Zyprexa (Olanzapine)


Indications

1.1 Schizophrenia

Oral ZYPREXA is indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia (ages 13-17), efficacy was established in one 6-week trial.

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 dyslipidemia. 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.

1.2 Bipolar I Disorder (Manic or Mixed Episodes)

Monotherapy — Oral ZYPREXA is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial. In adolescent patients with manic or mixed episodes associated with bipolar I disorder (ages 13-17), efficacy was established in one 3-week trial.

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 dyslipidemia. 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.

Adjunctive Therapy to Lithium or Valproate — Oral ZYPREXA is indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials.

1.3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder

Pediatric schizophrenia and bipolar I disorder are serious mental disorders; however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar I disorder should be part of a total treatment program that often includes psychological, educational and social interventions.

1.4 ZYPREXA IntraMuscular: Agitation Associated with Schizophrenia and Bipolar I Mania

ZYPREXA IntraMuscular is indicated for the treatment of acute agitation associated with schizophrenia and bipolar I mania.

Efficacy was demonstrated in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated adult inpatients with: schizophrenia or bipolar I disorder (manic or mixed episodes).

“Psychomotor agitation” is defined in DSM-IV as “excessive motor activity associated with a feeling of inner tension.” Patients experiencing agitation often manifest behaviors that interfere with their diagnosis and care, e.g., threatening behaviors, escalating or urgently distressing behavior, or self-exhausting behavior, leading clinicians to the use of intramuscular antipsychotic medications to achieve immediate control of the agitation.

1.5 ZYPREXA and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

Oral ZYPREXA and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar I disorder, based on clinical studies. When using ZYPREXA and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.

ZYPREXA monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

1.6 ZYPREXA and Fluoxetine in Combination: Treatment Resistant Depression

Oral ZYPREXA and fluoxetine in combination is indicated for the treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode), based on clinical studies in adult patients. When using ZYPREXA and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.

ZYPREXA monotherapy is not indicated for the treatment of treatment resistant depression.

contraindications

  • None with ZYPREXA monotherapy.
  • When using ZYPREXA and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax.
  • For specific information about the contraindications of lithium or valproate, refer to the Contraindications section of the package inserts for these other products.

adverse reactions

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

6.1 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, dose-dependent 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 physician 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.

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).

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%).

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

a Personality disorder is the COSTART term for designating nonaggressive objectionable behavior.

Adverse Reaction Percentage of Patients Reporting Event
Olanzapine
(N=248)
Placebo
(N=118)
Postural hypotension 5 2
Constipation 9 3
Weight gain 6 1
Dizziness 11 4
Personality disordera 8 4
Akathisia 5 1
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)
Adverse Reaction Percentage of Patients Reporting Event
Olanzapine
(N=125)
Placebo
(N=129)
Asthenia 15 6
Dry mouth 22 7
Constipation 11 5
Dyspepsia 11 5
Increased appetite 6 3
Somnolence 35 13
Dizziness 18 6
Tremor 6 3

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.

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
Body System/Adverse Reaction Percentage of Patients Reporting Event
Olanzapine
(N=532)
Placebo
(N=294)
Body as a Whole
Accidental injury 12 8
Asthenia 10 9
Fever 6 2
Back pain 5 2
Chest pain 3 1
Cardiovascular System
Postural hypotension 3 1
Tachycardia 3 1
Hypertension 2 1
Digestive System
Dry mouth 9 5
Constipation 9 4
Dyspepsia 7 5
Vomiting 4 3
Increased appetite 3 2
Hemic and Lymphatic System
Ecchymosis 5 3
Metabolic and Nutritional Disorders
Weight gain 5 3
Peripheral edema 3 1
Musculoskeletal System
Extremity pain (other than joint) 5 3
Joint pain 5 3
Nervous System
Somnolence 29 13
Insomnia 12 11
Dizziness 11 4
Abnormal gait 6 1
Tremor 4 3
Akathisia 3 2
Hypertonia 3 2
Articulation impairment 2 1
Respiratory System
Rhinitis 7 6
Cough increased 6 3
Pharyngitis 4 3
Special Senses
Amblyopia 3 2
Urogenital System
Urinary incontinence 2 1
Urinary tract infection 2 1

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
Percentage of Patients Reporting Event
Olanzapine Olanzapine Olanzapine
Placebo 5 ± 2.5 mg/day 10 ± 2.5 mg/day 15 ± 2.5 mg/day
Adverse Reaction (N=68) (N=65) (N=64) (N=69)
Asthenia 15 8 9 20
Dry mouth 4 3 5 13
Nausea 9 0 2 9
Somnolence 16 20 30 39
Tremor 3 0 5 7

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 Reaction Percentage of Patients Reporting Event
Olanzapine with lithium or valproate
(N=229)
Placebo with lithium or valproate
(N=115)
Dry mouth 32 9
Weight gain 26 7
Increased appetite 24 8
Dizziness 14 7
Back pain 8 4
Constipation 8 4
Speech disorder 7 1
Increased salivation 6 2
Amnesia 5 2
Paresthesia 5 2

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

a Denominator used was for females only (olanzapine, N=128; placebo, N=51).

