Faculty Information 2/15/2013

Transcription

1 Timothy Reilly, PharmD, BCPS, CGP, FASCP Clinical Assistant Professor Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey Faculty Information Presenter: Timothy Reilly, PharmD, BCPS, CGP, FASCP Clinical Assistant Professor Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey Piscataway, New Jersey Moderator: Elena Beyzarov, PharmD Director of Scientific Affairs Pharmacy Times Office of Continuing Professional Education Plainsboro, New Jersey Intended Audience: Pharmacists This activity is supported by an educational grant from Teva Pharmaceuticals, Ltd. 1

2 Disclosures and COI Resolution Timothy Reilly, PharmD, BCPS, CGP, FASCP, has disclosed faculty honoraria received from: New Jersey Society of Health-System Pharmacists, New Jersey Pharmacists Association, Trinitas Regional Medical Center. His spouse is an employee and stockholder for Johnson & Johnson. Pharmacy Times Office of Continuing Professional Education Planning Staff Judy V. Lum, MPA, Elena Beyzarov, PharmD, and Donna W. Fausak have no financial relationships with commercial interests to disclose. Pharmacy Times Office of Continuing Professional Education uses an anonymous peer review process to resolve all conflicts of interest (COI). The peer reviewers used for this activity have no relevant financial relationships with commercial interests to disclose. Disclaimer The contents of this webinar may include information regarding the use of products that may be inconsistent with or outside the approved labeling for these products in the United States. Pharmacists should note that the use of these products outside current approved labeling is considered experimental and are advised to consult prescribing information for these products. The information provided in this CPE activity is for continuing medical and pharmacy education purposes only and does not constitute any form of professional advice or referral. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the faculty or they may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not based on approved labeling or indications. Participants are encouraged to refer to primary references or full prescribing information resources for all products discussed. The opinions expressed in the content and provided verbally by faculty in this Webinar are solely those of the individual faculty members and do not reflect those of Pharmacy Times Office of Continuing Professional Education or the company providing commercial support for this CPE activity. 2

3 Learning Objectives At the end of this presentation, the pharmacist will be able to: Describe the epidemiology and pathophysiology of Parkinson s Disease (PD) Evaluate the management of early-stage and advanced stage PD Discuss current and emerging pharmacologic therapy and explore therapeutic challenges Examine dose titration strategies and management of treatment-related adverse effects Explore the pharmacist s role in optimizing treatment benefits and enforcing treatment adherence Timothy Reilly, PharmD, BCPS, CGP, FASCP Clinical Assistant Professor Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey tjreilly@pharmacy.rutgers.edu 3

4 Epidemiology Affects up to 1 million adults in the US Prevalence and incidence increases with age Usual age at diagnosis: 55 to 65 years Male predominance Chen JJ, et al. Chapter 68. Parkinson's Disease. In: Talbert RL et al, eds. Pharmacotherapy: A Pathophysiologic 4

5 Etiology Free radical production from dopamine degradation Aging Genetics Environmental factors Pesticides Heavy metals (eg, Fe, Mn) Rural living Well water Chen JJ et al. Chapter 68. Parkinson's Disease. In: Talbert RL et al, eds. Pharmacotherapy: A Pathophysiologic Pathophysiology Degeneration of dopamine (D)-producing neurons and presence of Lewey bodies in substantia nigra Initially in medulla oblongata, locus coeruleus, raphe nuclei, olfactory bulb Progresses to midbrain Possible implication of N-methyl-D-aspartate (NMDA) Adaptive Mechanisms Upregulation of D synthesis Downregulation of synaptic D reuptake Chen JJ et al. Chapter 68. Parkinson's Disease. In: Talbert RL et al, eds. Pharmacotherapy: A Pathophysiologic 5

6 Clinical Presentation Hallmark motor signs Resting tremor Rigidity Bradykinesia Chen JJ et al. Chapter 68. Parkinson's Disease. In: Talbert RL, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; Other signs/symptoms Posture/Movement: Postural instability, difficulty rising from seated position, diminished arm swing during ambulation, flexed posture, freezing at initiation of movement Decreased manual dexterity Voice/Throat: Dysarthria, hypophonia, dysphagia Hypomimia Micrographia Constipation, bladder dysfunction Mental status changes Common Causes of Secondary PD Antiemetics: metoclopramide, prochlorperazine Antipsychotics: haloperidol, risperidone, olanzapine Other agents: methyldopa 6

7 Drugs Used to Treat PD Any Stage of Disease MAO-B Inhibitors Dopamine Agonists Levodopa/Carbidopa Anticholinergics Amantadine Advanced Stage COMT Inhibitors Apomorphine 7

