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: C17H20N4S
CAS Number: 132539-06-1
Brands: Symbyax, Zyprexa, Zyprexa Zydis
Special Alerts:
[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.
The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.
BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.
RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .
[Posted 01/29/2010] Lilly and FDA notified healthcare professionals of changes to the Prescribing Information for olanzapine (Zyprexa) related to its indication for use in adolescents (ages 13-17) for treatment of schizophrenia and bipolar I disorder [manic or mixed episodes]. The revised labeling states that:
Section 1, Indications and Usage: When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and hyperlipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents.
Section 17.14, Need for comprehensive Treatment Program in Pediatric Patients: Olanzapine is indicated as an integral part of a total treatment program for pediatric patients with schizophrenia and bipolar disorder that may include other measures (psychological, educational, social) for patients with the disorder. Effectiveness and safety of olanzapine have not been established in pediatric patients less than 13 years of age.
For more information visit the FDA website at: and .
[Posted 05/02/2007] FDA notified healthcare professionals that the Agency proposed that makers of all antidepressant medications update the existing black box warning on the prescribing information for their products to include warnings about the increased risks of suicidal thinking and behavior in young adults ages 18 to 24 years old during the first one to two months of treatment. The proposed labeling changes also state that scientific data did not show this increased risk in adults older than 24 years of age and that adults 65 years of age and older taking antidepressants have a decreased risk of suicidality. The proposed updates apply to the entire category of antidepressants. Individuals currently taking prescribed antidepressant medications should not stop taking them and should notify their healthcare professional if they have concerns. Manufacturers of antidepressant medications will have 30 days to submit their revised product labeling and revised Medication Guides to FDA for review. See the FDA press release for the list of products affected by the proposed antidepressant product labeling changes. For more information visit the FDA website at: , and .
[Posted 07/19/2006] FDA notified healthcare professionals and consumers of important information from two recent studies that should be considered when making treatment decisions in pregnant women who take antidepressants. The studies included pregnant women who were treated with selective serotonin reuptake inhibitors (SSRIs), or in a few cases, other antidepressant medications.
One study illustrated the potential risk of relapsed depression after stopping antidepressant medication during pregnancy. In this study, women who stopped their medicine were five times more likely to have a relapse of depression during their pregnancy than were women who continued to take their antidepressant medicine while pregnant.
The second study suggests there may be additional, though rare, risks of taking SSRI medications during pregnancy. This study focused on newborn babies with persistent pulmonary hypertension (PPHN), which is a serious and life-threatening lung condition that occurs soon after birth. Babies born with PPHN have high pressure in their lung blood vessels and are not able to get enough oxygen into their bloodstream. In this study, PPHN was six times more common in babies whose mothers took an SSRI antidepressant after the 20th week of pregnancy compared to babies whose mothers did not take an antidepressant. The study was too small to compare the risk of one drug compared to another. The finding of PPHN in babies of mothers who used a SSRI antidepressant in the second half of pregnancy adds to concerns from previous reports that infants of mothers taking SSRIs late in pregnancy may experience difficulties such as irritability, difficulty feeding and in very rare cases, difficulty breathing.
Additionally, the labeling for paroxetine (Paxil) was recently changed to add information about findings in an epidemiologic study that suggests that exposure to the drug in the first trimester of pregnancy may be associated with an increased risk of cardiac birth defects.
Women who are pregnant or thinking about becoming pregnant should not stop any antidepressant medication without first consulting their physician. The FDA is seeking additional information about the possible risk of PPHN in newborn babies of mothers who took SSRI antidepressants in pregnancy. FDA has asked the sponsors of all SSRIs to change prescribing information to describe the potential risk for PPHN. For more information visit the FDA website at: and .
[Posted 07/19/2006] FDA notified healthcare professionals and consumers of new safety information regarding taking medications used to treat migraine headaches (triptans) together with certain types of antidepressant and mood disorder medications (selective serotonin reuptake inhibitors (SSRIs) and selective serotonin/norepinephrine reuptake inhibitors (SNRIs). A life-threatening condition called serotonin syndrome may occur when triptans are used together with a SSRI or a SNRI.