Body System/Adverse Reaction Percentage of Patients Reporting Event
Olanzapine with lithium or valproate
(N=229)
Placebo with lithium or valproate
(N=115)
Body as a Whole
Asthenia 18 13
Back pain 8 4
Accidental injury 4 2
Chest pain 3 2
Cardiovascular System
Hypertension 2 1
Digestive System
Dry mouth 32 9
Increased appetite 24 8
Thirst 10 6
Constipation 8 4
Increased salivation 6 2
Metabolic and Nutritional Disorders
Weight gain 26 7
Peripheral edema 6 4
Edema 2 1
Nervous System
Somnolence 52 27
Tremor 23 13
Depression 18 17
Dizziness 14 7
Speech disorder 7 1
Amnesia 5 2
Paresthesia 5 2
Apathy 4 3
Confusion 4 1
Euphoria 3 2
Incoordination 2 0
Respiratory System
Pharyngitis 4 1
Dyspnea 3 1
Skin and Appendages
Sweating 3 1
Acne 2 0
Dry skin 2 0
Special Senses
Amblyopia 9 5
Abnormal vision 2 0
Urogenital System
Dysmenorrheaa 2 0
Vaginitisa 2 0

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.

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
Body System/Adverse Reaction Percentage of Patients Reporting Event
Olanzapine
(N=415)
Placebo
(N=150)
Body as a Whole
Asthenia 2 1
Cardiovascular System
Hypotension 2 0
Postural hypotension 1 0
Nervous System
Somnolence 6 3
Dizziness 4 2
Tremor 1 0

6.2 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

a Percentage of patients with a Simpson-Angus Scale total score >3.

b Percentage of patients with a Barnes Akathisia Scale global score ≥2.

Percentage of Patients Reporting Event
Placebo Olanzapine
5 ± 2.5 mg/day
Olanzapine
10 ± 2.5 mg/day
Olanzapine
15 ± 2.5 mg/day
Parkinsonisma 15 14 12 14
Akathisiab 23 16 19 27

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

a Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis.

b Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor.

c Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia.

d Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia.

e Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching.

Percentage of Patients Reporting Event
Placebo
(N=68)
Olanzapine
5 ± 2.5 mg/day
(N=65)
Olanzapine
10 ± 2.5 mg/day
(N=64)
Olanzapine
15 ± 2.5 mg/day
(N=69)
Dystonic eventsa 1 3 2 3
Parkinsonism eventsb 10 8 14 20
Akathisia eventsc 1 5 11 10
Dyskinetic eventsd 4 0 2 1
Residual eventse 1 2 5 1
Any extrapyramidal event 16 15 25 32

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

a Categories are based on Standard MedDRA Queries (SMQ) for extrapyramidal symptoms as defined in MedDRA version 12.0.

Percentage of Patients Reporting Event
Placebo Olanzapine
Categoriesa (N=89) (N=179)
Dystonic events 0 1
Parkinsonism events 2 1
Akathisia events 4 6
Dyskinetic events 0 1
Nonspecific events 0 4
Any extrapyramidal event 6 10

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

a Percentage of patients with a Simpson-Angus Scale total score >3.

b Percentage of patients with a Barnes Akathisia Scale global score ≥2.

Percentage of Patients Reporting Event
Placebo Olanzapine
IM
2.5 mg
Olanzapine
IM
5 mg
Olanzapine
IM
7.5 mg
Olanzapine
IM
10 mg
Parkinsonisma 0 0 0 0 3
Akathisiab 0 0 5 0 0

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

a Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis.

b Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor.

c Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia.

d Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia.

e Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching.

Percentage of Patients Reporting Event
Placebo
(N=45)
Olanzapine
IM
2.5 mg
(N=48)
Olanzapine
IM
5 mg
(N=45)
Olanzapine
IM
7.5 mg
(N=46)
Olanzapine
IM
10 mg
(N=46)
Dystonic eventsa 0 0 0 0 0
Parkinsonism eventsb 0 4 2 0 0
Akathisia eventsc 0 2 0 0 0
Dyskinetic eventsd 0 0 0 0 0
Residual eventse 0 0 0 0 0
Any extrapyramidal events 0 4 2 0 0

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.

6.3 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 — chills, face edema, photosensitivity reaction, suicide attempt 1;  chills and fever, hangover effect, sudden death 1.
 
Cardiovascular System — cerebrovascular accident, vasodilatation.
 
Digestive System — abdominal distension, nausea and vomiting, tongue edema;  ileus, intestinal obstruction, liver fatty deposit.
 
Hemic and Lymphatic System — thrombocytopenia.
 
