the growing use of antipsychotics - wild apricot...label uses for antipsychotics compare and...
TRANSCRIPT
THE GROWING USE OF
ANTIPSYCHOTICS: AN UPDATE ON INDICATIONS,
MONITORING AND COUNSELING
Karen Moeller, PharmD, BCPP
Clinical Associate Professor
The University of Kansas, School of Pharmacy
Objectives
Discuss common FDA indications and off-
label uses for antipsychotics
Compare and contrast both typical and
atypical antipsychotics’ side effects, drug
interactions and monitoring parameters
Provide recommendations to patients,
caregivers, and healthcare providers for
managing antipsychotic side effects and
monitoring parameters
Case
20 year old male presents with 2 new prescriptions
Sertraline (Zoloft) 50 mg PO QAM
Quetiapine (Seroquel) 100 mg PO QHS
What is his Diagnosis?
Second Generation Antipsychotics
(SGA) IndicationsSchizophrenia/
Schizoaffective
disorder
Bipolar Mania Bipolar
Depression
Depression
adjunct
Irritability in
Autism
Aripiprazole
Asenapine
Brexipiprazole
Cariprazine
Clozapine+
Iloperidone
Lurasidone
Olanzapine
Paliperidone*
Quetiapine
Risperidone
Ziprasidone
Apripirazole#
Asenapine
Cariprazine
Olanzapine#
Quetiapine
Risperidone
Ziprasidone#
Lurasidone
Quetiapine
Aripiprazole
Brexipiprazole
Quetiapine ER
Aripiprazole
Risperidone
Pharmacist Letter, Feb 2015
TCPR, June 2011,
Schizophrenia
* Also indicated for schizoaffective #Also approved for Bipolar Maintenance
+ Clozapine indicated for treatment resistant Schizophrenia and reducing
suicidal behaviors in schizophrenia and schizoaffective
Off-label uses for SGA
Treatment-Refectory Depression
Insomnia
Anxiety, PTSD, OCD
Personality disorders (borderline personality disorder)
ADHD
Dementia
Eating disorders
Autism
Substance abuse
AHRQ. Off-label use of Atypical Antipsychotics: An update.
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0016529/pdf/PubMedHealth_PMH0016529.pdf
Antipsychotics1st Generation 2nd Generation
Thorazine® (chlorpromazine) Clozaril® (clozapine)
Mellaril® (thioridazine) Risperdal® (risperidone)*
Loxitane® (loxapine) Geodon® (ziprasidone)
Trilafon® (perphenazine) Seroquel® (quetiapine)
Stelazine® (trifluperazine) Zyprexa® (olanzapine)*
Navane® (thiothixene) Abilify® (aripiprazole)*
Prolixin® (fluphenazine)* Invega® (paliperidone)*
Haldol® (haloperidol) * Fanapt® (Iloperidone)
Saphris® (Asenapine)
Latuda® (Lurasidone)
Rexulti® (Brexiprazole)
Vraylar® (Cariprazine)*Available in a Long Acting Injection
Pharmacologic Properties
Receptor Effect by blocking the receptor
Dopamine Mesolimbic – relief of positive symptoms
Nigrostriatal – movement disorders, EPS
Tuberoinfundibular – hyperprolactinemia
Mesocortical – increase negative symptoms
Muscarinic Anticholinergic side effects
Alpha Adrenergic Orthostasis, hypotension
Histamine Weight gain, Sedation
First Generation Antipsychotics
(FGA) or Typicals
Second Generation Antipsychotics
(SGA) or Atypicals
Dopamine (D2)
Muscarinic
Alpha Adrenergic
Histamine
Dopamine (D2) / Serotonin (5-HT2A)
Muscarinic
Alpha Adrenergic
Histamine
Typical Antipsychotics
High
Potency
Low
potency
Agent Potency (MG)
chlorpromazine (Thorazine) 100
thioridazine (Mellaril) 100
mesoridazine (Serentil) 50
loxapine (Loxitane) 10
molindone (Moban) 10
perphenazine (Trilafon) 8
trifluoperazine (Stelazine) 5
thiothixene (Navane) 4
fluphenazine (Prolixin) 2
haloperidol (Haldol) 2
Atypical Antipsychotics (SGA)
Asenapine (Saphris®)
Clozapine (Clozaril®)*
Iloperidone (Fanapt®)
Lurasidone (Latuda®)
Olanzapine (Zyprexa®)*
Paliperidone (Invega®)
Risperidone(Risperdal®)*
Quetiapine(Seroquel®)*
Ziprasidone (Geodon®)*
* Generic formulation
Aripiprazole (Abilify®)*
Brexpiprazole(Rexulti®)
Cariprazine (Vraylar®)
Oral disintegrating
tablets ≠ sublingual
Long acting Injection
(e.g. Monthly)Immediately Release Injection
(e.g. work right away!)
