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Clozapine Underutilization: Addressing the Barriers

Clozapine Underutilization: Addressing the Barriers. Deanna L. Kelly, Pharm.D., BCPP Professor of Psychiatry Director, Treatment Research Program Maryland Psychiatric Research Center (MPRC) University of Maryland School of Medicine Raymond C. Love, Pharm.D., FASHP

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Clozapine Underutilization: Addressing the Barriers

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  1. Clozapine Underutilization:Addressing the Barriers Deanna L. Kelly, Pharm.D., BCPP Professor of Psychiatry Director, Treatment Research Program Maryland Psychiatric Research Center (MPRC) University of Maryland School of Medicine Raymond C. Love, Pharm.D., FASHP Professor of Pharmacy Practice and Science Director, Mental Health Pharmacy Program University of Maryland School of Pharmacy

  2. Overview:Summary of Project Purpose • Clozapine is a medication that exhibits unique efficacy and effectiveness for those with serious mental illness, despite side effects that present challenges to its use • These challenges have evolved into a set of barriers that discourage the use of clozapine • Proven approaches using interprofessional models of care can help meet the needs of patients receiving clozapine • State and local government, federal agencies, academic medical centers, prescribers and others all have vital roles to play in increasing access to clozapine • NASHMPD has commissioned a White Paper to help rectify the clozapine situation nationally

  3. NASMHPD Workgroup • Raymond C. Love, PharmD, BCPP, FASHP • Deanna Kelly, PharmD, BCPP • Oliver Freudenreich, MD, FAPM • MacKenzie A. Sayer, BS • Kathy Sanders, MD • Andrew J. McLean MD, MPH • Dale K. Adair, MD • Brian Hepburn, MD • Aaron J. Walker, MPA • Stuart Yael Gordon, JD

  4. CLOZAPINE EFFICACY, EFFECTIVENESS AND RISK TO BENEFIT PROFILE

  5. Comparison of Antipsychotic Efficacy Relative to Placebo Standardized Mean Difference from placebo (Hedge’s g) Leucht S, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013:382:951-62

  6. Clozapine Superiority Effectiveness Studies • Several large effectiveness studies suggest that clozapine: • averages significantly greater time to treatment discontinuation • is associated with significantly greater patient perceived ratings • is associated with significantly greater clinician ratings Lieberman JA, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–23; Lewis SW, et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull. 2006;32(4):715–23.

  7. Importance of Clozapine • The Schizophrenia Patient Outcomes Research Team (PORT) recommends that patients with persistent positive symptoms of schizophrenia receive an adequate trial of clozapine • More recent guidelines recommend clozapine after two failed antipsychotic trials • Harvard South Shore Program Algorithm • British Association for Psychopharmacology Guidelines • The National Institute for Health and Care Excellence (NICE) Clinical Guideline for Schizophrenia” • Early use is critical for young patients with schizophrenia who are treatment-refractory and in whom only clozapine offers a chance for improvement and course stabilization as the basis for recovery Buchanan, R.W., et al., Schizophr Bull, 2010; Osser, D.N., M.J. Roudsari, and T. Manschreck, Harv Rev Psychiatry; Barnes, T.R., J Psychopharmacol, 2011.National Institute for Health and Care Excellence, 2014; Agid, O., et al., J Clin Psychiatry, 2011.

  8. Broad Range of Effectiveness • Clozapine may have utility for a variety of other disorders and conditions • treatment of hostility and aggression • treatment-resistant bipolar disorder • psychogenic polydipsia/hyponatremia • Parkinson Disease Psychosis and psychosis in Lewy-Body dementia • Borderline Personality Disorder • tardive dyskinesia (TD) • Growing evidence also suggests clozapine may be an option in youth with early onset schizophrenia • Clozapine is the only antipsychotic with a Food and Drug Administration approval for suicidality and it has the lowest mortality rate among all antipsychotic treatments