Metabolic and Nutritional Disorders — alkaline phosphatase increased; bilirubinemia, hypoproteinemia.
 
Musculoskeletal System — osteoporosis.
 
Nervous System — ataxia, dysarthria, libido decreased, stupor;  coma.
 
Respiratory System — epistaxis;  lung edema.
 
Skin and Appendages — alopecia.
 
Special Senses — abnormality of accommodation, dry eyes;  mydriasis.
 
Urogenital System — amenorrhea 2, breast pain, decreased menstruation, impotence 2, increased menstruation 2, menorrhagia 2, metrorrhagia 2, polyuria 2, 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 — injection site pain.
 
Cardiovascular System — syncope.
 
Digestive System — nausea.
 
Metabolic and Nutritional Disorders — creatine phosphokinase increased.

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

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)

a Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence.

b Patients with the following MedDRA terms were counted in this category: abdominal pain, abdominal pain lower, abdominal pain upper.

Adverse Reactions Percentage of Patients Reporting Event
6 Week Trial
% Schizophrenia Patients
3 Week Trial
% Bipolar Patients
Olanzapine
(N=72)
Placebo
(N=35)
Olanzapine
(N=107)
Placebo
(N=54)
Sedationa 39 9 48 9
Weight increased 31 9 29 4
Headache 17 6 17 17
Increased appetite 17 9 29 4
Dizziness 8 3 7 2
Abdominal painb 6 3 6 7
Pain in extremity 6 3 5 0
Fatigue 3 3 14 6
Dry mouth 4 0 7 0

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])

a Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence.

b The terms alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic enzyme were combined under liver enzymes.

c Patients with the following MedDRA terms were counted in this category: lower respiratory tract infection, respiratory tract infection, respiratory tract infection viral, upper respiratory tract infection, viral upper respiratory tract infection.

Adverse Reaction Percentage of Patients Reporting Event
Olanzapine
(N=179)
Placebo
(N=89)
Sedationa 44 9
Weight increased 30 6
Increased appetite 24 6
Headache 17 12
Fatigue 9 4
Dizziness 7 2
Dry mouth 6 0
Pain in extremity 5 1
Constipation 4 0
Nasopharyngitis 4 2
Diarrhea 3 0
Restlessness 3 2
Liver enzymes increasedb 8 1
Dyspepsia 3 1
Epistaxis 3 0
Respiratory tract infectionc 3 2
Sinusitis 3 0
Arthralgia 2 0
Musculoskeletal stiffness 2 0

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

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 pre-existing 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.

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.

6.4 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, 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.

warnings and precautions

When using ZYPREXA and fluoxetine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

5.1 Elderly Patients with Dementia-Related Psychosis

Increased Mortality — Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ZYPREXA is not approved for the treatment of patients with dementia-related psychosis.

In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular Adverse Events (CVAE), Including Stroke — Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis.

5.2 Suicide

The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

5.3 Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue olanzapine if DRESS is suspected.

5.5 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapine’s specific metabolic profile is presented below.

Hyperglycemia and Diabetes Mellitus

Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting 140-200 mg/dL). Patients taking olanzapine should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL). The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucose level ≥200 mg/dL, and/or a baseline fasting glucose level ≥126 mg/dL). Olanzapine-treated patients had a greater mean HbA1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4-5 weeks), 6.1% of olanzapine-treated subjects (N=855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599). Table 2 shows short-term and long-term changes in fasting glucose levels from adult olanzapine monotherapy studies.

Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies

a Not Applicable.

  Up to 12 weeks exposure At least 48 weeks exposure
Laboratory Analyte Category Change (at least once)
from Baseline
Treatment Arm N Patients N Patients
Fasting
Glucose
Normal to High
(<100 mg/dL to ≥126 mg/dL)
Olanzapine 543 2.2% 345 12.8%
Placebo 293 3.4% NAa NAa
Borderline to High
(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)
Olanzapine 178 17.4% 127 26.0%
Placebo 96 11.5% NAa NAa

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487). In analyses of patients who completed 9-12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121). Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

Table 3: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies

a Not Applicable.

  Up to 12 weeks exposure At least 24 weeks exposure
Laboratory Analyte Category Change (at least once)
from Baseline
Treatment Arm N Patients N Patients
Fasting
Glucose
Normal to High
(<100 mg/dL to ≥126 mg/dL)
Olanzapine 124 0% 108 0.9%
Placebo 53 1.9% NAa NAa
Borderline to High
(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)
Olanzapine 14 14.3% 13 23.1%
Placebo 13 0% NAa NAa

Dyslipidemia

Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended.

Clinically significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4-6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies. Table 4 shows categorical changes in fasting lipids values.

Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies

a Not Applicable.

