Zyprexa Side Effects

Generic Name: olanzapine

Please note - some side effects for Zyprexa may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Zyprexa - for the Consumer

Zyprexa Intramuscular

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Zyprexa Intramuscular:

Constipation; dizziness; drowsiness; dry mouth; lightheadedness; pain, redness, or swelling at the injection site; weakness; weight gain.

Seek medical attention right away if any of these SEVERE side effects occur when using Zyprexa Intramuscular:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); abnormal thoughts; chest pain; confusion; decreased urination; fainting; fast, slow, or irregular heartbeat; fever, chills, or persistent sore throat; increased saliva production or drooling; increased sweating; memory loss; menstrual changes; muscle pain, weakness, or stiffness; new or worsening mental or mood changes (eg, depression, hallucinations); one-sided weakness; seizures; severe or prolonged dizziness or headache; shortness of breath; suicidal thoughts or actions; swelling of the hands, legs, or feet; symptoms of high blood sugar (eg, increased thirst, hunger, or urination; unusual weakness); symptoms of high prolactin levels (eg, enlarged breast size, decreased sexual ability, missed menstrual period, nipple discharge); tremor; trouble concentrating, speaking, or swallowing; trouble sitting still; trouble walking or standing; uncontrolled muscle movements (eg, arm or leg movements, twitching of the face or tongue, jerking or twisting); unusual bruising; vision changes; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Zyprexa

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Zyprexa:

Back or joint pain; constipation; cough; dizziness; drowsiness; dry mouth; increased appetite; indigestion; lightheadedness; numbness or tingling of the skin; restlessness; sore throat; weakness; weight gain.

Seek medical attention right away if any of these SEVERE side effects occur when using Zyprexa:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); abnormal thoughts; chest pain; confusion; decreased urination; fainting; fast, slow, or irregular heartbeat; fever, chills, or persistent sore throat; increased saliva production or drooling; increased sweating; memory loss; menstrual changes; muscle pain, weakness, or stiffness; new or worsening mental or mood changes (eg, depression, hallucinations); one-sided weakness; seizures; severe or prolonged dizziness or headache; shortness of breath; suicidal thoughts or actions; swelling of the hands, legs, or feet; symptoms of high blood sugar (eg, increased thirst, hunger, or urination; unusual weakness); symptoms of high prolactin levels (eg, enlarged breast size, decreased sexual ability, missed menstrual period, nipple discharge); tremor; trouble concentrating, speaking, or swallowing; trouble sitting still; trouble walking or standing; uncontrolled muscle movements (eg, arm or leg movements, jerking or twisting, twitching of the face or tongue); unusual bruising; vision changes; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Zyprexa Relprevv

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Zyprexa Relprevv:

Back pain; constipation; cough; diarrhea; dizziness; drowsiness; dry mouth; headache; increased appetite; lightheadedness; nausea; pain, redness, or swelling at the injection site; sore throat; stuffy nose; tiredness; vomiting; weight gain.

Seek medical attention right away if any of these SEVERE side effects occur when using Zyprexa Relprevv:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); abnormal thoughts; chest pain; confusion; decreased urination; disorientation; fainting; fast, slow, or irregular heartbeat; fever, chills, or persistent sore throat; increased saliva production or drooling; increased sweating; memory loss; menstrual changes; muscle pain, weakness, or stiffness; new or worsening mental or mood changes (eg, agitation, depression, hallucinations); one-sided weakness; seizures; severe or prolonged drowsiness, dizziness, or headache; shortness of breath; suicidal thoughts or actions; swelling of the hands, legs, or feet; symptoms of high blood sugar (eg, increased thirst, hunger, or urination; unusual weakness); symptoms of high prolactin levels (eg, enlarged breast size, decreased sexual ability, missed menstrual period, nipple discharge); tremor; trouble concentrating, speaking, or swallowing; trouble sitting still; trouble walking or standing; uncontrolled muscle movements (eg, arm or leg movements, twitching of the face or tongue, jerking or twisting); unusual bruising; vision changes; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Zyprexa Zydis Orally Disintegrating Tablets

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Zyprexa Zydis Orally Disintegrating Tablets:

Back or joint pain; constipation; cough; dizziness; drowsiness; dry mouth; increased appetite; indigestion; lightheadedness; numbness or tingling of the skin; restlessness; sore throat; weakness; weight gain.

