs daily is $401.12.

(4) Trihexyphenidyl: In China, trihexyphenidyl 2mg×100=¥3.7=$0.59. Therefore yearly cost (2mg three times daily) is approximately $6.50.

(5) Amantadine: In china, amantadine hydrochloride tablets: 100mg×100 = $ 1.12. Therefore yearly cost (100mg twice daily) is approximately $8.17.

c. Please provide any additional relevant information with reference

None

d. Is the product available in several low and middle income countries?

Trihexyphenidyl was included by National Essential Medicines List (NEML) (2009 edition) and National Essential Medical Insurance Medicine List (NEMIML) of China (2009 edition, 100% reimbursed). Amantadine was included by NEML and NEMIML(partially reimbursed). L/C was included by NEMIML(partially reimbursed). Pramipexole and selegiline were available in China, but not included by NEML nor NEMIML.

4. Assessment of public health need a. Please provide the public health need for this product (1‐2 sentences)

Table 1 The burden of inpatients with PD (data from China Health Statistics Yearbook 2011)

Total Cure Improvement Unhealed Death Average 5~14y 15~44y 45~59y ≥60y PD (%) ≤5y (%) patients (%) (%) (%) (%) cost (¥) (%) (%) (%) (%)

PD 36256226 23254 (0.1) 9.3 88 2.2 0.4 8002.7 0.4 0 2.2 14.6 82.8

b. Do guidelines (especially WHO guidelines) recommend this product? If yes, which ones? List 1 or 2 international preferable

Guideline recommended as following:

L/C [17‐21] and pramipexole [17‐20] were recommended as first‐choice option for early PD, and pramipexole could be used as anti‐depression therapy for PD patients. Selegiline was recommended as a symptomatic treatment for PD [17‐19,21]. Trihexyphenidyl only use in mild parkinsonian symptoms in people with no cognitive dysfunction [17], and in PD patients with tremor [18,20]. Amantadine was used as an antidyskinesia agent [17‐20].

5. Are there special requirements for use or training needed for safe/effective use? If yes, please provide details in 1‐2 sentences

Yes. L/C appropriate to adjust L/C dosage to reduce motor complications. L/C and Selegiline are contraindicated in . Pramipexole and Trihexyphenidyl should be titrated to a clinically efficacious dose. Amantadine should not be taken later than mid‐afternoon due to its ADR of insomnia, and patients with history of seizures and psychiatric symptoms should be monitored.

6. Is the proposed product registered by a stringent regulatory authority? Yes No√

7. Any other comments

Trihexyphenidyl is more available and cheaper than biperiden (WHO EML medicine).

8. What is your recommendation to the committee (please provide the rationale)

(1) We recommend L/C (4:1) replace L/C (10:1) in WHO EML, due to:

 L/C (4:1) was proved to be effective and safe for PD by high quality RCT. 2

 L/C (100/20) is more effective than L/C (100/10) for PD by another RCT.

(2) We recommend pramixezole be listed in WHO EML only if cost is not considered, due to:

 Pramixezole is efficient in treating PD patients by improving the total UPDRS scores and depression symptom in PD patients by improving the HAM‐D scores.  The adverse events of pramixezole included nervous system, circulating system, digestive system and endocrine system.  The cost of pramixezole ($ 2514 per year) is much higher than the other four anti‐parkinsons drugs (selegiline $401.12, levodopa $200, amantadine $8.17, benzhexol $6.4). (3) We recommend selegiline be listed in WHO EML only if cost is not considered, due to:

 Compared with placebo, selegiline do not appear to delay disease progression in terms of improved survival, but may improve patient’s compliance and symptoms.  The adverse events of selegiline included nervous system, circulating system, digestive system and endocrine system based on our included studies.  The cost of selegiline ($401.12per year) is higher than levodopa ($200.00per year), benzhexol ($6.40per year) and amantadine ($8.17per year). (4) We do not recommend trihexyphenidyl be listed in WHO EML. Unless WHO will keep medicine in EML, then we recommend trihexyphenidyl replace biperiden, since:

 There are insufficient clinical evidence on the efficacy and safety of trihexyphenidyl for PD.

