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Olanzapine

Pronunciation

Class: Atypical Antipsychotics
VA Class: CN709
Chemical Name: 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
Molecular Formula: C17H20N4SC23H16O6•C17H20N4S•H20
CAS Number: 132539-06-1
Brands: Symbyax, Zyprexa

Warning(s)

Special Alerts:

[Posted 05/10/2016]

AUDIENCE: Psychiatry, Dermatology, Patient

ISSUE: FDA is warning that the antipsychotic medicine olanzapine can cause a rare but serious skin reaction that can progress to affect other parts of the body. FDA is adding a new warning to the drug labels for all olanzapine-containing products that describes this severe condition known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

A search of the FDA Adverse Event Reporting System (FAERS) database identified 23 cases of DRESS reported with olanzapine worldwide since 1996, when the first olanzapine-containing product was approved. FAERS includes only reports submitted to FDA, so there are likely to be additional cases about which FDA is unaware. One patient taking olanzapine experienced DRESS and died; however, this patient was taking multiple medicines that could also have contributed to death (see the Data Summary section at for more information).

DRESS may start as a rash that can spread to all parts of the body. It can include fever and swollen lymph nodes and a swollen face. It causes a higher-than-normal number of infection-fighting white blood cells called eosinophils that can cause inflammation, or swelling. DRESS can result in injury to organs including the liver, kidneys, lungs, heart, or pancreas, and can lead to death. DRESS is a potentially fatal drug reaction with a mortality rate of up to 10%.

BACKGROUND: Olanzapine is an antipsychotic medicine used to treat mental health disorders schizophrenia and bipolar disorder. It can decrease hallucinations, in which people hear or see things that do not exist, and other psychotic symptoms such as disorganized thinking. Olanzapine is available under the brand names Zyprexa, Zyprexa Zydis, Zyprexa Relprevv, and Symbyax, and also as generics.

RECOMMENDATIONS: Patients taking olanzapine-containing products who develop a fever with a rash and swollen lymph glands, or swelling in the face, should seek medical care right away. The combined symptoms together are commonly seen in DRESS. Talk with your health care professional about any questions or concerns. Do not stop taking olanzapine or change your dose without first talking with your health care professional. Sudden stopping of the medicine can be harmful without your health care professional's direct supervision.

Health care professionals should immediately stop treatment with olanzapine if DRESS is suspected. There is currently no specific treatment for DRESS. The important ways to manage DRESS are early recognition of the syndrome, discontinuation of the offending agent as soon as possible, and supportive care. Treatment with systemic corticosteroids should be considered in cases with extensive organ involvement. When prescribing the medicine, explain the signs and symptoms of severe skin reactions to your patients and tell them when to seek immediate medical care.

For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for olanzapine to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of olanzapine and consists of the following: medication guide, elements to assure safe use, communication plan, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Warning(s)

  • Post-Injection Delirium/Sedation Syndrome (PDSS)
  • PDSS reported following injections of extended-release olanzapine pamoate (Zyprexa Relprevv); clinical manifestations were consistent with olanzapine overdosage, particularly sedation (including coma) and/or delirium.372 382 383 386 387 391 392 398

  • Extended-release olanzapine pamoate must be administered in a registered healthcare facility with ready access to emergency response services.372 382 398

  • After each injection, patients must be observed for at least 3 hours by a healthcare professional.372 382

  • Because of the risk of PDSS, extended-release olanzapine pamoate is available only through a restricted distribution program.372 382 (See REMS and see Restricted Distribution under Dosage and Administration.)

  • Increased Mortality in Geriatric Patients with Dementia-related Psychosis
  • Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1 26 101 382 399

  • Analyses of 17 placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.1 101 382 399

  • Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).1 101 382

  • Observational studies suggest that conventional or first-generation antipsychotic agents also may increase mortality in such patients.1 26 382 399

  • Antipsychotic agents, including olanzapine, are not approved for the treatment of dementia-related psychosis.1 26 101 382 399

Introduction

Thienobenzodiazepine-derivative; atypical or second-generation antipsychotic agent.1 2 4 7 14 16 17 18 19 20 22 26 119 315 The drug is structurally similar to clozapine.3 14 16 20

Uses for Olanzapine

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Schizophrenia

Orally (as olanzapine) and IM (as the long-acting olanzapine pamoate ester) for the acute and maintenance treatment of schizophrenia.1 2 3 4 6 7 14 16 20 21 22 26 105 205 206 219 220 221 223 224 225 226 239 305 306 307 309 310 311 315 334 337 354 357 358 359 360 361 362 369 382 383 384 385

IM (as short-acting olanzapine) for management of acute agitation in patients with schizophrenia for whom treatment with olanzapine is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care.1 98 102

American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for management of the acute phase of schizophrenia (including first psychotic episodes).26

Patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.2 26 28 400

Bipolar Disorder

Orally for acute treatment of mixed or manic episodes associated with bipolar I disorder (as monotherapy and as adjunctive therapy with lithium or valproate).1 36 37 41 100 244 245 246 247 248 249 250 251 252 308 370

Orally for maintenance treatment of bipolar I disorder (as monotherapy).1

Orally for treatment (in combination with fluoxetine) of acute depressive episodes associated with bipolar I disorder.1 312 313 397 Olanzapine monotherapy is not indicated for treatment of depressive episodes associated with bipolar I disorder.1

IM (as short-acting olanzapine) for management of acute agitation in patients with bipolar I disorder for whom treatment with olanzapine is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care.1 99

Treatment-resistant Depression

Orally for acute and maintenance therapy (in combination with fluoxetine) of treatment-resistant depression (major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dosage and duration in the current episode).1 312

Not indicated for treatment-resistant depression as monotherapy.1

Olanzapine Dosage and Administration

General

Restricted Distribution

  • Because of the risk of PDSS, extended-release olanzapine pamoate for injectable suspension (Zyprexa Relprevv) is available only under a restricted distribution program, the Zyprexa Relprevv Patient Care Program.372 382

  • The program is designed to ensure that the drug is administered in a registered healthcare facility with ready access to emergency response services and that patients are continuously monitored by a healthcare professional for at least 3 hours following each injection.372 382

  • Clinicians, healthcare facilities, pharmacists, and patients must be enrolled in the program before they can prescribe, dispense, and receive extended-release olanzapine pamoate.372 382 This formulation must not be dispensed directly to a patient.372 382

  • For additional information and to enroll in the program, contact the manufacturer at 877-772-9390 or visit .372 382

Administration

Administer olanzapine orally or by IM injection.1 312 Administer olanzapine pamoate only by IM injection.382 (See Possible Prescribing and Dispensing Errors under Cautions.)

