115© SEEd Tutti i diritti riservatiFarmeconomia e percorsi terapeutici 2008; 9(2) Synthetic DRUG PROFiLe Rotigotine patches (neupro) in early Parkinson’s disease Edited by AdRes Health Economics & Outcomes Research intRODUctiOn Parkinson’s disease (PD) is a neurodegenerative disorder secondary to the progressive loss of dopaminergic neurons in the substantia nigra (a portion of the midbrain responsible for movement initiation and coordination) and appearance of bradykinesia, resting tremor, ri- gidity and postural reflex impairment. The most common symptomatic therapy is levodopa, a dopamine precursor; however, long-term treatment leads to involuntary movements and response fluctuations which add to the complexities of later disease-management. Mo- notherapy with dopamine agonists may represent an alternative approach with a reduced likelihood of motor complications; these drugs, initially introduced as adjunctive therapy to levodopa, are less effective in controlling motor disability and tend to cause more side effects than levodopa itself. inDicatiOnS anD DOSinG Rotigotine is a new chemical substance belonging to the group of non-ergolinic dopamine agonists. This drug is used for the treatment of early-stage Parkinson disease as monotherapy, or with levodopa at all stages of the disease. The drug is available in transdermal patches of several sizes, containing different doses of rotigotine (Table I). Recently, the Committee for Medicinal Products for Human Use (CHMP) of the EMEA issued a positive opinion on marketing authorization for rotigotine for idiopathic Restless Legs Syndro- me (RLS) treatment. Rotigotine is currently included by AIFA (Agenzia Italiana del Farmaco) in a drug efficacy and safety monitoring program. In early PD, the starting dose is 2mg/24h (4mg/24h for advanced PD), increased every week by 2mg/24h until an effective dose is reached, or up to a maximum dose of 8mg/24h (16mg/24h for advanced PD). Size 10 cm2 20 cm2 30 cm2 40 cm2 Dose contained (mg) 4.5 9.0 13.5 18.0 Dose released (mg) 2 4 6 8 Table I All available presentations for rotigotine transdermal application PhaRmacOkineticS The drug in the patch is constantly and dose-proportionately released over 24-h, resulting in constant plasmatic concentrations with daily application. The absorption of rotigotine is not in- fluenced by gender, age, race, impaired renal or hepatic function. Rotigotine is widely distribu- ted into tissues and extensively metabolized; the drug and its metabolites are mainly excreted in urine and less in bile and stool. Address for correspondence sdp@advancedresearch.it Last revision june 2008 116 © SEEd Tutti i diritti riservati Farmeconomia e percorsi terapeutici 2008; 9(2) Absorption Bioavailability* High variability (1- 64%), mean 37% Cmax 7 ng/ml after 1mg/Kg administration Tmax 15-18 h (1- 27 h) Binding to plasma proteins 90.5-92.7% Metabolism and distribution Volume of distribution 84 l/kg Metabolism Dealkyilation/ monoidroxilation, conjugation with glucuronic or sulphate acid Enzimes CYP450: CYP2C19 Several sulphotransferases and UDP-glucorosyltransferases Biological activity of metabolites Not present Elimination Clearance 630 l/h Plasma terminal half-life 5-7 h Elimination 71% urine, 23% bile and faeces Interactions No interactions Table II Absorption, distribution, metabolism and elimination of rotigotine after transdermal administration FaRmacODynamicS Rotigotine acts like a typical dopamine-agonist: this drug shows a close structural and func- tional analogy to dopamine, with a similar receptor binding and functional profile. Rotigotine is an agonist at all dopamine receptors, showing highest affinity and activity via the D3 receptor (the most widely cited receptor in the inhibition of locomotor activity). eFFicacy anD SaFety The clinical development program for the rotigotine patch comprised four main studies (Phase III trials ): SP512 and SP513 to evaluate rotigotine efficacy in monotherapy in early-stage idiopathic PD; SP650 and SP515 to evaluate rotigotine efficacy in combination with levodopa in advanced idiopathic PD. SP512 and SP650 trials were placebo-controlled, whereas SP513 and SP515 were controlled against another dopamine agonist (ropinirole and pramipexole, respectively). The primary efficacy end-point for monotherapy trials was based upon