Dosage FormulationsTablet/
Capsule
Oral
Disintegrating
Injectable
(IM)
Rapid Acting
Long acting
Injectable
Aripiprazole* Tablet Yes Yes Yes
Asenapine SL tablet
Brexpiprazole Tablet
Cariprazine Capsule
Clozapine* Tablet Yes
Iloperidone Tablet
Lurasidone Tablet
Olanzapine* Tablet Yes Yes Yes
Quetiapine* Tablet
Risperidone* Tablet Yes Yes
Paliperidone Capsule Yes
Ziprasidone* Capsule Yes
* Generic formulations
General Side Effect Comparison
FGA > SGA
• Extrapyramidal Side Effects
• Neuroleptic malignant syndrome
SGA> FGA
• Weight gain
• Diabetes
• Hyperlipidemia
Extrapyramidal Side Effects
Dystonia
Severe Muscle Spasm
Parkinsonism
Blank facial expression
Rigidity
Tremors
Shuffling Gait
Akathisia
Restlessness
Can’t sit still
Pacing
Tx. Propranolol
Benzodiazepine
Tardive Dyskinesia's
Involuntary movement
Tx. Monitor and prevent
-Tx: Benztropine or Diphendydramine
Weight gain
Lipid abnormalities
Glucose intolerance / Diabetes
Weight gain of up to 25-50 pounds is common with clozapine, olanzapine
Agents with minimal weight gain – aripiprazole, lurasidone, ziprasidone
Main Side Effects for SGA
Overall Side Effects of Antipsychotics
Cardiovascular side effects QTc prolongation
Consider baseline EKG in all patients
Increase Prolactin Galactorrhea, gynecomastia, amenorrhea
FGA and risperidone/paliperidone
Drowsiness
Some are more than other
Usually resolves in a few week
Overall Side Effects of Antipsychotic
Anticholinergic Side Effects Dry Mouth
Constipation
Urinary retention
Blurred vision
Increase heart rate
Decreased sweating – can be deadly
Weight Gain
Orthostatic hypotension
Stroke
Typical Antipsychotics Comparison
Agent Sedation Anticholin
ergic
Cardiac
Orthostasis
EPS
chlorpromazine (Thorazine) High High High Low
thioridazine (Mellaril)
mesoridazine (Serentil)
loxapine (Loxitane)
molindone (Moban)
perphenazine (Trilafon)
trifluoperazine (Stelazine)
thiothixene (Navane)
fluphenazine (Prolixin)
haloperidol (Haldol) Very low Very low Very low Very High
Atypical ComparisonHigh Risk Low Risk
EPS/TD Risperidone
Paliperidone
Clozapine
Quetiapine
Akathisias Aripiprazole
Lurasidone
Clozapine
Quetiapine
Weight Gain
Glucose intolerance
Lipid abnormalities
Clozapine
Olanzapine
Aripiprazole, lurasidone,
ziprasidone
Hyperprolactinemia Risperidone
Paliperidone
Aripiprazole
QTc prolongations Ziprasidone
Iloperidone
Aripiprazole
Olanzapine
Orthostatic
Hypotension
Clozapine
Iloperidone
Sedation Clozapine
Quetiapine
Risperidone
Iloperidone
Lurasidone
Pharmacist Letter, Feb 2015; TCPR, June 2011, Schizophrenia
Medication Specific adverse effects
Aripiprazole – impulse control disorder
Asenapine – severe allergic rx (anaphylaxis, angioedema, rash, etc.)