  Up to 12 weeks exposure At least 48 weeks exposure
Laboratory Analyte Category Change (at least once)
from Baseline
Treatment Arm
N

Patients

N

Patients
Fasting
Triglycerides
Increase by ≥50 mg/dL Olanzapine 745 39.6% 487 61.4%
Placebo 402 26.1% NAa NAa
Normal to High
(<150 mg/dL to ≥200 mg/dL)
Olanzapine 457 9.2% 293 32.4%
Placebo 251 4.4% NAa NAa
Borderline to High
(≥150 mg/dL and <200 mg/dL to ≥200 mg/dL)
Olanzapine 135 39.3% 75 70.7%
Placebo 65 20.0% NAa NAa
 
Fasting Total
Cholesterol
Increase by ≥40 mg/dL Olanzapine 745 21.6% 489 32.9%
Placebo 402 9.5% NAa NAa
Normal to High
(<200 mg/dL to ≥240 mg/dL)
Olanzapine 392 2.8% 283 14.8%
Placebo 207 2.4% NAa NAa
Borderline to High
(≥200 mg/dL and <240 mg/dL to ≥240 mg/dL)
Olanzapine 222 23.0% 125 55.2%
Placebo 112 12.5% NAa NAa
 
Fasting LDL
Cholesterol
Increase by ≥30 mg/dL Olanzapine 536 23.7% 483 39.8%
Placebo 304 14.1% NAa NAa
Normal to High
(<100 mg/dL to ≥160 mg/dL)
Olanzapine 154 0% 123 7.3%
Placebo 82 1.2% NAa NAa
Borderline to High
(≥100 mg/dL and <160 mg/dL to ≥160 mg/dL)
Olanzapine 302 10.6% 284 31.0%
Placebo 173 8.1% NAa NAa

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescents, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 5 shows categorical changes in fasting lipids values in adolescents.

Table 5: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies

a Not Applicable.

  Up to 6 weeks exposure At least 24 weeks exposure
Laboratory Analyte Category Change (at least once)
from Baseline
Treatment Arm
N

Patients

N

Patients
Fasting
Triglycerides
Increase by ≥50 mg/dL Olanzapine 138 37.0% 122 45.9%
Placebo 66 15.2% NAa NAa
Normal to High
(<90 mg/dL to >130 mg/dL)
Olanzapine 67 26.9% 66 36.4%
Placebo 28 10.7% NAa NAa
Borderline to High
(≥90 mg/dL and ≤130 mg/dL to >130 mg/dL)
Olanzapine 37 59.5% 31 64.5%
Placebo 17 35.3% NAa NAa
 
Fasting Total
Cholesterol
Increase by ≥40 mg/dL Olanzapine 138 14.5% 122 14.8%
Placebo 66 4.5% NAa NAa
Normal to High
(<170 mg/dL to ≥200 mg/dL)
Olanzapine 87 6.9% 78 7.7%
Placebo 43 2.3% NAa NAa
Borderline to High
(≥170 mg/dL and <200 mg/dL to ≥200 mg/dL)
Olanzapine 36 38.9% 33 57.6%
Placebo 13 7.7% NAa NAa
 
Fasting LDL
Cholesterol
Increase by ≥30 mg/dL Olanzapine 137 17.5% 121 22.3%
Placebo 63 11.1% NAa NAa
Normal to High
(<110 mg/dL to ≥130 mg/dL)
Olanzapine 98 5.1% 92 10.9%
Placebo 44 4.5% NAa NAa
Borderline to High
(≥110 mg/dL and <130 mg/dL to ≥130 mg/dL)
Olanzapine 29 48.3% 21 47.6%
Placebo 9 0% NAa NAa

Weight Gain

Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight.

Olanzapine Monotherapy in Adults — In an analysis of 13 placebo-controlled olanzapine monotherapy studies, olanzapine-treated patients gained an average of 2.6 kg (5.7 lb) compared to an average 0.3 kg (0.6 lb) weight loss in placebo-treated patients with a median exposure of 6 weeks; 22.2% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of 8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a median exposure to event of 12 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients.

In long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

Table 6 includes data on adult weight gain with olanzapine pooled from 86 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified.

Table 6: Weight Gain with Olanzapine Use in Adults
Amount Gained
kg (lb)
6 Weeks
(N=7465)
(%)
6 Months
(N=4162)
(%)
12 Months
(N=1345)
(%)
24 Months
(N=474)
(%)
36 Months
(N=147)
(%)
≤0 26.2 24.3 20.8 23.2 17.0
0 to ≤5 (0-11 lb) 57.0 36.0 26.0 23.4 25.2
>5 to ≤10 (11-22 lb) 14.9 24.6 24.2 24.1 18.4
>10 to ≤15 (22-33 lb) 1.8 10.9 14.9 11.4 17.0
>15 to ≤20 (33-44 lb) 0.1 3.1 8.6 9.3 11.6
>20 to ≤25 (44-55 lb) 0 0.9 3.3 5.1 4.1
>25 to ≤30 (55-66 lb) 0 0.2 1.4 2.3 4.8
>30 (>66 lb) 0 0.1 0.8 1.2 2