  9. Risk to Benefit Profile • Clozapine use is associated with a variety of side effects, some of which are potentially serious • Common side effects include: hypersalivation, tachycardia, enuresis, sweating, eosinophilia, metabolic syndrome and constipation • Serious but rare side effects include: myocarditis (3% risk), cardiomyopathy (0.02-0.1% risk),seizures (1-3% risk), and severe neutropenia (0.05-0.86%) • Severe neutropenia risk has led the FDA to mandate regular blood draws to monitor the absolute neutrophil count (ANC) Sagy, R., A. Weizman, and N. Katz, IntClinPsychopharmacol, 2014. Mitchell, A.J., et al. Schizophr Bull, 2013. Raja, M.,. Curr Drug Saf, 2011. Ronaldson, K.J., P.B. Fitzgerald, and J.J. McNeil, ActaPsychiatrScand, 2015.. Layland, J.J., D. Liew, and D.L. Prior,. Med J Aust, 2009; Williams, A.M. and S.H. Park, CNS Drugs, 2015.. Honigfeld, G., et al.,. J Clin Psychiatry, 1998. Munro, J., et al., Br J Psychiatry, 1999. Lahdelma, L. and B. Appelberg, J Clin Psychiatry, 2012.. Drew, L., Psychiatry, 2013. Balda, M.V., et al., IntClinPsychopharmacol, 2015

  10. Risk to Benefit Profile (cont.) • The decision to use clozapine requires a thorough consideration of both its risks and benefits, a thoughtful patient centered approach and a system that facilitates safe and appropriate use • Often ignored in risk-benefit discussions are the medical risks of not using clozapine • Other antipsychotics and polypharmacy have medical risks • Poorly treated psychiatric illness can complicate medical treatment Hill, M. and O. Freudenreich, Clozapine: key discussion points for prescribers. ClinSchizophrRelat Psychoses, 2013. 6(4): p. 177-85; Misawa, F., et al., Is antipsychotic polypharmacy associated with metabolic syndrome even after adjustment for lifestyle effects?: a cross-sectional study.BMC Psychiatry, 2011. 11: p. 118.

  11. Clozapine Cost-Effectiveness • N=479 clozapine starts compared to N=2240 polypharmacy starts • Continuously enrolled Medicaid patients, 6 months prior and 12 months post • Significantly fewer emergency department visits • Significantly lower overall costs • $21,315 all cause lower • $17,457 mental illness related • $10,582 lower for schizophrenia Velligan, et al. Psychiatric Services2015;66(2):127-33

  12. CLOZAPINE UNDERUTILIZATION

  13. Estimated Antipsychotic Market Share by Year Percent of Market Share in US Adapted from: Gallini A, et al. Diffusion of antipsychotics in the US and French markets. 1998-2008. Psychiatric Services 2013;64:680-7; Meltzer HY. Clozapine: balancing safety with superior antipsychotic efficacy. Clinical Schiz and Related Psychoses 2012;134-144; IMS Health 2004-2008

  14. Clozapine Use by State Torrey EF, et al. Clozapine for Treating Schizophrenia: a comparison of the States. Treatment Advocacy Center, November 2015

  15. Percentage = total number of prescriptions for second-generation antipsychotics (denominator does not include conventional antipsychotics) January 2000 Conley RR, et al. A comparison of Clozapine use in Maryland and in Victoria, Australia. Psychiatric Services 2005;56:320-3

