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Olanzapine: Comprehensive Guidelines for Safe and Effective Use, Esquemas y mapas conceptuales de Ciencias Médicas

Detailed guidelines for the use of olanzapine, an atypical antipsychotic medication. It covers a wide range of topics, including monitoring requirements, special populations, contraindications, and potential advantages and disadvantages of the drug. The comprehensive information presented can help healthcare professionals make informed decisions when prescribing olanzapine, ensuring optimal patient outcomes and minimizing the risk of adverse effects. The document delves into specific considerations for renal, hepatic, and cardiac impairment, as well as for elderly, pediatric, and pregnant patients. It also highlights the importance of vigilance for rare but serious adverse events, such as diabetic ketoacidosis. Overall, this document serves as a valuable resource for healthcare providers to navigate the safe and effective use of olanzapine in the management of various psychiatric conditions.

Tipo: Esquemas y mapas conceptuales

2023/2024

Subido el 29/08/2024

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OLANZAPINE
THERAPEUTICS
Brands Zyprexa
Symbyax (olanzapine-fl uoxetine
combination)
Relprevv
see index for additional brand names
G e n e r i c ? Yes
Class
Neuroscience-based Nomenclature:
dopamine and serotonin receptor
antagonist (DS-RAn)
Atypical antipsychotic (serotonin-
dopamine antagonist; second-generation
antipsychotic; also a mood stabilizer)
Commonly Prescribed for
(bold for FDA approved)
Schizophrenia (ages 13 and older)
Maintaining response in schizophrenia
Acute agitation associated with
schizophrenia (intramuscular)
Acute mania/mixed mania (monotherapy
and adjunct to lithium or valproate) (ages
13 and older)
Bipolar maintenance
Acute agitation associated with bipolar I
mania (intramuscular)
Bipolar depression [in combination with
fl uoxetine (Symbyax)]
Treatment-resistant depression [in
combination with fl uoxetine (Symbyax)]
Other psychotic disorders
Behavioral disturbances in dementias
Behavioral disturbances in children and
adolescents
Disorders associated with problems with
impulse control
Borderline personality disorder
How the Drug Works
Blocks dopamine 2 receptors, reducing
positive symptoms of psychosis and
stabilizing affective symptoms
Blocks serotonin 2A receptors, causing
enhancement of dopamine release in
certain brain regions and thus reducing
motor side effects and possibly improving
cognitive and affective symptoms
Interactions at a myriad of other
neurotransmitter receptors may contribute
to olanzapine’s effi cacy
Specifi cally, antagonist actions at 5HT2C
receptors may contribute to effi cacy for
cognitive and affective symptoms in some
patients
5HT2C antagonist actions plus serotonin
reuptake blockade of fl uoxetine add to
the actions of olanzapine when given
as Symbyax (olanzapine-fl uoxetine
combination)
How Long Until It Works
Psychotic and manic symptoms can
improve within 1 week, but it may take
several weeks for full effect on behavior
as well as on cognition and affective
stabilization
Classically recommended to wait at least
4–6 weeks to determine effi cacy of drug,
but in practice some patients require up
to 16–20 weeks to show a good response,
especially on cognitive symptoms
IM formulation can reduce agitation in
15–30 minutes
If It Works
Most often reduces positive symptoms in
schizophrenia but does not eliminate them
Can improve negative symptoms, as well
as aggressive, cognitive, and affective
symptoms in schizophrenia
Most schizophrenic patients do not have a
total remission of symptoms but rather a
reduction of symptoms by about a third
Perhaps 5–15% of schizophrenic patients
can experience an overall improvement
of greater than 50–60%, especially when
receiving stable treatment for more than
a year
Such patients are considered super-
responders or “awakeners” since they
may be well enough to be employed, live
independently, and sustain long-term
relationships
Many bipolar patients may experience a
reduction of symptoms by half or more
Continue treatment until reaching a plateau
of improvement
After reaching a satisfactory plateau,
continue treatment for at least a year after
fi rst episode of psychosis
pf3
pf4
pf5
pf8
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OLANZAPINE