Establish tolerability with oral olanzapine prior to initiating extended-release olanzapine pamoate IM therapy.382

Oral Administration

Administer olanzapine orally as conventional tablets, orally disintegrating tablets, or capsules (in fixed combination with fluoxetine) once daily without regard to meals.1 312 If persistent or troublesome daytime sedation occurs with olanzapine monotherapy, consider evening administration.26 259 Administer fixed-combination olanzapine and fluoxetine capsules (e.g., Symbyax) in the evening.312

Just prior to administration of orally disintegrating tablets, gently remove tablet from blister packet; do not push tablet through foil.1 With dry hands, peel open blister package, place tablet on tongue to dissolve, and swallow with or without liquid.1

IM Administration of Short-acting Olanzapine (e.g., Zyprexa IntraMuscular)

Short-acting (immediate-release) olanzapine (10 mg per vial) is used for agitation associated with schizophrenia or bipolar mania; do not confuse this formulation with the long-acting olanzapine pamoate formulation (Zyprexa Relprevv; available in 210-, 300-, and 405-mg vial strengths) used for schizophrenia.1 382

Administer only by IM injection; inject drug slowly and deeply into the muscle mass.1 Do not administer IV or sub-Q.1

Reconstitution

Reconstitute short-acting olanzapine for injection by adding 2.1 mL of sterile water for injection to vial containing 10 mg of olanzapine to provide a solution containing approximately 5 mg/mL.1 Do not use other solutions to reconstitute olanzapine for injection.1

Use immediately (within 1 hour) following reconstitution.1 If necessary, the reconstituted solution may be stored for up to 1 hour at 20–25°C; after 1 hour, discard any unused portion.1

IM Administration of Long-acting Olanzapine Pamoate (Zyprexa Relprevv)

Long-acting olanzapine pamoate (available in 210-, 300-, and 405-mg vial strengths) is used for schizophrenia; do not confuse this formulation with the short-acting (immediate-release) olanzapine formulation (e.g., Zyprexa IntraMuscular; 10 mg per vial) used for agitation associated with schizophrenia or bipolar mania.1 382

Administer only by deep IM injection into the gluteal area; do not administer IV or sub-Q.382 A healthcare professional should administer the injection every 2–4 weeks.382 (See Dosage under Dosage and Administration.)

Following insertion of the needle into the gluteal muscle for the IM injection, aspirate for several seconds to ensure that no blood is drawn into the syringe.382 If blood appears in the syringe, withdraw the needle and discard the syringe and dose.382 Use a new convenience kit for the new dose with a new syringe and needle.382 Do not massage injection site following IM administration.382

Precautions related to Risk of PDSS

Extended-release olanzapine pamoate must be administered in a registered healthcare facility (e.g., hospital, clinic, residential treatment center, community healthcare center) with ready access to emergency response services.372 382 (See Post-injection Delirium/Sedation Syndrome [PDSS] in the Boxed Warning and also under Cautions.)

Discuss the potential risk of PDSS with patients and provide a medication guide each time extended-release olanzapine pamoate is prescribed and administered.382 386

After each injection, continuously monitor patients at the healthcare facility for at least 3 hours.372 382 Patients should be alert, oriented, and absent of any signs and symptoms of PDSS prior to being released; all patients should be accompanied to their destination upon leaving the healthcare facility.372 382

Patients should not drive or operate heavy machinery for the remainder of the day following the injection and should be vigilant for symptoms of PDSS and able to obtain medical assistance if needed.372 382

If PDSS is suspected, institute close medical supervision and monitoring in a facility capable of resuscitation.382

Reconstitution

Consult manufacturer’s labeling for instructions for using components of the Zyprexa Relprevv Convenience Kit for reconstitution of olanzapine pamoate powder for suspension.382 Reconstitute only with diluent supplied by manufacturer.382

Reconstituted olanzapine pamoate suspension remains stable for up to 24 hours in the vial.382 If not used immediately, shake the vial vigorously to resuspend the drug prior to administration.382

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as olanzapine and olanzapine pamoate; dosage expressed in terms of olanzapine.1 382

Adjust olanzapine dosage carefully according to individual requirements and response, using the lowest possible effective dosage.1 20

Pediatric Patients

Schizophrenia
Oral

Adolescents 13–17 years of age: Initially, 2.5 or 5 mg once daily.1 May increase to a target dosage of 10 mg daily.1

Make subsequent dosage adjustments in increments or decrements of 2.5 or 5 mg daily.1

Effective dosage in clinical studies generally ranged from 2.5–20 mg daily (mean dosage of about 11 mg daily).1 369

Optimum duration of therapy not known, but maintenance therapy with olanzapine is well established in adults.1 In responsive patients, continue the drug beyond the acute response at the lowest effective dosage; periodically reassess need for continued maintenance therapy.1

Bipolar Disorder
Manic or Mixed Episodes: Monotherapy
Oral

Adolescents 13–17 years of age: Initially, 2.5 or 5 mg once daily.1 May increase to a target dosage of 10 mg daily.1

Make subsequent dosage adjustments in increments or decrements of 2.5 or 5 mg daily.1

Effective dosage in clinical studies generally ranged from 2.5–20 mg daily (mean dosage of about 9 mg daily).1

Optimum duration of therapy not known, but maintenance therapy with olanzapine is well established in adults.1 In responsive patients, continue the drug beyond the acute response at the lowest effective dosage; periodically reassess need for continued maintenance therapy.1

Acute Depressive Episodes
Oral

Children and adolescents 10–17 years of age: Initially 2.5 mg in combination with 20 mg of fluoxetine, or 3 mg in fixed combination with 25 mg of fluoxetine (e.g., Symbyax) once daily in the evening.1 312

Increase dosage according to patient response and tolerance as indicated to a target dosage of olanzapine 6–12 mg with fluoxetine 25–50 mg daily.1 312

If elect to use combined olanzapine and fluoxetine therapy for extended periods, periodically reevaluate the long-term risks and benefits for the individual patient.1 312

Adults

Schizophrenia
Oral

Initially, 5–10 mg, usually as a single daily dose.1 20 26 Within several days, may increase by 5 mg daily, to a target dosage of 10 mg daily.1 20

Make subsequent dosage adjustments at intervals of not less than 7 days, usually in increments or decrements of 5 mg once daily.1 20

Increasing dosage beyond 10 mg daily usually does not result in greater efficacy; such increases generally should occur only after assessment of the patient’s clinical status.1

Optimum duration of therapy currently is not known, but maintenance therapy with antipsychotic agents is well established.1 23 25 In responsive patients, continue as long as clinically necessary and tolerated, but at lowest possible effective dosage; reassess need for continued therapy periodically.1 20

IM, Extended-release Olanzapine Pamoate

Establish tolerability with oral olanzapine prior to initiating extended-release olanzapine pamoate IM (Zyprexa Relprevv) therapy.382

For patients established on oral olanzapine 10 mg daily, recommended initial dosage is 210 mg every 2 weeks or 405 mg every 4 weeks for first 8 weeks.382 After 8 weeks, recommended maintenance dosage is 150 mg every 2 weeks or 300 mg every 4 weeks.382

For patients established on oral olanzapine 15 mg daily, recommended initial dosage is 300 mg every 2 weeks for first 8 weeks.382 After 8 weeks, recommended maintenance dosage is 210 mg every 2 weeks or 405 mg every 4 weeks.382

