Issues in Emerging Health Technologies

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1 Issues in Emerging Health Technologies Issue 12 Dec 2000 Entacapone: Adjunctive Use in Patients with Advanced Parkinson s Disease Summary Based on current evidence, entacapone provides clinically important improvement in function for patients with Parkinson s disease (PD) suffering from symptoms of motor fluctuations. Long-term efficacy data beyond 6-month follow-up are not currently available. Entacapone was generally well tolerated in clinical trials. Most adverse events are mild and do not lead to discontinuation of treatment. The impact of entacapone on disease progression is unclear. There is no evidence to consider adjunctive therapy with entacapone at the onset of levodopa therapy. 1 The ability of entacapone to delay the onset of motor fluctuations in PD patients not currently experiencing these fluctuations, requires further study. The Technology Entacapone is manufactured by Orion Corporation, Orion Pharma (Espoo, Finland) and marketed in North America under the trade name Comtan, by Novartis Pharmaceuticals Corporation (East Hanover, N.J , USA). The clinical symptoms of Parkinson s disease are caused by the death of cells that produce dopamine in the midbrain. The cause of this cell death is unknown and it results in a reduction and deficiency of dopamine. Dopamine is used by nerves to transmit impulses. Levodopa, which is metabolized to dopamine, is the mainstay treatment for parkinsonian symptoms. Levodopa is predominantly metabolized by the enzymes dopa decarboxylase (DDC) to dopamine and by catechol-omethyltransferase (COMT) to 3-0-methyldopa (3-OMD). 2 Entacapone is in the drug class called nitrocatechols, which are selective and reversible inhibitors of COMT. Entacapone, which is to be taken with levodopa and a DDC inhibitor, inhibits COMT in peripheral tissues resulting in an increase in the bioavailability of circulating levodopa without increasing the peak concentration or absorption of levodopa. 3 The resultant increased and more sustained levels of levodopa are theorized to produce more consistent dopaminergic stimulation and therefore decrease motor complications associated with peak levodopa concentrations. Entacapone taken alone has no effect on parkinsonian symptoms. 4 Regulatory Status Comtan was licensed in the European Union in September and approved for use in the United States (FDA) on October 19, It is to be used with levodopa and a DDC inhibitor in the treatment of patients with idiopathic

2 Parkinson s disease who experience motor fluctuations. As of October 2000, entacapone has not been approved for use in Canada. Patient Group Parkinson s disease (PD) is a chronic neurodegenerative disorder characterized clinically the by onset of bradykinesia (slowness of movement), rigidity, and resting tremor. 5 The presence of two of these symptoms is usually used to make the diagnosis. Clinical symptoms only become apparent once 70-80% of the dopaminergic neurons have died. 5 PD accounts for approximately 2.6% of all neurological diagnoses. 6 The annual incidence is estimated to be approximately 20.5/100,000 while the prevalence is approximately 300/100, The prevalence increases with age (few patients under 45 years have Parkinson s, while up to 2% of those older than 85 years have the disease). 8 The mean age at onset in Canada is estimated at 52 years. 9 In later stages of PD progression many patients suffer from increased disability due to levodopa-related motor fluctuations. 8,10-12 These include dyskinesias (involuntary movements), end-of-dose or wearing-off effect and the on-off effect. Wearing-off occurs when the therapeutic effect starts to decline prior to the timing of the next dose. 11 On-off effect refers to the sudden and usually unpredictable shift between mobile and immobile states and occurs with no relation to the timing of medication 13 or plasma levodopa concentrations. Current Treatments At this time, treatment for PD is limited to controlling the symptoms rather than preventing further neuronal degeneration. Various drugs are used, alone or in combination, to treat Parkinson s. These include dopaminergic agents (dopamine agonists, amantadine), levodopa combined with a DDC inhibitor, the monoamine oxidase type B inhibitor selegiline, and anticholinergic agents. 14 When treating patients with advanced PD a balance is sought between increasing on time (time with symptom improvement) while avoiding dyskinesias. Later stage disease is invariably treated with levodopa therapy combined with a peripherally acting DDC inhibitor such as benserazide or carbidopa. 10,11,15,16 This combination increases the percent of the oral dose of levodopa reaching the brain from about 1% to 5-10%. 1,17,18 The effectiveness of levodopa treatment diminishes over time. About 75% of patients develop motor fluctuation complications after approximately six years of therapy. 10 Wearingoff fluctuations are associated with low plasma levels of levodopa, whereas dyskinesias are usually linked with higher plasma levels. 19 Possibly more troublesome and more difficult to deal with are the on-off effects, due to their sudden and unpredictable nature. To reduce fluctuations in response to levodopa, currently available treatment options include adjustment of levodopa dose regime, use of controlled-release levodopa, use of concurrent dopamine agonists, and, where available, concurrent use of a COMT inhibitor. 11 Combination therapy with other antiparkinsonian agents (selegilene, amantadine, and anticholinergic agents) are substantially less effective than the above mentioned strategies. 11 Surgical options exist for patients with disabling motor fluctuations who do not respond to medical therapy. Adjustments of levodopa dose regime or use of controlled-release levodopa are not usually sufficient to provide relief from troublesome on-off motor fluctuations 11 thus necessitating the addition of another agent. The necessity of dose titration for dopamine agonists may confer some advantage to the use of entacapone when additive treatment is considered. 20 Dopamine agonists improve end-of-dose wearing off but are thought to be less effective in eliminating the on-off fluctuations and may cause psychotic disturbances. 21