  16. Clozapine Underutilization • In patients with two adequate failed antipsychotic trials the mean time to clozapine initiation was 47.7 months (range 0-219) with 5 trials prior • 68% of patients had 3 or more trials before clozapine initiation (mean prior therapy was ~ 8 yrs) • Time from diagnosis to clozapine initiation increased from 1996 to 2003 • Polypharmacy is higher than clozapine use with little evidence based guidance (approximately 20%) • Why the delay and underuse of clozapine? Howes OD, et al. Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. Br J of Psychiatry 2012;201:481-5; Alessi-Severini S, et al. Clozapine prescribing in a Canadian outpatient population. PLoS ONE 2013 epub ahead of print; Nielsen J, et al. Geographical and temporal variations in clozapine prescription for schizophrenia. European Neuropsychopharmacology 2012;22:818-824; Gören JL, et al. Antipsychotic prescribing pathways, polypharmacy, and clozapine use in treatment of schizophrenia. Psychiatric Services 2013;64:527-33; Gallego JA, et al. Prevalence and correlates of antipsychotic polypharmacy: a systematic review and meta-regression of global and regional trends form 1970s to 2009. Schizophr Res 2012;138:18-28

  17. Mortality Risk is Not Greater • Mortality with clozapine lower compared to other antipsychotic medications (HR = 0.74) (N=66,881 patients Finland) • Mortality is lower with clozapine compared to other antipsychotic medications (OR = 0.23) (N=6,987 patients Denmark) • Our group- finds mortality risk is same with clozapine compared to other antipsychotics both on survival analysis and autopsy findings Tiihonen J, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study. Lancet 2009;374:620-7; Kiviniemi M, et al. Antipsychotics and mortality in first onset schizophrenia: prospective Finnish register study with 5 year follow-up. Schizophr Res 2013;150:274-280; Kelly DL, et al. Cardiac-Related Abnormalities at Autopsy in People with severe mental illness treated with clozapine or risperidone. Schizophr Res 2009;107:134-8

  18. BARRIERS TO CLOZAPINE

  19. Overcoming Barriers to Use • Prescriber knowledge and comfort • Patient and family knowledge and comfort • Clozapine clinics • Hospitals and formularies • Registration in ClozapineREMS • Point of care monitoring • Pharmacogenetic testing Sections we review in White Paper

  20. Overcoming Barriers to Use • Assistance in clozapine initiation • Use in correctional systems and forensic settings • Managing side effects • Improving transitions of care • Suicide and emergency hotlines • Working with Medicaid and managed care companies • Blood draw ease and monitoring Sections we review in White Paper

  21. Barriers to Clozapine Use N=60 psychiatrists -52% thought offering an inpatient hospitalization to start would help -76% of public agency psychiatrists thought it would help Percent of Psychiatrists Reporting Significant Barrier Adapted from: NC Division of Mental Health, Developmental Disabilities and Substance Abuse Services and the North Carolina Psychiatric Association; http://naminc.org/nn/0910Conf/clozapineresearch.pdf

  22. Clinician Perceived Barriers to Clozapine 144 respondents: 56% psychiatrists, 18% nursing, 16% pharmacy staff, 5% social work Pharmacists report more familiarity with clozapine than other professionals (68% pharmacists and 27% psychiatrists) to NICE schizophrenia guidelines Percent of clinicians ranking as a very frequent barrier to clozapine Adapted from: Gee S, et al. Practitioner attitudes to clozapine. Acta Psychiatrica Scandinavia 2013;1-9

  23. Highest Ranking Barriers to Clinical Use Side effects Cardiomyopathy Metabolic syndrome Agranulocytosis Clinical Need for closer monitoring Regular blood work Non-adherence to blood work Non-clinical Lack of centralized system Time spent on admin. tasks N=277/860 (32%) psychiatrists responded, N=255 available for analysis Kelly DL, et al. Clinical Schizophrenia and Related Psychoses, in press. Mean score: 1= not a barrier; 5= a significant barrier.

  24. Kelly DL, in press

  25. Patient’s Attitudes to Clozapine • N=1284, 27 clozapine clinics in UK • 86% feel better on clozapine • 89% prefer clozapine to other antipsychotics • 87% think advantages outweigh disadvantages • 28% rank frequent blood work as biggest disadvantage Taylor et al. Clozapine- a survey of patient perspectives. Psychiatr Bull 2000;24:450-2.