 Trihexyphenidyl is more available and cheaper than biperiden.

(5) We do not recommend amantadine list in WHO EML, due to:

 Guidelines recommend amantadine used as an antidyskinesia agent (C)  Only those with will be eligible for amantadine, and the patients (especially elderly and those with cognitive decline) should be warned about potential onset, or increase of, visual hallucinations.  Amantadine might be used for early PD but should not be a drug of first choice (D).

References:

1. WW Tourtellotte, K Syndulko, AR Potvin, et al. Increased ratio of carbidopa to levodopa in treatment of Parkinson's disease. Arch Neurol, 1980, 37(11): 723‐6.

2. S Fahn, D Oakes, I Shoulson, et al. Levodopa and the progression of Parkinson's disease. N Engl J Med, 2004, 351(24): 2498‐508.

3. Möller JC, Oertel WH, Köster J, et al. Long‐term efficacy and safety of pramipexole in advanced Parkinson's disease: results from a European multicenter trial. Mov Disord. 2005 May;20(5):602‐10.

4. Clarke CE, Patel S, Ives N, et al. Should PD treatment be started immediately on diagnosis or delayed until functional disability develops? Meta‐analysis of delayed‐start design trials. Mov Disord. 2011 Jun;26(7):1187‐93.

5. Carl E Clarke, Julie Speller, J A Clarke, et al. Pramipexole for levodopa‐induced complications in Parkinson's disease. Cochrane Database of Systematic Reviews.2000(2):CD002261. 2009 updated

6. Leentjens AF, Koester J, Fruh B, et al. The effect of pramipexole on mood and motivational symptoms in Parkinson's disease: a meta‐analysis of placebo‐controlled studies. Clin Ther. 2009 Jan; 31(1):89‐98.

7. Turnbull K, Caslake R, Macleod A, et al. inhibitors for early Parkinson's disease. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD004898. DOI: 10.1002/14651858.CD004898.pub2.

8. R Katzenschlager, C Sampaio, J Costa, et al. Anticholinergics for symptomatic management of Parkinson's disease. Cochrane Database Syst Rev, 2003(2): CD003735.

9. RV Magnus. A comparison of biperiden hydrochloride (Akineton) and benzhexol (Artane) in the treatment of drug‐induced Parkinsonism. J Int Med Res, 1980, 8(5): 343‐6.

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10. Crosby N, Deane KH, Clarke CE. Amantadine in Parkinson's disease. Cochrane Database of Systematic Reviews. 2003(1):CD003468.

11. Crosby NJ, Deane KHO, Clarke CE. Amantadine for dyskinesia in Parkinson's disease. Cochrane Database of Systematic Reviews. 2003(2):CD003467.

12. Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence‐based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004. Movement Disorders. May 2005;20(5):523‐539.

13. Myllylä VV, Sotaniemi KA, Hakulinen P, et al. Selegiline as the primary treatment of Parkinson's disease‐‐a long‐term double‐blind study.Acta Neurol Scand. 1997 ,95(4):211‐8.

14. Pålhagen S, Heinonen EH, Hägglund J, et al. Selegiline delays the onset of disability in de novo parkinsonian patients. Swedish Parkinson Study Group.Neurology. 1998,51(2):520‐5.

15. Shoulson I, Oakes D, Fahn S, et al. Impact of sustained deprenyl (selegiline) in levodopa‐treated Parkinson's disease: a randomized placebo‐controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial.Ann Neurol. 2002,51(5):604‐12.

16. Sawada H, Oeda T, Kuno S, et al. Amantadine for in parkinson's disease: A randomized controlled trial. PLoS ONE. 2010;5(12).