3 Dosage and Potential Cost The recommended dosage of entacapone is one 200 mg tablet taken orally, without regard to meals, with each levodopa/ddc dose. 22 It can be administered with standard or extendedrelease preparations of levodopa/ddc inhibitor. In the U.S. the wholesale price of Comtan is $1.68/200 mg tablet. 23 The number of tablets taken per day is dependent upon the number of concurrent levodopa tablets (combined with a DDC inhibitor). The maximum daily dose is 8x200 mg. 22 The average dose frequency in one trial was 5.8 times a day. 24 This translates into US$9.75/day, or about C$14.50/day: about 1.5 times more expensive than the most costly dopamine agonist (pergolide). 25 Generic versions of levodopa (250 mg)/ carbidopa (25 mg)(apo-levocarb) cost about $0.38 per tablet. 25 This combination, including Comtan, would result in a per day drug cost of about $ Using Sinemet, or Sinemet CR in place of generic formulations doubles the cost of the levodopa/carbidopa. 25 Some small savings will occur with the reduction of levodopa dose. Improved and consistent motor function should enhance the quality of life of an individual with PD, and may lead to cost savings in other resource uses. Projected Rate of Diffusion Currently about 1/100 Canadians over the age of 60 is diagnosed with PD. There is no cure. Given that many PD patients are living into their eighties 26 the number of patients experiencing disabling motor fluctuations is likely to increase. Entacapone will provide an additional way to manage late stage motor fluctuations associated with levodopa therapy. This will be of greatest benefit for patients whose symptoms are not optimally controlled with existing therapies. A PD consensus group examined the use of entacapone, from approval in the United Kingdom in September 1998 to March 1999, and found worldwide use by approximately 20,000 patients per year. 1 Tolcapone (Tasmar ), the first COMT inhibitor marketed in many countries (approved in Canada, October 1997), 27 has been taken off the market in both Europe and Canada (November 1998), due to reports of several deaths from fatal fulminant hepatitis. 2,28 Although there have been no such reports with entacapone, concern may limit uptake of therapy with any COMT inhibitor. Concurrent Developments New drugs are being designed to work within neurons while others are being designed to slow neuronal death. Work on non-drug interventions includes research into neurotrophic growth factors as a means of neuroprotection, gene transfer 29 and surgical management. Three surgical approaches which have been used in a limited number of patients are ablative surgery (pallidotomy or thalmotomy), deep brain stimulation, and cell transplant. 5 Spheramine (Titan), made from cultured dopamine-producing human retinal-pigmented epithelial cells to be implanted into the brains of PD patients, is undergoing phase I/II trials. 30 Animal studies of Spheramine have shown promising results. 31 Assessing the Evidence Five phase III randomized controlled trials evaluating entacapone have been fully published 19,24,32-34 while two phase III trials are available in abstract form. 35,36 All of these trials reported, as an outcome, duration of effect or mean on time, often measured through the use of home diaries. Several secondary outcomes were also gathered in these studies, including impact on the Unified Parkinson Disease Rating Scale (UPDRS: a rating tool to follow the longitudinal course of Parkinson s disease) and global evaluation, as well as adverse events. The two largest published studies 19,24 and the abstracts were similar in design, evaluating entacapone over six months. The remaining studies were smaller and of