  26. Patient and Clinician Attitudes to Clozapine Percent of Physicians Adapted from: Hodge K and Jesperson S. Side-effects and treatment with clozapine: a comparison between the views of consumers and their clinicians. Int J Mental Health Nurs 2008;17:2-8

  27. Psychiatrists and Severe Neutropenia • Psychiatrists overestimate real risk of severe neutropenia (agranulocytosis) • 23% think risk is >1% • 67% don’t know risk is greatest in first 6 months • Psychiatrists are 5X more likely than patients to rate severe neutropenia risk as most problematic issue with clozapine Nielsen J, et al. Psychiatrist’s attitude towards and knowledge of clozapine treatment. J Psychopharmacol 2010;24:965-71.

  28. STRATEGIES FOR IMPROVED USE

  29. Ranking of Solutions Kelly DL, et al. Clin Schizophernia and Related Psychoses, 2016

  30. Solutions Survey • Second survey sent to top clozapine prescribers in medicaid • 94 sent; 21 returned (22.3%) • Top ranked solutions: 1. POC fingerstick (3.75) 2. BEN support (3.63) 3. Education program for families (3.50) 4. Centralized Clozapine Clinic (3.40) 5. Education program for physicians (3.35) Kelly, et al. unpublished

  31. Solutions Survey • Physicians that have <15 years experience: 1. Centralized Clinic (5.0) 2. POC fingerstick (4.67) 3. Backup prescriber (4.33) 4. Inpatient referral (4.0) 5. Education program for families and transportation for patients (3.67) Kelly, et al. unpublished data

  32. NEW GUIDELINES FOR CLOZAPINE MONITORING

  33. Summary of Changes • Clozapine now managed through one entity - The Risk Evaluation and Mitigation Strategy (REMS) • Certification of prescribers, designees, and pharmacies • New thresholds for clozapine discontinuation - Provisions for BEN patients - Only ANC levels reported - Prescribers can continue treatment with rationale • Non-Rechallenge Master File discontinued - Agranulocytosis no longer in terminology

  34. Summary of Unchanged • No change in frequency of blood draws • With exception that three times weekly instead of twice weekly at lower cut off values • No point of care monitoring approvals • No hematology consults required - Recommended under certain conditions • No changes in labeling other than around neutropenia

  35. What happened to “agranulocytosis”? • No mention of agranulocytosis in new FDA guidelines; now defined as severe neutropenia • Mild Neutropenia - ANC 1,000-1,499/mm3 • Moderate Neutropenia - ANC 500-999/mm3 • Severe Neutropenia - ANC <500/mm3

  36. New thresholds for monitoring (general) **Providers may continue treatment outside these ranges with rationale

  37. Neutropenia in People of African Descent • Normative WBC ranges established in Caucasians • Lower WBC and ANC in African vs. European descent • Benign Ethnic Neutropenia • The occurrence of neutropenia (<1500 cells/mm3), defined by normative data in white populations, in individuals of other ethnic groups who are otherwise healthy and who do not have repeated or severe infections • Linked to allelic variant of Duffy (FY) Antigen for Receptor Chemokine (DARC) Gene • ANC difference related to this factor is sufficient to explain the observed racial difference Haddy TB, e tal. Benign ethnic neutropenia: what is a normal absolute neutrophil count? J Lab Clin Med, 1999;133:15-22. Shoenfeld Y, et al. Benign familial leukopenia and neutropenia in different ethnic groups. Eur J Haematol, 1988;41:273-7. Reich D, et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet, 2009;5:e1000360.

  38. Mean ANC by DARC Genotype (FY allelic distribution) Epidemiologic Cohort of 6,005 Self- Identified African Americans (AA) Reich D, et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet, 2009;5:e1000360.

