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Parkinson’s Disease Foundation

PD ExpertBriefing: PD Medications: Managing Side Effects

Led By: Hubert H. Fernandez, M.D. Cleveland Clinic Lerner College of Medicine

This session was recorded on: Tuesday, April 8, 2014 at 1:00 PM ET. PD Medications: Managing Side Effects

Hubert H. Fernandez, M.D., F.A.A.N., F.A.N.A. Professor of Medicine (Neurology) Cleveland Clinic Lerner College of Medicine Head of Movement Disorders Cleveland Clinic, OH, USA Disclosures I have, over the past 12 months, been a paid consultant, paid speaker or performed clinical research under contract with:

AbbVie, Acadia, Avid, Biotie, Britannia, Chelsea Therapeutics, Civitas, EMD Serono, Eli Lilly, Forest Laboratories, Huntington Study Group, Ipsen, Merck, Merz, Michael J. Fox Foundation, National Parkinson Foundation, NIH/NINDS, Novartis, Parkinson Study Group, Prostrakan/Kyowa Hakko, Pfizer, Rhythm, Synosia, Teva, US WorldMeds, Zambon Pharmaceuticals

However, I have no owner interest in any pharmaceutical company. What Are Our Current Symptomatic Treatment Options for Early PD? Sites of Action of Current PD Drugs MAO-B inhibitors: selegiline Dopamine Substantia Nigra rasagiline agonists: Amantadine bromocriptine Levodopa pramipexole ropinirole BBB rotigotine GABA DA

ACh

DDC COMT dopamine levodopa 3-OMD Anticholinergics: Striatum trihexyphenidyl benztropine Carbidopa COMT inhibitors: tolcapone entacapone Adapted from www.wemove.org Symptomatic Treatment of Early PD

. Carbidopa/levodopa (Sinemet IR, Sinemet CR, Parcopa, Stalevo [with entacapone])

. Dopamine agonist (ropinirole, pramipexole, rotigotine patch)

. MAO inhibitors (selegiline, rasagiline)

. Amantadine

. Trihexyphenidyl (artane) Treatment of PD with Levodopa

. Improves tremor, rigidity and bradykinesia in PD, particularly in early stages of PD

. Rapid onset, well tolerated

. Decreases mortality

. However, 80% of people with PD taking it have motor complications after 5-10 years (major source of disability) Treatment of PD with Levodopa

. Improves tremor, rigidity and bradykinesia in PD, particularly in early stages of PD

. Rapid onset, well tolerated

. Decreases mortality

. However, 80% of people taking it have motor complications after 5-10 years (major source of disability) Levodopa Superiority vs Dopamine Agonists Levodopa Superiority vs Dopamine Agonists

Total* Pramipexole vs Motor* Levodopa (UPDRS) Activitie s of Daily Living* Levodopa Superiority vs Dopamine Agonists Dyskinesias: Sydney 15-Year Multi-Center Longitudinal Study Dyskinesias Dyskinesias Requiring Dyskinesias Resistant to Medication Adjustments Medication Adjustments

• 15 yr F/U: 94% dyskinesias, 96% “end-of-dose failure • Dyskinesias: non-disabling in the majority

Hely et al, 2005 Perception of Dyskinesias in Pe0ple with PD

Patient characteristics Early Untreated Treated Treated Group I GroupNo dyskinesias II GroupDyskinesias III Number of patients 52 102 105 Number of male 33(63.5%) 53 (52.0%) 71 (67.6%) Current age (in 62.4 (12.7) 65.4 (13.9) 64.1 (9.3) years) (SD) Age at diagnosis 60.4 (12.6) 60.5 (11.6) 53.8 (9.7) (SD) Time followed in 10.98(20.71) 37.6 (33.2) 77.3 (53.7) our clinic (months) Number of new pts 23 13 2 to clinic UPDRS III score 19.7 (9.79) 21.9 (9.5) 24.8 (12.1) UPDRS Q32 0 0 1.5 (0.96) UPDRS Q33 0 0 1.0 (0.92) Lang Fahn 0 0 5.6 (4.9) Dyskinesia Scale score