Seek medical attention right away if any of these SEVERE side effects occur when using Zyprexa Zydis Orally Disintegrating Tablets:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); abnormal thoughts; chest pain; confusion; decreased urination; fainting; fast, slow, or irregular heartbeat; fever, chills, or persistent sore throat; increased saliva production or drooling; increased sweating; memory loss; menstrual changes; muscle pain, weakness, or stiffness; new or worsening mental or mood changes (eg, depression, hallucinations); one-sided weakness; seizures; severe or prolonged dizziness or headache; shortness of breath; suicidal thoughts or actions; swelling of the hands, legs, or feet; symptoms of high blood sugar (eg, increased thirst, hunger, or urination; unusual weakness); symptoms of high prolactin levels (eg, enlarged breast size, decreased sexual ability, missed menstrual period, nipple discharge); tremor; trouble concentrating, speaking, or swallowing; trouble sitting still; trouble walking or standing; uncontrolled muscle movements (eg, arm or leg movements, jerking or twisting, twitching of the face or tongue); unusual bruising; vision changes; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Zyprexa Side Effects - for the Professional

Zyprexa

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 8661 adult patients with approximately 4165 patient-years of exposure to oral olanzapine and 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 patients from 88 additional oral olanzapine clinical trials as of December 31, 2001; and (5) 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. In addition, 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, is included below.

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.

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 in Combination with 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

a Personality disorder is the COSTART term for designating non-aggressive 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.

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

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

Commonly Observed Adverse Reactions in Short-Term Trials of Oral Olanzapine in Combination with Lithium or Valproate

In the Bipolar I Disorder (manic or mixed episodes) combination 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 12: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Combination 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

Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term Trials of Olanzapine in Combination with Lithium or Valproate

Table 13 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 13: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials of Oral Olanzapine in Combination with 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.

Adverse Reactions Occurring at an Incidence of 1% or More among Intramuscular Olanzapine for Injection-Treated Patients in Short-Term, Placebo-Controlled Trials

Table 14 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 14: 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

Additional Findings Observed in Clinical Trials

Dose Dependency of Adverse Reactions in Short-Term, Placebo-Controlled Trials

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 15: 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 16: 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 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 [see Clinical Studies (14.3)]. Patient assessments were conducted during the 24 hours following the initial dose of intramuscular olanzapine for injection. There were no statistically significant differences from placebo.

Table 17: 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 18: 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

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

Adverse Reaction	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)
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

Differences among Fixed-Dose Groups Observed in Other Olanzapine Clinical Trials

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 patients with Schizophrenia or Schizoaffective Disorder, differences among 3 dose groups were observed for the following safety outcomes: weight gain, prolactin elevation, fatigue and dizziness. 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. Incidence of treatment-emergent 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%) with significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day; fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) with significant differences between 10 vs 40 and 20 vs 40 mg/day; and dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) with significant differences between 20 vs 40 mg, was observed.

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 attempt1; Rare: chills and fever, hangover effect, sudden death1.

 

Cardiovascular System — Infrequent: cerebrovascular accident, vasodilatation.

 

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

 

Hemic and Lymphatic System — Infrequent: leukopenia, thrombocytopenia.

 

Metabolic and Nutritional Disorders — Infrequent: alkaline phosphatase increased, 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 20.

Table 20: 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 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 21.

Table 21: 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 [see Warnings and Precautions (5)].

Laboratory Changes — An assessment of the premarketing experience for olanzapine revealed an association with asymptomatic increases in ALT, AST, and GGT. In placebo-controlled olanzapine monotherapy studies in adults, clinically significant ALT elevations (≥3 times the upper limit of the normal range) were observed in 2% (6/243) of patients exposed to olanzapine compared to none (0/115) of the placebo patients. None of these patients experienced jaundice. In 2 of these patients, liver enzymes decreased toward normal despite continued treatment and, in 2 others, enzymes decreased upon discontinuation of olanzapine. In the remaining 2 patients, 1, seropositive for hepatitis C, had persistent enzyme elevations for 4 months after discontinuation, and the other had insufficient follow-up to determine if enzymes normalized.