the UPDRS II/III score (Unified Parkinson’s disease rating scale, a compilation of various PD assessment scales, the most frequently used for evaluating treatment responses), whereas for the evaluation of rotigotine in combination with levodopa the primary variable was the change in absolute time spent “off” (time during which PD symptoms are most prominent). The safety profile of rotigotine can be considered typical of a dopamine-agonistic agent, with adverse reactions (AEs) like nausea, somnolence, vomiting, fatigue and constipation; the only exception is the high frequency of skin reactions in the application site. An increased frequency of AEs was observed in adjuvant therapy with levodopa, as compared to monotherapy. Study Design Comparator Efficacy Safety Monotherapy SP512 277 pts with early PD randomized 1:1 Double-blind, multi center, placebo-controlled Placebo 20% Improvement P: 19% pts Rt: 48% pts (p < 0.0001) Change in UPDRS II/III* score P: 1.31 Rt: -3.98 (p < 0.0001) AEs ≥ 5% subjects: P: 57% pz Rt: 76% pz Rp: 70% pz AEs typical of a dopamine agonist, with an higher frequency of skin reaction in the application site (P = 14%, Rt = 37%, Rp = 8%) SP513 561 pts with early PD randomized 1:1:1 Double-blind, multi center, placebo-controlled, active treatment Placebo, ropinirole 20% Improvement P: 30% pts Rt: 52% pts (p < 0.0001) Rp: 70% pts (p < 0.0001) Change in UPDRS II/III* score P: - 2.33 Rt: -6.83 Rp: -10.78 Not showed non-inferiority to Rp Continued next page > 117© SEEd Tutti i diritti riservatiFarmeconomia e percorsi terapeutici 2008; 9(2) Study Design Comparator Efficacy Safety Adjoint to levodopa SP650 351 pts with advanced PD (≥ 2.5 h “OFF”/day) non adequately controlled by levodopa, randomized 1:1:1 Double-blind, placebo- controlled Placebo Reduction in “off” time ≥ 30% P: 34.5% Rt 18mg: 56.6% (p < 0.001) Rt 27mg: 55.1% (p < 0.001) Change in “off” time (hrs) P: 0.9 Rt 18mg: 2.7 (p < 0.001) Rt 27mg: 2.1 (p = 0.003) AEs ≥ 5% subjects: P: 62.6% pz Rt: 73.0% pz Rp: 70.3 % pz AEs typical of a dopamine agonist, with an higher frequency of skin reaction in the application site (P: 20.1%, Rt: 39.9%, Pr: 11.9%) SP515 506 pts with advanced PD (≥ 2.5 h “OFF”/day) non adequately controlled by levodopa, randomized 2:2:1 Double-blind, placebo- controlled. Placebo, pramipexole Reduction in “off” time ≥ 30% Pr: 35% Rt: 59.7% (p < 0.001) P: 67% (p < 0.001) Change in “off” time (hrs) P: 0.88 Rt: 2.46 (p < 0.0001) Pr: 2.81 (p < 0.0001) Showed non-inferiority to Pr Table III Summary of main studies investigating efficacy and safety of rotigotine monotherapy for early PD (SP512, versus placebo; SP513, versus placebo and ropinirole) or for advanced PD, in combination with levodopa (SP650, versus placebo; SP515, versus placebo and pramipexole) * UPDRS score (Unified Parkinson’s disease rating scale) in part II (daily activities) and III (motor evaluations) of questionnaire is the primary efficacy end-point for monotherapy trials; maximum score is 160 (52 + 108) points (worst scenario) and the absence of disease signs is associated with a 0 score AEs = adverse events ; P = placebo; Pr = pramipexole; Rp = ropinirole; Rt = rotigotine ecOnOmic evaLUatiOnS We were not able to retrieve any published economic evaluation on the use of rotigotine in Parkinson disease. In table IV we calculated monthly pharmaceutical costs for available therapies for PD treatment. For each formulation we valorized minimum and maximum dosing (from the Summary Product Characteristics - SPCs) and DDD (Defined Daily Dose) for one month of therapy, using retail price. For packages with identical price we considered the less costly one. This is not to be intended as a cost-minimization analysis, but as a simple overlook of currently available treatments. Drug and dosing range Reimbursed price / package Price of therapy (1 month) Category Active principle (DDD) < > DDD Anticholinergics biperidene (10 mg ) 2 mg 4.29 3.2175 21.45 10.725 4 mg 5.33 3.198 9.594 7.995 5 mg 2.94 35.28 70.56 35.28 Antihistaminics orfenadrine (200 mg) 50 mg 2.12 2.544 10.176 5.088 Levodopa and derivates levodopa + benserazide (600 mg) 100+25 mg 4.71 - - 28.26 200+50 mg 16.84 - - 30.312 s.r. 100+25 mg 5.56 - - 33.36 levodopa + carbidopa (600 mg) 100+25 mg 4.98 8.964 23.904 17.928 250+25 mg 6.68 2.004 32.064 9.6192 s.r. 100+25 