APNA 34th Annual Conference Session 4022: Saturday, October 3

APNA 34th Annual Conference

Session 4022: Saturday, October 3

DISCLOSURES

? Over the past twelve months, Rob

Cotes has received research

funding from Alkermes, Lundbeck,

Otsuka, and Roche. He is a paid

consultant to Saladax Biomedical

and the American Psychiatric

Association. His research is also

supported by the Foundation for

Excellence in Mental Health Care,

the Jim and Billie Ellis Foundation,

the John and Polly Sparks

Foundation, and the Betty and

Davis Fitzgerald Foundation.



Demystifying Clozapine to Support Recovery of

Patients with Persistent Psychosis

Robert Cotes, MD

Donna Rolin, PhD, APRN, PMHCNS�\BC, PMHNP�\BC

Physician Expert, APA/SMI Adviser

Clinical Nurse Expert, APA / SMI Adviser

PMHNP Program Director, University of Texas at Austin School of Nursing

Associate Professor, Emory University School of Medicine

? Donna Rolin presents no

disclosures.

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LEARNING OUTCOMES

? Demonstrate best practices for implementing clozapine prescribing in

routine clinical care.

? Recall team�\based models for treating persistent psychosis.

? Apply side�\effect assessment and education to patients with psychosis.

PERSISTENT PSYCHOSIS

Prevalence

Definition

Effective treatments

Systematic Approach



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Treatment Resistant Schizophrenia (TRS)

Prevalence of TRS

? Causes considerable suffering, including

34 billion dollars in direct medical costs

to the US

? High rate of suicidal ideation (44%)

? High rates of smoking (56%) and

substance abuse (51%)

? Likely includes 20�\30% of individuals

with schizophrenia

? 392 never�\treated patients with schizophrenia

? Remission rates at 3 years during follow up treatment

?

?

?

?

Kennedy, J. L., Altar, C. A., Taylor, D. L., Degtiar, I., & Hornberger, J. C. (2014). The social and economic burden of

treatment�\resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol, 29(2), 63�\76.

Conley, R. R., & Kelly, D. L. (2001). Management of treatment resistance in schizophrenia. Biol Psychiatry, 50(11),

898�\911.

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60.3% symptoms

45.4% functioning

57.0% subjective wellbeing

14% never fulfilled any remission criteria

Lambert, M., Naber, D., Schacht, A., Wagner, T., Hundemer, H. P., Karow, A., . . . Schimmelmann, B. G. (2008). Rates and predictors of remission and recovery during 3 years in 392 never�\treated patients with

schizophrenia. Acta Psychiatr Scand, 118(3), 220�\229.

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Robert O. Cotes, M.D.

Donna Rolin, PhD, APRN, PMHCNS�\BC, PMHNP�\BC

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APNA 34th Annual Conference

Session 4022: Saturday, October 3

Defining TRS

Treatment Resistant Schizophrenia (TRS)

? Highlights of TRIPP Guidelines (minimum requirement)

? Clozapine is the only medication approved by

the US FDA for TRS

? 4.8% of people with schizophrenia are

prescribed clozapine in the US

? Many clinicians do not have clinical

competencies necessary to prescribe

clozapine, and many organizations do not

have supports in place.

? Current symptoms are moderate in severity with at least moderate functional

impairment despite:

? 2 or more antipsychotic medication trials

? Antipsychotic dose equivalent to ��600 mg chlorpromazine per day

? Antipsychotic trial �� 6 weeks at therapeutic dosage

? ��80% of prescribed doses taken

Howes, O. D., McCutcheon, R., Agid, O., de Bartolomeis, A., van Beveren, N. J., Birnbaum, M. L., . . . Correll, C. U. (2017). Treatment�\Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP)

Working Group Consensus Guidelines on Diagnosis and Terminology. Am J Psychiatry, 174(3), 216�\229.

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Olfson, M., Gerhard, T., Crystal, S., & Stroup, T. S. (2016). Clozapine for Schizophrenia: State Variation in Evidence�\Based Practice. Psychiatr

Serv, 67(2), 152.

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When to Use Clozapine

A Systematic Approach to TRS

? Recommends clozapine after ��minimal or no response to two trials of

antipsychotic medication��

? Recommends that patients with schizophrenia be treated with clozapine if

the risk for suicide attempts or suicide remains substantial despite other

treatments.