For patients established on oral olanzapine 20 mg daily, recommended initial and maintenance dosage is 300 mg every 2 weeks.382

Efficacy demonstrated in clinical studies within dosage range of 150–300 mg administered every 2 weeks and with 405 mg administered every 4 weeks.382 383 385

A lower initial dosage of 150 mg every 4 weeks recommended in patients who are debilitated, who may be predisposed to hypotensive reactions, who exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years), or who may be more sensitive to the pharmacodynamic effects of the drug.382

Optimum duration of therapy not known, but long-term efficacy demonstrated over a 24-week period.382 383 In addition, long-term use of oral olanzapine has been shown to maintain treatment response in patients with schizophrenia.354 382 If used for an extended period, periodically reassess need for continued maintenance therapy.382

Acute Agitation associated with Schizophrenia
IM, Short-acting Olanzapine

Initially, 10 mg of short-acting olanzapine (e.g., Zyprexa IntraMuscular).1 Consider lower doses (2.5, 5, or 7.5 mg) when clinically warranted.1

In clinical trials, efficacy in controlling agitation in patients with schizophrenia or bipolar mania demonstrated in a dosage range of 2.5–10 mg.1 98 99 102

If agitation persists, may administer subsequent single doses of up to 10 mg.1 However, efficacy of repeated doses was not systematically evaluated in controlled trials.1

Assess patients for orthostatic hypotension prior to administration of any subsequent IM doses.1 (See Orthostatic Hypotension under Cautions.)

If ongoing therapy is indicated, may initiate oral olanzapine 5–20 mg daily as soon as clinically appropriate.1

Bipolar Disorder
Manic or Mixed Episodes: Monotherapy
Oral

Initially, usually 10 or 15 mg once daily.1 Make dosage adjustments in increments or decrements of 5 mg daily, at intervals of not less than 24 hours.1

Effective dosage in clinical studies generally ranged from 5–20 mg daily.1 36 37 41 244 245 247 250 252

If elect to use olanzapine for extended periods, periodically reevaluate the long-term usefulness for the individual patient.1

Manic or Mixed Episodes: Combination Therapy
Oral

Initially, 10 mg once daily when administered with lithium or valproate.1 41

Effective dosage of olanzapine in clinical studies generally ranged from 5–20 mg daily.1 41

No dosage adjustment of lithium or valproate is required when used in combination with olanzapine.1

If elect to use olanzapine for extended periods, periodically reevaluate the long-term usefulness for the individual patient.1

Acute Depressive Episodes
Oral

Initially, 5 mg in combination with 20 mg of fluoxetine, or 6 mg in fixed combination with 25 mg of fluoxetine (e.g., Symbyax) once daily in the evening.1 312

Increase dosage according to patient response and tolerance as indicated to a target dosage of olanzapine 5–12.5 mg with fluoxetine 20–50 mg daily.1 312

In clinical trials, antidepressive efficacy was demonstrated at olanzapine dosages ranging from 6–12 mg daily and fluoxetine dosages ranging from 25–50 mg daily.312

If elect to use combined olanzapine and fluoxetine for extended periods, periodically reevaluate the long-term risks and benefits for the individual patient.1 312

Acute Agitation associated with Bipolar Mania
IM, Short-acting Olanzapine

Initially, 10 mg of short-acting olanzapine (e.g., Zyprexa IntraMuscular).1 Consider lower doses (2.5, 5, or 7.5 mg) when clinically warranted.1

In clinical trials, efficacy in controlling agitation in patients with schizophrenia or bipolar mania demonstrated in a dosage range of 2.5–10 mg.1 98 99 102

If agitation persists, may administer subsequent single doses of up to 10 mg.1 However, efficacy of repeated doses was not systematically evaluated in controlled trials.1

Assess patients for orthostatic hypotension prior to administration of any subsequent IM doses.1 (See Orthostatic Hypotension under Cautions.)

If ongoing therapy is indicated, may initiate oral olanzapine 5–20 mg daily as soon as clinically appropriate.1

Treatment-resistant Depression
Oral

Initially, 5 mg in combination with 20 mg of fluoxetine, or 6 mg in fixed combination with 25 mg of fluoxetine (e.g., Symbyax) once daily in the evening.1 312

Increase dosage according to patient response and tolerance as indicated to a target dosage of olanzapine 5–20 mg with fluoxetine 20–50 mg daily.1 312

In clinical trials, antidepressive efficacy was demonstrated at olanzapine dosages ranging from 6–18 mg daily and fluoxetine dosages ranging from 25–50 mg daily.1 312

Optimum duration of therapy not known; periodically reassess need for continued maintenance therapy.1 312

Prescribing Limits

Pediatric Patients

Schizophrenia
Oral

Adolescents 13–17 years of age: Safety of dosages >20 mg daily not established.1

Acute Agitation associated with Schizophrenia
IM, Short-acting Olanzapine

Safety of dosages >30 mg daily or of 10-mg doses given more frequently than 2 hours after the initial dose and 4 hours after the second dose not established.1

Bipolar Disorder
Manic or Mixed Episodes: Monotherapy
Oral

Adolescents 13–17 years of age: Safety of dosages >20 mg daily not established.1

Acute Depressive Episodes
Oral

Children and adolescents 10–17 years of age: Dosages >12 mg of olanzapine with 50 mg of fluoxetine not evaluated in clinical trials.1 312

Adults

Schizophrenia
Oral

Safety of dosages >20 mg daily not established.1 20

IM, Extended-release Olanzapine Pamoate

Safety and efficacy of dosages >405 mg every 4 weeks or 300 mg every 2 weeks not established.382

Acute Agitation associated with Schizophrenia
IM, Short-acting Olanzapine

Safety of dosages >30 mg daily or of 10-mg doses given more frequently than 2 hours after the initial dose and 4 hours after the second dose not established.1

Bipolar Disorder
Manic or Mixed Episodes
Oral

Safety of dosages >20 mg daily (as monotherapy or combination therapy with lithium or valproate) not established.1

Acute Depressive Episodes
Oral

Dosages >18 mg of olanzapine with 75 mg of fluoxetine in fixed combination for acute depressive episodes not evaluated in clinical studies.1 312

Acute Agitation associated with Bipolar Mania
IM, Short-acting Olanzapine

Safety of dosages >30 mg daily or of 10-mg doses given more frequently than 2 hours after the initial dose and 4 hours after the second dose not established.1

Special Populations

In debilitated patients, in those predisposed to hypotension, in those who may be particularly sensitive to the effects of olanzapine, or in those who might metabolize olanzapine slowly (e.g., nonsmoking women ≥65 years of age), initial oral olanzapine dosage of 5 mg daily, 2.5 mg of short-acting olanzapine IM, or 150 mg of long-acting olanzapine pamoate IM every 4 weeks; when indicated, adjust dosage with caution.1 26 382

When used in combination with fluoxetine for acute depressive episodes in bipolar disorder or treatment-resistant depression, an oral dosage of 2.5–5 mg of olanzapine and 20 mg of fluoxetine, or 3–6 mg of olanzapine in fixed combination with 25 mg of fluoxetine (e.g., Symbyax), is recommended in patients predisposed to hypotension, those with hepatic impairment, or those who might metabolize the drugs(s) slowly (e.g., female gender, geriatric age, nonsmoking status); when indicated, adjust dosage with caution.1 312

Hepatic Impairment

Manufacturer states that olanzapine dosage adjustment is not necessary in patients with hepatic impairment.1 (See Pharmacokinetics.)