Within the larger premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT elevation to >200 IU/L was 2% (50/2381). Again, 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.

Among 2500 adult patients in oral olanzapine clinical trials, about 1% (23/2500) discontinued treatment due to transaminase increases.

In placebo-controlled olanzapine monotherapy studies in adolescents, clinically significant ALT elevations (change from <3 times the upper limit of normal at baseline to ≥3 times the upper limit of the normal range) were observed in 12% (21/174) of patients exposed to olanzapine compared to 2% (2/87) of the placebo-treated patients. Discontinuation due to transaminase increases occurred in 3.4% (6/179) of patients exposed to olanzapine.

Rare postmarketing reports of hepatitis have been received. Very rare cases of cholestatic or mixed liver injury have also been reported in the postmarketing period.

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 [see Warnings and Precautions (5.14)], with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK.

Given the concern about neutropenia associated with other psychotropic compounds and the finding of leukopenia associated with the administration of olanzapine in several animal models [see Nonclinical Toxicology (13.2)], careful attention was given to examination of hematologic parameters in premarketing studies with olanzapine. There was no indication of a risk of clinically significant neutropenia associated with olanzapine treatment in the premarketing database for this drug.

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 (≥3 X ULN in patients with ALT at baseline <3 X ULN), (12.1% vs 2.3%); elevated AST (27.6% vs 3.8%); low total bilirubin (22.1% vs 6.7%); elevated GGT (10.1% vs 1.2%); and elevated prolactin (47.4% vs 6.8%).

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 [see Warnings and Precautions (5.8)].

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), diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea or vomiting), jaundice, neutropenia, pancreatitis, priapism, rash, 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.

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Side Effects by Body System - for Healthcare Professionals

Nervous system

Somnolence may occur more frequently at higher dosages.

Placebo-controlled clinical trials involving patients receiving olanzapine with either valproate or lithium for the treatment of bipolar mania reported a discontinuation rate of 3% due to somnolence.

At least one case of olanzapine-associated neuroleptic malignant syndrome has been reported. Fever, altered consciousness, autonomic dysfunction and muscle rigidity are the hallmarks of the neuroleptic malignant syndrome. The neuroleptic malignant syndrome is associated with a case mortality rate of about 20%. Immediate discontinuation of neuroleptic therapy, consideration of dantrolene therapy, as well as intensive monitoring and supportive care are indicated if the syndrome occurs.

A 52 year old male on long-term lithium therapy for the treatment of bipolar l disorder reported sleep-related eating disorder (SRED) occurring within days of initiating treatment with olanzapine 10 mg per day for an acute manic phase. The incidents of SRED disappeared rapidly and definitively after olanzapine therapy was discontinued.

Lower (worse) baseline scores predicted greater cognitive improvement. Change In cognitive performance was weakly related to change in symptom scores.

Nervous system side effects have frequently included somnolence, tremor, insomnia, dizziness, speech disorder, abnormal gait, amnesia, paresthesia, apathy, confusion, tremor, akathisia, hypertonia, articulation impairment, incoordination, abnormal dreams, emotional lability, agitation, nervousness, and hostility. Akinesia, alcohol misuse, antisocial reaction, ataxia, CNS stimulation, cogwheel rigidity, delirium, dementia, depersonalization, dysarthria, facial paralysis, hypesthesia, hypokinesia, hypotonia, incoordination, stimulant misuse, stupor, stuttering, tardive dyskinesia, vertigo, and withdrawal syndrome have also been reported. Circumoral paresthesia, coma, encephalopathy, neuralgia, neuropathy, nystagmus, paralysis, subarachnoid hemorrhage, tobacco misuse, and sleep related eating disorder have been reported rarely. Seizures (including a case of fatal status epilepticus) have been reported in 0.9% of treated patients during premarketing clinical trials. Rare cases of neuroleptic malignant syndrome and somnambulism have been reported. A case of Parkinsonism has also been reported.

