Tardive Dyskinesia Overview

Transcription

1 Jason P. Caplan, MD, FAPM Professor & Chair of Psychiatry Creighton University School of Medicine Phoenix, AZ Tardive Dyskinesia Overview Associated with use of dopamine receptor blockers (DRBs), including all antipsychotic medications (FGA & SGA), as well as metoclopramide DRBs exhibit a spectrum of risk for movement disorders including extrapyramidal symptoms (EPS), akathisia, and tardive dyskinesia (TD), depending on variables in treatment and individual patient susceptibility The risk of relapse without antipsychotics for patients diagnosed with psychosis is greater than 50% Expanded clinical indications and use for antipsychotics (eg, bipolar disorder, anxiety, chemotherapy induced N/V) continue to perpetuate the risk of EPS/TD Annual incidence of TD with SGAs is 3.9% vs. 5.5% with FGAs Cost concerns continue to drive use of FGAs in some health care settings FGA=first generation antipsychotic; SGA=second generation antipsychotic Caroff SN. Neurol Clin

2 Tardive Dyskinesia Chronic movement disorder Potentially irreversible symptoms Comparison between FGAs and SGAs [n=11,493] 41 study, random effects meta analysis and meta regression Global TD prevalence = 25.3% Current: SGA 20.7% vs. FGA 30.0% (P=0.002) Lower TD prevalence in FGA naive patients vs. SGA treated with FGA history (P<0.001) Carbon M, et al. J Clin Psychiatry Tardive Dyskinesia Pathophysiology Four hypotheses 1. D2 receptor upregulation in nigrostriatal pathway resulting in hypersensitivity to dopamine 2. Loss of cholinergic interneurons in the basal ganglia 3. Disruption of GABA/glutamate axis resulting in hyperstimulation 4. Oxidative stress underlying all three of the above Kim J, et al. Drugs Context. 2014; Rana AQ, et al. Drug Des Devel Ther

3 Tardive Dyskinesia Risk Factors Increased age (higher incidence and lower remissions over age 50) Female gender Postmenopausal Head injury Substance abuse (including tobacco) Primary mood disorder Concurrent medical disease (diabetes) Use of antipsychotics in high doses Exposure to antipsychotics over time History of acute EPS with antipsychotics (Parkinsonism, dystonia, akathisia) Exposure to anticholinergics Saltz BL, et al. JAMA. 1991; Ganzini L, et al. Psychopharmacol Bull. 1992; Woerner MG, et al. Am J Psychiatry. 1993; Woerner MG, et al. Am J Psychiatry. 1998; Chan HY, et al. J Clin Psychiatry. 2010; Müller T. Expert Opin Investig Drugs Tardive Dyskinesia Monitoring American Psychiatric Association Practice Guideline: Low risk patients On SGA: Annually On FGA: Every 6 months High risk patients On SGA: Every 6 months On FGA: Every 3 months APA Practice Guideline for the Treatment of Patients with Schizophrenia

4 EPS: Tardive Dyskinesia Common clinical presentation Oral and facial abnormalities including chewing, grimacing, blinking, lip smacking Writhing movements of face, neck, back, trunk, and extremities Clinical implications associated with the development of TD Remission vs. Suppression of symptoms Historically limited treatment intervention options APA Practice Guideline for the Treatment of Patients with Schizophrenia. 2010; Caroff SN, et al. J Clin Psychiatry. 2011; Lerner V and Miodownik C. Curr Psychiatry Rep. 2011; Correll CU, Schenk EM. Curr Opin Psychiatry. 2008; Leucht S, et al. Lancet Differential Diagnosis Acute Dystonia Associated with first exposure or dose increase Minutes to hours Akathisia Associated with first exposure or dose increase Minutes to hours Drug induced Parkinsonism Weeks to months 4

5 Steven C. Stoner, PharmD, BCPP Chair and Clinical Professor UMKC School of Pharmacy Division of Pharmacy Practice and Administration Kansas City, MO Traditional Approach to Managing TD Discontinue anticholinergic medications If a DRB is required, consider switching to an SGA Clozapine Quetiapine Bhidayasiri R, et al. Neurology. 2013; Rana AQ, et al. Drug Des Devel Ther