Extended-release IM olanzapine pamoate (Zyprexa Relprevv) not specifically studied in patients with hepatic impairment.382

Renal Impairment

Manufacturer states that olanzapine dosage adjustment is not necessary in patients with renal impairment.1 (See Pharmacokinetics.)

Extended-release IM olanzapine pamoate (Zyprexa Relprevv) not specifically studied in patients with renal impairment.382

Geriatric Patients

Consider a lower initial dosage of olanzapine in geriatric patients.1 382

Careful dosage titration of oral olanzapine recommended in patients >65 years of age.1 26

Consider a lower initial IM dose of 5 mg of short-acting olanzapine.1

Cautions for Olanzapine

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Manufacturer states none known with oral or short-acting IM olanzapine monotherapy or with extended-release IM olanzapine pamoate.1 382

  • When used in combination with fluoxetine, consider the usual contraindications associated with fluoxetine.1

  • When used as adjunctive therapy with lithium or valproate, refer to prescribing information for those other drugs.1

Warnings/Precautions

Warnings

Post-injection Delirium/Sedation Syndrome (PDSS)

Manifestations consistent with olanzapine overdosage, particularly sedation and/or delirium, reported following extended-release olanzapine pamoate (Zyprexa Relprevv) injection.372 382 383 386 387 392 398 Reported in <0.1% of injections382 386 387 and approximately 2% of patients who received injections for up to 46 months.382 In some cases, the events correlated with a rapid, greater than expected increase in serum olanzapine concentrations to supratherapeutic ranges,382 387 398 but the mechanism by which the drug entered the bloodstream is not known.382 398

Manifestations of PDSS include dizziness, confusion, disorientation, malaise, slurred speech, altered gait, ambulation difficulties, weakness, agitation, extrapyramidal symptoms, hypertension, convulsions, and reduced levels of consciousness (mild sedation to coma).382 383 386 Onset generally has ranged from soon after the injection to >3 hours after the injection; patients have largely recovered by 72 hours.382 383 386

Because the risk of PDSS is the same at each injection, the risk is cumulative (i.e., increases with the number of injections).382 384

FDA reviewed 2 unexplained deaths that occurred 3–4 days after the patients received an appropriate dose of extended-release olanzapine pamoate (well beyond the REMS-required 3-hour post-injection monitoring period).391 398 Both patients had very high postmortem blood concentrations of olanzapine.391 398 Results of FDA's review were inconclusive; unclear whether PDSS caused the deaths, but the possibility that the deaths were due to rapid but delayed entry of the drug into the bloodstream following IM injection could not be excluded.391 398 FDA recommends that clinicians continue to follow the REMS requirements and recommendations in the manufacturer's prescribing information.391 398 (See Post-Injection Delirium/Sedation Syndrome [PDSS] in Boxed Warning and see Restricted Distribution and also Precautions related to Risk of PDSS under Dosage and Administration.)

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.1 26 101 382 399

Antipsychotic agents, including olanzapine, are not approved for the treatment of dementia-related psychosis.1 26 101 382 399 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning, see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions, and also see Dysphagia under Cautions.)

Sensitivity Reactions

Allergic reactions (e.g., anaphylactoid reaction, angioedema, pruritus, urticaria, rash) reported.1 312 Discontinue olanzapine if alternative etiology of rash or other allergic manifestation cannot be identified.312

Other Warnings and Precautions

Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis

Increased incidence of adverse cerebrovascular effects (stroke and TIAs), including fatalities, observed in geriatric patients with dementia-related psychosis receiving olanzapine in placebo-controlled studies.1 382 Olanzapine is not approved for the treatment of patients with dementia-related psychosis.1 382 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Suicide

Attendant risk with psychotic illness and bipolar disorder; closely supervise high-risk patients.1 382 Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.1

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents, including olanzapine.1 26 176 177 178 179 180 181 182 183 184 185 186 201 315 382

Immediately discontinue therapy and initiate supportive and symptomatic therapy if NMS occurs.1 382 Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.1 178 179 185 201 382

Metabolic Changes

Atypical antipsychotic agents are associated with metabolic changes that may increase cardiovascular and cerebrovascular risk (e.g., hyperglycemia, dyslipidemia, weight gain).1 382 (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents, including olanzapine.1 43 44 45 46 47 48 49 50 51 52 53 54 55 56 70 71 72 73 77 95

Closely monitor patients with diabetes mellitus for worsening glycemic control and perform fasting glucose testing at baseline and periodically for patients with risk factors for diabetes (e.g., obesity, family history of diabetes).1 44 45 46 47 48 49 50 51 52 53 54 55 If manifestations of hyperglycemia occur, perform fasting blood glucose testing.1 44 45 46 47 48 49 50 51 52 53 54 55

Some patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other patients, hyperglycemia resolved with discontinuance of the antipsychotic.1

Dyslipidemia

Undesirable changes in lipid parameters observed with olanzapine use.1 382 Clinically important, and sometimes very high (>500 mg/dL), elevations in triglyceride concentrations possible.1 382 Modest average increases in total cholesterol concentrations also have occurred.1

The manufacturers recommend appropriate clinical monitoring, including baseline and periodic follow-up lipid evaluations, in patients receiving the drug.1 373 382

Weight Gain

Weight gain reported.1 36 129 130 131 132 133 140 247 253 280 350 351 369 373 382 In placebo-controlled trials, approximately 22% of adults and 41% of adolescent patients receiving olanzapine monotherapy gained ≥7% of their baseline body weight.1

Consider potential consequences of weight gain prior to starting olanzapine therapy.1 373 382 Patients should receive regular monitoring of weight.1 373 382 (See Pediatric Use under Cautions.)

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, may occur in patients receiving antipsychotic agents.1

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.1 In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.1

APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months.26 Consider discontinuance of olanzapine if signs and symptoms of tardive dyskinesia occur.1 However, some patients may require treatment despite the presence of the syndrome.1

Orthostatic Hypotension

Risk of orthostatic hypotension associated with dizziness, tachycardia, and syncope, particularly early in treatment, because of olanzapine's α1-adrenergic blocking activity.1 Syncope reported in 0.6, 0.3, and 0.1% of patients receiving oral olanzapine, immediate-release IM olanzapine, and extended-release IM olanzapine pamoate, respectively, in clinical studies.1 382 May reduce risk of orthostatic hypotension and syncope by initiating oral therapy at a dosage of 5 mg once daily.1

Hypotension, bradycardia with or without hypotension, tachycardia, and syncope reported with immediate-release IM olanzapine injection.1

Use oral or IM olanzapine with caution in patients with known cardiovascular disease (e.g., heart failure, history of MI, ischemic heart disease, conduction abnormalities), cerebrovascular disease, and/or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).1 382

Risk of clinically important orthostatic hypotension associated with use of maximum recommended IM dosages of immediate-release olanzapine injection (i.e., three 10-mg IM doses given 2–4 hours apart).1 If drowsiness or dizziness occurs, patients should remain recumbent until examination indicates that they are not experiencing orthostatic hypotension, bradycardia, and/or hypoventilation.1 Assess patients for orthostatic hypotension prior to administration of any subsequent IM doses.1 Administration of additional IM doses to patients with clinically significant postural change in BP is not recommended.1

Use oral or IM olanzapine with caution in patients receiving other drugs that can induce hypotension, bradycardia, or respiratory and CNS depression (e.g., benzodiazepines).1 382 (See Specific Drugs under Interactions.)

