Drugs for Parkinson s Disease

This Clinical Resource gives subscribers additional insight related to the Recommendations published in July 2017 ~ Resource #330705 Drugs for Parkinson s Disease Parkinson s disease is characterized by tremor, rigidity, and bradykinesia. 1,2 Initial treatments often include low-dose carbidopa/levodopa or a dopamine agonist. 1 Eventually, efficacy wanes because Parkinson s is a progressive disease. Suboptimal control can be managed by increasing the dose of the dopamine agonist or levodopa, but this approach increases the chance of dopamine agonist side effects (e.g., neuropsychiatric side effects, sedation, sleep attacks). 5 It can also cause or worsen dopamine-associated dyskinesias. 5,6 So most clinicians prefer to use a combination of agents rather than increase the dose of a single agent after the initial honeymoon. 5 This period of good control lasts about five years with levodopa, after which motor fluctuations (e.g., wearing off, on-off phenomenon) and dyskinesias develop. 5,6 The chart below outlines the place in therapy of common meds used to treat Parkinson s motor symptoms. Tips for managing motor symptoms in more advanced disease and other therapeutic pearls are also included. Tapering is covered in footnote a. Parkinson s Dementia and Dementia with Lewy Bodies is covered in a separate chart. Drug or Drug Class Role in Therapy Comments Levodopa-carbidopa (Sinemet, generics; Sinemet CR, generics; Rytary [U.S.]; Parcopa [U.S.; generics only, brand not available]; Duopa [U.S.]; Duodopa [Canada]) Most effective drug for Parkinson s symptoms. 1 Can be used first-line, especially in older patients (e.g., over 70 years). 1,7 Levodopa-benserazide (Prolopa [Canada]) Levodopa-carbidopaentacapone (Stalevo, generics [U.S.]) Note: Rytary is not interchangeable with other carbidopalevodopa products. See product labeling or www.rytary.com for dosing conversion. Long-term use associated with dyskinesias and motor fluctuations (on-off, wearing off). 1,5 Other side effects include nausea (take with food), loss of appetite, orthostasis (use lowest dose necessary, stop alpha antagonists), confusion (reduce or stop anticholinergics or sedating meds), hallucinations (reduce dose), constipation, dry mouth, headache. 5,7 Either an immediate- or controlled-release product can be used for initial therapy. 1 Oral disintegrating tablets (U.S. only) are an option for patients with difficulty swallowing. For suboptimal therapeutic response, consider dose increase (not preferred) or addition of dopamine agonist. 5 But this may worsen any preexisting dyskinesia. 18 For peak dose dyskinesias, consider levodopa dose reduction +/- add or increase dopamine agonist, or add amantadine. 2,5,6 Controlled-release levodopa-carbidopa does not reduce off time better than immediaterelease. 2 However, Rytary (U.S.), which provides quicker onset and more stable levels than controlled-release and a longer duration than immediate-release, reduces off time by about 1 hr/day compared to immediate-release. 16,17,19 Only preliminary evidence is available comparing Rytary with controlled-release levodopa-carbidopa. 17 Rytary costs ~$700/month compared to $200/month for generic products. Other options to reduce off time include the addition of MAO-B inhibitor, dopamine agonist, or COMT inhibitor. 2,9 May require levodopa-carbidopa dose reduction. 2 End of dose wearing off can also be addressed by increasing the dose or giving the dose before the effect of the previous dose wears off. Poses higher risk of dyskinesias. 5