? Suggests that patients with schizophrenia be treated with clozapine if the

risk for aggressive behavior remains substantial despite other treatments

? 5 C��s

American Psychiatric Association. (2019). The American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia (Draft Guideline). from

�\practice�\guidelines

Roerig, J. L. (2019). Clozapine augmentation strategies. Ment Health Clin, 9(6), 336�\348.

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Correct Diagnosis

Comorbidities

Compliance

Concentration of Antipsychotics

Continuous psychosocial stressors

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Care and Staffing Models for Use of Clozapine

CARE & STAFFING MODEL

STRUCTURE

? Complexity of Implementation

? Patient Selection Process

? Indications

? Treatment team identification

? Patient discussions

Successful Use of Clozapine

REMS Registry & Monitoring/Reporting

? Leadership of clozapine systems

? Psychiatrists

? Psychiatric Mental Health Nurses are well suited to lead clozapine systems



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Robert O. Cotes, M.D.

Donna Rolin, PhD, APRN, PMHCNS�\BC, PMHNP�\BC

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APNA 34th Annual Conference

Session 4022: Saturday, October 3

Successful Care and Staffing Models

Clozapine Survey (SMIA)

? Multidisciplinary clinic

? Psychiatrist or PMHNP, nurse, pharmacist, case manager, rehabilitation

? One prescriber or multiple prescribers, usually with a psychiatrist medical director

? One�\stop shopping: Vital signs, education, lab test, prescriber when needed,

dispense, REMS

? Lab or point of care ANC testing

? Virtual team

? Psychiatrist or PMHNP prescriber, pharmacist, laboratory

? Clozapine management organization: labs, dispensing, REMS, manage side�\effects,

travel and logistical issues

N=81

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Clozapine Survey

Easing Burden of Clozapine

N=81

? Laboratories

? Most labs accept standing orders, or can place standing order in EMR

? Request results to be faxed to the pharmacy

? Consider point of care testing with automated REMS reporting and dispensing

? Pharmacies

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Ese pharmacy with clozapine experience

Many will accept refills on clozapine prescriptions

Many will dispense after they check the ANC themselves

Most will report the ANC to the REMS in place of clinician reporting

Some pharmacies and states allow collaborative arrangements to increase role of

pharmacist

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Easing Burden of Clozapine

Easing Burden of Clozapine

Prescriber

? Patients

?

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?

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Weekly or monthly visits are not always necessary

Can often check in by phone or video telehealth

Need to evaluate for side�\effects, manage titration, and handle barriers

Engage families or other supports

Communicate confidence and usual course of clozapine titration and response

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Robert O. Cotes, M.D.

Donna Rolin, PhD, APRN, PMHCNS�\BC, PMHNP�\BC

Patient

? 2020 American Psychiatric Association. All rights reserved.

Laboratory

Pharmacy

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REMS

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APNA 34th Annual Conference

Session 4022: Saturday, October 3

CLOZAPINE REMS�\The

Single Shared

SystemFrequency

for Clozapine

Recommended

Monitoring

and Clinical Decisions by ANC Level

FAMILY PERSPECTIVE & ROLE IN CARE

Recommended Monitoring Frequency and

Clinical Decisions by ANC Level

ANC Level

Engaging the patient��s family/support system can be a tremendous benefit

? Ask the person who they consider to be a source of support for them

? Secure releases of information

? Invite them into sessions to explain

o What��s involved in Clozapine therapy �C benefits and challenges

o What they can expect and look for

o How they can be supportive of their loved one

Treatment Recommendation

Normal range for a new patient �\ Initiate treatment

�\ If treatment interrupted

�\ General population

�\ ? 30 days, con nue monitoring as

�\ (ANC �� 1500/?L)

before

�\ ? 30 days, monitor as if new

BEN POPULATION

patient

�\ BEN Population

�\ (ANC �� 1000/?L)

�\ Obtain at least two baseline �\ Discontinuation for reasons other than

ANC levels before initiating

neutropenia (other conditions or side

treatment

effects)