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia temporally related to antipsychotic agents, including olanzapine, reported during clinical trial and/or postmarketing experience.1 376 378 382 Agranulocytosis also reported.1 382

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and a history of drug-induced leukopenia or neutropenia.1 382 Monitor CBC frequently during the first few months of therapy in patients with such risk factors.1 382 Discontinue olanzapine at the first sign of a decline in WBC count in the absence of other causative factors.1 382

Carefully monitor patients with clinically important neutropenia for signs and symptoms of infection (e.g., fever) and treat promptly if they occur.1 382 Discontinue olanzapine if severe neutropenia (ANC <1000/mm3) occurs; monitor WBC until recovery occurs.1 382

Dysphagia

Esophageal dysmotility and aspiration associated with the use of antipsychotic agents.1 Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer’s dementia.1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Seizures

Seizures reported in 0.9 and 0.15% of adults receiving oral olanzapine or extended-release IM olanzapine pamoate, respectively.1 382

Use with caution in patients with a history of seizures or conditions known to lower the seizure threshold (e.g., dementia of the Alzheimer’s type); conditions that lower seizure threshold may be more prevalent in patients ≥65 years of age.1 20 24 171 172 174 175 315 382

Cognitive and Motor Impairment

Dose-related somnolence commonly occurs with olanzapine (26% of patients).1 Sedation occurred in 8% of patients receiving extended-release IM olanzapine pamoate.382

Judgment, thinking, or motor skills may be impaired.1 382 (See Specific Drugs under Interactions and also see Advice to Patients.)

Body Temperature Regulation

Disruption of the body’s ability to reduce core body temperature possible with antipsychotic agents.1 382

Use appropriate caution in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).1 382

Hyperprolactinemia

May cause elevated serum prolactin concentrations, which may persist during chronic administration and cause clinical disturbances (e.g., galactorrhea, amenorrhea, gynecomastia, impotence); chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density.1 281 283 300 301 302 (See Pediatric Use under Cautions.)

Olanzapine is considered to be relatively low to moderate among antipsychotic agents in its potential for inducing hyperprolactinemia.26 281 377

If contemplating olanzapine therapy in a patient with previously detected breast cancer, consider that approximately one-third of human breast cancers are prolactin dependent in vitro.1

Concomitant Illnesses

Constipation, dry mouth, and tachycardia may occur, possibly related to the drug’s anticholinergic effects; use with caution in patients with clinically important prostatic hypertrophy, angle-closure glaucoma, or history of paralytic ileus or related conditions.1 382

Not adequately evaluated in patients with a recent history of MI or unstable cardiovascular disease.1 382 Risk of orthostatic hypotension; use with caution in patients with cardiovascular disease.1 382 (See Orthostatic Hypotension under Cautions.)

Phenylketonuria

Orally disintegrating tablets contain aspartame (e.g., NutraSweet), which is metabolized in the GI tract to provide phenylalanine; consult manufacturer's labeling for specific information regarding phenylalanine content of individual preparations and dosage strengths.1 30 31 32 33 34

Combination Therapy with Lithium, Valproate, or Fluoxetine

Consider cautions, precautions, and contraindications associated with lithium, valproate, or fluoxetine when olanzapine is used in conjunction with these drugs.1 312

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarities in spelling, dosage intervals, and tablet strengths of Zyprexa and Zyrtec (cetirizine hydrochloride, an antihistamine) may result in errors.97

Specific Populations

Pregnancy

Category C.1 312 382

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.1 312 379 380 381 382 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.1 312 379 380 381 382

Lactation

Distributed into milk.1 110 111 112 113 319 Women receiving olanzapine should not breast-feed.1

Pediatric Use

Safety and efficacy of oral olanzapine for the treatment of schizophrenia or manic or mixed episodes associated with bipolar I disorder established in short-term clinical trials in adolescents (13–17 years of age).1 369 370 The recommended initial dosage for adolescents is lower than that for adults (see Dosage under Dosage and Administration).1 Safety and efficacy of oral olanzapine for the treatment of schizophrenia or manic or mixed episodes associated with bipolar I disorder not established in pediatric patients <13 years of age.1 35 Compared with adults in clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in serum concentrations of total cholesterol, triglycerides, LDL-cholesterol, prolactin, and hepatic aminotransferases.1 369 370 373

When deciding among the alternative treatments available for adolescents with schizophrenia or bipolar disorder, consider the increased potential for weight gain and dyslipidemia with olanzapine in adolescents as compared with adults.1 373 Also consider the potential long-term risks when prescribing olanzapine to adolescents; in many cases, this may lead to consideration of other drugs first in such patients.1 373

Initiate drug therapy for pediatric schizophrenia and bipolar I disorder only after performing a thorough diagnostic evaluation and carefully considering risks associated with medication treatment.1 373 Medication treatment should only be part of a total treatment program that often includes psychological, educational, and social interventions.1 373

Safety and efficacy of oral olanzapine in combination with fluoxetine for the treatment of acute depressive episodes associated with bipolar disorder not established in pediatric patients <10 years of age.1 312

Safety and efficacy of oral olanzapine in combination with fluoxetine for the treatment of treatment-resistant depression not established in patients <18 years of age.1 312

Safety and efficacy of short-acting IM olanzapine not established in patients <18 years of age.1

Safety and efficacy of extended-release IM olanzapine pamoate not established in patients <18 years of age.382

Geriatric Use

Safety of oral olanzapine in patients ≥65 years of age with schizophrenia does not appear to differ from that in younger adults with schizophrenia; however, tolerability profile of olanzapine in geriatric patients with dementia-related psychosis may differ from that in younger patients with schizophrenia.1

The manufacturer states that the presence of factors that might decrease the clearance of or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower initial dosage in geriatric patients.1 312 382 (See Special Populations under Dosage and Administration.)

Geriatric patients with dementia-related psychosis treated with antipsychotic agents, including olanzapine, are at an increased risk of death;1 26 101 382 399 increased incidence of adverse cerebrovascular events also observed in geriatric patients with dementia-related psychosis receiving oral olanzapine.1 Olanzapine is not approved for the treatment of patients with dementia-related psychosis.1 382 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning, see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions, and also see Dysphagia under Cautions.)