mg 8.12 9.744 43.848 29.232 s.r. 200+50 mg 9.93 19.86 79.44 29.79 m.r. 100+25 mg 9.21 11.052 44.208 33.156 m.r. 200+50 mg 11.01 22.02 33.03 33.03 melevodopa + carbidopa (600 mg) 100 mg 9.12 27.36 54.72 54.72 125 mg 9.12 9.12 54.72 43.776 250 mg 9.12 9.12 54.72 21.888 Continued next page > 118 © SEEd Tutti i diritti riservati Farmeconomia e percorsi terapeutici 2008; 9(2) Drug and dosing range Reimbursed price / package Price of therapy (1 month) Category Active principle (DDD) < > DDD Admantane derivates amantadine (200 mg)* 100 mg 7.1 10.65 21.3 21.3 Dopamine agonists non ergot derived apomorphine 30 mg 21.67 65.01 650.1 - 50 mg** 39.402268 118.2 472.8 - rotigotine (6 mg) 2 mg 96.04 102.9 102.9 308.7 4 mg 100.36 107.5286 107.5286 161.2929 6 mg 130.47 139.7893 139.7893 139.7893 8 mg 160.56 172.0286 172.0286 129.0214 ropinirole (6 mg) 0.25 mg 4.75 40.71429 244.2857 162.8571 0.5 mg 8.68 37.2 223.2 148.8 1 mg 10.44 22.37143 134.2286 89.48571 2 mg 20.82 29.74286 118.9714 89.22857 5 mg 44.04 31.45714 125.8286 75.49714 pramipexole (2.5 mg) 0.25 mg 16.52 33.04 297.36 165.2 1 mg 65.16 65.16 293.22 162.9 Dopamine agonists ergot derived cabergoline (3 mg) 1 mg 19.16 28.74 172.44 86.22 2 mg 38.02 28.515 171.09 85.545 bromocriptine (40 mg) 5 mg 11.53 11.53 46.12 92.24 10 mg 14.66 10.995 43.98 87.96 pergolide (3 mg) 0.05 mg 8.63 8.63 172.6 517.8 0.25 mg 16.48 12.36 247.2 148.32 1 mg 18.2 27.3 136.5 81.9 dihydroergocryptine (60 mg)* 20 mg 34.88 26.16 313.92 156.96 MAO B inhibitors selegiline (5 mg)* 1.25 mg 40.56 40.56 40.56 162.24 5 mg 17.04 10.224 20.448 10.224 10 mg 18.36 11.016 22.032 11.016 rasagiline (1 mg) 1 mg 135.55 145.2321 145.2321 145.2321 Other dopaminergic substances tolcapone (450 mg) 100 mg 165.33 148.797 297.594 223.1955 entacapone (1 g) 200 mg 116.02 34.806 348.06 174.03 Table IV Monthly pharmaceutical costs for different available therapies for PD treatment (Informatore Farmaceutico 2008) * Not in the Italian reimbursement list; **Ex-factory price PRODUct OveRvieW name of the medicinal Product Neupro marketing authorisation holder SCHWARZ PHARMA Ltd active Substance Rotigotine Pharmaco-therapeutic Group Dopamine agonist atc code N04BC09 Date of issue of marketing authorisation valid throughout the european Union 15 February 2006 119© SEEd Tutti i diritti riservatiFarmeconomia e percorsi terapeutici 2008; 9(2) ReFeRenceS AIFA – Agenzia Italiana del Farmaco – Elenco dei farmaci sottoposti a monitoraggio intensivo avail- able on http://www.agenziafarmaco.it/REGISTRAZIONE_FARMACO/sectionb998.html?target=&area_ tematica=REGISTRAZIONE_FARMACO§ion_code=AIFA_FARMACOV_MONIT_INT&cache_session=false DeRuiter J, Holston PL, DeRuiter AP. New Drug Review. PharmD US Pharm 2007; 32: 26-38 Giladi N, Boroojerdi B, Korczyn AD, Burn DJ, Clarke CE, Schapira AH; SP513 investigators. Rotigotine transdermal patch in early Parkinson’s disease: a randomized, double-blind, controlled study versus placebo and ropinirole. Mov Disord 2007; 22: 2398-404 Hughes G, Burn D. Diagnosis and management of Parkinson’s disease. Prescribe 2006 Informatore Farmaceutico 2008, Ed. Elsevier Masson, updated to May, 2008 Jankovic J, Watts RL, Martin W, Boroojerdi B. SP 512 Study Group. Transdermal rotigotine: double-blind, pla- cebo-controlled trial in Parkinson disease. Arch Neurol 2007; 64: 676-82 LeWitt PA, Lyons KE, Pahwa R; SP 650 Study Group. Advanced Parkinson disease treated with rotigotine trans- dermal system: PREFER Study. Neurology 2007; 68: 1262-7 NEUPRO – EPAR summary for the public Neupro Scientific Discussion – European Medicines Agency (EMEA), 2006 available on http://www.emea. europa.eu/humandocs/PDFs/EPAR/neupro/062606en6.pdf Neupro Scientific Discussion – European Medicines Agency (EMEA), 2007 available on http://www.emea. europa.eu/humandocs/PDFs/EPAR/neupro/Neupro-H-626-II-03-AR.pdf Poewe WH, Rascol O, Quinn N, Tolosa E, Oertel WH, Martignoni E, et al.; SP 515 Investigators. Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson’s disease: a double-blind, double-dummy, ran- domised controlled trial. Lancet Neurol 2007; 6: 513-20 Post-authorisation summary of positive opinion for Neupro – Committee for Medicinal Products for Human Use (CHMP) – European Medicines Agency (EMEA), 2008 available on http://www.emea.europa.eu/pdfs/human/ opinion/Neupro_17478808en.pdf - - - - - - - - - - - -