4 shorter duration. One study 32 compared entacapone plus standard levodopa (Sinemet ) with entacapone plus controlled-release levodopa (Sinemet CR). Entacapone was given as a 200 mg dose with each dose of levodopa. All studies consistently reported: A statistically significant improvement in on time. Mean baseline on time, as reported in one study, 24 was reported as 9.2 hours. The duration of the improvement ranged from an additional 0.5 hours 32 to 2.1 hours. 33 The study comparing entacapone with standard or controlled-release levodopa found greater improvement with the controlled-release levodopa regime (0.5hrs vs. 0.8hrs). 32 Patients experiencing lower baseline on time were seen to derive greater benefit. 19 An improvement based on the UPDRS rating scale. The improvement was noted predominantly with subscales II (activities of daily living) and III (motor function), but was also seen in total scores. Again, the controlled-release levodopa regime showed greater improvement than the standard preparation. 32 A decrease required in levodopa dosing, ranging from 12% 19 to 50%. 24 The decrease in levodopa dosing was required due to increased dopaminergic effects which lead to increased dyskinesias (a regularly reported adverse event attributed to levodopa). 24 Adverse Effects Worsening of dyskinesias (both duration and magnitude), nausea, diarrhea, and urine discoloration occurred more often in patients treated with entacapone. 24,35,37-39 Although nausea and diarrhea were experienced more frequently in the entacapone treated patients, few patients withdrew from trials for these reasons (2-5%). 24,37 Patients on entacapone also complained of shortness of breath (8%), ataxia (7%), forgetfulness, vomiting and somnolence (4%) significantly more often than those taking placebo (p = 0.03). 19 The increase in dyskinesias is not surprising as this is a side effect of levodopa therapy. The dyskinesias tended to occur early in treatment and were usually managed by reducing the dose of levodopa. 24 Implementation Issues The studies cited above have demonstrated that entacapone enhances therapeutic response to levodopa by increasing on time. However a number of concerns and questions exist. How truly blind were the patients to the medications in the trials? The subjectivity (home diaries) of the assessment of the primary outcome ( on time) and the fact that almost 37% of patients in one study noted urine discoloration 19 may have led to exaggerated effects. To the credit of the investigators they evaluated whether patients knew what drug (entacapone or placebo) they were taking. Although a high proportion of patients guessed their treatment assignment correctly, the majority reported improvement in symptoms, or lack thereof, as the reason for their guess. It is unclear if the investigators became unblinded, which could have biased their global evaluation. For what period of time will the patient benefit from the drug? The currently available efficacy data covers only a 6-month follow-up period. Although no cases of hepatic failure have been noted with entacapone, none were noted during clinical trials with tolcapone either (see Projected Rate of Diffusion ).

5 1. Brooks DJ, Forsyth D, Playfer JR, Williams AC. The role of entacapone in the management of Parkinson s disease. Hosp Med 2000;61(4): Rivest J, Barclay CL, Suchowersky O. COMT inhibitors in Parkinson s disease. Can J Neurol Sci 1999;26 Suppl 2:S34-S Holm KJ, Spencer CM. Entacapone. A review of its use in Parkinson s disease. Drugs 1999;58(1): Ahlskog JE. Treatment of motor complications in advancing Parkinson s disease: which drugs and when? Formulary 2000;35: Schapira AH. Science, medicine, and the future: Parkinson s disease. BMJ 1999;318(7179): Available: 318/7179/ Rajput AH, Uitti RJ, Stern W, Laverty W. Early onset Parkinson s disease in Saskatchewan environmental considerations for etiology. Can J Neurol Sci 1986;13(4): Rajput AH. Frequency and cause of Parkinson s disease. Can J Neurol Sci 1992;19(1 Suppl): Ben-Shlomo Y, Sieradzan K. Idiopathic Parkinson s disease: epidemiology, diagnosis and management. Br J Gen Pract 1995;45(394): Svenson LW, Platt GH, Woodhead SE. Geographic variations in the prevalence rates of Parkinson s disease in Alberta. Can J Neurol Sci 1993;20(4): Lambert D, Waters CH. Comparative tolerability of the newer generation antiparkinsonian agents. Drugs Aging 2000;16(1): Ahlskog JE. Medical treatment of laterstage motor problems of Parkinson disease. Mayo Clin Proc 1999;74(12): Flaherty JF, Gidal BE. Parkinson s disease: chapter 51. In: Young LY, Koda-Kimble MA, editors. Applied therapeutics: the clinical use of drugs. Vancouver (WA): Applied Therapeutics; p Lang AE, Lozano AM. Parkinson s disease. Second of two parts. N Engl J Med 1998;339(16): Drug Therapies for Parkinson s Disease. Informed 1998;4(4):7-8. Available: (accessed 6 Sept 2000). 15. Evidente VGH, Adler CH. Pharmacologic options for managing Parkinson s disease. Formulary 1997;32: Hughes AJ. Achievements and future possibilities in the drug treatment of Parkinson s disease. In: Palmer KJ, editor. Drug treatment issues in Parkinson s disease. Auckland (NZ): Adis International; p Martínez-Martín P, O Brien CF. Extending levodopa action: COMT inhibition. Neurology 1998;50(6 Suppl 6):S27-S Comtess: entacapone: a COMT inhibitor for treatment of Parkinson s disease. Chester, England: Adis International; Entacapone improves motor fluctuations in levodopa-treated Parkinson s disease patients. Parkinson Study Group. Ann Neurol 1997;42(5): Davis TL. Catechol-O-methyltransferase inhibitors in Parkinson s disease: guidelines for effective use. In: Palmer KJ, editor. Drug treatment issues in Parkinson s disease. Auckland (NZ): Adis International; p Agid Y, Destee A, Durif F, Montastruc JL, Pollak P. Tolcapone, bromocriptine, and Parkinson s disease. French Tolcapone Study Group [letter]. Lancet 1997;