(Clinical Resource #330705: Page 2 of 6) Drug or Drug Class Role in Therapy Comments Dopamine agonist (pramipexole [Mirapex, generics; Mirapex ER, (U.S.), generics], ropinirole [Requip, generics; Requip XL (U.S.)], generics; rotigotine [Neupro]) Monoamine oxidase type B (MAO-B) inhibitors (selegiline [generic tablets; Eldepryl capsules, generics (U.S.); Zelapar (U.S.)]; rasagiline [Azilect], generics; safinamide [Xadago; U.S.]) Not as effective as levodopa-carbidopa for Parkinson s symptoms. 1 Can be used first-line, especially in younger patients (less than 50 years). 1,7 Can be added to levodopa to reduce off time, improve symptoms, or manage dyskinesias due to levodopa-carbidopa. 2,5,6 Mild to moderate benefit. 1,4 Can be used first-line (not safinamide) 1,15 Can be added to levodopa to reduce off time. 2,15 May have antidepressant effects. 1 Insufficient evidence of neuroprotection. 21,22 More expensive than levodopa-carbidopa. 1 Side effects similar to levodopa-carbidopa. 10 Lower risk of dyskinesias, wearing off, and on-off fluctuations than levodopa-carbidopa. 1 Higher risk of hallucinations, sleepiness, and edema than levodopa-carbidopa. 1 May impair impulse control (e.g., gambling, shopping). Warn patient. Management includes dose reduction or discontinuation. Consider referral. 10,13 May cause excessive daytime sleepiness. Caution patient about driving. May require stimulant or switch to levodopa. 10 In event of confusion, consider switch to levodopa or reduce/stop anticholinergic or sedating medications. 10 Rasagiline and safinamide are better-studied for reducing off time, but no proof they work better than selegiline. 2,15 All increase on time by about one hour more than placebo, similar to entacapone. 2,15 Note that transdermal selegiline (Emsam) has not been studied for Parkinson s disease. It is FDA-approved for depression only. 20 It achieves higher plasma levels than oral. 20 Safinamide is a reversible MAO-B inhibitor; the others are irreversible. The clinical significance of this difference is unknown. Safinamide is also glutamatergic. Animal models suggest this may confer neuroprotection, and post hoc clinical trial analysis suggests it may provide analgesia. 22 May cause hallucinations, or orthostasis, especially selegiline plus levodopa. 2,4,11,15 Other side effects include: nausea and insomnia. 11,15 Selegiline can be particularly activating; give in morning and/or at noon. 5,11 Selegiline and rasagiline may also cause dry mouth, constipation, and vivid dreams. 11 May worsen dyskinesias when used with levodopa or other dopaminergics; consider dose reduction of dopaminergics. 4,15 Many potential drug interactions due to MAO inhibition (e.g., antidepressants [commonly combined, however], tramadol, meperidine, methadone, dextromethorphan, amphetamines, other MAO inhibitors [e.g., linezolid]). 3,11,15 Check product labeling for contraindications, and monitor patients on other combinations (e.g., for agitation, confusion, diarrhea, fever, hallucinations, hypertension, increased heart rate, muscle twitching, tremor, seizure). 3,11

(Clinical Resource #330705: Page 3 of 6) Drug or Drug Class Role in Therapy Comments Catechol-O-methyl transferase (COMT) inhibitor Adjunct to levodopacarbidopa; not for monotherapy. 9 Prolongs the duration of action of levodopa. 9 Combo product with levodopa-carbidopa plus entacapone (Stalevo) available. Decreases pill burden and may cost less than separate Rxs for Comtan plus carbidopa/levodopa. (entacapone [Comtan, Can be added to Addition of COMT inhibitor can increase levodopa-carbidopa side effects, including generics]; tolcapone levodopa to reduce off dyskinesias. Levodopa dose may need to be decreased. 9 [U.S.; Tasmar, time. 2,9 Entacapone can cause orange urine. 9 generics]) Tolcapone requires liver function test monitoring. 9 COMT inhibitors also cause gastrointestinal side effects. 9 Amantadine Mild to modest immediate benefit for most symptoms. 1,8 Can be used as monotherapy, to target tremor, or added to levodopa in later disease for dyskinesias. 2,5,8 Efficacy may wane after weeks or months. 8 Side effects include: cognitive impairment, confusion, insomnia, hallucinations, livedo reticularis (cosmetic problem only). 5,8 Well-tolerated in younger patients. 1,5 Requires renal dose adjustment. 5 Anticholinergics (trihexyphenidyl, benztropine) Initial monotherapy or adjunct, especially if tremor is main symptom and patient is young. 1,12 Risk of cognitive impairment and confusion; use with caution in patients over 60 years of age. 12 Other side effects include: dry mouth, urinary retention, constipation, drowsiness. 12 Apomorphine (Apokyn, generics [U.S.]; Movapo [Canada]) Continued Indicated for acute, intermittent treatment of off episodes in advanced disease. 14,24 Subcutaneous injection. 14,24 Short duration of action. Average frequency of dosing in clinical trials was three times daily. 14,24 Must pre-treat with an antiemetic (trimethobenzamide [U.S. only] recommended) to prevent nausea/vomiting, but not a 5-HT3 antagonist (e.g., ondansetron) due to risk of profound hypotension (contraindication). 14 Per Canadian labeling, can use domperidone with caution