  39. Reich D, Nalls MA, Kao WHL, Akylbekova EL, et al. (2009) Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene. PLoS Genet 5(1): e1000360. doi:10.1371/journal.pgen.1000360 http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000360

  40. Clozapine in African American Patients • Less likely to be initiated on clozapine -10.3% vs. 15.3% of 2911 inpatients in Maryland • More likely to be dc’s from clozapine - 42% vs. 23% after two years • More likely to be dc’s for neutropenia (5.3% vs. 2.4%) • Less likely to develop severe neutropenia (0.62% vs. 0%) Kelly DL, et al. Clozapine Utilization and Outcomes by Race in a Public Mental Health System: 1994-2000. J Clin Psychiatry, 2006;67:1404-11; Kelly DL, et al. Clozapine Underutilization and discontinuation in African-Americans Due to Leucopenia. Schizophrenia Bulletin, 2007; 33: 1221-4. 

  41. Largest Agranulocytois Cohort to Date • The NIMH funded Clozapine Induced Agranulocytosis Consortium (CIAC), collected data on an international sample of 482 CLZ-treated patients, including 161 agranulocytosis cases and 321 CLZ treated patients without agranulocytosis. • Of the 161 agranulocytosis cases, most were EA and only 5 worldwide in the consortium were AA, again suggesting rare occurrence of severe neutropenia and agranulocytosis risk in AA • Results: • HLA-DQB1 (OR=0.19, 95 CI: 0.12-0.29) • HLA-B (OR=3.3, 95% CI: 2.3-4.9) Goldstein, J.I., et al., Clozapine-induced Agranulocytosis/granulocytopenia Is Associated with Rare HLA-DQB1 and HLA_B Alleles. Nature Communications 2014;5:4757

  42. Clozapine Treatment in Patients with Benign Neutropenia • Retrospective single site study • Data collection of patients with benign neutropenia who received clozapine with modified individual monitoring parameters • Primary outcome: difference in ANC values after initiation of clozapine compared to before clozapine • Secondary outcomes: • Within-participant fluctuations in ANC • Patient outcome on clozapine • Excluded patients receiving lithium Davis, Kelly et al, J Clin Psych, manuscript in press.

  43. Demographic Characteristics Davis, Kelly et al, J Clin Psych, manuscript in press.

  44. Mean Lowest ANC and Overall Mean ANC Values Median time period for documentation was 230 days prior and 364 days post Davis, Kelly et al, J Clin Psych, manuscript in press. 2.63 2.13 1.5 1.4 p = 0.224 p < 0.001 Before Clozapine After Clozapine

  45. Results • No cases of severe neutropenia (ANC < 500 cells/mm3) • ANC < 1000 cells/mm3: • 1/271 (0.4%) prior and 3/1096 (0.3%) after (p=0.795) • No patients were discontinued for falling below their modified guideline parameters • 5 patients had modified guidelines discontinued and successfully remain on manufacturer guidelines to date • 2 patients discontinued due to thrombocytopenia: • 1)Thrombocytopenia at baseline, no change with clozapine • 2) Normal platelets at baseline. With clozapine, steady decline to minimum of 93x103/μL. Improved, but not recovered to baseline 4 months after clozapine discontinuation. Davis, Kelly et al, J Clin Psych, manuscript in press.

  46. Incidents of Laboratory Values Below Cutoff New Mild Neutropenia Davis, Kelly et al, J Clin Psych, manuscript in press. Percent of Laboratory Values below FDA Cut-Offs 31.4% After Clozapine (n = 1096) Before Clozapine (n = 271) 16.0% 13.3% p < 0.001 p < 0.001 2.1% (ANC < 2.0x103 cells/mm3) (ANC < 1.5x103 cells/mm3)

  47. Incidents of Laboratory Values Below Cutoff Davis, Kelly et al, J Clin Psych, manuscript in press. Percent of Laboratory Values below Modified Guidelines 4.2% After Clozapine (n = 716) Before Clozapine (n = 212) 1.9% 1.8% p = 0.36 p < 0.001 0.5% p = 0.04 0.1% 0.0%

  48. New provisions for BEN patients **Providers may continue treatment outside these ranges with rationale

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