THERAPEUTICS

Brands • Zyprexa

  • Symbyax (olanzapine-fl uoxetine combination)
  • Relprevv see index for additional brand names

Generic? Yes

Class

  • Neuroscience-based Nomenclature: dopamine and serotonin receptor antagonist (DS-RAn)
  • Atypical antipsychotic (serotonin- dopamine antagonist; second-generation antipsychotic; also a mood stabilizer)

Commonly Prescribed for

(bold for FDA approved)

  • Schizophrenia (ages 13 and older)
  • Maintaining response in schizophrenia
  • Acute agitation associated with schizophrenia (intramuscular)
  • Acute mania/mixed mania (monotherapy and adjunct to lithium or valproate) (ages 13 and older)
  • Bipolar maintenance
  • Acute agitation associated with bipolar I mania (intramuscular)
  • Bipolar depression [in combination with fl uoxetine (Symbyax)]
  • Treatment-resistant depression [in combination with fl uoxetine (Symbyax)]
  • Other psychotic disorders
  • Behavioral disturbances in dementias
  • Behavioral disturbances in children and adolescents
  • Disorders associated with problems with impulse control
  • Borderline personality disorder

How the Drug Works

  • Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms
  • Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms - Interactions at a myriad of other neurotransmitter receptors may contribute to olanzapine’s effi cacy

✽ Specifi cally, antagonist actions at 5HT2C

receptors may contribute to effi cacy for cognitive and affective symptoms in some patients

✽ 5HT2C antagonist actions plus serotonin

reuptake blockade of fl uoxetine add to the actions of olanzapine when given as Symbyax (olanzapine-fl uoxetine combination)

How Long Until It Works

  • Psychotic and manic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior as well as on cognition and affective stabilization
  • Classically recommended to wait at least 4–6 weeks to determine effi cacy of drug, but in practice some patients require up to 16–20 weeks to show a good response, especially on cognitive symptoms
  • IM formulation can reduce agitation in 15–30 minutes

If It Works

  • Most often reduces positive symptoms in schizophrenia but does not eliminate them
  • Can improve negative symptoms, as well as aggressive, cognitive, and affective symptoms in schizophrenia
  • Most schizophrenic patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third
  • Perhaps 5–15% of schizophrenic patients can experience an overall improvement of greater than 50–60%, especially when receiving stable treatment for more than a year
  • Such patients are considered super- responders or “awakeners” since they may be well enough to be employed, live independently, and sustain long-term relationships
  • Many bipolar patients may experience a reduction of symptoms by half or more
  • Continue treatment until reaching a plateau of improvement
  • After reaching a satisfactory plateau, continue treatment for at least a year after fi rst episode of psychosis

OLANZAPINE (continued) ✽ Get waist circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profi le

  • Determine if the patient is
    • overweight (BMI 25.0–29.9)
    • obese (BMI ≥30)
    • has pre-diabetes (fasting plasma glucose 100–125 mg/dL)
    • has diabetes (fasting plasma glucose

      126 mg/dL) - has hypertension (BP >140/90 mm Hg) - has dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol)

  • Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management Monitoring after starting an atypical antipsychotic ✽ BMI monthly for 3 months, then quarterly ✽ Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching antipsychotics ✽ Blood pressure, fasting plasma glucose, fasting lipids within 3 months and then annually, but earlier and more frequently for patients with diabetes or who have gained >5% of initial weight
  • Treat or refer for treatment and consider switching to another atypical antipsychotic for patients who become overweight, obese, pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving an atypical antipsychotic ✽ Even in patients without known diabetes, be vigilant for the rare but life-threatening onset of diabetic ketoacidosis, which always requires immediate treatment, by monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness, and clouding of sensorium, even coma
  • Patients with liver disease should have blood tests a few times a year
  • Patients with low white blood cell count (WBC) or history of drug-induced leucopenia/neutropenia should have complete blood count (CBC) monitored frequently during the fi rst few months and olanzapine should be discontinued at the fi rst sign of decline of WBC in the absence of other causative factors
  • For second and subsequent episodes of psychosis, treatment may need to be indefi nite
  • Even for fi rst episodes of psychosis, it may be preferable to continue treatment indefi nitely to avoid subsequent episodes
  • Treatment may not only reduce mania but also prevent recurrences of mania in bipolar disorder

If It Doesn’t Work

  • Try one of the other atypical antipsychotics (risperidone, quetiapine, ziprasidone, aripiprazole, paliperidone, amisulpride, asenapine, iloperidone, lurasidone)
  • If 2 or more antipsychotic monotherapies do not work, consider clozapine
  • Some patients may require treatment with a conventional antipsychotic
  • If no fi rst-line atypical antipsychotic is effective, consider higher doses or augmentation with valproate or lamotrigine
  • Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection
  • Consider initiating rehabilitation and psychotherapy such as cognitive remediation
  • Consider presence of concomitant drug abuse

Best Augmenting Combos

for Partial Response or

Treatment Resistance

  • Valproic acid (valproate, divalproex, divalproex ER)
  • Other mood-stabilizing anticonvulsants (carbamazepine, oxcarbazepine, lamotrigine)
  • Lithium
  • Benzodiazepines
  • Fluoxetine and other antidepressants may be effective augmenting agents to olanzapine for bipolar depression, psychotic depression, and for unipolar depression not responsive to antidepressants alone (e.g., olanzapine- fl uoxetine combination)

Tests

Before starting an atypical antipsychotic ✽ Weigh all patients and track BMI during treatment

  • Get baseline personal and family history of diabetes, obesity, dyslipidemia, hypertension, and cardiovascular disease

OLANZAPINE (continued) with a mood-stabilizing anticonvulsant, such as valproate or lamotrigine

  • Clearance of olanzapine is slightly reduced in women compared to men, so women may need lower doses than men
  • Children and elderly should generally be dosed at the lower end of the dosage spectrum ✽ Olanzapine intramuscularly can be given short-term, both to initiate dosing with oral olanzapine or another oral antipsychotic and to treat breakthrough agitation in patients maintained on oral antipsychotics
  • Treatment should be suspended if absolute neutrophil count falls below 1,000/mm^3

Overdose

  • Rarely lethal in monotherapy overdose; sedation, slurred speech

Long-Term Use

  • Approved to maintain response in long- term treatment of schizophrenia
  • Approved for long-term maintenance in bipolar disorder
  • Often used for long-term maintenance in various behavioral disorders

Habit Forming

  • No

How to Stop

  • See Switching section of individual agents for how to stop olanzapine
  • Rapid oral discontinuation may lead to rebound psychosis and worsening of symptoms

Pharmacokinetics

  • Metabolites are inactive
  • Parent drug has 21–54 hour half-life
  • Substrate for CYP450 1A2 and 2D
  • Food does not affect absorption

Drug Interactions

  • May increase effect of antihypertensive agents
  • May antagonize levodopa, dopamine agonists
  • Dose may need to be lowered if given with CYP450 1A2 inhibitors (e.g., fl uvoxamine); raised if given in conjunction with CYP 1A2 inducers (e.g., cigarette smoke, carbamazepine)
  • Intramuscular formulation 5 mg/mL, each vial contains 10 mg (available in some countries)
  • Depot 210 mg, 300 mg, 405 mg
  • Olanzapine-fl uoxetine combination capsule (mg equivalent olanzapine/mg equivalent fl uoxetine) 6 mg/25 mg, 6 mg/50 mg, 12 mg/25 mg, 12 mg/50 mg