Dose group differences with respect to weight gain have been observed. 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, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. Mean increase in weight in adolescents was greater than in adults. In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

Table 7: Weight Gain with Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials
Olanzapine-treated patients Placebo-treated patients
Mean change in body weight from baseline (median exposure = 3 weeks) 4.6 kg (10.1 lb) 0.3 kg (0.7 lb)
Percentage of patients who gained at least 7% of baseline body weight 40.6% 9.8%
(median exposure to 7% = 4 weeks) (median exposure to 7% = 8 weeks)
Percentage of patients who gained at least 15% of baseline body weight 7.1% 2.7%
(median exposure to 15% = 19 weeks) (median exposure to 15% = 8 weeks)

In long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb); (median exposure of 201 days, N=179). The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively. Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal (N=106), overweight (N=26) and obese (N=17). Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24 weeks of exposure.

Table 8 shows data on adolescent weight gain with olanzapine pooled from 6 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified. Little clinical trial data is available on weight gain in adolescents with olanzapine beyond 6 months of treatment.

Table 8: Weight Gain with Olanzapine Use in Adolescents
Amount Gained
kg (lb)
6 Weeks
(N=243)
(%)
6 Months
(N=191)
(%)
≤0 2.9 2.1
0 to ≤5 (0-11 lb) 47.3 24.6
>5 to ≤10 (11-22 lb) 42.4 26.7
>10 to ≤15 (22-33 lb) 5.8 22.0
>15 to ≤20 (33-44 lb) 0.8 12.6
>20 to ≤25 (44-55 lb) 0.8 9.4
>25 to ≤30 (55-66 lb) 0 2.1
>30 to ≤35 (66-77 lb) 0 0
>35 to ≤40 (77-88 lb) 0 0
>40 (>88 lb) 0 0.5

5.6 Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine, drug discontinuation should be considered. However, some patients may require treatment with olanzapine despite the presence of the syndrome.

For specific information about the warnings of lithium or valproate, refer to the Warnings section of the package inserts for these other products.

5.7 Orthostatic Hypotension

Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonistic properties.

From an analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, orthostatic hypotension was recorded in ≥20% (1277/6030) of patients.

For oral olanzapine therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg QD. A more gradual titration to the target dose should be considered if hypotension occurs.

Hypotension, bradycardia with or without hypotension, tachycardia, and syncope were also reported during the clinical trials with intramuscular olanzapine for injection. In an open-label clinical pharmacology study in nonagitated patients with schizophrenia in which the safety and tolerability of intramuscular olanzapine were evaluated under a maximal dosing regimen (three 10 mg doses administered 4 hours apart), approximately one-third of these patients experienced a significant orthostatic decrease in systolic blood pressure (i.e., decrease ≥30 mmHg). Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in phase 2-3 oral olanzapine studies and in 0.3% (2/722) of olanzapine-treated patients with agitation in the intramuscular olanzapine for injection studies. Three normal volunteers in phase 1 studies with intramuscular olanzapine experienced hypotension, bradycardia, and sinus pauses of up to 6 seconds that spontaneously resolved (in 2 cases the reactions occurred on intramuscular olanzapine, and in 1 case, on oral olanzapine). The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs. For intramuscular olanzapine for injection therapy, patients should remain recumbent if drowsy or dizzy after injection until examination has indicated that they are not experiencing postural hypotension, bradycardia, and/or hypoventilation.

Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk.

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression. Concomitant administration of intramuscular olanzapine and parenteral benzodiazepine is not recommended due to the potential for excessive sedation and cardiorespiratory depression.

5.8 Falls

ZYPREXA may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9 Leukopenia, Neutropenia, and Agranulocytosis

Class Effect — In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including ZYPREXA. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ZYPREXA should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue ZYPREXA and have their WBC followed until recovery.

5.10 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s disease. Olanzapine is not approved for the treatment of patients with Alzheimer’s disease.

5.11 Seizures

During premarketing testing, seizures occurred in 0.9% (22/2500) of olanzapine-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. Olanzapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Olanzapine is not approved for the treatment of patients with Alzheimer’s disease. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.12 Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse reaction associated with olanzapine treatment, occurring at an incidence of 26% in olanzapine patients compared to 15% in placebo patients. This adverse reaction was also dose related. Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing database.

Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely.

5.13 Body Temperature Regulation

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing olanzapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

5.14 Use in Patients with Concomitant Illness

Clinical experience with olanzapine in patients with certain concomitant systemic illnesses is limited.

Olanzapine exhibits in vitro muscarinic receptor affinity. In premarketing clinical trials with olanzapine, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for discontinuations from olanzapine, but olanzapine should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma, or a history of paralytic ileus or related conditions.

In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following treatment-emergent adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis.