Group I – early PD patients who are not on dopaminergic medicationsHung et al, 2009 Group II – PD patients who are on dopaminergic medications but do not have dyskinesias Group III – PD patients who are on dopaminergic medications and have dyskinesias UPDRS – Unified Parkinson’s Disease Rating Scale Level of Concern about Dyskinesia

40 not concerned mildly concerned 30 very concerned

percentage 20 extremely concerned

0 Group I Group II Group III

Early Treated Treated with Untreated No Dyskinesias Dyskinesias

Hung et al, 2009 Individual Preference: Dyskinesia or Parkinsonism

90 80 70 60 dyskinesia 50 parkinsonism 40 Undecided percentage 30 20 10 0 Group I Group II Group III

Hung et al, 2009 Dopamine Agonists

. Mirapex® (pramipexole) . Requip® (ropinirole) . Neupro® (rotigotine) . Now with once daily tablet or generic . Dopamine agonists have been shown to delay motor complications The Dopamine Agonist Advantage

Initial Dopamine 50 Levodopa Agonist Therapy 40 Pergolide Delays the Onset of 30

Dyskinesia (%) Incidence Lees AJ, et al. Neurology. 2001;57(9):1687-1694. 10

50 0 Levodopa Dyskinesias Motor complications Ropinirole Oertel WH, et al. Mov Disord. 2006;21(3):343-353. 50 Levodopa P=0.01 40 Pramipexole P=0.001 30

0 20

Dyskinesia Dyskinesia before Disabiling Incidence (%) Incidence Incidence(%) suppl levodopa dyskinesia 10 P=0.11 Rascol O, et al. N Engl J Med. 2000;342(20):1484-1491. 0 Dyskinesia Wearing off On-off CALM-PD Study Group. JAMA. 2000;284(15):1931-1938. Dopamine Agonists: Problems

. Does not control symptoms as well as levodopa . Long titration period . Associated with more side effects in older people . Associated with “sleep attacks” and leg swelling/edema . Associated with compulsive and impulsive behavior Sleep Attacks Weight Gain and Leg Swelling Ropinirole vs L-dopa as Initial Therapy: Adverse Events*†

27.4% 25.1% 23.6% 19.1%

17.3% % Patients %

5.6%

Hallucinations Somnolence Insomnia

* Reports of AEs occurring in 10% of either group in study population over 5 years. † Patients often had more than 1 adverse event. Rascol et al. N Engl J Med. 2000;342:1484-1491. CALM-PD Outcomes: Adverse Events

Pramipexole Levodopa 40 P=.003 30 32.4%

20 P=.01 P=.002 17.3% 17.9% % Patients of % P=.03 10 14.6% 9.3% 8.0% 0 3.3% 4.0% Somnolence Hallucinations Generalized Peripheral Edema Edema

Parkinson Study Group. JAMA. 2000;284:1931-1938. Rotigotine Patch Compulsive and Impulsive Disorders in PD

• Compulsive behavior • Impulse Control – Compulsive Disorder (ICD) dopaminergic – Pathological gambling medication use – Hypersexuality – Punding – Compulsive shopping – Excessive spending – Binge eating Dopamine Levodopa agonists DOMINION Study: Dopamine Agonists and ICD • Cross-sectional study of over 3,000 people with PD • People with PD on dopamine agonists (DAs) were two to three times more likely to develop ICD (class finding) • Associated factors: – Young age – Single – Family History of ICD – Levodopa treatment • Modifications to DA and/or levodopa is important for treatment Weintraub D, et al. The Movement Disorder Society’s 12th International Congress of Parkinson’s Disease and Movement Disorders; 2008, Chicago. Punding, Gambling, Hypersexuality, Binge Eating

Feature Punding Gambling Hypersexuality Binge eating 1% (BED) 8% Prevalence 8.25% 7.8% 4.3% (subthreshold) Young age √ √ Male dominance √ Dopamine agonist √ √ Anxious and angry √ Sleep deprived √ STN DBS √ Impulsive nature √ √ √ Compulsive nature √ *Shapiro, Okun, Rodriguez, & Fernandez 2006; *Cooper, *Wood, Okun, Rodriguez, & Fernandez 2009; *Nguyen, *Shapiro, Okun, Rodriguez & Fernandez 2008; *Zahodne, *Susatia, Bowers, Okun, Rodriguez, Malaty, Fernandez 2010 What is Punding? Emerging Theme…!