Serotonin syndrome occurs when the body has too much of a chemical found in the nervous system (serotonin). Each of the above medications (triptans, SSRIs, and SNRIs), cause an increase in serotonin levels. Symptoms of serotonin syndrome may include restlessness, hallucinations, loss of coordination, fast heart beat, rapid changes in blood pressure, increased body temperature, overactive reflexes, nausea, vomiting, and diarrhea.
Healthcare professionals prescribing a triptan, SSRI or SNRI should keep in mind that triptans are often used intermittently and either the triptan, SSRI or SNRI may be prescribed by a different physician; weigh the potential risk of serotonin syndrome with the expected benefit of using the above combination; discuss the possibility of serotonin syndrome with patients if a triptan and an SSRI or SNRI will be used together; and follow patients closely during treatment if a triptan and an SSRI or SNRI are used together.
Patients taking a triptan along with an SSRI or SNRI should talk to their doctor before stopping their medication and should immediately seek medical attention if they experience any of the above symptoms. FDA requested that all manufacturers of triptans, SSRIs and SNRIs update their prescribing information to warn of the possibility of serotonin syndrome when these medications are taken together. For more information visit the FDA website at: and .
REMS:
FDA approved a REMS for olanzapine to ensure that the benefits of a drug 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 ().
- Increased Mortality in Geriatric Patients
Substantially higher mortality rate (4.5%) in geriatric patients with dementia-related psychosis† receiving atypical antipsychotic agents (e.g., olanzapine, aripiprazole, quetiapine, risperidone) compared with those receiving placebo (2.6%).1 101
Most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia.)1 101
Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.1 101 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)
Introduction
Atypical or second-generation antipsychotic agent.2 4 7 14 16 17 18 19 20 22 26
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
Symptomatic management of schizophrenia.1
IM 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
Bipolar Disorder
Short-term management (alone or in combination with lithium or divalproex sodium [e.g., valproate sodium, valproic acid]) of acute mixed or manic episodes and maintenance of treatment response in patients with bipolar I disorder.1 36 37
Management (in fixed-combination with fluoxetine) of acute depressive episodes in patients with bipolar depression (bipolar disorder, depressed).c
IM 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
Olanzapine Dosage and Administration
Administration
Administer orally or by deep IM injection.1 (See Possible Prescribing and Dispensing Errors under Cautions.)
Oral Administration
Administer orally as conventional tablets, orally disintegrating tablets, or capsules (in fixed combination with fluoxetine) once daily without regard to meals.1 c Administer fixed-combination olanzapine and fluoxetine capsules in the evening.c
Just prior to administration, gently remove orally disintegrating 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
Administer by IM injection slowly and deeply into the muscle mass.1 Do not administer IV or sub-Q.1
Reconstitution
Reconstitute 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
Following reconstitution, use immediately (within 1 hour).1 Discard any unused portion.1
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.
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
Bipolar Disorder
Acute Mania: Monotherapy
Oral
Initially, 10–15 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
If elect to use olanzapine for extended periods, periodically reevaluate the long-term usefulness for the individual patient.1
Acute Mania: Combination Therapy
Oral
Initially, 10 mg once daily when administered with lithium or divalproex sodium.1
Effective dosage of olanzapine in clinical studies generally ranged from 5–20 mg daily.1
No dosage adjustment for lithium or divalproex sodium is required when used in combination with olanzapine.1
Acute Depression: Combination Therapy
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.
Oral
Initially, 6 mg in fixed combination with 25 mg of fluoxetine (Symbyax 6/25) once daily in the evening.c
Increase dosage according to patient response and tolerance as indicated.c
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.c
If elect to use combined olanzapine and fluoxetine for extended periods, periodically reevaluate the long-term risks and benefits for the individual patient.c
Acute Agitation in Schizophrenia and Bipolar Mania
IM
Initially, 10 mg.1 Consider lower doses (2.5, 5, or 7.5 mg) when clinically warranted.1
In clinical trials, efficacy of IM olanzapine for controlling agitation in patients with schizophrenia or bipolar mania was 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 Cardiovascular Effects under Cautions.)