Olanzapine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risk of orthostatic hypotension with olanzapine, caution should be observed in cardiac patients.

5.15 Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events1 (2% [49/3240] of females), sexual function-related events2 (2% [150/8136] of females and males), and breast-related events3 (0.7% [23/3240] of females, 0.2% [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events1 (1% [2/168] of females), sexual function-related events2 (0.7% [3/454] of females and males), and breast-related events3 (2% [3/168] of females, 2% [7/286] of males).

1 Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.
2 Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.
3 Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Dose group differences with respect to prolactin elevation have been observed. 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 prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.

5.16 Use in Combination with Fluoxetine, Lithium, or Valproate

When using ZYPREXA and fluoxetine in combination, the prescriber should also refer to the Warnings and Precautions section of the package insert for Symbyax. When using ZYPREXA in combination with lithium or valproate, the prescriber should refer to the Warnings and Precautions sections of the package inserts for lithium or valproate.

5.17 Laboratory Tests

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended.

general medication guide

Medication Guide

ZYPREXA® (zy-PREX-a)

(olanzapine)

Tablet

ZYPREXA® ZYDIS® (zy-PREX-a ZY-dis)

(olanzapine)

Tablet, Orally Disintegrating

Read the Medication Guide that comes with ZYPREXA before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor or pharmacist if there is something you do not understand or you want to learn more about ZYPREXA.

What is the most important information I should know about ZYPREXA?

ZYPREXA may cause serious side effects, including:

  1. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis).
  2. High blood sugar (hyperglycemia).
  3. High fat levels in your blood (increased cholesterol and triglycerides), especially in teenagers age 13 to 17 or when used in combination with fluoxetine in children age 10 to 17.
  4. Weight gain, especially in teenagers age 13 to 17 or when used in combination with fluoxetine in children age 10 to 17.

These serious side effects are described below.

  1. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). ZYPREXA is not approved for treating psychosis in elderly people with dementia.
  2. High blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could lead to:
    • a build up of acid in your blood due to ketones (ketoacidosis)
    • coma
    • death

    Your doctor should do tests to check your blood sugar before you start taking ZYPREXA and during treatment. In people who do not have diabetes, sometimes high blood sugar goes away when ZYPREXA is stopped. People with diabetes and some people who did not have diabetes before taking ZYPREXA need to take medicine for high blood sugar even after they stop taking ZYPREXA.

    If you have diabetes, follow your doctor’s instructions about how often to check your blood sugar while taking ZYPREXA.

    Call your doctor if you have any of these symptoms of high blood sugar (hyperglycemia) while taking ZYPREXA:
    • feel very thirsty
    • need to urinate more than usual
    • feel very hungry
    • feel weak or tired
    • feel sick to your stomach
    • feel confused or your breath smells fruity
  3. High fat levels in your blood (cholesterol and triglycerides). High fat levels may happen in people treated with ZYPREXA, especially in teenagers (13 to 17 years old), or when used in combination with fluoxetine in children (10 to 17 years old). You may not have any symptoms, so your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking ZYPREXA and during treatment.
  4. Weight gain. Weight gain is very common in people who take ZYPREXA. Teenagers (13 to 17 years old) are more likely to gain weight and to gain more weight than adults. Children (10 to 17 years old) are also more likely to gain weight and to gain more weight than adults when ZYPREXA is used in combination with fluoxetine. Some people may gain a lot of weight while taking ZYPREXA, so you and your doctor should check your weight regularly. Talk to your doctor about ways to control weight gain, such as eating a healthy, balanced diet, and exercising.

What is ZYPREXA?

ZYPREXA is a prescription medicine used to treat:

  • schizophrenia in people age 13 or older.
  • bipolar disorder, including:
    • manic or mixed episodes that happen with bipolar I disorder in people age 13 or older.
    • manic or mixed episodes that happen with bipolar I disorder, when used with the medicine lithium or valproate, in adults.
    • long-term treatment of bipolar I disorder in adults.
  • episodes of depression that happen with bipolar I disorder, when used with the medicine fluoxetine (Prozac®) in people age 10 or older.
  • episodes of depression that do not get better after 2 other medicines, also called treatment resistant depression, when used with the medicine fluoxetine (Prozac), in adults.

ZYPREXA has not been approved for use in children under 13 years of age. ZYPREXA in combination with fluoxetine has not been approved for use in children under 10 years of age.

The symptoms of schizophrenia include hearing voices, seeing things that are not there, having beliefs that are not true, and being suspicious or withdrawn.

The symptoms of bipolar I disorder include alternating periods of depression and high or irritable mood, increased activity and restlessness, racing thoughts, talking fast, impulsive behavior, and a decreased need for sleep.

The symptoms of treatment resistant depression include decreased mood, decreased interest, increased guilty feelings, decreased energy, decreased concentration, changes in appetite, and suicidal thoughts or behavior.