How to Dose

  • Initial 5–10 mg once daily orally; increase by 5 mg/day once a week until desired effi cacy is reached; maximum approved dose is 20 mg/day
  • For intramuscular formulation, recommended initial dose 10 mg; second injection of 5–10 mg may be administered 2 hours after fi rst injection; maximum daily dose of olanzapine is 20 mg, with no more than 3 injections per 24 hours
  • For olanzapine-fl uoxetine combination, recommended initial dose 6 mg/25 mg once daily in evening; increase dose based on effi cacy and tolerability; maximum generally 18 mg/75 mg

Dosing Tips – Oral

More may be more:^ raising usual dose above 15 mg/day can be useful for acutely ill and agitated patients and some treatment-resistant patients, gaining effi cacy without many more side effects ✽ Some heroic uses for patients who do not respond to other antipsychotics can occasionally justify dosing over 30 mg/day and short-term up to 90 mg/day

  • For high doses in treatment-resistant or violent patients, monitor therapeutic drug levels and target generally higher than the usual range of 5–75 mg/mL (i.e., greater than 125 mg/mL), but keep below the toxic range associated with QTc prolongation (700–800 mg/mL)
  • See also the Switching section, after Pearls, for initiating both oral and long- acting injectable
  • Rather than raise the dose above these levels in acutely agitated patients requiring acute antipsychotic actions, consider augmentation with a benzodiazepine or conventional antipsychotic, either orally or intramuscularly
  • Rather than raise the dose above these levels in partial responders, consider augmentation

(continued) OLANZAPINE

Other Warnings/

Precautions

  • Olanzapine is associated with a rare but serious skin condition known as Drug Reaction with Eosinophilia (DRESS). DRESS may begin as a rash but can progress to others parts of the body and can include symptoms such as fever, swollen lymph nodes, swollen face, inflammation of organs, and an increase in white blood cells known as eosinophilia. In some cases, DRESS can lead to death. Clinicians prescribing olanzapine should inform patients about the risk of DRESS; patients who develop a fever with rash and swollen lymph nodes or swollen face should seek medical care. Patients are not advised to stop their medication without consulting their prescribing clinician.
  • Use with caution in patients with conditions that predispose to hypotension (dehydration, overheating)
  • Use with caution in patients with prostatic hypertrophy, angle-closure glaucoma, paralytic ileus
  • Patients receiving the intramuscular formulation of olanzapine should be observed closely for hypotension
  • Intramuscular formulation is not generally recommended to be administered with parenteral benzodiazepines; if patient requires a parenteral benzodiazepine it should be given at least 1 hour after intramuscular olanzapine
  • Olanzapine should be used cautiously in patients at risk for aspiration pneumonia, as dysphagia has been reported

Do Not Use

  • If there is a known risk of angle-closure glaucoma (intramuscular formulation)
  • If patient has unstable medical condition (e.g., acute myocardial infarction, unstable angina pectoris, severe hypotension and/or bradycardia, sick sinus syndrome, recent heart surgery) (intramuscular formulation)
  • If there is a proven allergy to olanzapine

SPECIAL POPULATIONS

Renal Impairment

  • No dose adjustment required for oral formulation
  • Not removed by hemodialysis
  • For intramuscular formulation, consider lower starting dose (5 mg)

Hepatic Impairment

  • May need to lower dose
  • Patients with liver disease should have liver function tests a few times a year
  • For moderate to severe hepatic impairment, starting oral dose 5 mg; increase with caution
  • For intramuscuar formulation, consider lower starting dose (5 mg)

Cardiac Impairment

  • Drug should be used with caution because of risk of orthostatic hypotension

Elderly

  • Some patients may tolerate lower doses better
  • Increased incidence of stroke
  • For intramuscular formulation, recommended starting dose is 2.5–5 mg; a second injection of 2.5–5 mg may be administered 2 hours after fi rst injection; no more than 3 injections should be administered within 24 hours
  • Although atypical antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with dementia-related psychosis
  • Elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