17. Parkinson's Disease: National clinical guideline for diagnosis and management in primary and secondary care2006, London: Royal College of Physicians of London.

18. 中国帕金森病治疗指南(第二版)[J]. 中华神经科杂志, 2009, 42(5): 352‐355.

19. D Grimes, J Gordon, B Snelgrove, et al. Canadian Guidelines on Parkinson's Disease. Can J Neurol Sci, 2012, 39(4 Suppl 4): S1‐30.

20. J Carr, B Kies, and J Fine. Guideline for the treatment of Parkinson's disease. S Afr Med J, 2009, 99(10): 755‐6, 758.

21. DG Grosset, GJ Macphee, and M Nairn. Diagnosis and pharmacological management of Parkinson's disease: summary of SIGN guidelines. BMJ, 2010, 340: b5614.

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Attachment 1: Comparison of Application and Evaluation for anti-parkinsonism medicines: Levodopa/carbidopa(L/C)

Items Data of Application Data of Evaluation 1.Included Studies No. of IS No. of IP Additional Total No. of IS No. of IP No. of IS No. of IP Efficacy SR/meta analysis - - 0 0 0 0 RCT 1 361 6 410 7 771 CCT - - 10 364 10 364 Case series 1 32 18 395 19 427 Case report - - 2 2 2 2 Safety - - 5 5 5 5 Applicability 1 - 5 - 6 - Economical Evaluation 1 175 1 100 2 275 2.Outcomes of Evaluation Efficacy Mortality 20% (4/20) Idem Idem Symptom control UPDRS, PLB vs L/C(150vs300vs600) Symptom, L/C(100:20 vs 100:10) UPDRS,7.8/1.9/1.9/1.4 7.8/1.9/1.9/1.4 n=361 100:20 > 100:10 Symptom,100:20 > 100:10

Safety# Nervous system √ Depression(0.08),Dizziness(0.06), √ One upper limb tremor exacerbation case √ Idem + 1 upper limb tremor Somnolence(0.06),Insomnia(0.05), Tremor(0.05) report exacerbation case Motor system √ Dystonia(0.16),Freezing of √ One 'on-off' exacerbation case report √ Idem + 1 'on-off' exacerbation gait(0.07),Falls(0.05),Myalgia(0.03),Dyskinesia(0.02) case Digestive system √ Nausea(0.26),Constipation(0.08), - √ Idem Dyspepsia(0.06),Diarrhea(0.03) Respiratory system √ Upper respiratory infection(0.11),Sinusitis(0.05) - √ Idem

Circulatory system √ Hypertension(0.02),Coronary artery disorder*(0.02) √ One hypertensive crisis case report √ Idem + 1 hypertensive crisis case* Urinary system √ Urinary tract infection(0.01) - √ Idem Reproductive system - - - Endocrine system - - - Others √ Wearing off(0.18),Back pain(0.06), √ One burning mouth syndrome and 1 skin √ Idem + 1 burning mouth syndrome + (0.06),Chest pain*(0.05) rash case report 1 skin rash case Applicability For early PD For early PD

Economical Evaluation 700 USD per year 200 USD per year in China, controlled-release L/C may be more cost-effective in PD patients with motor fluctuations than standard L/C. 3.Quality of Evidence A A

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4.Recommendation First-choice option for early PD. First-choice option for early PD.