Some of your symptoms may improve with treatment. If you do not think you are getting better, call your doctor.

What should I tell my doctor before taking ZYPREXA?

ZYPREXA may not be right for you. Before starting ZYPREXA, tell your doctor if you have or had:

  • heart problems
  • seizures
  • diabetes or high blood sugar levels (hyperglycemia)
  • high cholesterol or triglyceride levels in your blood
  • liver problems
  • low or high blood pressure
  • strokes or “mini-strokes” also called transient ischemic attacks (TIAs)
  • Alzheimer’s disease
  • narrow-angle glaucoma
  • enlarged prostate in men
  • bowel obstruction
  • phenylketonuria, because ZYPREXA ZYDIS contains phenylalanine
  • breast cancer
  • thoughts of suicide or hurting yourself
  • any other medical condition
  • are pregnant or plan to become pregnant. It is not known if ZYPREXA will harm your unborn baby.
  • are breast-feeding or plan to breast-feed. ZYPREXA can pass into your breast milk and may harm your baby. You should not breast-feed while taking ZYPREXA. Talk to your doctor about the best way to feed your baby if you take ZYPREXA.

Tell your doctor if you exercise a lot or are in hot places often.

The symptoms of bipolar I disorder, treatment resistant depression, or schizophrenia may include thoughts of suicide or of hurting yourself or others. If you have these thoughts at any time, tell your doctor or go to an emergency room right away.

Tell your doctor about all the medicines that you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. ZYPREXA and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if it is safe to take ZYPREXA with your other medicines. Do not start or stop any medicine while taking ZYPREXA without talking to your doctor first.

How should I take ZYPREXA?

  • Take ZYPREXA exactly as prescribed. Your doctor may need to change (adjust) the dose of ZYPREXA until it is right for you.
  • If you miss a dose of ZYPREXA, take the missed dose as soon as you remember. If it is almost time for the next dose, just skip the missed dose and take your next dose at the regular time. Do not take two doses of ZYPREXA at the same time.
  • To prevent serious side effects, do not stop taking ZYPREXA suddenly. If you need to stop taking ZYPREXA, your doctor can tell you how to safely stop taking it.
  • If you take too much ZYPREXA, call your doctor or poison control center at 1-800-222-1222 right away, or get emergency treatment.
  • ZYPREXA can be taken with or without food.
  • ZYPREXA is usually taken one time each day.
  • Take ZYPREXA ZYDIS as follows:
    • Be sure that your hands are dry.
    • Open the sachet and peel back the foil on the blister. Do not push the tablet through the foil.
    • As soon as you open the blister, remove the tablet and put it into your mouth.
    • The tablet will disintegrate quickly in your saliva so that you can easily swallow it with or without drinking liquid.
  • Call your doctor if you do not think you are getting better or have any concerns about your condition while taking ZYPREXA.

What should I avoid while taking ZYPREXA?

  • ZYPREXA can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how ZYPREXA affects you.
  • Avoid drinking alcohol while taking ZYPREXA. Drinking alcohol while you take ZYPREXA may make you sleepier than if you take ZYPREXA alone.

What are the possible side effects of ZYPREXA?

Serious side effects may happen when you take ZYPREXA, including:

  • See “What is the most important information I should know about ZYPREXA?”, which describes the increased risk of death in elderly people with dementia-related psychosis and the risks of high blood sugar, high cholesterol and triglyceride levels, and weight gain.
  • Increased incidence of stroke or “mini-strokes” called transient ischemic attacks (TIAs) in elderly people with dementia-related psychosis (elderly people who have lost touch with reality due to confusion and memory loss). ZYPREXA is not approved for these patients.
  • Neuroleptic Malignant Syndrome (NMS): NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including ZYPREXA. NMS can cause death and must be treated in a hospital. Call your doctor right away if you become severely ill and have any of these symptoms:
    • high fever
    • excessive sweating
    • rigid muscles
    • confusion
    • changes in your breathing, heartbeat, and blood pressure.
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS can occur with ZYPREXA. Features of DRESS may include rash, fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctor immediately if you experience any of these signs.
  • Tardive Dyskinesia: This condition causes body movements that keep happening and that you can not control. These movements usually affect the face and tongue. Tardive dyskinesia may not go away, even if you stop taking ZYPREXA. It may also start after you stop taking ZYPREXA. Tell your doctor if you get any body movements that you can not control.
  • Decreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heartbeat, or fainting.
  • Difficulty swallowing, that can cause food or liquid to get into your lungs.
  • Seizures: Tell your doctor if you have a seizure during treatment with ZYPREXA.
  • Problems with control of body temperature: You could become very hot, for instance when you exercise a lot or stay in an area that is very hot. It is important for you to drink water to avoid dehydration. Call your doctor right away if you become severely ill and have any of these symptoms of dehydration:
    • sweating too much or not at all
    • dry mouth
    • feeling very hot
    • feeling thirsty
    • not able to produce urine.