Punding Gambling

Hyper- sexuality Anticholinergics

. Examples: trihexyphenidyl (Artane®) benztropine (Cogentin®)

. Indications: tremor, drooling

. Benefits: Cost effective, thought to be most effective for tremor control

. Side effects: confusion, dry mouth, constipation, blurry vision, urinary retention, cognitive impairment MAO-B Inhibitors

. Irreversibly bind to brain MAO-B

. Loss of effect is dependent on MAO-B turnover in the brain – half-life ~30 days

. Formulations

. Oral (and orally-disintegrating tablets)

. Selegiline (Deprenyl®): approved as adjunct therapy (moderate to advanced PD)

. Rasagiline (Azilect®): approved as monotherapy (early PD) and adjunct therapy (moderate to advanced PD) Fowler JS, et al. Synapse. 1994;18(2):86-93. Elmer LW, Bertoni JM. Expert Opin Pharmacother. 2008;9(16):2759-2772. Rasagiline for Early Monotherapy

. One dose; no titration . Great tolerability; including elderly . No sleep attacks; minimal reports of compulsive or impulsive behavior

. Food interaction warning . Potential drug interaction . No head-to-head trial vs. agonists or selegiline Rasagiline for Early Monotherapy

. One dose; no titration . Great tolerability; including elderly . No sleep attacks; minimal reports of compulsive or impulsive behavior

. Food interaction warning . Potential drug interaction . No head-to-head trial vs. agonists or selegiline Motor Complications

. Motor fluctuations

. End-of-dose deterioration . Delayed onset of response

. Drug-resistant “offs” . Random oscillation (“on-off” phenomenon) . Freezing (unpredictable inability to initiate or finish a movement) . Dyskinesias (abnormal involuntary movements)

. Peak-dose, diphasic or wearing-off

Adler & Ahlskog, eds. Parkinson’s Disease and Movement Disorders: Diagnosis and Treatment Guidelines for the Practicing Physician. Totowa, NJ: Humana Press; 2000. Sensitivity to Levodopa: Early vs Advanced PD Managing Dyskinesias

. Lower frequent doses of levodopa

. Add dopamine agonist (DA) or MAO-B inhibitor while lowering levodopa dose

. Clozapine

. Amantadine

. Deep brain stimulation Amantadine

Amantadine vs placebo for . Mechanism: NMDA antagonist, dopamine levodopa-induced dyskinesias releasing agent Amantadine* Placebo* P value†

. Indications: Early PD, Total 22.0 (13.2) 29.0 (12.6) 0.004 dyskinesias, fatigue dyskinesia Maximal 5.2 (2.6) 6.3 (2.2) 0.02 . Benefits: Mild dyskinesia symptomatic benefit, UPDRS 3.2 (1.6) 4.3 (1.5) 0.02 effective for dyskinesias IVa dyskinesia . Side effects: Leg swelling, livedo UPDRS III 38.4 (14.8) 41.7 (13.0) 0.04 motor off reticularis, UPDRS III 22.3 (12.1) 23.4 (9.0) 0.44 NS neuropsychiatric, motor on anticholinergic

*Mean score (SD) †Wilcox signed-rank test Amantadine

Amantadine vs placebo for . Mechanism: NMDA antagonist, dopamine levodopa-induced dyskinesias releasing agent Amantadine* Placebo* P value†

*Mean score (SD) †Wilcox signed-rank test Levido Reticularis COMT Inhibitors

. Tolcapone (Tasmar®) and Levodopa time-concentration Entacapone (Comtan®) curve with/without entacapone . Effects: . Increase t1/2 levodopa Levodopa/carbidopa . Decrease plasma levodopa peak- + entacapone trough variations, resulting in reduction of OFF periods . Adjunctive therapy to levodopa