6 Additional Treatment Interventions for Tardive Dyskinesia Ginkgo biloba Amantadine Clonazepam Tetrabenazine Pyridoxine Melatonin Vitamin E Botulinum toxin Zonisamide Levetiracetam Branched chain amino acids Omega 3 fatty acids Bhidayasiri R, et al. Neurology. 2013; Rana AQ, et al. Drug Des Devel Ther Vesicular Monoamine Transporter 2 (VMAT2): Proposed Role in Tardive Dyskinesia VMAT2 responsible for monoamine transport from cellular cytosol into synaptic vesicles VMAT2 inhibitors bind to distinct sites on the protein and inhibit its activity, thereby reducing monoamine concentrations in the synaptic cleft Muller T. Expert Opin Investig Drugs

7 Case Assessment Considerations: LB, a 67 year old Female with Schizophrenia PMH: Treated since the age of 22 for schizophrenia (paranoia, auditory and visual hallucinations, aggression), hyperlipidemia, hypertension, +tobacco use (1 ppd) HPI: Recently observed with oral facial movements (lip puckering and chewing movements; hand movements, and truncal twisting), psychosis well controlled Psychiatric Medication History: Haloperidol, fluphenazine, chlorpromazine, thiothixene, risperidone, olanzapine, quetiapine, lithium carbonate, divalproex sodium, lorazepam, clonazepam, trihexyphenidyl, diphenhydramine Current Medications: Iloperidone 8 mg po BID Haloperidol 2 mg po at bedtime Benztropine 0.5 mg po BID Atorvastatin 40 mg po daily Lisinopril 10 mg po daily Tetrabenazine (TBZ) VMAT2 reversible inhibitor Treatment used for schizophrenia in the 1970s; obtained FDA approval in 2009 for Huntington s disease May have therapeutic application in wide variety of hyperkinetic movement disorders Requires dosing titration and TID dosing Numerous adverse effects limit its clinical use; some serious and potentially fatal: Sedation, parkinsonism, EPS, dysphagia, hypotension, neuroleptic malignant syndrome Depression, suicidality (BOXED WARNING) Guay DR. Am J Geriatr Pharmacother

8 Deutetrabenazine VMAT2 reversible inhibitor Deutetrabenazine is a novel molecule structurally related to tetrabenazine Incorporates deuterium in lieu of hydrogen at 1 o metabolism sites Deuteration of TBZ results in a more than 2 fold increase in systemic exposure to total (α+β) HTBZ, a near doubling of half life The increased half life of total (α+β) HTBZ allows for administration of lower doses of deutetrabenazine compared with TBZ, thus permitting comparable plasma exposure with lower peak and higher trough concentrations FDA approved for both Tardive Dyskinesia (8/30/17) and Huntington s disease (4/4/17) BID dosing for TD (doses 12 mg/day should be divided) Huntington Study Group. JAMA. 2016; Stamler D, et al. Neurology. 2013; Deutetrabenazine Prescribing Information, August ARM TD (NCT ; Phase II/III) 12 week, DBRPC study of adults 6 week titration (placebo or 12 mg to 48 mg/day) plus 6 weeks of maintenance treatment AIMS (Abnormal Involuntary Movement Scale), CGIC (Clinical Global Impression of Change), PGIC (Patient Global Impression of Change), and mcdq 24 (modified Craniocervical Dystonia Questionnaire) AIM TD (NCT ; Phase III) 12 week, DBRPC study Dose finding of placebo, 12, 24, or 36 mg BID titrated over 4 weeks and maintained x 8 additional weeks AIMS, CGIC, PGIC, and mcdq 24 RIM TD (NCT ; Phase III) Open label, 54 week safety study AIMS, CGIC, and PGIC DBRPC=double blind, randomized, placebo controlled Deutetrabenazine Clinical Trials Fernandez HH, et al. Neurology. 2017; Anderson KE, et al. Lancet Psychiatry. 2017; 8

9 Pooled Analysis of Short Term ARM TD and AIM TD Studies AIMS Response Rate ( 50% reduction) 30% deutetrabenazine vs. 15% placebo (NNT = 7) Week 12 AIMS Improvement Change Deutetrabenazine 3.3 and placebo 1.5 Significant improvement in 6 of 7 AIMS items CGIC Treatment Success 47% deutetrabenazine vs. 33% placebo (NNT = 8) Citrome L. Int J Clin Pract RIM TD: Open Label Long Term Study (N=304) Anderson K, et al. APA 2017 Annual Meeting

