Side Effects of Zyprexa (olanzapine)

Zyprexa (olanzapine) is an atypical antipsychotic used to treat schizophrenia and acute manic episodes associated with bipolar I disorder.

The exact mechanism of action of Zyprexa is not known. It may work by blocking receptors for several neurotransmitters (chemicals that nerves use to communicate with each other) in the brain. It binds to alpha-1, dopamine, histamine H-1, muscarinic, and serotonin type 2 (5-HT2) receptors. 

Common side effects of Zyprexa include

• inability to sit still (akathisia),
• constipation,
• dizziness,
• drowsiness,
• insomnia,
• dry mouth,
• dizziness on standing,
• tremor, and
• weight gain.

Serious side effects of Zyprexa include

• extrapyramidal effects (sudden, often jerky, involuntary motions of the head, neck, arms, body, or eyes),
• tardive dyskinesia (involuntary movements of the mouth, tongue, jaw, or eyelids),
• increased risk of elevated blood sugar levels and diabetes,
• increased prolactin levels (abnormal menstruation, sexual dysfunction, and breast enlargement), and
• severe sedation, coma, and/or delirium after an injection of extended release Zyprexa. 

Drug interactions of Zyprexa include carbamazepine, omeprazole, and rifampin, which can reduce blood concentrations of Zyprexa, possibly necessitating higher doses of Zyprexa.

• Smoking may reduce blood concentrations of Zyprexa.
• Ciprofloxacin, diltiazem, erythromycin, and fluvoxamine may increase blood levels of Zyprexa, and the dose of Zyprexa may need to be reduced.
• Zyprexa can cause orthostatic hypotension, a drop in blood pressure upon standing up that may cause dizziness or even fainting.
• Taking Zyprexa with benzodiazepines or alcohol can exaggerate the orthostatic hypotension caused by Zyprexa.

There are no adequate studies of Zyprexa in pregnant women. Zyprexa should only be administered to pregnant women if the benefits justify the unknown risks.

Zyprexa is excreted into breast milk. It is recommended Zyprexa not be used by breastfeeding mothers.

WARNING

• Elderly patients with dementia related psychosis treated with antipsychotics are at an increased risk of death.
• When using olanzapine and fluoxetine in combination, also refer to the boxed warning section of the package insert for Symbyax.

Common side effects

Common side effects seen with olanzapine are:

• an inability to sit still (akathisia),
• constipation,
• dizziness,
• drowsiness,
• insomnia,
• dry mouth,
• orthostatic hypotension,
• tremor, and
• weight gain.

Several disorders of movement also may occur with olanzapine, for example, extrapyramidal effects (sudden, often jerky, involuntary motions of the head, neck, arms, body, or eyes). Tardive dyskinesia (involuntary movements of the mouth, tongue, jaw, or eyelids) also may occur in 1 in 100 patients receiving olanzapine.

Some cases can be irreversible. The likelihood of developing tardive dyskinesia increases with prolonged treatment.

There may be an increased risk of elevated blood sugar levels and diabetes with olanzapine as well as the other antipsychotic medications in its class. Patients should be tested during treatment for elevated blood sugar.

Additionally, persons with risk factors for diabetes, including obesity or a family history of diabetes, should have their fasting levels of blood sugar tested before starting treatment and periodically throughout treatment to detect the onset of diabetes. Any patient developing symptoms that suggest diabetes during treatment should be tested for diabetes.

Patients may develop severe sedation, coma, and or delirium after an injection of extended release olanzapine. Patients must be examined for 3 hours after receiving an injection.

Olanzapine may increase prolactin levels. Increased prolactin levels may manifest as abnormal menstruation, sexual dysfunction, and breast enlargement.

When using Zyprexa and fluoxetine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

Clinical Trials In Adults

The information below for olanzapine is derived from a clinical trial database for olanzapine consisting of 10,504 adult patients with approximately 4765 patient-years of exposure to olanzapine plus 722 patients with exposure to intramuscular olanzapine for injection.