6 22. New drug overview: entacapone. Am J Health Syst Pharm 2000;57(15): Entacapone for Parkinson s disease. Med Lett Drugs Ther 2000;42(1070): Rinne UK, Larsen JP, Siden Å, Worm- Petersen J. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Nomecomt Study Group. Neurology 1998;51(5): Pharmaceuticals: November 1 to November 30, 2000 [catalog]. Concord (ON): Kohl & Frisch Limited; Speaking Notes for Allan Rock, Minister of Health at the XIII International Congress on Parkinson s Disease, Vancouver, BC, July 26, Ottawa: Health Canada; Available: speeches/26july99mine.htm (accessed 6 Sept 2000). 27. Therapeutic Products Programme, Health Canada. Notices of Compliance (NOC): Drugs [database online]. Available: htmleng/noc_drugs.html (accessed 5 Oct 2000). 28. Robertson S. Tolcapone (Tasmar ). Can Adverse Drug React Newsl 1999;9(2):7. Available: n2_e.html (accessed 4 Oct 2000). 29. Phillips P. Several classes of new drugs emerging for Parkinson disease. JAMA 1999;282(10): Available: ffull/jmn html (accessed 3 Oct 2000). 30. Spheramine: Titan s novel treatment for Parkinson s disease. South San Francisco (CA): Titan Pharmaceuticals; Available: spheramine.htm (accessed 15 Sept 2000). 31. Portyansky E. Promising research brings hope to Parkinson s patients. Drug Topics 1999;143:40. Available: journals/d/data/1999/1018/d1parkinsons 10b.html (accessed 14 Sept 2000) 32. Piccini P, Brooks DJ, Korpela K, Pavese N, Karlsson M, Gordin A. The catechol-omethyltransferase (COMT) inhibitor entacapone enhances the pharmacokinetic and clinical response to Sinemet CR in Parkinson s disease. J Neurol Neurosurg Psychiatry 2000;68(5): Ruottinen HM, Rinne UK. Entacapone prolongs levodopa response in a one month double blind study in parkinsonian patients with levodopa related fluctuations. J Neurol Neurosurg Psychiatry 1996;60(1): Merello M, Lees AJ, Webster R, Bovingdon M, Gordin A. Effect of entacapone, a peripherally acting catechol- O-methyltransferase inhibitor, on the motor response to acute treatment with levodopa in patients with Parkinson s disease. J Neurol Neurosurg Psychiatry 1994;57(2): Poewe W, Deuschl G, Celomen Study Group. The effect of entacapone in patients with Parkinson s disease (PD): an Austrian-German long-term multicentre study (Celomen Study) [abstract]. Eur J Neurol 1999;6 Suppl 3: Sagar H, Brooks D. The UK-Irish doubleblind study of entacapone in Parkinson s disease. UK-Irish Entacapone Study Group [abstract]. Mov Disord 2000;15 Suppl 3: Myllylä VV, Filomen Study Group. Longterm safety of entacapone as an adjunct to levodopa in non-fluctuating and fluctuating patients with Parkinson s disease [abstract]. Mov Disord 1998;13(Suppl 2):294.

7 38. Ruottinen HM, Rinne UK. A double-blind pharmacokinetic and clinical dose-response study of entacapone as an adjuvant to levodopa therapy in advanced Parkinson s disease. Clin Neuropharmacol 1996;19(4): Ruottinen HM, Rinne UK. Effect of one month s treatment with peripherally acting catechol-o-methyltransferase inhibitor, entacapone, on pharmacokinetics and motor response to levodopa in advanced parkinsonian patients. Clin Neuropharmacol 1996;19(3): This brief was prepared by Ms. Laura McAuley; CCOHTA and has been peer reviewed. The contents of this early assessment are current as of publication date, however new information is anticipated. Obtain further copies from CCOHTA by ; pubs@ccohta.ca or from the Publications section of our web site; ISSN Publications Agreement Number