10 RIM TD: AIMS Results Mean AIMS reduction 5.1 points 5.4 points in prior treatment group Week 6 treatment response: CGIC (58%) and PGIC (53%) Week 54 response: CGIC (72%) and PGIC (59%) Anderson K, et al. APA 2017 Annual Meeting RIM TD: Safety Adverse Event All Patients in Open Label Extension EAIR (Number of patients/patient year); (n=304) Headache 0.10 (21/200.3) Somnolence 0.11 (22/201.5) Depression 0.11 (22/206.1) Suicidality 0.02 (5/213.4) Anxiety 0.12 (24/201.5) Diarrhea 0.08 (17/203.4) Nasopharyngitis 0.08 (17/206.2) Fatigue 0.07 (14/203.1) Akathisia and Restlessness 0.02 (4/212.9) Somnolence and Sedation 0.12 (24/200.9) Parkinsonism 0.05 (10/209.3) Anderson K, et al. APA 2017 Annual Meeting

11 Deutetrabenazine Practical Issues FDA Approval for Tardive Dyskinesia 8/30/17 (Huntington s Disease (HD) 4/4/17) Warning for depression and suicidality in patients with HD Dose Availability: 6 mg, 9 mg, 12 mg tablets Tardive Dyskinesia Treatment Initiate at 6 mg po twice daily, titrate up at weekly intervals by 6 mg per day to a tolerated dose that reduces chorea or tardive dyskinesia, up to a maximum daily dose of 48 mg (24 mg po twice daily) Maximum dose in poor CYP2D6 metabolizers is 36 mg per day Maximum dose with concomitant use of strong CYP2D6 inhibitors is 36 mg per day Total daily doses of 12 mg or above should given in two divided doses Take with food Adverse reactions (HD studies): somnolence, diarrhea, dry mouth, fatigue Adverse reactions (TD studies): nasopharyngitis, insomnia Procurement: sharedsolutions.com Deutetrabenazine Prescribing Information & Product Website, August Valbenazine (VBZ) Novel, highly selective reversible VMAT2 inhibitor Pharmacokinetics: Orally active agent with two active metabolites also highly selective for VMAT2: NBI [(+)α dihydrotetrabenazine] and NBI Unique pharmacokinetic profile results in reduced peak plasma concentrations and variability that may improve safety/tolerability Once daily dosing (T 1/2 =20 hours) FDA approved for Tardive Dyskinesia on 4/11/17 O Brien CF, et al. Mov Disord. 2015; Valbenazine Prescribing Information, August

12 Valbenazine Clinical Trials KINECT 1 (NCT ; Phase II) 6 wk, DBRPC study in adults 100 mg dose reduced symptoms on AIMS score KINECT 2 (NCT ; Phase II) 6 wk, DBRPC dose titration study of adults on 25 to 75 mg Psychiatric stability analysis Change in AIMS Score, CGI TD, and PGIC KINECT 3 (NCT ; Phase III) 6 wk, DBRPC study of adults on 40 or 80 mg 52 week, long term extension study Change in AIMS Score, CGI TD, and PGIC KINECT 4 Open label (with dose escalation / reduction) based on efficacy / tolerability Change in AIMS Score, CGI TD, and PGIC DBRPC=double blind, randomized, placebo controlled Summary of KINECT 3 Acute and Extension Studies Change in AIMS Score AIMS Responders ( 50% Reduction) Effect Size KINECT 3 6 week Study 40 mg dose % mg dose % 0.90 KINECT 3 End of 48 weeks 40 mg dose % 80 mg dose % Hauser RA, et al. Am J Psychiatry. 2017; Factor SA, et al. J Clin Psychiatry

13 KINECT 4: Study Design Marder, SR et al. ACNP Congress 2017; Palm Springs, CA. KINECT 4: AIMS Results Marder, SR et al. ACNP Congress 2017; Palm Springs, CA. 13