Children and Adolescents

  • Approved for use in schizophrenia and manic/ mixed episodes (ages 13 and older for both)
  • Clinical experience and early data suggest olanzapine is probably safe and effective for behavioral disturbances in children and adolescents

(continued) OLANZAPINE ✽ Controversial as to whether olanzapine has more risk of diabetes and dyslipidemia than other antipsychotics

  • Cigarette smoke can decrease olanzapine levels and patients may require a dose increase if they begin or increase smoking ✽ A short-acting intramuscular dosage formulation is available
  • Long-acting intramuscular dosage formulation is also approved
  • Patients with inadequate responses to atypical antipsychotics may benefi t from determination of plasma drug levels and, if low, a dosage increase even beyond the usual prescribing limits
  • Patients with inadequate responses to atypical antipsychotics may also benefi t from a trial of augmentation with a conventional antipsychotic or switching to a conventional antipsychotic
  • However, long-term polypharmacy with a combination of a conventional antipsychotic with an atypical antipsychotic may combine their side effects without clearly augmenting the effi cacy of either
  • For treatment-resistant patients, especially those with impulsivity, aggression, violence, and self-harm, long-term polypharmacy with 2 atypical antipsychotics or with 1 atypical antipsychotic and 1 conventional antipsychotic may be useful or even necessary while closely monitoring
  • In such cases, it may be benefi cial to combine 1 depot antipsychotic with 1 oral antipsychotic
  • Although a frequent practice by some prescribers, adding 2 conventional antipsychotics together has little rationale and may reduce tolerability without clearly enhancing effi cacy

Usual Dosage Range

  • 150–300 mg/2 weeks or 300– mg/4 weeks

How to Dose

  • Conversion from oral: dose should be loaded during the initial 8 weeks based on the prior stable oral dose of olanzapine Daily oral olanzapine dose LAI dose: fi rst 8 weeks LAI dose: after 8 weeks 10 mg 210 mg/ weeks OR 405 mg/4 weeks 150 mg/ weeks OR 300 mg/ weeks 15 mg 300 mg/2 weeks 210 mg/ weeks OR 405 mg/ weeks 20 mg 300 mg/2 weeks 300 mg/ weeks
  • Oral supplementation may be needed if adequate loading is not used
  • Maximum dose 300 mg/2 weeks

Dosing Tips

  • With LAIs, the absorption rate constant is slower than the elimination rate constant, thus resulting in “flip-flop” kinetics—i.e., time to steady-state is a function of absorption rate, while concentration at steady-state is a function of elimination rate
  • The rate-limiting step for plasma drug levels for LAIs is not drug metabolism, but rather slow absorption from the injection site
  • In general, 5 half-lives of any medication are needed to achieve 97% of steady-state levels
  • The long half-lives of depot antipsychotics mean that one must either adequately load the dose (if possible) or provide oral supplementation
  • The failure to adequately load the dose leads either to prolonged cross-titration

PAMOATE

Vehicle Water Tmax 3–4 days T1/2 with multiple dosing 30 days Time to reach steady state 3 months Able to be loaded Yes Dosing schedule (maintenance) 2 weeks or 4 weeks Injection site Intramuscular gluteal Needle gauge 19 Dosage forms 210 mg, 300 mg, 405 mg Injection volume 150 mg/mL (range 1.0–2.7 mL)

OLANZAPINE (continued)

SWITCHING FROM ORAL ANTIPSYCHOTICS TO OLANZAPINE PAMOATE

Loading period Initiation at: Switch to: Maintenence period Expected Olanzapine Levels Without Oral Coverage 4 405 mg/4 weeks 300 mg/2 weeks 300 mg/4 weeks 210 mg/2 weeks 150 mg/2 weeks 0 8 12 16 20 24 0 10 20 30 Time (weeks) Average olanzapine plasma concentration at each injection (ng/ml) 50 40