8 MAO-B Inhibitors Mechanism of Action: irreversible inhibition of D degradation Slow decline of motor function Questionable disease modification Drug Interactions: Antidepressants, St. John s Wort Sympathomimetics Dextromethorphan Meperidine, tramadol, methadone Tyramine-containing foods Well tolerated as monotherapy (arthralgia, dyspepsia, depression, flu syndrome) AZILECT (rasagiline) package insert. Revised August MAO-B Inhibitors: Preparations Rasagiline AZILECT mg po daily Avoid high tyramine content foods (eg, aged cheeses) Metabolized by CYP1A2: ciprofloxacin AZILECT (rasagiline) package insert. August ZELAPAR (selegiline ODT) package insert. February Selegiline tablets (Mylan) package insert. November EMSAM (selegiline transdermal) package insert. August Selegiline Tablets: 5 mg po at breakfast and lunch Avoid all tyramine-containing foods ODT: ZELAPAR 1.25 mg daily; escalate to 2.5 mg daily after 6 weeks Faster onset than tablets Avoid all tyramine-containing foods Patch (EMSAM) Not approved for PD 8

9 Amantadine Mechanism of Action: D agonist and NMDA antagonist 300 mg/day, in divided doses Renally eliminated Adverse Effects: dizziness, confusion, dry mouth, hallucinations, livedo reticularis Anticholinergic Agents Mechanism of Action: Common Adverse Effects ACh Dopamine Included in 2012 Update to the Beers Criteria Useful for rigidity and tremor Preparations: Benztropine Trihexyphenidyl J Am Geriatr Soc. 2012;60:

10 Dopamine Agonists More consistent effects than levodopa Nonergot vs ergot-derived Mechanism of action: non-ergot agonist with full intrinsic activity at D2 receptor Significant adverse effects: nausea, sleep attacks, orthostatic hypotension, lack of impulse control, hallucinations, withdrawal, melanoma Lower risk for dyskinesias Ann Neurol. February 2011;69: MIRAPEX (pramipexole) package insert. Revised September REQUIP (ropinirole) package insert. Revised May Dopamine Agonists: Preparations Oral Agents (also extended release) Pramipexole (MIRAPEX ) mg po TID titrated weekly to 1.5 mg po TID Renally eliminated Ropinirole (REQUIP ) 0.25 mg po TID titrated weekly to 1 mg po TID Metabolized by CYP1A2 Ciprofloxacin Estrogens Transdermal Product Rotigotine (NEUPRO ) 2 mg patch daily titrated weekly by 2 mg up to 8 mg Caution in patients with sulfite allergy Dose-dependent application site reactions Hypertension, tachycardia, weight gain, and fluid retention MIRAPEX (pramipexole) package insert. Revised September REQUIP (ropinirole) package insert. Revised May NEUPRO (rotigotine transdermal) package insert. Revised April 2o12 10

11 Levodopa/Carbidopa Mechanism of action: Levodopa: precursor of dopamine Carbidopa: peripheral L-amino acid decarboxylase inhibitor Maximum required daily dose: mg Effective half life: 1.5 hours Common adverse effects: orthostasis, dyskinesias, motor fluctuations, psychosis Formulations: Immediate release Controlled release Orally disintegrating COMT Inhibitors Mechanism of action: in combination with carbidopa, reduce peripheral conversion of levodopa Extends levodopa half life to 2 to 2.5 hours Drug interactions: epinephrine, norepinephrine, dobutamine, methyldopa Adverse effects: diarrhea, colitis COMTAN (entacapone) package insert. Revised April

12 COMT Inhibitor Formulations Entacapone COMTAN 200 mg with each levodopa/carbidopa dose STALEVO Carbidopa/levodopa/ entacapone combination product Tolcapone TASMAR 100 mg po TID Risk of liver injury must monitor AST/ALT Patients must show clinical benefit within 3 weeks COMTAN (entacapone) package insert. Revised April STALEVO (carbidopa/levodopa/entacapone) package insert. Revised April TASMAR (tolcapone) package insert. Revised June Apomorphine (APOKYN ) Parenteral nonergot D agonist On response within 20 minutes of injection; duration ~100 minutes 2-6 mg/injection; usually 0.06 mg/kg (pen is labeled in ml) Complicated test dose and titration procedure required Rotate injection site Adverse effects: nausea/vomiting; dizziness, hallucinations, ISR, orthostasis, somnolence, hypotension, QTc prolongation Drug Interactions: 5HT3 antagonists; QTc-prolonging drugs, antihypertensives APOKYN (apomorphine) package insert. Revised February

13 Suggested Treatment Algorithm Initial treatment: MAO-B Inhibitor Augmenting treatment: Tremor: Amantadine If <65 y, consider anticholinergics Bradykinesia, rigidity, tremor: Amantadine Dopamine replacement: dopamine agonist, carbidopa/levodopa Chen JJ, et al. Chapter 68. Parkinson's Disease. In: Talbert RL, et al., eds. Pharmacotherapy: A Pathophysiologic 13