? Including the patient and the family in the treatment process can yield the

best outcomes

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ANC Monitoring

�\ Weekly from initiation to 6 months

�\ Every 2 weeks from 6 to 12 months

�\ Monthly after 12 months

�\ See section ��Discontinuation of

Treatment�� of the full Prescribing

Information

�\

zapineUI/prescribingInformation.s#

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Moderate Neutropenia

(500 to 999/?L)*

GENERAL POPULATION

�\ Recommend hematology consultation

�\ Interrupt treatment for suspected

clozapine induced neutropenia

�\ Resume treatment once ANC

normalizes to �� 1000/?L

GENERAL POPULATION

�\ Daily until ANC �� 1000/?L, then

�\ Three times weekly until ANC �� 1500/?L

�\ Once ANC �� 1500/?L, check ANC weekly

for 4 weeks, then return to patient��s last

��Normal Range�� ANC monitoring

interval**

BEN POPULATION

�\ Recommend hematology consultation

�\ Continue treatment

BEN POPULATION

�\ Three times weekly until ANC �� 1000/?L or

�� patient��s known baseline.

�\ Once ANC �� 1000/?L or patient��s known

baseline, then check ANC weekly for 4

weeks, then return to patient��s last

��Normal Range�� ANC monitoring

interval**

Planning for Continuation of Clozapine During Emergencies

(such as coronavirus COVID�\19 pandemic)

? Emergencies/Disasters/Pandemics �\ prevent patients from coming to a

clinic or laboratory for necessary assessments or blood monitoring

? First is to consider whether the patient is appropriate for the creation of

an extra clozapine supply

? Access to point�\of�\care (POC) ANC testing

? Plan for remote follow�\up

? For more stable patients, a phone call may be sufficient.

? Also, the U.S. FDA has the authority to change guidance during major

crises.

* Confirm all initial reports of ANC less than 1500/?L (ANC �� 1000/?L for BEN patients) with a repeat ANC measurement within 24 hours

** If clinically appropriate

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Update from the FDA regarding COVID�\19,

Clozapine REMS, and blood monitoring

Point of Care (POC) Technology

? A new portable device (Athelas One) provides WBC and ANC monitoring results within

6 minutes by capillary draw

? Per communication with FDA and Clozapine REMS, prescribers and pharmacies have discretion

to order and dispense clozapine without an absolute neutrophil count reported within the

specified time frames. [This information is current as released on 1/23/2020; obtained on

3/22/2020.]

? Drop of blood goes into test strip to create peripheral blood smear

? Device images and automatically analyzes the cells morphologically with machine

learning and pathologist oversight, and then generates + clears the final count report

? Uses computer vision and our remote pathology lab on the backend using CLIA lab

? Clinicians receive results on computer or app

? Connects via WIFI or Ethernet

? Can integrate automatically with ClozapineREMS



? Potential for reimbursement with testing

? The following is posted on the Clozapine REMS website (click to view full guidance):

? ***Important Program Update (as of 01/23/2020; updated 4/20/2020)***

? ANC Current Lab Requirements Absolute Neutrophil Count not current (i.e., within 7, 15, or 31

days of the lab draw date) based on the patient��s monitoring frequency (MF) will not prevent a

patient from receiving clozapine from the pharmacy. Although ��ANC not current�� will not

prevent a patient from receiving clozapine from the pharmacy, pharmacies are encouraged to

submit the ANC to the Clozapine REMS Program when the pharmacist is made aware of a more

current ANC than the most recent lab value reported in the PDA response.

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Robert O. Cotes, M.D.

Donna Rolin, PhD, APRN, PMHCNS�\BC, PMHNP�\BC

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APNA 34th Annual Conference

Session 4022: Saturday, October 3

Validation of ANC

? Has been rigorously clinical validated across 800

patients, and especially in patients exhibiting

drug�\induced neutropenia at the Dale Lab in

University of Washington

OUTCOMES

? More than 30,000 ANC tests have been run on

the Athelas One device platform to�\date

Monitoring effectiveness

Side effect monitoring & management

? Recently granted Class II FDA device clearance

in US

? First in class in US for this type of technology



r=0.94

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Monitoring for Side Effects: Myocarditis

Monitoring Effectiveness

? Myocarditis is a rare, but potentially serious side effect of clozapine. It can be fatal.