Clinical studies of olanzapine in combination with fluoxetine did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger patients.1 312

Clinical studies of extended-release IM olanzapine pamoate did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger patients.382

Common Adverse Effects

Oral olanzapine therapy in adults with schizophrenia: Postural hypotension, constipation, weight gain, dizziness, personality disorder, akathisia.1

Oral olanzapine therapy in adolescents with schizophrenia: Sedation, weight gain, headache, increased appetite, dizziness, abdominal pain, pain in the extremities, fatigue, dry mouth.1

Oral olanzapine therapy for manic or mixed episodes associated with bipolar disorder (as monotherapy) in adults: Asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor.1

Oral olanzapine therapy for manic or mixed episodes associated with bipolar disorder (as monotherapy) in adolescents: Sedation, weight gain, increased appetite, headache, fatigue, dizziness, dry mouth, abdominal pain, pain in the extremities.1

Oral olanzapine therapy for manic or mixed episodes associated with bipolar disorder (as adjunctive therapy with lithium or valproate) in adults: Dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia.1

Olanzapine IM (short-acting injection) for agitation associated with schizophrenia or bipolar mania in adults: Somnolence.1

Olanzapine pamoate IM (long-acting) therapy in adults: Headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, vomiting.382

Interactions for Olanzapine

Direct glucuronidation and CYP-mediated oxidation are main metabolic pathways.1 116 In vitro studies suggest that CYP1A2 and CYP2D6 and the flavin-containing monooxygenase system are involved in oxidation; however, CYP2D6-mediated oxidation appears to be a minor pathway.1 116

Appears to have little potential to inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A.1 116

Although metabolized by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably alter drug clearance.1 116

Drugs Affecting Hepatic Microsomal Enzymes

CYP1A2 or glucuronyl transferase enzyme inhibitors and inducers: Potential pharmacokinetic interaction (altered olanzapine metabolism).1 116

Drugs Metabolized by Hepatic Microsomal Enzymes

Inhibitors of CYP 1A2, 2C9, 2C19, 2D6, or 3A: Clinically important pharmacokinetic interactions unlikely.1 116

Specific Drugs

Drug

Interaction

Comment

Alcohol

Pharmacokinetic interaction unlikely1 116 382

Potential additive CNS effects; alcohol potentiates orthostatic hypotension observed with olanzapine1 382

Advise patients to avoid alcohol 1 382

Antacids (aluminum- and magnesium-containing)

Pharmacokinetic interaction unlikely1 116

Anticholinergic agents

Possible disruption of body temperature regulation1 382

Use with caution 1 382

Benzodiazepines (parenteral) (e.g., lorazepam)

Potential additive CNS and cardiovascular effects (excessive sedation and cardiorespiratory depression) during concurrent parenteral administration1 382

Increased somnolence during concurrent parenteral administration of short-acting olanzapine and lorazepam; no effect on pharmacokinetics of either drug1

Concurrent use of short-acting IM olanzapine with parenteral benzodiazepines not recommended1

If administered concurrently, carefully evaluate for excessive sedation and cardiorespiratory depression1 382

Biperiden

Pharmacokinetic interaction unlikely1 116

Carbamazepine

Carbamazepine (200 mg twice daily) increased clearance of olanzapine (single 10-mg dose) by about 50%;1 116 effect may be greater with higher carbamazepine dosages1 116

Consider increase in olanzapine dosage during concurrent use1 116

Charcoal

Decreased peak plasma concentrations and AUC of oral olanzapine1 116

Charcoal may be useful in treatment of olanzapine overdose1 116

Cimetidine

Pharmacokinetic interaction unlikely1 116

CNS agents

Potential additive CNS effects1

Use with caution1

Desipramine

Pharmacokinetic interaction unlikely1

Diazepam (oral)

Potential additive CNS and orthostatic hypotension effects; no effect on diazepam pharmacokinetics1

Use with caution1

Dopamine agonists

Potential antagonistic effects1

Fluoxetine

Small increase in peak olanzapine concentrations and small decrease in olanzapine clearance1 116 312 330

Not considered clinically important; dosage modification not routinely recommended1 116 312 330

Fluvoxamine

Decreased clearance and increased peak concentrations of olanzapine 1 151 152 153 155 156

Use with caution; consider lower olanzapine dosage1 151 152 153 156

Consider monitoring plasma olanzapine concentrations151 152 153 156

Hypotensive agents

Additive hypotensive effects1

Use with caution1

Imipramine

Pharmacokinetic interaction unlikely1 282

Lamotrigine

No substantial change in olanzapine or lamotrigine pharmacokinetics;284 331 however, time to reach peak lamotrigine concentrations may be substantially prolonged331

Mild sedative effects reported284 331

Routine dosage adjustment not necessary; however, lamotrigine dosage adjustment for therapeutic reasons may be necessary in some patients when initiating or discontinuing olanzapine therapy284

Careful monitoring of patients receiving high dosages of olanzapine and lamotrigine recommended by some clinicians284

Levodopa

Potential antagonistic effects1

Lithium

Pharmacokinetic interaction unlikely1 116

Although combined olanzapine and lithium therapy generally well tolerated,1 41 apparent lithium toxicity and adverse extrapyramidal effects reported rarely348

No dosage adjustment of lithium necessary during concomitant administration1

Omeprazole

Possible increase in olanzapine clearance1

Consider increase in olanzapine dosage during concurrent use1

Rifampin

Possible increase in olanzapine clearance1 116

Consider increase in olanzapine dosage during concurrent use1 116

Sertraline

Sertraline does not appear to substantially affect olanzapine pharmacokinetics156

Smoking

Olanzapine clearance approximately 40% higher in smokers; olanzapine concentrations generally lower in smokers compared with nonsmokers1 134 135 141 142 144

Manufacturer states that routine dosage adjustment is not recommended in smokers1

Some clinicians recommend monitoring patient's smoking consumption and considering olanzapine dosage adjustment in patients who have reduced or increased their smoking and/or are not responding adequately or are experiencing dose-related adverse reactions to the drug134 138

Monitoring olanzapine concentrations may be helpful in patients who smoke and have other factors associated with substantial alterations in olanzapine metabolism (e.g., geriatric patients, women, concurrent fluvoxamine use)141

Theophylline

Pharmacokinetic interaction unlikely1 116

Valproic acid

Clinically important pharmacokinetic interaction unlikely,1 although substantially decreased olanzapine concentrations reported in several olanzapine-treated patients following initiation of valproate349

Routine dosage adjustment of valproate not necessary during concomitant administration1

Warfarin

Pharmacokinetic interaction unlikely1 116

Olanzapine Pharmacokinetics

Absorption

Bioavailability

Well absorbed after oral administration, with peak plasma concentrations attained in approximately 6 hours (range: 5–8 hours).1 290 About 40% of oral dose is metabolized before reaching systemic circulation.1

Steady-state concentrations achieved after approximately 7 days of continuous oral dosing and are approximately twice those observed following single-dose administration.1 116 290

Exhibits linear and dose-proportional pharmacokinetics when given orally within the clinical dosage range.1 116 143 290

Conventional and orally disintegrating olanzapine tablets are bioequivalent.1 115

Fixed-combination olanzapine/fluoxetine capsules: Pharmacokinetics expected to resemble those of the individual components.312 Olanzapine pharmacokinetics slightly altered, but effects not clinically important.312 (See Specific Drugs under Interactions.)