14 KINECT 4: Safety and Tolerability Treatment Emergent Adverse Events a Valbenazine 40 mg (n=35) Valbenazine 80 mg (n=107) Valbenazine mg (n=11) All Subjects (n=153) Summary, n (%) Any TEAE 22 (62.9) 66 (61.7) 11 (100.0) 99 (64.7) Any serious AE 3 (8.6) 17 (15.9) 1 (9.1) 21 (13.7) Any TEAE leading to discontinuation 7 (20.0) 11 (10.3) 0 (0.0) 18 (11.8) TEAEs reported in 5% of all subjects by preferred term, n (%) Urinary tract infection 3 (8.6) 9 (8.4) 1 (9.1) 13 (8.5) Headache 2 (5.7) 6 (5.6) 0 (0.0) 8 (5.2) 64.7% of all subjects had >1 TEAE after Week 4 through Week 48 One death was due to breast cancer, which was determined not to be related to the study drug Change from baseline in vital signs, ECG, and laboratory test were generally small and not clinically significant Valbenazine was generally well tolerated and no unexpected safety signals were found a In subjects who received at least 1 dose of study drug, reported post Week 4 to Week mg: never had a dose increase to 80 mg; 80 mg: received 40 mg and increased to 80 mg, without a subsequent dose reduc on; mg: dose reduction from 80 to 40 mg. TEAE, treatment emergent adverse event. Marder, SR et al. ACNP Congress 2017; Palm Springs, CA. Valbenazine Practical Issues FDA Approval for Tardive Dyskinesia 4/11/17 Dose Availability: 40 mg, 80 mg capsule Tardive Dyskinesia Treatment Initiate at 40 mg po daily; increase to 80 mg po daily after one week Maintain at 40 mg if moderate or severe hepatic impairment Reduce dose to 40 mg with strong CYP3A4 inhibitors Avoid use with strong CYP3A4 inducers Consider dose reduction in CYP2D6 poor metabolizers or with concomitant CYP2D6 inhibitors (based on tolerability) Take with or without food Avoid use in patients with congenital long QT syndrome or arrhythmias associated with prolong QT interval Adverse Reaction(s): somnolence (6 week studies) Procurement: inbracesupportprogram.com Valbenazine Prescribing Information & Product Website, October

15 Jason P. Caplan, MD, FAPM Steven C. Stoner, PharmD, BCPP Moderator Sabrina Livezey, PharmD Case Presentation 1: EB, a 71 year old Female with Schizophrenia PMH: Schizophrenia, type 2 diabetes mellitus, hypertension, hyperlipidemia, tardive dyskinesia HPI: Presents to follow up appointment with psychiatrist. Her husband passed away since last appt and she is coping with this loss. She has good support system provided by family/friends. Allergies: Risperidone (GI intolerance and hand tremor) Medications: Amantadine 100 mg po BID Gabapentin 300 mg po BID Lisinopril 10 mg po once daily Metformin 1,000 mg po BID Mirtazapine 45 mg po every evening Simvastatin 10 mg po every evening Trazodone 50 mg po at bedtime Ziprasidone 80 mg po every evening 15

16 Case Presentation 1: EB, a 71 year old Female with Schizophrenia Additional Information: EB is adherent with medications. She has been stable on ziprasidone, mirtazapine, and trazodone for several years, but she has prominent TD that is not well controlled on amantadine. Physical Exam: Dystonia with muscle strength/tone Tardive movements of the periorbital area and tongue thrusting with intermittent trunk movements are observed Shifting in seat throughout appt with choreiform movements of her fingers and feet AIMS today=16 (previous AIMS=11 six months ago) Has not been aware of movements in the past, but admits today of noticing them more and is worried how others will perceive her now that she is attending activity center Case Presentation 1: EB, a 71 year old Female with Schizophrenia EKG: Regular rate/rhythm, HR = 70 bpm QTc interval = 461 msec EB is initiated on deutetrabenazine at a dose of 6 mg po BID and titrated to 12 mg po BID. The psychiatrist has decided not to increase the dose until another EKG is performed and evaluated at the lower dose because of concomitant medications that also may prolong QTc. 16

17 Role of the Pharmacist in Assisting with Deutetrabenazine Procurement Website includes resources for: Financial assistance (eligibility, copay, navigating Medicare Part D, other programs) Training and nurse support Educational resources (patient focused; personalized communications via , mail, or phone; tracking tool) Register and complete fields per instructions Select This Option Role of the Pharmacist in Assisting with Deutetrabenazine Procurement 17