This database includes:

• (1) 2500 patients who participated in multiple-dose oral olanzapine premarketing trials in schizophrenia and Alzheimer's disease representing approximately 1122 patient-years of exposure as of February 14, 1995;
• (2) 182 patients who participated in oral olanzapine premarketing bipolar I disorder (manic or mixed episodes) trials representing approximately 66 patient-years of exposure;
• (3) 191 patients who participated in an oral olanzapine trial of patients having various psychiatric symptoms in association with Alzheimer's disease representing approximately 29 patient-years of exposure;
• (4) 5788 additional patients from 88 oral olanzapine clinical trials as of December 31, 2001;
• (5) 1843 additional patients from 41 olanzapine clinical trials as of October 31, 2011; and
• (6) 722 patients who participated in intramuscular olanzapine for injection premarketing trials in agitated patients with schizophrenia, bipolar I disorder (manic or mixed episodes), or dementia.

Also included below is information from the premarketing 6-week clinical study database for olanzapine in combination with lithium or valproate, consisting of 224 patients who participated in bipolar I disorder (manic or mixed episodes) trials with approximately 22 patient-years of exposure.

• The conditions and duration of treatment with olanzapine varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure.
• Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analytes, ECGs, chest x-rays, and results of ophthalmologic examinations.
• Certain portions of the discussion below relating to objective or numeric safety parameters, namely, dosedependent adverse reactions, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia and have not been duplicated for bipolar I disorder (manic or mixed episodes) or agitation. However, this information is also generally applicable to bipolar I disorder (manic or mixed episodes) and agitation.
• Adverse reactions during exposure were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized reaction categories.
• In the tables and tabulations that follow, MedDRA and COSTART Dictionary terminology has been used to classify reported adverse reactions.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

The reported reactions do not include those reaction terms that were so general as to be uninformative. Reactions listed elsewhere in labeling may not be repeated below. It is important to emphasize that, although the reactions occurred during treatment with olanzapine, they were not necessarily caused by it. The entire label should be read to gain a complete understanding of the safety profile of olanzapine.

• The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials.
• Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators.
• The cited figures, however, do provide the prescribing healthcare provider with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactions incidence in the population studied.

Incidence Of Adverse Reactions In Short-Term, Placebo-Controlled And Combination Trials

The following findings are based on premarketing trials of

• (1) oral olanzapine for schizophrenia, bipolar I disorder (manic or mixed episodes), a subsequent trial of patients having various psychiatric symptoms in association with Alzheimer's disease, and premarketing combination trials, and
• (2) intramuscular olanzapine for injection in agitated patients with schizophrenia or bipolar I mania.

Adverse Reactions Associated With Discontinuation Of Treatment In Short-Term, Placebo-Controlled Trials

Schizophrenia

Overall, there was no difference in the incidence of discontinuation due to adverse reactions (5% for oral olanzapine vs 6% for placebo). However, discontinuations due to increases in ALT were considered to be drug related (2% for oral olanzapine vs 0% for placebo).

Bipolar I Disorder (Manic Or Mixed Episodes) Monotherapy

Overall, there was no difference in the incidence of discontinuation due to adverse reactions (2% for oral olanzapine vs 2% for placebo).

Agitation

Overall, there was no difference in the incidence of discontinuation due to adverse reactions (0.4% for intramuscular olanzapine for injection vs 0% for placebo).

Adverse Reactions Associated With Discontinuation Of Treatment In Short-Term Combination Trials

Bipolar I Disorder (Manic Or Mixed Episodes), Olanzapine As Adjunct To Lithium Or Valproate

In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 11% for the combination of oral olanzapine with lithium or valproate compared to 2% for patients who remained on lithium or valproate monotherapy.

Discontinuations with the combination of oral olanzapine and lithium or valproate that occurred in more than 1 patient were:

• somnolence (3%),
• weight gain (1%), and
• peripheral edema (1%).

Commonly Observed Adverse Reactions In Short-Term, Placebo-Controlled Trials

The most commonly observed adverse reactions associated with the use of oral olanzapine (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) were:

Table 9: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Trials - SCHIZOPHRENIA

Table 10: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 3-Week and 4-Week Trials - Bipolar I Disorder (Manic or Mixed Episodes)

Olanzapine Intramuscular

There was 1 adverse reaction (somnolence) observed at an incidence of 5% or greater among intramuscular olanzapine for injection-treated patients and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) during the placebo-controlled premarketing studies.

The incidence of somnolence during the 24 hour IM treatment period in clinical trials in agitated patients with schizophrenia or bipolar I mania was 6% for intramuscular olanzapine for injection and 3% for placebo.