Short-acting IM olanzapine (Zyprexa IntraMuscular): Rapidly absorbed following IM administration, with peak plasma concentrations occurring within 15–45 minutes.1 382 Peak olanzapine concentrations after 5-mg IM dose average about 5 times higher than those following a 5-mg oral dose.1 AUCs are similar following oral and IM administration.1 Exhibits linear pharmacokinetics when given IM within the clinical dosage range.1 Onset of antipsychotic action evident within 24 hours after IM administration, but may occur within 2 hours.207

Extended-release IM olanzapine (Zyprexa Relprevv): Following deep IM gluteal administration, slow dissolution of the pamoate ester (which is practically insoluble) results in prolonged plasma olanzapine concentrations over a period of weeks to months.382 IM injection every 2 or 4 weeks provides plasma olanzapine concentrations similar to those achieved with daily oral dosing.382 Steady-state olanzapine concentrations achieved with IM dosages of 150–405 mg every 2 or 4 weeks are within the range achieved with oral olanzapine dosages of 5–20 mg daily.382 Plasma concentrations generally reach a peak within the first week following each injection.382

Food

Food does not affect rate or extent of oral absorption.1 290

Distribution

Extent

Extensively distributed throughout the body.1 146 290

Olanzapine and its glucuronide metabolite cross the placenta.114 381 Distributed into milk in humans;1 110 111 112 113 319 mean infant dose at steady state estimated to be about 1.8% of maternal dose.1

Plasma Protein Binding

93% (mainly to albumin and α1-acid glycoprotein).1 139 290

Elimination

Metabolism

Metabolized to inactive metabolites, principally via direct glucuronidation and oxidation via CYP isoenzymes (mainly CYP1A2) and the flavin-containing monooxygenase system, with minor contribution of CYP2D6.1 116

Elimination Route

Excreted in urine (57%) and feces (30%); 7% of dose is excreted in urine as unchanged drug.1

Half-life

Oral administration: 21–54 hours.1 116 139

IM administration of short-acting olanzapine injection: Half-life similar to that observed with oral administration.1

IM administration of extended-release olanzapine pamoate injection: Approximately 30 days.382 Exposure to olanzapine may persist for months after a single long-acting IM injection.382

Special Populations

In patients with severe renal impairment, pharmacokinetics were similar to healthy individuals.1

Not appreciably removed by hemodialysis, probably due to large volume of distribution and extensive protein binding.1 116 119 146

Although hepatic impairment may be expected to reduce clearance, a study in patients with clinically important cirrhosis (Child-Pugh class A and B) revealed little effect on the pharmacokinetics of olanzapine.1

In children and adolescents 10–18 years of age treated with oral olanzapine for schizophrenia, clearance at steady state was approximately half of that in adults but was similar to that reported in nonsmoking male and female schizophrenic patients.1 116 148 290 Elimination half-life averaged 37.2 hours in this study.148

In geriatric patients, the mean elimination half-life of orally administered olanzapine was about 1.5 times that of younger patients.1

In women, clearance of olanzapine is approximately 30% lower than in men; there were no apparent differences between men and women in efficacy or adverse effects.1

In smokers, olanzapine clearance is about 40% higher than in nonsmokers, although dosage adjustment is not recommended.1

Combined effects of age, smoking, and gender may contribute to substantial pharmacokinetic differences in populations.1

Stability

Storage

Oral

Conventional and Orally Disintegrating Tablets

20–25°C (may be exposed to 15–30°C).1 Store orally disintegrating tablets in their original sealed blister.1 Protect from light and moisture.1

Fixed-combination (with Fluoxetine) Capsules

Tight containers at 25°C (may be exposed to 15–30°C).312 Protect from moisture.312

Parenteral

Immediate-release Olanzapine Powder for IM Injection (e.g., Zyprexa IntraMuscular)

20–25°C (may be exposed to 15–30°C).1 Protect from light and avoid freezing.1

Reconstituted solution may be stored for up to 1 hour at 20–25°C, if necessary; after 1 hour, discard any unused portion.1

Extended-release Olanzapine Pamoate Powder for IM Injection (Zyprexa Relprevv)

Store at room temperature (not to exceed 30°C).382

Reconstituted suspension may be stored for up to 24 hours at room temperature; once withdrawn into syringe for administration, use immediately.382

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Drug Compatibility
Admixture Compatibility1

Incompatible

Diazepam

Haloperidol

Lorazepam

Actions

  • Exact mechanism of antipsychotic action has not been fully elucidated; may involve antagonism at serotonin type 2 (5-hydroxytryptamine [5-HT2A, 5-HT2C]), type 3 (5-HT3), type 6 (5-HT6),4 8 19 20 21 and dopamine receptors.1 4 6 7 16 17 18 19 20 21 22 164 288 289 290 315 333

  • Exact mechanism(s) in treatment of acute manic or mixed episodes associated with bipolar disorder not known;1 347 antagonism and downregulation of 5-HT2A receptors may play a role.347 In addition, mood-stabilizing action may be caused at least in part by antagonism of dopamine type 2 (D2) receptors.347

  • Although not clearly established, efficacy of IM olanzapine in acute agitation appears to be due, at least in part, to its distinct calming effects rather than solely to nonspecific sedation.104

  • Antagonism at other receptors (e.g., α1-adrenergic receptors, muscarinic receptors, histamine H1 receptors) may contribute to other therapeutic and adverse effects (e.g., orthostatic hypotension, anticholinergic effects, sedative effects) observed with olanzapine.1 2 6 7 16 17 20

  • Possesses little or no affinity for β-adrenergic, γ-aminobutyric acid (GABA), or benzodiazepine receptors.1 16 20

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of informing patients, their families, and caregivers about the potential benefits and risks associated with olanzapine therapy, counseling them about its appropriate use, and advising them to read the patient information (medication guide) for the drug.1 312 382

  • Importance of informing patients receiving extended-release olanzapine pamoate (Zyprexa Relprevv) of the risk of PDSS each time they receive an injection.382 398 Advise patients that they should be observed at a healthcare facility for at least 3 hours following each IM injection, must be accompanied to their destination upon leaving the facility, and should not drive or operate heavy machinery for the remainder of the day after each injection.382 Importance of providing a copy of the medication guide for patients to read each time they receive an injection of extended-release olanzapine pamoate.382 398 Advise patients and caregivers to immediately notify the clinician if symptoms of PDSS occur (e.g., CNS depression ranging from mild sedation to coma, dizziness, confusion or disorientation, slurred speech, altered gait, difficulty ambulating, weakness, agitation, extrapyramidal symptoms, hypertension, convulsions).382

  • Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death1 312 374 380 382 and that such patients treated with olanzapine had a substantially higher incidence of adverse cerebrovascular events (e.g., stroke, TIA) compared with placebo.1 312 374 380 382 Importance of informing patients and caregivers that olanzapine is not approved for treating geriatric patients with dementia-related psychosis.1 312 374 382

  • Risk of NMS, which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, confusion, and kidney damage.1 382

  • Potential risk of hyperglycemia-associated adverse reactions; importance of regular monitoring for worsening of glucose control.1 382 Advise diabetic patients to follow their clinician’s instructions regarding the frequency of blood glucose monitoring.1 382

  • Risk of dyslipidemia.1 382 Importance of regular lipid profile monitoring.1 382

  • Risk of weight gain.1 382 Importance of monitoring body weight during therapy.1 382

  • Risk of orthostatic hypotension, especially during initial oral dosage titration and when using concomitant drugs that may increase the orthostatic effect of olanzapine (e.g., diazepam, alcohol).1 382 Advise patients to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better.1 382 Advise patients to notify their clinician if they experience signs and symptoms of orthostatic hypotension, including dizziness, fast or slow heart beat, or fainting.1 382

  • Risk of somnolence/sedation and impairment of judgment, thinking, or motor skills; advise patients to exercise caution when driving or operating hazardous machinery until they gain experience with the drug’s effects.1 382 In addition, because of the risk of PDSS, advise patients receiving extended-release olanzapine pamoate injection that they should not drive or operate heavy machinery for the remainder of the day after each injection.382

  • Importance of avoiding alcohol during olanzapine therapy.1 382

  • Importance of informing adolescent patients and/or their caregivers that adolescent patients receiving oral olanzapine are likely to gain more weight, experience increased sedation, and have greater increases in serum concentrations of total cholesterol, triglycerides, LDL-cholesterol, prolactin, and hepatic aminotransferases compared with adults; advise such patients about the potential long-term risks associated with olanzapine therapy and that the risks may lead them to consider other drugs first.1

  • Importance of avoiding overheating or dehydration.1 382 Advise patients to immediately notify their clinician if they become severely ill and have any symptoms of dehydration (e.g., sweating too much or not at all, dry mouth, feeling very hot or thirsty, unable to produce urine).1 382

  • Importance of informing patients with phenylketonuria that olanzapine orally disintegrating tablets contain aspartame.1 30 31 32 33 34

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., diabetes mellitus, seizures, dementia, cardiovascular or cerebrovascular disease).1 312 382

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 312 381 382 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions).1 312 381 382 Importance of advising patients not to stop taking olanzapine if they become pregnant without consulting their clinician; abruptly discontinuing antipsychotic agents may cause complications.381 Importance of advising patients not to breast-feed during olanzapine therapy.1 312 382

  • Importance of informing patients of other important precautionary information.1 312 382 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Long-acting IM olanzapine pamoate (Zyprexa Relprevv) is available only through a restricted distribution program.382 (See Restricted Distribution under Dosage and Administration.)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Olanzapine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2.5 mg*

Zyprexa

Lilly

5 mg*

Zyprexa

Lilly

7.5 mg*

Zyprexa

Lilly

10 mg*

Zyprexa

Lilly

15 mg*

Zyprexa

Lilly

20 mg*

Zyprexa

Lilly

Tablets, orally disintegrating

5 mg*

Zyprexa Zydis

Lilly

10 mg*

Zyprexa Zydis

Lilly

15 mg*

Zyprexa Zydis

Lilly

20 mg*

Zyprexa Zydis

Lilly

Parenteral

For injection, for IM use only

10 mg*

Zyprexa IntraMuscular

Lilly

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Olanzapine Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

3 mg with Fluoxetine Hydrochloride 25 mg (of fluoxetine)*

Symbyax

Lilly

6 mg with Fluoxetine Hydrochloride 25 mg (of fluoxetine)*

Symbyax

Lilly

6 mg with Fluoxetine Hydrochloride 50 mg (of fluoxetine)*

Symbyax

Lilly

12 mg with Fluoxetine Hydrochloride 25 mg (of fluoxetine)*

Symbyax

Lilly

12 mg with Fluoxetine Hydrochloride 50 mg (of fluoxetine)*

Symbyax

Lilly

Olanzapine Pamoate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injectable suspension, extended-release, for IM use only

210 mg (of olanzapine)

Zyprexa Relprevv (available as a convenience kit containing single-use vial, needles, syringe, and diluent)

Lilly

300 mg (of olanzapine)

Zyprexa Relprevv (available as a convenience kit containing single-use vial, needles, syringe, and diluent)

Lilly

405 mg (of olanzapine)

Zyprexa Relprevv (available as a convenience kit containing single-use vial, needles, syringe, and diluent)

Lilly

AHFS DI Essentials. © Copyright, 2004-2016, Selected Revisions May 10, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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5. Lilly, Indianapolis, IN: Personal communication.

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9. Sandoz Pharmaceuticals. Clozaril (clozapine) prescribing information. East Hanover, NJ; 1991 Apr 15.

10. Reviewers’ comments (personal observations) on clozapine 28:16.08.

11. Lipsitz L. Orthostatic hypotension in the elderly. N Engl J Med. 1989; 321:952-7. [IDIS 259578] [PubMed 2674714]

12. Montamat SC, Cusack BJ, Vestal RE. Management of drug therapy in the elderly. N Engl J Med. 1989; 321:303-9. [IDIS 257650] [PubMed 2664519]

13. Anon. Now we understand antipsychotics? Lancet. 1990; 336:1222-3. Editorial.

14. Keks N. Schizophrenia. Aust J Hosp Pharm. 1996; 26:93-6.

15. Ryan PM. Epidemiology, etiology, diagnosis, and treatment of schizophrenia. Am J Hosp Pharm. 1991; 48:1271-80. [PubMed 1677528]

16. Moore NA, Calligaro DO, Wong DT et al. The pharmacology of olanzapine and other new antipsychotic agents. Curr Opin Invest Drugs. 1993; 2:281-93.

17. Moore NA, Tye NC, Axton MS et al. The behavioral pharmacology of olanzapine, a novel “atypical” antipsychotic agent. J Pharmacol Exp Ther. 1992; 262:P545-51. [PubMed 1354253]

18. Meltzer HY. Role of serotonin in the action of atypical antipsychotic drugs. Clin Neurosci. 1995; 3:64-75. [PubMed 7583621]

19. Roth BL, Craigo SC, Choudhary MS et al. Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors. J Pharmacol Exp Ther. 1994; 268:1403-10. [PubMed 7908055]

20. Fulton B, Goa KL. Olanzapine: a review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses. Drugs. 1997; 53:282-98.

21. Tollefson GD, Beasley CM, Tran PV et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry. 1997; 154:457-65. [IDIS 384214] [PubMed 9090331]

22. Tollefson GD, Sanger TM. Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine. Am J Psychiatry. 1997; 154:466-74. [IDIS 384215] [PubMed 9090332]

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