. Adverse effects: mcg/L Levodopa], Levodopa/carbidopa . Diarrhea + placebo . Urine discoloration . Fulminant liver failure in several cases treated with tolcapone . Combination levodopa/ carbidopa/entacapone now Stocchi F, et al. J Neural Transmission. 2004;111:173-180. available . Bioequivalence demonstrated vs levodopa/carbidopa + entacapone COMT Inhibitors for Wearing Off Using Entacapone as an Adjunct to DDCI/Levodopa

Rinne UK, et al. Neurology. 1998;51(5):1309-1314. Parkinson Study Group. Ann Neurol. 1997;42(5):747-755. P < 0.001 15 2.0 P < 0.05 1.5 10 1.0 0.5 5 0 0 -0.5 time ‘on‘ of proportion in Change 2 4 8 16 24 Change in daily ‘on‘ time (h) time Change‘on‘ in daily W B 2 4 8 16 24 Withdrawal Time (weeks) Time (weeks) Brooks DJ, et al. J Neurol Neurosurg Psychiatry. 2003;74(8):1071-1079. Poewe WH, et al. Acta Neurol Scand. 2002;105(4):245-255. 12 P < 0.01 1.5 11.5 * 11 *P < 0.05 1 10.5 10 0.5 (h) time ‘on’ Total 9.5

9 (meanof monthsand4 6) Change in daily ‘on’ time (h) time Change‘on’ in daily B 2 6 16 24 0 Entacapone Placebo Time (weeks)

Levodopa/DDCI plus entacapone Levodopa/DDCI plus placebo Rasagiline for Wearing Off

2.0 Rasagiline 0.5 mg 1.82 Rasagiline 1 mg Placebo 1.19 1.0 0.79 Reduction in mean total daily “Off” 0.0 Increase in mean total daily “On” -1.0 -0.91

Change from baseline (hours)baseline from Change -1.41 -2.0 -1.85 *Parkinson's Rasagiline: Efficacy & Safety in the Treatment of “Off” Parkinson Study Group. Arch Neurol. 2005; 62(2):241-248. Rasagiline versus Entacapone

Rasagiline 1 mg 1.5 Entacapone 200 mg 1.13 1.01 1.0 Placebo

0.5 Reduction in mean 0.27 total daily “Off” 0.0 Increase in mean total daily “On” -0.5 -0.4

-1.0 All Patients on LD/DDI Change from baseline (hours)baseline from Change -1.18 -1.2 -1.5 *Lasting effect in Adjunct therapy with Rasagiline Given Once daily Rascol O, et al. Lancet. 2005;365(9463):947-954. Rasagiline versus Entacapone

Rasagiline 1 mg 1.5 Entacapone 200 mg 1.13 1.01 1.0 Placebo

0.5 Reduction in mean 0.27 total daily “Off” 0.0 Increase in mean total daily “On” -0.5 -0.4

. Short-acting dopamine agonist

. Subcutaneous injection

. Main indication– “rescue” therapy for:

. Unpredictable “offs”

. “Off” periods in people who cannot swallow

. “Off” periods not controlled with oral medications

. Painful “off” periods

. Trimethobenzamide pretreatment necessary

. Can be halted after 6 weeks of apomorphine therapy

. First dose requires BP monitoring

. Side effects: injection site reaction, nausea, falls, dyskinesias, dizziness, somnolence (sleepiness) Apomorphine Injections Net Effect of PD Medications in Improving “Off” State in Placebo-Controlled Trials