  • Discontinuation of oral antipsychotic can begin immediately if adequate loading is pursued
  • How to discontinue oral formulations
    • Down-titration is not required for: amisulpride, aripiprazole, brexpiprazole, cariprazine, olanzapine, paliperidone ER
    • 1-week down-titration is required for: iloperidone, lurasidone, risperidone, ziprasidone, asenapine, quetiapine
    • 4+-week down-titration may be required for: clozapine from oral antipsychotic or to sub- therapeutic antipsychotic plasma levels for weeks or months in patients who are not receiving (or adhering to) oral supplementation
  • Because plasma antipsychotic levels increase gradually over time, dose requirements may ultimately decrease from initial; obtaining periodic plasma levels can be benefi cial to prevent unnecessary plasma level creep - The time to get a blood level for patients receiving LAI is the morning of the day they will receive their next injection - Advantages: effi cacy advantage of oral olanzapine - Disadvantages: 3-hour post-injection monitoring required due to risk (0.2%) of post-injection delirium from vascular breach - Response threshold is generally 21 ng/mL; plasma levels greater than 176 ng/mL are generally not well tolerated

OXAZEPAM

THERAPEUTICS

Brands • Serax

see index for additional brand names

Generic? Yes

Class

  • Neuroscience-based Nomenclature: GABA positive allosteric modulator (GABA-PAM)
  • Benzodiazepine (anxiolytic)

Commonly Prescribed for

(bold for FDA approved)

  • Anxiety
  • Anxiety associated with depression
  • Alcohol withdrawal
  • Catatonia

How the Drug Works

  • Binds to benzodiazepine receptors at the GABA-A ligand-gated chloride channel complex
  • Enhances the inhibitory effects of GABA
  • Boosts chloride conductance through GABA-regulated channels
  • Inhibits neuronal activity presumably in amygdala-centered fear circuits to provide therapeutic benefi ts in anxiety disorders

How Long Until It Works

  • Some immediate relief with fi rst dosing is common; can take several weeks with daily dosing for maximal therapeutic benefi t

If It Works

  • For short-term symptoms of anxiety – after a few weeks, discontinue use or use on an “as-needed” basis
  • For chronic anxiety disorders, the goal of treatment is complete remission of symptoms as well as prevention of future relapses
  • For chronic anxiety disorders, treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped
  • For long-term symptoms of anxiety, consider switching to an SSRI or SNRI for long-term maintenance
  • If long-term maintenance with a benzodiazepine is necessary, continue treatment for 6 months after symptoms resolve, and then taper dose slowly
  • If symptoms reemerge, consider treatment with an SSRI or SNRI, or consider restarting the benzodiazepine; sometimes benzodiazepines have to be used in combination with SSRIs or SNRIs for best results

If It Doesn’t Work

  • Consider switching to another agent or adding an appropriate augmenting agent
  • Consider psychotherapy, especially cognitive behavioral psychotherapy
  • Consider presence of concomitant substance abuse
  • Consider presence of oxazepam abuse
  • Consider another diagnosis, such as a comorbid medical condition

Best Augmenting Combos

for Partial Response or

Treatment Resistance

  • Benzodiazepines are frequently used as augmenting agents for antipsychotics and mood stabilizers in the treatment of psychotic and bipolar disorders
  • Benzodiazepines are frequently used as augmenting agents for SSRIs and SNRIs in the treatment of anxiety disorders
  • Not generally rational to combine with other benzodiazepines
  • Caution if using as an anxiolytic concomitantly with other sedative hypnotics for sleep

Tests

  • In patients with seizure disorders, concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

SIDE EFFECTS

How Drug Causes Side Effects

  • Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at benzodiazepine receptors
  • Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal
  • Side effects are generally immediate, but immediate side effects often disappear in time