#Safety data mainly based on L/C(300mg:70mg/day) from Fahn 2004 study. Attachment 2: Comparison of Application and Evaluation for anti-parkinsonism medicines: Pramixezole Items Data of Application Data of Evaluation Additional Total 1.Included Studies No. of IS No. of IP No. of IS No. of IP No. of IS No. of IP SR/meta analysis 1 669 7 15017 8 15686 RCT 3 311 56 8658 59 8969 Efficacy CCT - - 28 - 28 - Case series - - 10 - 10 - Case report - - 2 - 2 - Safety - - 54 300+ 54 300+ Applicability 1 - 5 - 6 - Economical Evaluation - - 13 - 13 - 2.Outcomes of Evaluation Efficacy Mortality - - - Symptom control √ UPDRS total score,: √UPDRS total score: PPX vs PLB［MD=-13.2，95%CI（-15.53，-10.51），P<0.00001］ PPX vs PLB PPX vs BR［OR=2.66，95%CI（1.41,5.02），P=0.003］ 4.4 CI95%（2.3-6.5）P<0.0001 PPX+L-dopa vs L-dopa［MD=-9.35，95%CI（-13.83，-1.23），P<0.0001］ √HAM-D score: PPX vs other drugs ［MD=1.08，95%CI（0.75，2.9），P<0.00001］ Safety Nervous system √ Hallucinations, Confusion √ Dizziness15.5%, Dyskinesia12.9%, Insomnia8.2%, Somnolence8.6%, Hallucination6.6%, Confusion3.0%, headache6.5%, Dreams anomaly3.5% case report:Impulse Control Disorders,5 Sudden sleep attacks,psychotic disorder

Motor system √ Dyskinesia √ case report:8 camptocormia，3 antecollis，dropped head syndrome Digestive system √ Nausea √ Nausea17.2%,Constipation5.5% Respiratory system - - Circulatory system √ Postural hypotension √Postural hypotension, heart failure* Urinary system - - Reproductive system - - Endocrine system - √ case report:2 SIADH，significant weight increase，dysaphrodisia

Others √ Peripheral oedema √Peripheral oedema Applicability For early PD For early PD Economical Evaluation 0.7mg tid，￡786/y in UK 0.5mg tid, ¥15696/y= $2514/y in China

3.Quality of Evidence A A 6

4.Recommendation First-choice option for early PD First-choice option for early PD. Depression in PD patients.

Attachment 3: Comparison of Application and Evaluation for anti-parkinsonism medicines: Selegiline Items Data of Application Data of Evaluation Additional Total 1.Included Studies No. of IS No. of IP No. of IS No. of IP No. of IS No. of IP SR/meta analysis 1 2193 4 5037 5 7230 RCT - - 58 13574 58 13574 Efficacy CCT - - 6 477 6 477 Case series - - 2 386 2 386 Case report - - 0 0 0 0 Safety - - 7 - 7 - Applicability 1 - 5 - 6 - Economical Evaluation - - 2 - 2 - 2.Outcomes of Evaluation Efficacy Mortality selegiline(84/615) selegiline vs placebo： selegiline(83/566) vs placebo(77/551) selegiline vs placebo： vs placebo(82/611) ［OR=1.03，95%CI（0.73，1.44）， selegiline(218/582) + other therapy vs ［RR=1.06，95%CI（0.80，1.41），P=0.70］ selegiline(210/475) P=0.87］ other therapy(182/554) selegiline + other therapy vs other + other therapy vs selegiline + other therapy vs other therapy： other therapy：［OR=1.25，95%CI（0.91， ［RR=1.10，95%CI（0.97，1.24），P=0.14］ therapy(178/451) 1.71），P=0.16］ Symptom control _ selegiline vs placebo： _ selegiline vs placebo： ［MD=-4.57，95%CI（-5.70，-3.44）， ［SMD=-0.46，95%CI（-0.74，-0.18）， P<0.00001］ P=0.001］ selegiline + other therapy vs other selegiline + other therapy vs other therapy：［MD=-4.12，95%CI（-6.58， therapy：［SMD=-2.72，95%CI（-7.29， -1.65），P=0.0011］ 1.85），P=0.24］ Safety nervous system √(hallucinations) √(vertigo, hallucinations, depression, 17.27% dizziness, anxiety) motor system _ _ _ digestive system _ √(nausea, dry mouth, constipation) 12.04% respiratory system _ _ _ circulatory system √(postural hypotension) √(postural hypotension, palpitation) 4.28% urinary system _ _ _ reproductive system _ _ _ endocrine system _ √(sweat) 1.27% others _ _ _ Applicability initial or add-on treatment for PD symptomatic treatment for PD. 7