? Usually occurs within 2�\3 weeks of starting clozapine

? Inflammation of the heart muscle

? Symptom relief

? positive symptoms decreased: disorganization, hallucinations, delusions

? Clozapine blood levels

?

?

?

?

? symptoms are non�\specific: fever, fatigue, flu�\like symptoms, chest pain, tachycardia,

palpitations, hypotension, dyspnea, signs of heart failure, electrocardiographic changes

there is no therapeutic level or window: symptoms and side�\effects guide dosage

levels useful for adherence, more side�\effects, less efficacy, drug�\drug interactions

steady state: more than 3 days after a patient is stable on a dose

trough: 12 hours after the last dose

? Management: discontinue clozapine and obtain cardiac evaluation upon suspicion

of myocarditis

? diagnostic evaluation include EKG, C�\reactive protein (CRP) and troponin (I and T subtypes),

and cardiac MRI

? Clozapine levels and efficacy

? efficacy usually starts at levels above 250 ng/ml

? greatest efficacy at levels above 350 ng/ml

? risk of seizures increases at levels above 1000 ng/L

? If a patient has had myocarditis on clozapine, the decision regarding whether to

restart clozapine is made on a case�\by�\case basis.

? If the benefit of outweighs the risks, the clinician may consider restarting clozapine in

consultation with a cardiologist, after a complete cardiac evaluation, and with close monitoring

? Norclozapine levels

Schulte P (2003) What is an adequate trial with clozapine? Therapeutic drug monitoring and time to response in treatment�\refractory schizophrenia. Clinical Pharmacokinetics 42: 607�C618

Williams, A. M., & Park, S. H. (2015). Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs, 29(2), 101�\111.

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Ronaldson, K. J., Fitzgerald, P. B., Taylor, A. J., Topliss, D. J., & McNeil, J. J. (2011). A new monitoring protocol for clozapine�\induced myocarditis based on an analysis of 75 cases and 94 controls. Aust N

Z J Psychiatry, 45(6), 458�\465.

Cook, S. C., Ferguson, B. A., Cotes, R. O., Heinrich, T. W., & Schwartz, A. C. (2015). Clozapine�\Induced Myocarditis: Prevention and Considerations in Rechallenge. Psychosomatics, 56(6), 685�\690.

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Monitoring for Side Effects: Seizures

Monitoring for Side Effects: Weight Gain

? Significant weight gain occurs in one third of patients who take clozapine

? Weight and BMI should be measured monthly for 6 months then quarterly

? Seizures are an uncommon, but a potentially serious side effect of

clozapine.

? patients should weigh themselves weekly at home

? between 2% and 4% of patients taking clozapine have a seizure during

treatment

? the risk for seizure may be dose related

? patients should not drive while clozapine is titrated

? Obesity is associated with hyperlipidemia, hyperglycemia, hypertension

? it is easier to prevent weight gain than to lose weight

? 5�\10 lb. weight gain should lead to intervention

? a substantial proportion of patients who take clozapine improve, and are able to

engage better with psychoeducational weight loss interventions

? Management: seizures can usually be controlled with dosage

reduction or adding an antiepileptic medication such as valproate

? Management

? taper or discontinue other medications that cause weight gain

? metformin can reduce body weight and reverse metabolic problems

? others: orlistat, topiramate, naltrexone�\bupropion,

liraglutide

Pacia, S. V., & Devinsky, O. (1994). Clozapine�\related seizures: experience with 5,629 patients. Neurology, 44(12), 2247�\2249.

Williams, A. M., & Park, S. H. (2015). Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs, 29(2), 101�\111.

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Robert O. Cotes, M.D.

Donna Rolin, PhD, APRN, PMHCNS�\BC, PMHNP�\BC

Nemani, K. L., Greene, M. C., Ulloa, M., Vincenzi, B., Copeland, P. M., Al�\Khadari, S., & Henderson, D. C. (2019). Clozapine, Diabetes Mellitus, Cardiovascular Risk and Mortality: Results of a 21�\Year

Naturalistic Study in Patients with Schizophrenia and Schizoaffective Disorder. Clin Schizophr Relat Psychoses, 12(4), 168�\176.

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