Adverse Reactions Occurring At An Incidence Of 2% or More Among Oral Olanzapine-Treated Patients In Short-Term, Placebo-Controlled Trials

Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with oral olanzapine (doses ≥2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of placebo-controlled trials.

Table 11: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Oral Olanzapine

Dose Dependency Of Adverse Reactions

A dose group difference has been observed for fatigue, dizziness, weight gain and prolactin elevation. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant differences between 10 vs 40 and 20 vs 40 mg/day.

The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 vs 40 mg. Dose group differences were also noted for weight gain and prolactin elevation.

The following table addresses dose relatedness for other adverse reactions using data from a schizophrenia trial involving fixed dosage ranges of oral olanzapine. It enumerates the percentage of patients with treatment-emergent adverse reactions for the 3 fixed-dose range groups and placebo. The data were analyzed using the Cochran-Armitage test, excluding the placebo group, and the table includes only those adverse reactions for which there was a trend.

Table 12: Percentage of Patients from a Schizophrenia Trial with Treatment-Emergent Adverse Reactions for the 3 Dose Range Groups and Placebo

Commonly Observed Adverse Reactions In Short-Term Trials Of Oral Olanzapine As Adjunct To Lithium Or Valproate

In the bipolar I disorder (manic or mixed episodes) adjunct placebo-controlled trials, the most commonly observed adverse reactions associated with the combination of olanzapine and lithium or valproate (incidence of ≥5% and at least twice placebo) were:

Table 13: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Adjunct to Lithium or Valproate Trials - Bipolar I Disorder (Manic or Mixed Episodes)

Adverse Reactions Occurring At An Incidence Of 2% Or More Among Oral Olanzapine-Treated Patients In Short-Term Trials Of Olanzapine As Adjunct To Lithium Or Valproate

Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with the combination of olanzapine (doses ≥5 mg/day) and lithium or valproate and with incidence greater than lithium or valproate alone who participated in the acute phase of placebo-controlled combination trials.

Table 14: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials of Oral Olanzapine as Adjunct to Lithium or Valproate

For specific information about the adverse reactions observed with lithium or valproate, refer to the Adverse Reactions section of the package inserts for these other products.

Adverse Reactions Occurring At An Incidence Of 1% or More Among Intramuscular Olanzapine For Injection-Treated Patients In Short-Term, Placebo-Controlled Trials

Table 15 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 1% or more of patients treated with intramuscular olanzapine for injection (dose range of 2.5-10 mg/injection) and with incidence greater than placebo who participated in the short-term, placebo-controlled trials in agitated patients with schizophrenia or bipolar I mania.

Table 15: Treatment-Emergent Adverse Reactions: Incidence in Short-Term (24 Hour), Placebo-Controlled Clinical Trials with Intramuscular Olanzapine for Injection in Agitated Patients with Schizophrenia or Bipolar I Mania

Extrapyramidal Symptoms

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

Table 16: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia - Acute Phase

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

Table 17: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia - Acute Phase

The following table enumerates the percentage of adolescent patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy (dose range: 2.5 to 20 mg/day).

Table 18: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in Placebo-Controlled Clinical Trials of Oral Olanzapine in Schizophrenia and Bipolar I Disorder - Adolescents

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during controlled clinical trials comparing fixed doses of intramuscular olanzapine for injection with placebo in agitation.

Patients in each dose group could receive up to 3 injections during the trials. Patient assessments were conducted during the 24 hours following the initial dose of intramuscular olanzapine for injection.

Table 19: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dose, Placebo-Controlled Clinical Trial of Intramuscular Olanzapine for Injection in Agitated Patients with Schizophrenia

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions in the same controlled clinical trial comparing fixed doses of intramuscular olanzapine for injection with placebo in agitated patients with schizophrenia.

Table 20: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dose, Placebo-Controlled Clinical Trial of Intramuscular Olanzapine for Injection in Agitated Patients with Schizophrenia

Dystonia, Class Effect

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue.

While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use.

Other Adverse Reactions

Other Adverse Reactions Observed During The Clinical Trial Evaluation Of Oral Olanzapine

Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 mg/day) in clinical trials. This listing is not intended to include reactions

• (1) already listed in previous tables or elsewhere in labeling,
• (2) for which a drug cause was remote,
• (3) which were so general as to be uninformative,
• (4) which were not considered to have significant clinical implications, or
• (5) which occurred at a rate equal to or less than placebo.

Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole - Infrequent: chills, face edema, photosensitivity reaction, suicide attempt^1; Rare: chills and fever, hangover effect, sudden death¹.

Cardiovascular System - Infrequent: cerebrovascular accident, vasodilatation.

Digestive System - Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit.

Hemic and Lymphatic System - Infrequent: thrombocytopenia.

Metabolic and Nutritional Disorders - Frequent: alkaline phosphatase increased; Infrequent: bilirubinemia, hypoproteinemia.

Musculoskeletal System - Rare: osteoporosis.

Nervous System - Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma.

Respiratory System - Infrequent: epistaxis; Rare: lung edema.

Skin and Appendages - Infrequent: alopecia.

Special Senses - Infrequent: abnormality of accommodation, dry eyes; Rare: mydriasis.

Urogenital System - Infrequent: amenorrhea², breast pain, decreased menstruation, impotence², increased menstruation², menorrhagia², metrorrhagia², polyuria², urinary frequency, urinary retention, urinary urgency, urination impaired.

¹ These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.
² Adjusted for gender.

Other Adverse Reactions Observed During The Clinical Trial Evaluation Of Intramuscular Olanzapine For Injection

Following is a list of treatment-emergent adverse reactions reported by patients treated with intramuscular olanzapine for injection (at 1 or more doses ≥2.5 mg/injection) in clinical trials.

This listing is not intended to include reactions

• (1) already listed in previous tables or elsewhere in labeling,
• (2) for which a drug cause was remote,
• (3) which were so general as to be uninformative,
• (4) which were not considered to have significant clinical implications, or
• (5) for which occurred at a rate equal to or less than placebo.

Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients.

Body as a Whole - Frequent: injection site pain.

Cardiovascular System - Infrequent: syncope.

Digestive System - Infrequent: nausea.

Metabolic and Nutritional Disorders - Infrequent: creatine phosphokinase increased.

Clinical Trials In Adolescent Patients (age 13 to 17 years)

Commonly Observed Adverse Reactions In Oral Olanzapine Short-Term, Placebo-Controlled Trials

Adverse reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg) reported with an incidence of 5% or more and reported at least twice as frequently as placebo-treated patients are listed in Table 21.

Table 21: Treatment-Emergent Adverse Reactions of ≥5% Incidence among Adolescents (13-17 Years Old) with Schizophrenia or Bipolar I Disorder (Manic or Mixed Episodes)

Adverse Reactions Occurring At An Incidence Of 2% Or More Among Oral Olanzapine-Treated Patients In Short- Term (3-6 weeks), Placebo-Controlled Trials

Adverse reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg) reported with an incidence of 2% or more and greater than placebo are listed in Table 22.

Table 22: Treatment-Emergent Adverse Reactions of ≥2% Incidence among Adolescents (13-17 Years Old) (Combined Incidence from Short-Term, Placebo-Controlled Clinical Trials of Schizophrenia or Bipolar I Disorder [Manic or Mixed Episodes])

Vital Signs And Laboratory Studies

Vital Sign Changes

Oral olanzapine was associated with orthostatic hypotension and tachycardia in clinical trials. Intramuscular olanzapine for injection was associated with bradycardia, hypotension, and tachycardia in clinical trials.

Laboratory Changes

Olanzapine Monotherapy In Adults

• An assessment of the premarketing experience for olanzapine revealed an association with asymptomatic increases in ALT, AST, and GGT.
• Within the original premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT elevations to >200 IU/L was 2% (50/2381). None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued.
• In placebo-controlled olanzapine monotherapy studies in adults, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patients exposed to placebo.
• ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0.3% (4/1196) of placebo-treated patients.
• ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine.
• No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule.
• From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, high GGT levels were recorded in ≥1% (88/5245) of patients.
• Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with preexisting conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.
• Olanzapine administration was also associated with increases in serum prolactin, with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK.
• From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, elevated uric acid was recorded in ≥3% (171/4641) of patients.