Drug/Trial Dose Net reduction in off time (hours) % Net Reduction Ropinirole (Rascol, 1996) 6.6 mg/d -0.6 hrs 19% Ropinirole (Pahwa, 2007) 18.8 mg/d -1.6 hrs Ropinirole (Lieberman, 1998) <24 mg/d -0.31 7% Pramipexole (Guttman, 1997) 3.36 mg/d -2.3 hrs 12% Pramipexole (Lieberman,1997) <4.5 mg/d -1.7 hrs 24% Selegiline (Waters, 2004) 2.5 mg/d -1.6 hrs 23% Selegiline (Ondo, 2006) 2.5 mg/d Not significant Not significant Rasagiline (PRESTO, 2005) 1.0 mg/d -0.94 hrs 14% Rasagiline (LARGO, 2005) 1.0 mg/d -0.8 hrs 14% Entacapone (LARGO, 2005) 200 mg/levo -0.8 hrs 14% Entacapone (Poewe, 2002) 200 mg/levo -0.7 hrs 12% Entacapone (Rinne, 1998) 200 mg/levo -1.2 hrs 22% Tolcapone (Rajput, 1997) 200 TID -1.8 hrs 28% Tolcapone (Adler, 1998) 200 TID -2.2 hrs Tolcapone (Kurth, 1997) 200 TID -1.77 hrs Apomorphine (Dewey, 2001) 5.4 mg/d 34% Treatment Options for Wearing Off and Advanced PD

Oral agents Apomorphine Duodopa (LCIG) DBS • 1-1.5 hours • 2-3 hours more 4 hours more • 4 hours more more “on” time “on” time “on” time “on time A Multidisciplinary Team Approach Is Often Necessary

Tribal Council, Dar Es Salaam, Tanzania A Multidisciplinary Team Approach is often necessary

Occupational therapist Physical Speech therapist Therapist

Neurologist Internist

Psychologist Neurosurgeon

Psychiatrist Patient GI specialist

Tribal Council, Dar Es Salaam, Tanzania Non-Motor Signs and Symptoms

. Craniofacial - masked faces, sialorrhea (drooling), anosmia (loss of sense of smell), hypophonia (soft speech), dysarthria (motor speech disorder), dysphagia (difficulty swallowing)

. Sensory – pain

. Autonomic - urinary disturbance, constipation, sexual dysfunction

. Neuropsychiatric - depression, anxiety, apathy, cognitive impairment, psychosis

. Other – fatigue, sleep disturbance, seborrheic dermatitis, eye abnormalities Non-Motor Signs and Symptoms

. Craniofacial - masked faces, sialorrhea (drooling), anosmia (loss of sense of smell), hypophonia (soft speech), dysarthria (motor speech disorder), dysphagia (difficulty swallowing)

. Sensory – pain

. Autonomic - urinary disturbance, constipation, sexual dysfunction

. Neuropsychiatric - depression, anxiety, apathy, cognitive impairment, psychosis

. Other – fatigue, sleep disturbance, seborrheic dermatitis, eye abnormalities PD Pipeline: A Message of Hope

Phase I Other NLX-P101 Levodopa L-dopa prodrug PYM-50028 Phase II NeuroDerm TAK-065 ProSavin XP-21279 GPI-1485 VP-025 Phase III Mitoquinone/ ACR-343 Mitiquinol Marketed Pimavanserin Madopar A2a AntagonistST-1535 Carbidopa COMT Inhibitor Levodopa Duodopa Istradefylline Entacapone Talcapone COMT MK-0657 FP-0011 Carbergoline Apomorphine Inhibitor Glutamate Orion /NMDA Bromocriptine Rasagiline Rotigotine Antagonist Neu-120 Safinamide Ropinirole Lisuride patch

Pramipexole Lisuride sc Inhaled Apomorphine MAOB Inhibitor Pardoprunox Nasal Apomorphine Dihydrexidine Nasal Rotigotine Aplindore Pramipexole Biadhesive tblt extended release Sublingual Apomorphine

Dopamine Agonist Acknowledgement

Movement Disorders Team Center for Neurological Restoration Cleveland Clinic THANK YOU! Questions and Discussion

56 Upcoming PD ExpertBriefings

When PD Interferes with Gastrointestinal Function Tuesday, June 24, 1:00 PM - 2:00 PM ET Peter A. LeWitt, M.D., Professor of Neurology, Wayne State University School of Medicine and Director, Parkinson’s Disease and Movement Disorder Program, Henry Ford Hospital

57 Resources from PDF

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