Clozapine – agranulocytosis, myocarditis
Olanzapine long acting injection
Sedation- Delirium syndrome
Severe skin reaction
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Ziprasidone and Olanzapine
Black Box Warnings
Increased Mortality in Elderly Patients with Dementia Related Psychosis
Causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
All antipsychotics
Increase suicidally in adolescents and young adults < 25 years old
Antipsychotics with bipolar depression or adjunct depression indications
Monitoring Baseline Follow-up
Blood Pressure/
Orthostatic hypotension
X Every visit
Weight X Monthly for 1st 3 months, then quarterly
Waist Circumference X Annually
Glucose intolerance X At 3 months, then annually (if normal)
Hyperlipidemia X At 3 months, then annually (if normal)
Prolactin X Assess through interview at each visit; if
symptoms present – order prolactin level
EPS
Akathisia
Parkinsonism
Tardive Dyskinesia
X
X
X
Every visit (Barnes Akathisia Scale)
Every visit (Simpson Angus Scale)
Every 3 month – FGA; Every 6 months SGA
(AIMS or Discus rating scale)
EKG X Consider cardiac risk factors
Schizophrenia treatment guidelines 2010; Diabetes Care, 27(2), 2004
Second Generation Antipsychotics
(SGA) IndicationsSchizophrenia/
Schizoaffective
disorder
Bipolar Mania Bipolar
Depression
Depression
adjunct
Irritability in
Autism
Aripiprazole
Asenapine
Brexipiprazole
Cariprazine
Clozapine+
Iloperidone
Lurasidone
Olanzapine
Paliperidone*
Quetiapine
Risperidone
Ziprasidone
Apripirazole#
Asenapine
Cariprazine
Olanzapine#
Quetiapine
Risperidone
Ziprasidone#
Lurasidone
Quetiapine
Apripirazole
Brexipiprazole
Quetiapine ER
Apripirazole
Risperidone
Pharmacist Letter, Feb 2015
TCPR, June 2011,
Schizophrenia
* Also indicated for schizoaffective #Also approved for Bipolar Maintenance
+ Clozapine indicated for treatment resistant Schizophrenia and reducing
suicidal behaviors in schizophrenia and schizoaffective
SGA: D2 / 5-HT2a Antagonist
PO dosing CYP 450
Metabolism
Comments
Asenapine
(Saphris)
10 – 20 mg 1A2 - Sublingual tablet- No food or drink 10 minutes after dose- Odd taste- DO NOT SWALLOW
- Akathisia and somnolence
- Unit dose packing may make it hard for
people to open
Iloperidone
(Fanapt)
12-24 mg 3A4
2D6
- Slow titration due to orthostatic
hypotension
-Significant QTc prolongation
Lurasidone
(Latuda)
40-160 mg 3A4 -Contraindicated with strong CYP3A4
inhibitors and inducers
- Must take with 350 calories of food
- Akathisia (recommended to take at night
to minimize side effect)
SGA: D2 / 5-HT2a AntagonistPO
dosing/day
CYP 450
Metabolism
Comments
Olanzapine
(Zyprexa)
10 – 20 mg 1A2 -High weight gain-Long acting injection - must monitor for 3 hrs(Sedation/delirium syndrome); restricted distribution-Avoid parental benzos with rapid acting IM
Paliperidone
(Invega)
3-12 mg N/A - Active metabolite of risperidone
- Ghost tablets will appear in stool
- Long acting monthly and three-month
injection
- May increase prolactin
- Good for patients with hepatic dysfunction
Risperidone
(Risperdal)
1-6 mg 2D6 - May increase prolactin
- Every two week long-acting injection
- Dosages greater than 6 mg increase EPS
Quetiapine
(Seroquel)
150- 800
mg
3A4 - Sedation
- XR take with light meal or snack
Ziprasidone
(Geodon
40-160 mg 3A4 - QT prolongation
- Take with food
Partial D2 agonist / 5-HT2a Antagonist
PO dosing CYP 450
Metabolism
Comments
Aripiprazole
(Abilify)
5-15 mg 3A4
2D6