18 Case Presentation 2: JJ, a 65 year old Female with Schizoaffective Disorder PMH: Schizoaffective disorder, hypertension, GERD, tardive dyskinesia caused by long term use of quetiapine, FGAs, and metoclopramide Allergies: None Medications: Quetiapine 50 mg in the morning and 100 mg po at bedtime Tetrabenazine 25 mg po TID Escitalopram 10 mg po once daily in the morning HCTZ 12.5 mg po once daily in the morning Omeprazole 20 mg po once daily in the morning before breakfast HPI: Has tolerated tetrabenazine well, but now dealing with formulary issues after an insurance change and it is no longer covered. The neurologist wants to convert JJ to deutetrabenazine. Conversion from Tetrabenazine to Deutetrabenazine When converting from tetrabenazine to deutetrabenazine, there is no washout period or overlap period for the medications. It is recommended to finish the scheduled tetrabenazine dosing for the day, then initiate deutetrabenazine therapy the next day at the equivalent dose (approximately half the daily dose of tetrabenazine). This patient was initiated on deutetrabenazine 18 mg po BID based on prescribing information: Current tetrabenazine daily dosage Initial regimen of deutetrabenazine 12.5 mg 6 mg once daily 25 mg 6 mg twice daily 37.5 mg 9 mg twice daily 50 mg 12 mg twice daily 62.5 mg 15 mg twice daily 75 mg 18 mg twice daily 87.5 mg 21 mg twice daily 100 mg 24 mg twice daily Deutetrabenazine Package Information, August

19 Case Presentation 3: JA, a 66 year old Male with Major Depressive Disorder PMH: Major depression, diabetes mellitus type 1, hypertension, tardive dyskinesia Medications: Bupropion XL 150 mg po once daily in the morning Carbidopa levodopa mg po four times daily Lisinopril 20 mg po daily in the morning Humalog insulin pump HPI: Presents today for first time in neurology clinic. Had been started on carbidopalevodopa by another provider for a right hand tremor along with tongue tremor. Although his hand movements have improved, he reports that the tongue movements are continuous. JA s wife tells you that he was recently taken off metoclopramide, which he had taken for 10 years. The neurology resident performs a physical exam with AIMS assessment and determines that the patient has TD. Role of the Pharmacist in Assisting with Valbenazine Procurement inbracesupportprogram.com Website includes resources for: Financial assistance (eligibility, copay, navigating Medicare Part D, other programs) Educational resources for patient and caregivers Register and complete PDF forms per instructions inbracesupportprogram.com 19

20 Role of the Pharmacist in Assisting with Valbenazine Procurement inbracesupportprogram.com Role of the Pharmacist in Assisting with Valbenazine Procurement inbracesupportprogram.com 20

21 Manufacturer Offered Patient Assistance Medication specific Copay assistance cards Patients with commercial insurance only Some manufacturer hubs require own Benefits Investigation Patient Assistance Program (PAP) Patients that have no insurance coverage Patients with insurance that have denied coverage of requested medication Financial Assistance: Additional Options to Consider National and community based programs Disease state and/or medication specific considerations Consideration for Medicare Part D patients Commercial patients may also seek assistance HealthWell Foundation and National Organization for Rare Disorders (NORD) offer funds for treatment of tardive dyskinesia Personal application required (demographics and financial information) 21

22 Case Presentation 4: AD, a 40 year old Male with Bipolar Disorder PMH: Bipolar disorder, hypertension, tardive dyskinesia Allergies: None Medications: Ginkgo Biloba 240 mg po once daily Losartan 50 mg po once daily in the morning Lithium Carbonate 600 mg po TID HPI: Presents today for follow up psychiatry appointment. Risperidone 0.5 mg po TID was discontinued several months ago after taking for 5 years. TD does not appear to be wellcontrolled today, so provider would like to make changes to current regimen. Liver enzymes have been slightly elevated (AST = 65 U/L and ALT = 72 U/L) over the past few years with routine lab work. Case Presentation 4: AD, a 40 year old Male with Bipolar Disorder Valbenazine is not contraindicated in hepatic dysfunction and is selected for AD. Prior authorization has been approved for this agent through his commercial insurance plan with a copay of $250 per month. 22