Oral therapy should replace IM therapy as soon as possible.1
Prescribing Limits
Adults
Schizophrenia
Oral
Safety of dosages >20 mg daily not established.1 20
Bipolar Disorder
Oral
Safety of dosages >20 mg daily not established.1
Dosages >18 mg of olanzapine and 75 mg of fluoxetine in fixed-combination for acute depressive episodes not evaluated in clinical studies.c
Acute Agitation in Schizophrenia and Bipolar Mania
IM
Safety of dosages >30 mg daily or of 10-mg IM doses given more frequently than 2 hours after the initial dose and 4 hours after the second dose not established.1
Special Populations
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.
Initially, 5 mg orally daily or 2.5 mg IM 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); when indicated, adjust dosage with caution.1
In fixed combination with fluoxetine for acute depressive episodes in bipolar disorder, an oral dosage of 6 mg of olanzapine and 25 mg of fluoxetine (Symbyax 6/25) is recommended for initial and maintenance therapy in patients predisposed to hypotension, in 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.c
Geriatric Patients
Careful dosage titration of oral olanzapine recommended in patients >65 years of age; initiate therapy at low end of dosage range.1 26
Consider a lower initial IM dose of 5 mg.1
Cautions for Olanzapine
Contraindications
Known hypersensitivity to olanzapine or any ingredient in the formulation.1
Warnings/Precautions
Warnings
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.
Increased Mortality in Geriatric Patients with Dementia-related Psychosis
Possible increased risk of death with use of atypical antipsychotics in geriatric patients with dementia-related psychosis.1 101 (See Boxed Warning and see Geriatric Use under Cautions.)
Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.1 101
Hyperglycemia and Diabetes Mellitus
Severe hyperglycemia, sometimes 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 preexisting diabetes mellitus for worsening of glucose control and perform fasting glucose tests 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, test for diabetes mellitus.1 44 45 46 47 48 49 50 51 52 53 54 55
Cerebrovascular Effects
Adverse cerebrovascular effects (e.g., stroke, transient ischemic attack), sometimes fatal, reported in geriatric patients with dementia-related psychosis receiving olanzapine.1 (See Geriatric Use under Cautions.)
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported.1
Tardive Dyskinesia
Tardive dyskinesia, a syndrome of potenially irreversible, involuntary dyskinetic movements, may occur in patients receiving antipsychotic agents.1 Consider discontinuance of olanzapine if signs and symptoms of tardive dyskinesia occur.1
Sensitivity Reactions
Allergic reactions (e.g., anaphylactoid reaction, angioedema, pruritus, urticaria, rash) reported.1 c Discontinue olanzapine if alternative etiology of rash or other allergic manifestation cannot be identified.c
General Precautions
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
Cardiovascular Effects
Orthostatic hypotension reported with oral olanzapine, particularly during initial dosage titration period.1
Hypotension, bradycardia with or without hypotension, tachycardia, and syncope reported with IM olanzapine.1
Use oral or IM olanzapine with caution in patients with known cardiovascular or cerebrovascular disease and/or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).1
Risk of clinically important orthostatic hypotension associated with use of maximum recommended IM dosages of olanzapine (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 (See Specific Drugs under Interactions.)
Nervous System Effects
Possible risk of seizures; 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, geriatric patients).1
Disruption of the body’s ability to reduce core body temperature possible; use caution in patients exposed to conditions that may contribute to an elevation in core body temperature (e.g., dehydration, extreme heat, strenuous exercise, concomitant use of anticholinergic agents).1
Somnolence reported.1 Potential impairment of judgment, thinking, or motor skills.1
Endocrine Effects
Elevated prolactin concentrations reported; modest elevation persists during chronic administration.1
Metabolic Effects
Weight gain possible; patients with low body mass index (BMI) may be more susceptible than normal or overweight patients.1
Hepatic Effects
Clinically important ALT increases (≥3 times the ULN) possible; use with caution in patients with manifestations of hepatic impairment, those with preexisting conditions associated with limited hepatic functional reserve, and those treated with potentially hepatotoxic drugs.1 Periodically assess transaminases in patients with hepatic disease.1
GI Effects
Esophageal dysmotility and aspiration possible;1 use with caution in patients at risk for aspiration pneumonia (e.g., geriatric patients, those with advanced Alzheimer’s dementia).1
Suicide
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.