Adjunctive depression
Akathisia
Considered the most
“activating” SGA
Brexipiprazole
(Rexulti)
1-4 mg 3A4
2D6
Adjunctive depression
Similar to aripiprazole
Possibly less activating
Cariprazine
(Vraylar)
1.5 – 6 mg 3A4
2D6
Similar to aripiprazole
Possibly less activating
Not recommend to be use
with 3A4 inducers
dosing recommendations with inhibitors and inducers
The partial agonist may help stabilize the dopamine system
without causing hypo dopaminergic conditions
Clozapine (Clozaril)
Reserved for treatment resistant patients
Reduces the risk of suicide in Schizophrenia
Many Side effects Agranulocytosis (REMS program)
Seizures at doses > 600 mg/day
Orthostatic hypotension – must titrate slowly
Myocarditis
Sedation
Weight gain, diabetes
Sialorrhea
Must me a registered pharmacy to dispense
Monitor ANC weekly x 6 months, then every 2 weeks X 6 months, then monthly
www.clozapinerems.com
Atypical Drug InteractionsDrug Major
CYP450
Metabolic
Enzyme
Increase AP
Concentration
Decrease AP
Concentration
Aripiprazole 3A4,
2D6
Protease inhibitors (PI),
ketoconazole, clarithromycin
paroxetine, fluoxetine
carbamazepine
Clozapine 1A22C19, 2D6,
3A4(minor)
Fluvoxamine, ciprofloxacin,
paroxetine, fluoxetine
Cigarette Smoking
Lurasidone 3A4 PI, ketoconazole, clarithromycin,
diltiazem
Rifampin,
Carbamazepine
Olanzapine 1A2 Fluvoxamine, ciprofloxacin Cigarette Smoking
Risperidone 2D6 Paroxetine, fluoxetine
Quetiapine 3A4 PI, clarithromycin, ketoconazole carbamazepine
Ziprasidone 3A4 PI, clarithromycin, ketoconazole carbamazepine
Other Drug interactions
Antiarrhythmics
Amiodarone
Flecainide
Quinidine
Antibiotics
Clarithromycin, Erythromycin
Fluconazole
Quinolones
Others
Methadone
Citalopram
Ondansetron
Stimulants Enhance dopamine
release
Increase psychosis, mania
Dopamine agonist Levodopa
If patient has Parkinson's and psychosis, consider a weak dopamine blocker (e.g. quetiapine)
QTc prolonging drugs Pharmacodynamics
Choice of Antipsychotic
Need to consider
History of prior response
Cost/ability to obtain medication
Matching patient-specific characteristics
with adverse effect profile of selected
agent
Efficacy
Side effects
Efficacy: Are SGA better than FGA
Clozapine is considered the most effective antipsychotic
Controversial topic
Most guidelines recommend SGA before FGA
SGA are often viewed as safer than SGA
Landmark Studies Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE).
Cost Utility of the latest Antipsychotic Drugs in Schizophrenia (CUtLASS)
Lieberman JA, et al. N Engl J Med 2005;353:1209-23
Jones RB, et al. Arch Gen Psychiatry. 2006; 62 (10):1079-87
CATIE and CUtLASS: Key findings
CATIE
1493 patients - FGA vs SGAPrimary endpoint: all-cause discontinuationPts stayed on olanzapine longer than other APOlanzapine-highest rates of metabolic abnormalitiesNo difference in QOL and cognitive symptoms
CUtLASS
• 277 patients, FGA vs SGA
• No difference in QOL
• Significant improvement in symptoms with clozapine over other SGA
Conclusion: SGA and FGA are similar in effectiveness, compliance and QOL
Controversies with Antipsychotic
Off label uses
Multiple Antipsychotics
High dose Antipsychotics
Use in children
Off-label uses for SGA
Treatment-Refectory Depression
Insomnia
Anxiety, PTSD, OCD
Personality disorders (borderline personality disorder)
ADHD
Dementia
Eating disorders
Autism
Substance abuse
Nausea / VomitingAHRQ. Off-label use of Atypical Antipsychotics: An update.