14 Beginning Treatment With MAO-B Inhibitor: The TEMPO Trial Patients: Untreated, early PD patients Anticholinergics allowed Interventions: Rasagiline 1 mg or 2 mg or placebo Outcomes: Both agents had better UPDRS scores than placebo No difference in time to need more therapy between groups Overall, drug was well tolerated Arch Neurol. 2002;59: Beginning Treatment With MAO-B Inhibitor: The ADAGIO Trial Patients: Untreated, early PD patients Interventions: Phase 1: Rasagiline 1 mg or 2 mg or 1 mg or 2 mg placebo Phase 2: active group continue treatment; placebo switch to active treatment Outcomes: Patients receiving 1 mg had slower rate of worsening than placebo patients Early start 1 mg group had less worsening in UPDRS than delayed start group 2 mg rasagiline dose demonstrated negative results No tyramine or serotonin reactions noted N Engl J Med. 2009;361:

15 Choosing Between Dopamine Replacements Dopamine Agonists Levodopa/Carbidopa Dyskinesias Reduced 10% per year Common adverse effects Orthostasis, nausea Orthostasis Half life Long Short Best tolerated by Young patients Older patients Other benefits Reduced free radical formation? Neuropsychopharmacology. 2012;37: Ann Neurol 2011;69: Early Exposure to Levodopa: The ELLDOPA trial Patients: Untreated, early-stage PD Interventions: Placebo L/C 50/12.5 TID L/C 100/25 TID L/C 200/50 TID 40-week treatment, 3 day step down, 2-week assessment Outcomes: Dose-response seen from weeks 9 to 40 Deterioration seen in all treatment groups at week 42, but not to same level as placebo AEs seen in 600 mg group: Dyskinesia Nausea Infection Hypertonia Headache N Engl J Med. 2004;351:

16 Motor Fluctuations End-of-Dose Wearing Off Delayed-on/No-on Freezing Dyskinesia Off-Period 16

17 End-of-Dose Wearing Off Increase frequency of levodopa administration Add additional agents: COMT Inhibitor MAO-B inhibitor Apomorphine D agonist Controlled release formulations Sipping levodopa/carbidopa suspension Delayed-On or No-On Causes Delayed gastric emptying Decreased absorption Treatments Ensure empty stomach Chew/crush tablet with glass of water Dosage formulation ODTs Avoid controlled-release Apomorphine rescue Chen JJ, et al. Chapter 68. Parkinson's Disease. In: Talbert RL, et al., eds. Pharmacotherapy: A Pathophysiologic 17

18 Freezing Frequently related to anxiety PT is mainstay of therapy Pharmacologic treatment Increase levodopa/carbidopa dose Add D agonist or MAO-B inhibitor Dyskinesias Peak striatal dopamine levels Treatments Change to IR products Smaller, more frequent levodopa doses Reduce dose of other agents Amantadine Clozapine(?) Ann Neurol 2-11;69:

19 Off-Period Dystonia Frequently occurs in early morning hours Treatments: Long-acting dopamine agonist Sustained-release carbidopa/levodopa Baclofen Local injection of botulinum toxin Adherence Issues Adherent patients are 67% less likely to develop PD complications Hospitalizations Office visits Ancillary care visits Cost of nonadherence: ~$5000/year AND Only 1/3 of patients are adherent 80% of the time Mov Disord. 2010;25: Mov Disord. 2008;23:

20 How Can the Pharmacist Help? Coaching and encouragement at refills Refill reminders Auto-fills Pill boxes Alternate routes/frequencies Referral to special programs Home care Transitional care 20

21 Novel Delivery Methods Continuous subcutaneous apomorphine Efficacy as monotherapy 64% reduction in dyskinesia Maximal improvement at 12 months Skin inflammation, cognitive/psychiatric disorders Intraintestinal levodopa/carbidopa Micronized in methylcellulose gel Continuous infusion with boluses prn Long-term stable responses with decreases in off time 94.7% of patients with dyskinesias improved Ann Neurol. 2011;69: Adenosine A 2A Antagonists A 2A receptors found along with D2 receptors in striatum A 2A receptors mediate glutamate and GABA activity Preladenant: modest effects Phase II trials: SYN 115 BII 014 Neuropsychopharmacology. Reviews February 2012;37:

22 Glutamate Receptor-Related Compounds Glutamate is overexpressed in PD NMDA receptor is 1 subfamily of glutamate receptors Amantadine is currently the only effective drug with anti-nmda activity Memantine, riluzole, and remacemide are not beneficial Neuropsychopharmacology Reviews. February 2012;37: Other Compounds Under Development Methylphenidate: low doses may be useful for gait disturbances Fipamezole: alpha 2c adrenoceptor antagonist Phase IIb trials demonstrate efficacy for dyskinesia Neuropsychopharmacology Reviews February 2012;37:

23 Thank You! 23