Attendant risk with psychotic illnesses; closely supervise high-risk patients.1 Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.1
Anticholinergic Effects
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.1
Phenylketonuria
Each 5, 10, 15, or 20 mg Zyprexa Zydis orally disintegrating tablet contains aspartame (e.g., Nutrasweet), which is metabolized in the GI tract to provide 0.34, 0.45, 0.67, or 0.9 mg of phenylalanine per tablet, respectively.1 30 31 32 33 34
Combination Therapy with Lithium, Divalproex Sodium, or Fluoxetine
Consider cautions, precautions, and contraindications associated with lithium, divalproex sodium, or fluoxetine when olanzapine is used in conjunction with these drugs.1 c
Specific Populations
Pregnancy
Category C.1
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.
Lactation
Distributed into milk in humans.1 Women receiving olanzapine should not breast-feed.1
Pediatric Use
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.
Safety and efficacy not established in children <18 years of age.1 35
Geriatric Use
Safety 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
Lower initial dosages and slower titration during the initial dosing period may be advisable in some geriatric patients. (See Special Populations under Dosage and Administration.)1
Possible increased risk of death in geriatric patients with dementia-related psychosis.1 101 Substantial (1.6- to 1.7-fold) increase in mortality rate reported in geriatric patients with dementia who received atypical antipsychotic agents (e.g., olanzapine, aripiprazole, quetiapine, risperidone) fortreatment of behavioral disorders; most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).1 101 In addition, adverse cerebrovascular effects, sometimes fatal, reported in geriatric patients with dementia-related psychosis receiving olanzapine.1 (See Cerebrovascular Effects under Cautions.)
Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.1 101 (See Boxed Warning.)
Common Adverse Effects
With oral therapy, somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, personality disorder (i.e., non-aggressive objectionable behavior), weight gain, increased appetite, tremor, postural hypotension, akathisia.1
With parenteral therapy, somnolence.1
Interactions 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.
Metabolized by CYP1A2 and CYP2D6; CYP2D6 appears to be a minor pathway. Also metabolized by direct glucuronidation.1 Appears to have little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.1
Drugs Affecting Hepatic Microsomal Enzymes
CYP1A2 or glucuronyl transferase enzyme inhibitors and inducers; pharmacokinetic interaction (altered olanzapine metabolism).1
Specific Drugs
Drug | Interaction | Comment |
|---|---|---|
Alcohol | Potential additive CNS effects; concomitant use with alcohol potentiates orthostatic hypotension observed with olanzapine1 | Advise patients to avoid alcohol 1 |
Antacids (aluminum- and magnesium-containing) | Pharmacokinetic interaction unlikely1 | |
Biperiden | Pharmacokinetic interaction unlikely1 | |
Benzodiazepines (parenteral) (e.g., lorazepam) | Potential additive CNS and cardiovascular effects (excessive sedation and cardiorespiratory depression) during concurrent parenteral administration1 Increased somnolence during concurrent parenteral administration of olanzapine and lorazepam; no effect on pharmacokinetics of either drug1 | Concurrent use of IM olanzapine with parenteral benzodiazepines not recommended1 If administered concurrently, carefully evaluate for excessive sedation and cardiorespiratory depression1 |
Charcoal | Decreased peak plasma concentrations and AUC of oral olanzapine1 | Charcoal may be useful in treatment for olanzapine overdose1 |
Cimetidine | Pharmacokinetic interaction unlikely1 | |
CNS agents | 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 maximum plasma olanzapine concentrations and decrease in olanzapine clearance1 | Not considered clinically important;c dosage modification not routinely recommended1 |
Fluvoxamine | Decreased clearance and increased maximum plasma concentrations of olanzapine 1 | Consider lower olanzapine dosage 1 |
Hypotensive agents | Additive hypotensive effects1 | Use with caution1 |
Imipramine | Pharmacokinetic interaction unlikely1 | |
Levodopa | Potential antagonistic effects1 | |