(Clinical Resource #330705: Page 4 of 6) Drug or Drug Class Role in Therapy Comments Apomorphine, continued and careful consideration of its QT prolonging effect. Avoid antidopaminergic drugs (e.g., haloperidol). 24 Other labeled warnings: hypotension, syncope, QT prolongation, cardiac events, hallucinations, psychosis, excessive sleepiness, priapism, dyskinesia, impulse control. 14,24 Other side effects: yawning, runny nose, edema. 14,24 Reduce dose in renal impairment. 14,24 a. Tapering: A syndrome resembling neuroleptic malignant syndrome can occur when antiparkinson drugs are stopped abruptly. A four-week taper has been suggested as a general rule. 23 Safinamide labeling recommends reducing the dose to 50 mg for one week before discontinuation. 15 Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

(Clinical Resource #330705: Page 5 of 6) Project Leader in preparation of this clinical resource (330705): Melanie Cupp, Pharm.D., BCPS References 1. Miyasaki JM, Martin W, Suchowersky O, et al. Practice parameter: initiation of treatment for Parkinson s disease: an evidence-based review: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2002;58:11-7. 2. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidencebased review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:983-95. 3. Clinical Resource, Facts About Serotonin Syndrome. Pharmacist s Letter/Prescriber s Letter. October 2016. 4. Robottom BJ. Efficacy, safety, and patient preference of monoamine oxidase B inhibitors in the treatment of Parkinson s disease. Patient Prefer Adherence 2011;5:57-64. 5. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson s disease (2001): treatment guidelines. Neurology 2001;56(11 Suppl 5):S1-88. 6. Aviles-Olmos I, Martinez-Fernandez R, Foltynie T. L-dopa-induced dyskinesias in Parkinson s disease. Eur Neurol J 2010;2:91-100. 7. National Parkinson Foundation. Parkinson s Toolkit. Levodopa. http://www.toolkit.parkinson.org/content/levodopa. 8. National Parkinson Foundation. Parkinson s Toolkit. Other medications. http://www.toolkit.parkinson.org/content/othermedications. (Accessed May 31, 2017). 9. National Parkinson Foundation. Parkinson s Toolkit COMT inhibitors. http://www.toolkit.parkinson.org/content/comtinhibitors. 10. National Parkinson Foundation. Parkinson s Toolkit. Dopamine http://www.toolkit.parkinson.org/content/dopamineagonists. agonists. 11. National Parkinson Foundation. Parkinson s Toolkit. MAO-B inhibitors. http://www.toolkit.parkinson.org/content/mao-binhibitors. 12. National Parkinson Foundation. Parkinson s Toolkit. Anti-cholinergics. http://www.toolkit.parkinson.org/content/anticholinergics. (Accessed May 31, 2017). 13. National Parkinson Foundation. Parkinson s Toolkit. Impulse control disorders. http://www.toolkit.parkinson.org/node/102. 14. Product information for Apokyn. Tercica, Inc. Brisbane, CA 94005. March 2017. 15. Product information for Xadago. US WorldMeds LLC. Louisville, KY 40241. March 2017. 16. Product information for Rytary. Impax. Hayward, CA 94544. November 2016. 17. Tetrud J, Nausieda P, Kreitzman D, et al. Conversion to carbidopa and levodopa extendedrelease (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson s disease. J Neurol Sci 2017;373:116-23. 18. National Parkinson Foundation. Parkinson s Toolkit. Dyskinesia. http://www.toolkit.parkinson.org/node/151. 19. Mao ZL, Modi NB. Dose-response analysis of the effect of carbidopa-levodopa extended-release capsules (IPX066) in levodopa-naïve patients with Parkinson disease. J Clin Pharmacol 2016;56:974-82. 20. Product information for Emsam. Mylan Specialty L.P. Morgantown, WV 26505. March 2015. 21. Oertel WH, Berardelli A, Bloem BR, et al. Early (uncomplicated) Parkinson s disease. In: Gilhus NE, Barnes MP, Brainin M, eds. European Handbook of Neurolgical Management Vol 1. 2 nd ed. West Sussex, UK: Wiley-Blackwell; 2011: 217-36. 22. Blair HA, Dhillon S. Safinamide: a review in Parkinson s disease. CNS Drugs 2017;31:169-76. 23. Anon. A practical guide to stopping medicines in older people. BPJ 2010;27:10-23.http://www.bpac.org.nz/BPJ/2010/April/docs/bpj_2 7_stop_guide_pages_10-23.pdf. (Accessed June 8, 2017). 24. Product monograph for Movapo. Paladin Labs. St- Laurent, QC H4M 2P2. November 2016. Cite this document as follows: Clinical Resource, Drugs for Parkinson s Disease. Pharmacist s Letter/Prescriber s Letter. July 2017.