Economical Evaluation 160.92 USD per year 401.12 USD per year in China 3.Quality of Evidence A A Selegiline may be used as a symptomatic treatment for people with PD, but the Selegiline may be used both as initial and add-on 4.Recommendation cost of it is higher than levodopa（$200.00）, benzhexol ($6.40) and amantadine treatment for people with PD. ($8.17). We do not recommend selegiline included to the WHO EML. Attachment 4: Comparison of Application and Evaluation for anti-parkinsonism medicines: Trihexyphenidyl

Items Data of Application Data of Evaluation 1.Included Studies No. of IS No. of IP Additional Total No. of IS No. of IP No. of IS No. of IP Efficacy SR/meta analysis - - 1 67 1 67 RCT - - 2 67 2 67 CCT - - 11 14 11 14 Case series - - 5 116 5 116 Case report - - 1 1 1 1 Safety - - 19 19 19 19 Applicability - - 5 - 5 - Economical Evaluation - - 0 0 0 0 2.Outcomes of Evaluation Efficacy Mortality - - Symptom control - Neural function improved Idem

Safety Nervous system - √ Seven mental anomaly cases report √ Idem

Motor system - √ One myasthenia gravis case report √ Idem Digestive system - - - Respiratory system - - - Circulatory system - - - Urinary system - - - Reproductive system - - - Endocrine system - - - Others - √ Four toxicosis, two drug dependence, √ Idem one blindness*, one dysphonia plicae ventricularis, one fever, one spider angiomas cases report

Applicability Replace biperiden for PD Young PD patients with tremor

Economical Evaluation 263 USD per year 6.5 USD per year in China

3.Quality of Evidence D C

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4.Recommendation Replace biperiden for PD. Not recommended as first-choice option for PD.

Attachment 5: Comparison of Application and Evaluation for anti-parkinsonism medicines: Amantadine Items Data of Application Data of Evaluation 1.Included Studies No. of IS No. of IP Additional Total No. of IS No. of IP No. of IS No. of IP Efficacy SR/meta analysis 1 215 2 547 3 762 RCT - - 12 212 12 212 cross-over study - - 12 343 12 343 CCT 1 40 4 175 5 215 Case series - - 17 1187 17 1187 Case report - - 6 6 6 6 Safety 1 38 43 173 43 179 Applicability 1 - 1 - 2 - Economical Evaluation - - 2 - 2 -

2.Outcomes of Evaluation Efficacy Mortality - - - Symptom control amantadine reduces dyskinesia in amantadine is effective for dyskinesias in Idem Parkinson’s disease Parkinson’s disease

Safety Nervous system √ visual hallucinations,insomnia √ 53.23%,N=14 eg:visual Idem hallucination,tircdncss,giddiness,headache， insomnia,depression Motor system - √ 1.61%，N=4 eg:myoclonus Idem Digestive system - √ 35.48% eg:Dryness of mouth,constipation Idem

Respiratory system - - - Circulatory system - √ N=3,eg:Circulatory disorders Idem Urinary system - √ 1.61%,eg:Frequency Micturition Idem Reproductive system - - - Endocrine system - - - Others - √ 18.99% N=14 eg: livedo reticularis,corneal edema Idem 9

Applicability for dyskinesia in PD for dyskinesia in PD Economical Evaluation 26.32 USD per year 8.17 USD per year 3.Quality of Evidence C C 4.Recommendation for dyskinesia in PD for dyskinesia in PD

Abbreviations：SR:systematic review, RCT:randomized controlled trial, CCT:controlled , IS:included studies, IP:included patients, PLB:placebo, PD:Parkinson's disease, PPX:pramixezole, BR:bromocriptine, √:reported, *:serious adverse reaction, ‐:no reports found

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