Lithium | Pharmacokinetic interaction unlikely1 | No dosage adjustment of lithium necessary during concomitant administration1 |
Omeprazole | Possible increase in olanzapine clearance1 | Increase in olanzapine dosage may need to be considered1 |
Rifampin | Possible increase in olanzapine clearance1 | Increase in olanzapine dosage may need to be considered1 |
Theophylline | Pharmacokinetic interaction unlikely1 | |
Valproate | Clinically important pharmacokinetic interaction unlikely1 | No dosage adjustment of valproate necessary during concomitant administration1 |
Warfarin | Pharmacokinetic interaction unlikely1 |
Olanzapine Pharmacokinetics
Absorption
Bioavailability
Well absorbed after oral administration, with peak plasma concentrations attained in approximately 6 hours.1 Rapidly absorbed following IM administration, with peak plasma concentrations generally attained within 15–45 minutes.1
About 40% of oral dose is metabolized before reaching systemic circulation.1
Conventional and orally disintegrating olanzapine tablets are bioequivalent.1
IM administration of a 5-mg dose results in a maximum plasma olanzapine concentration that is an average of about fivefold higher than that resulting from a 5-mg oral dose.1 AUCs are similar following oral and IM administration.1
Food
Food does not affect rate or extent of oral absorption.1
Distribution
Extent
Extensively distributed throughout the body.1
Olanzapine crosses the placenta.b Distributed into milk in humans; mean infant dose at steady state estimated to be about 1.8% of maternal dose.1
Plasma Protein Binding
93% (mainly albumin and α1-acid glycoprotein).1
Elimination
Metabolism
Metabolized to inactive metabolites, principally via direct glucuronidation and oxidation by CYP1A2 and the flavin-containing monooxygenase system, with minor contribution of CYP2D6.1 a
Elimination Route
Excreted in urine (57%) and feces (30%); 7% of dose is excreted in urine as unchanged drug.1
Half-life
21–54 hours.1
Special Populations
In patients with severe renal impairment, pharmacokinetics were similar to healthy individuals.1
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 geriatric patients, the mean elimination half-life 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
Tablets and Orally Disintegrating Tablets
20–25°C (may be exposed to 15–30°C).1 Protect from light and moisture.1
Fixed-combination (with Fluoxetine) Capsules
Tight containers at 25°C (may be exposed to 15–30°C).c Protect from moisture.c
Parenteral
Powder for Injection
20–25°C (may be exposed to 15–30°C).1 Protect from light and avoid freezing.1
The reconstituted solution may be stored for up to 1 hour at 20–25°C, if necessary; after 1 hour, discard any unused portion.1
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
Drug Compatibility
Incompatible |
|---|
Diazepam |
Haloperidol |
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),16 type 6 (5-HT6),4 18 19 20 21 and dopamine receptors.1 4 6 7 16 17 18 19 20 21 22
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.
Risk of excessive weight gain, orthostatic hypotension, disruption of regulation of body temperature, and somnolence.1
Importance of avoiding overheating or dehydration.1
Importance of informing patients with phenylketonuria that olanzapine orally disintegrating tablets contain aspartame.1 30 31 32 33 34
Importance of avoiding driving, operating machinery, or performing hazardous tasks until the patient gains experience with drug’s effects.1
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).1 c
Importance of avoiding alcohol during olanzapine therapy.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing patients of other important precautionary information.1 c (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
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 (with aspartame and parabens) | Lilly | |
10 mg | Zyprexa Zydis (with aspartame and parabens) | Lilly | ||
15 mg | Zyprexa Zydis (with aspartame and parabens) | Lilly | ||
20 mg | Zyprexa Zydis (with aspartame and parabens) | Lilly | ||
Parenteral | For injection | 10 mg | Zyprexa Intramuscular | Lilly |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 6 mg with Fluoxetine Hydrochloride 25 mg (of fluoxetine) | Symbyax | Lilly |
6 mg with Fluoxetine Hydrochloride 50 mg (of fluoxetine) | Symbyax | Lilly | ||
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