Olanzapine Monotherapy In Adolescents

In placebo-controlled clinical trials of adolescent patients with schizophrenia or bipolar I disorder (manic or mixed episodes), greater frequencies for the following treatment-emergent findings, at anytime, were observed in laboratory analytes compared to placebo:

• elevated ALT (≥3X ULN in patients with ALT at baseline <3X ULN), (12% vs 2%);
• elevated AST (28% vs 4%);
• low total bilirubin (22% vs 7%);
• elevated GGT (10% vs 1%); and
• elevated prolactin (47% vs 7%).

In placebo-controlled olanzapine monotherapy studies in adolescents, clinically significant ALT elevations (change from <3 times ULN at baseline to ≥3 times ULN) were observed in 12% (22/192) of patients exposed to olanzapine compared to 2% (2/109) of patients exposed to placebo.

ALT elevations ≥5 times ULN were observed in 4% (8/192) of olanzapine-treated patients, compared to 1% (1/109) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No adolescent patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule.

ECG Changes

In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc (Fridericia corrected), and PR intervals.

Olanzapine use was associated with a mean increase in heart rate compared to placebo (adults: +2.4 beats per minute vs no change with placebo; adolescents: +6.3 beats per minute vs -5.1 beats per minute with placebo). This increase in heart rate may be related to olanzapine's potential for inducing orthostatic changes.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Zyprexa. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to Zyprexa therapy include the following:

• allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria),
• cholestatic or mixed liver injury,
• diabetic coma,
• diabetic ketoacidosis,
• discontinuation reaction (diaphoresis, nausea or vomiting),
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),
• hepatitis,
• jaundice,
• neutropenia,
• pancreatitis,
• priapism,
• rash,
• restless legs syndrome,
• rhabdomyolysis,
• stuttering¹, and
• venous thromboembolic events (including pulmonary embolism and deep venous thrombosis).

Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported.

¹ Stuttering was only studied in oral and long acting injection (LAI) formulations.

The risks of using olanzapine in combination with other drugs have not been extensively evaluated in systematic studies.

Potential For Other Drugs To Affect Olanzapine

Diazepam

The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine.

Cimetidine And Antacids

Single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids did not affect the oral bioavailability of olanzapine.

Inducers Of CYP1A2

Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance.

Alcohol

Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics. The coadministration of alcohol (i.e., ethanol) with olanzapine potentiated the orthostatic hypotension observed with olanzapine.

Inhibitors Of CYP1A2

Fluvoxamine

Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine.

Inhibitors Of CYP2D6

Fluoxetine

Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. When using Zyprexa and fluoxetine in combination, also refer to the Drug Interactions section of the package insert for Symbyax.

Warfarin

Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics.

Inducers Of CYP1A2 Or Glucuronyl Transferase

Omeprazole and rifampin may cause an increase in olanzapine clearance.

Charcoal

The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral olanzapine by about 60%. As peak olanzapine levels are not typically obtained until about 6 hours after dosing, charcoal may be a useful treatment for olanzapine overdose.

Potential For Olanzapine To Affect Other Drugs

CNS Acting Drugs

Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrally acting drugs and alcohol.

Antihypertensive Agents

Olanzapine, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents.

Levodopa And Dopamine Agonists

Olanzapine may antagonize the effects of levodopa and dopamine agonists.

Lorazepam (IM)

Administration of intramuscular lorazepam (2 mg) 1 hour after intramuscular olanzapine for injection (5 mg) did not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. However, this co-administration of intramuscular lorazepam and intramuscular olanzapine for injection added to the somnolence observed with either drug alone.

Lithium

Multiple doses of olanzapine (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant olanzapine administration does not require dosage adjustment of lithium.

Valproate

Olanzapine (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate.

Effect Of Olanzapine On Drug Metabolizing Enzymes

In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.

Imipramine

Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

Warfarin

Single doses of olanzapine did not affect the pharmacokinetics of warfarin.

Diazepam

Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite Ndesmethyldiazepam. However, diazepam co-administered with olanzapine increased the orthostatic hypotension observed with either drug given alone.

Alcohol

Multiple doses of olanzapine did not influence the kinetics of ethanol.

Biperiden

Multiple doses of olanzapine did not influence the kinetics of biperiden.

Theophylline

Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.

Drug Abuse And Dependence

Dependence

In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the daily oral MRHD (20 mg) and rhesus monkeys administered oral doses up to 8 times the daily oral MRHD based on mg/m² body surface area.

Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic, and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.

Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of olanzapine (e.g., development of tolerance, increases in dose, drug-seeking behavior).