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0016529/pdf/PubMedHealth_PMH0016529.pdf
Evidence for off-label antipsychotics use
Promising
General anxiety disorder
- quetiapine
OCD – risperidone
Modest/mixed
PTSD- risperidone
Personality disorders
Dementia – aripiprazole,
olanzapine, risperidone
Lack of Studies/ Efficacy
Insomnia
Substance abuse
Eating disorders
ADHD
AHRQ. Off-label use of Atypical Antipsychotics: An update.
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0016529/pdf/PubMedHealth_PMH0016529.pdf
Antipsychotic Polypharmacy
Use of two or more antipsychotics together
Common practice
Controlled trials do not support combined use
Increased side effects than efficacy
Increase mortality
Short term use during AP switch may be appropriate
Last-line opinion in guidelines
Rationale for use of AP polypharmacy must be
documented on discharge from psychiatric
hospitalizations
Current Psychiatry July 2008
High dose antipsychotics
Rationale for use
Patients in clinical trials are not “usual patients”
Treatment response is consider ~ 20% symptoms
reduction in clinical trials
Up to 30% of patients are treatment refectory
Allows for monotherapy versus polypharmacy
Common agents dosed above the max
Aripiprazole, Olanzapine, Quetiapine, Ziprasidone
Mixed evidence on efficacy
PCN Frontier Review 2015
Antipsychotics in Children
2 – 4 fold increase in last 15 years
Risk factors: Minorities, Medicaid enrollees, foster care
Efficacy in psychosis, bipolar disorder, autism
Lack of efficacy in behavior or ADHD
Long term effects are unclear
Metabolic effects may be higher than adults
Hyperprolactinemia effects?
EPS tends to be higher
Cardiovascular safety – limited data
Schenider, C et al. Journal of Psychopharmacology 28(7): 2014
Five DON’T to prescribing AP
http://www.choosingwisely.org/wp-content/uploads/2015/02/APA-Choosing-Wisely-List.pdf
Don’t Prescribe AP to patients for any indication without
appropriate initial evaluation and appropriate ongoing
monitoring
Routinely prescribe 2 or more antipsychotics concurrently
Use antipsychotics as 1st choice to treat behavioral and
psychological symptoms of depression
Routinely prescribe antipsychotic medications as 1st line
intervention for insomnia in adults
Routinely prescribe an AP medication to treat behavioral
and emotional symptoms of childhood mental disorders in
the absence of approved or evidence supported indications
Final Thoughts
Treatment Adherence
Very low in psychiatric patients
70-80% of patients admitted to the hospital
stopped their medication
Remind patients that adhering to treatment/
medications helps to prevent relapse
Non
Adherence
Treatment Success
Side Effects
Complex Dosing
regimen
FamilyCost
Denial of illness
Treatment
Failure
How can pharmacist help?
Counseling points
Side effects often go away
Some side effects can be treated
What to do with specific SE
Medication take time to work. Be patient
You may still have symptoms while on the medication
but your symptoms should be diminished
Long term treatment is necessary – even when they
feel better
Give them tools to remember to take their medications
Pill box; bubble packs
Summary
Antipsychotics are useful for many indications
SGA have significant metabolic effects and patients should be monitored annually
Tardive dyskensia should be assessed every 3 months for FGA and every 6 months for SGA
Important to make sure that safe prescribing practices are occurring (remember the 5 don’t)
Important that patients understand the value of their medication
Resources for pharmacists
National Alliance on Mental illness (NAMI) www.nami.org
College of psychiatric and neurologic pharmacists (CPNP) www.cpnp.org