Common side effects of ZYPREXA include: lack of energy, dry mouth, increased appetite, sleepiness, tremor (shakes), having hard or infrequent stools, dizziness, changes in behavior, or restlessness.

Other common side effects in teenagers (13-17 years old) include: headache, stomach-area (abdominal) pain, pain in your arms or legs, or tiredness. Teenagers experienced greater increases in prolactin, liver enzymes, and sleepiness, as compared with adults.

Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the possible side effects with ZYPREXA. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ZYPREXA?

  • Store ZYPREXA at room temperature, between 68°F to 77°F (20°C to 25°C).
  • Keep ZYPREXA away from light.
  • Keep ZYPREXA dry and away from moisture.

Keep ZYPREXA and all medicines out of the reach of children.

General information about ZYPREXA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ZYPREXA for a condition for which it was not prescribed. Do not give ZYPREXA to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about ZYPREXA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ZYPREXA that was written for healthcare professionals. For more information about ZYPREXA call 1-800-Lilly-Rx (1-800-545-5979).

What are the ingredients in ZYPREXA?

Active ingredient: olanzapine

Inactive ingredients:

Tablets — carnauba wax, crospovidone, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, and other inactive ingredients. The color coating contains: Titanium Dioxide, FD&C Blue No. 2 Aluminum Lake, or Synthetic Red Iron Oxide.

ZYDIS — gelatin, mannitol, aspartame, sodium methyl paraben, and sodium propyl paraben.

Medication Guide revised October 6, 2016

Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA

Copyright © 2009, 2016, Eli Lilly and Company. All rights reserved.

ZYP-0001-MG-20161006

overdosage

10.1 Human Experience

In premarketing trials involving more than 3100 patients and/or normal subjects, accidental or intentional acute overdosage of olanzapine was identified in 67 patients. In the patient taking the largest identified amount, 300 mg, the only symptoms reported were drowsiness and slurred speech. In the limited number of patients who were evaluated in hospitals, including the patient taking 300 mg, there were no observations indicating an adverse change in laboratory analytes or ECG. Vital signs were usually within normal limits following overdoses.

In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and 1 patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Eli Lilly and Company has received reports of fatality in association with overdose of olanzapine alone. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine.

10.2 Management of Overdose

For current information on the management of ZYPREXA (olanzapine) overdose, contact a certified poison control center (1-800-222-1222 or www.poison.org). The possibility of multiple drug involvement should be considered. In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation, which may include intubation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. 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.

The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

There is no specific antidote to olanzapine. Therefore, appropriate supportive measures should be initiated. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. (Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of olanzapine-induced alpha blockade.) Close medical supervision and monitoring should continue until the patient recovers.

For specific information about overdosage with lithium or valproate, refer to the Overdosage section of the package inserts for these products. For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax package insert.

description

ZYPREXA (olanzapine) is an atypical antipsychotic that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. The molecular formula is C17H20N4S, which corresponds to a molecular weight of 312.44. The chemical structure is:

Olanzapine is a yellow crystalline solid, which is practically insoluble in water.

ZYPREXA tablets are intended for oral administration only.

Each tablet contains olanzapine equivalent to 2.5 mg (8 μmol), 5 mg (16 μmol), 7.5 mg (24 μmol), 10 mg (32 μmol), 15 mg (48 μmol), or 20 mg (64 μmol). Inactive ingredients are carnauba wax, crospovidone, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, and other inactive ingredients. The color coating contains Titanium Dioxide (all strengths), FD&C Blue No. 2 Aluminum Lake (15 mg), or Synthetic Red Iron Oxide (20 mg). The 2.5, 5, 7.5, and 10 mg tablets are imprinted with edible ink which contains FD&C Blue No. 2 Aluminum Lake.

ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) is intended for oral administration only.

Each orally disintegrating tablet contains olanzapine equivalent to 5 mg (16 μmol), 10 mg (32 μmol), 15 mg (48 μmol) or 20 mg (64 μmol). It begins disintegrating in the mouth within seconds, allowing its contents to be subsequently swallowed with or without liquid. ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) also contains the following inactive ingredients: gelatin, mannitol, aspartame, sodium methyl paraben, and sodium propyl paraben.

ZYPREXA IntraMuscular (olanzapine for injection) is intended for intramuscular use only.

Each vial provides for the administration of 10 mg (32 μmol) olanzapine with inactive ingredients 50 mg lactose monohydrate and 3.5 mg tartaric acid. Hydrochloric acid and/or sodium hydroxide may have been added during manufacturing to adjust pH.

Zyprexa Package Photos

About the Author

Truman Lewis
Truman has been a bureau chief and correspondent in D.C., Los Angeles, Phoenix and elsewhere, reporting for radio, television, print and news services, for more than 30 years. Most recently, he has reported extensively on health and consumer issues for ConsumerAffairs.com and FairfaxNews.com.