(Clinical Resource #330705: Page 6 of 6) Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com

This Clinical Resource gives subscribers additional insight related to the Recommendations published in July 2017 ~ Resource #330705 Parkinson s Disease Therapy Algorithm These are examples of a stepwise approach to Parkinson s disease therapy. 1-10 It is not inclusive of all therapy options. Dopamine agonists = ropinirole, pramipexole; MAO-B inhibitors = selegiline, rasagiline, safinamide; anticholinergics = benztropine, trihexyphenidyl; COMT-inhibitors = tolcapone, entacapone. Also see our chart, Drugs for Parkinson s Disease. MAO-B inhibitor: Mild to modest benefit; insufficient evidence of neuroprotection. Safinamide not 1 st -line. Amantadine: Mild to modest benefit, especially tremor. Used in younger patients. Anticholinergic: Used for tremor in younger patients. Levodopa-carbidopa: Most effective drug for Parkinson s symptoms. a Good choice for elderly. Dopamine agonist: Not as effective as levodopa. Elderly do not tolerate as well as levodopa. Suboptimal therapeutic response Suboptimal therapeutic response Add levodopa-carbidopa or dopamine agonist. Taper amantadine or anticholinergic if stopped. Options for levodopa peak dose dyskinesias: Reduce levodopa dose +/- add or increase dopamine agonist Add amantadine If COMT inhibitor recently added, consider levodopa dose reduction a. Some clinicians delay levodopa use to delay motor complications. b. Combination therapy preferred. Increase dose or add dopamine agonist (may require levodopa dose reduction). b Increase dose or add levodopa-carbidopa. b Options to reduce off time: Add COMT inhibitor if on levodopa (may require levodopa dose reduction) Add dopamine agonist to levodopa/carbidopa or vice versa Add MAO-B inhibitor to levodopa Decrease levodopa dosing interval by 30 to 60 min.

(Clinical Resource #330705: Page 2 of 2) Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Project Leader in preparation of this clinical resource (330705): Melanie Cupp, Pharm.D., BCPS References 1. Miyasaki JM, Martin W, Suchowersky O, et al. Practice parameter: initiation of treatment for Parkinson s disease: an evidence-based review: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2002;58:11-7. 2. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidencebased review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:983-95. 3. Product information for Xadago. US WorldMeds. Louisville, KY 40241. March 2017. 4. Robottom BJ. Efficacy, safety, and patient preference of monoamine oxidase B inhibitors in the treatment of Parkinson s disease. Patient Prefer Adherence 2011;5:57-64. 5. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson s disease (2001): treatment guidelines. Neurology 2001;56(11Suppl 5):S1-88. 6. National Parkinson Foundation. Parkinson s Toolkit. Levodopa. http://www.toolkit.parkinson.org/content/levodopa. 7. National Parkinson Foundation. Parkinson s Toolkit Other Medications. http://www.toolkit.parkinson.org/content/othermedications. (Accessed May 31, 2017). 8. National Parkinson Foundation. Parkinson s Toolkit COMT inhibitors. http://www.toolkit.parkinson.org/content/comtinhibitors. 9. National Parkinson Foundation. Parkinson s Toolkit. Anticholinergics. http://www.toolkit.parkinson.org/content/anticholinergics. (Accessed May 31, 2017). 10. Tarsy D. Motor fluctuations and dyskinesia in Parkinson disease. November 3, 2014. UptoDate. Cite this document as follows: Clinical Resource, Parkinson s Disease Therapy Algorithm. Pharmacist s Letter/Prescriber s Letter. July 2017. Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 2017 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com