Olanzapine has been associated with improvement on cognitive test performance in patients in the early stages of schizophrenia.

Cardiovascular

Cardiovascular side effects have frequently included postural hypotension, tachycardia, and hypertension. Atrial fibrillation, bradycardia, cerebrovascular accident, congestive heart failure, heart arrest, hemorrhage, migraine, pallor, palpitation, vasodilatation, and ventricular extrasystoles have also been reported. Arteritis, heart failure, venous thromboembolism, and pulmonary embolus have been reported rarely.

An increased risk of mortality, possibly due to heart failure or sudden death, has been reported with the use of atypical antipsychotic agents, including olanzapine, in the treatment of behavioral disorders in the elderly patient with dementia.

Collective data gathered from 17 placebo-controlled clinical studies (n=5106) involving the use of atypical antipsychotic agents, including olanzapine, for the treatment of behavioral disorders in the elderly patient with dementia showed a risk of death 1.6 to 1.7 times greater in the drug treated patient than in the placebo treated patient. The average length of duration for the trials was 10 weeks with the cause of death in the majority of cases, though not all, reported as either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Similar results (i.e., increased risk of mortality with atypical antipsychotics) were reported in another meta-analysis involving elderly dementia patients that consisted of 15 randomized, placebo-controlled trials (n=3353) of 10 to 12 weeks in duration. Olanzapine is not approved by the FDA for use in the treatment of behavioral disorders in elderly patients with dementia.

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack) which included fatalities have been reported in trials of olanzapine on elderly patients with dementia-related psychosis. There was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine when compared to patients treated with placebo. However, the association between the use of atypical antipsychotics (i.e., risperidone, olanzapine) and the risk of cerebrovascular events appears to be somewhat controversial. The results of a case-control study found no increased risk of cerebrovascular events in elderly patients treated with atypical antipsychotics.

The results of a large retrospective cohort study appear to indicate that atypical antipsychotic agents (i.e., risperidone, olanzapine, clozapine, quetiapine) increase the risk of venous thromboembolism in elderly patients; however, these events seem to be rare.

A 24 year old, nonsmoking healthy female participating in a pharmacokinetic study developed hypotension and bradycardia within approximately 1 to 2 hours following a single 5 mg oral dose. Serum samples revealed a shorter Tmax of 3 hours and a higher Cmax of 13 ng/mL compared to the average Tmax and Cmax of 5 hours and 7.3 ng/mL, respectively.

Metabolic

The results of the large scale clinical trial noted that treatment related changes in glucose tolerance were largely explained by changes in insulin sensitivity.

In one study, mean weight gain during olanzapine treatment trended toward a plateau after the initial 39 weeks with no further significant gain for up to three years. A higher baseline body mass index was predictive of a lower long-term weight gain. However, dose was not a significant predictor of greater long-term weight change.

Because olanzapine may stimulate appetite and increase weight gain, olanzapine meets the Beers criteria as a medication that is potentially inappropriate for use in older adults.

Clinical placebo-controlled trials involving patients receiving olanzapine with either valproate or lithium for the treatment of bipolar mania reported a discontinuation rate of 1% due to weight gain.

Based on a case report, it has been suggested that olanzapine's hypertriglyceridemic effects may be unrelated to its propensity to cause weight gain.

Metabolic side effects have frequently included weight gain. Binge eating and increases in food craving have been associated with olanzapine. Acidosis, cyanosis, increased alkaline phosphatase, bilirubinemia, dehydration, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hyperlipidemia, hyperuricemia, hypoglycemia, hypokalemia, and hyponatremia have also been reported. Gout, hyperkalemia, hypernatremia, hypoproteinemia, ketosis, and water intoxication have been reported rarely. A large scale clinical trial at clinically relevant doses has reported significant reductions in glucose tolerance during treatment with olanzapine.

Gastrointestinal

Gastrointestinal side effects have frequently included dry mouth, increased appetite, thirst, constipation, dyspepsia, increased salivation, vomiting, and flatulence. Dysphagia, esophagitis, fecal impaction, fecal incontinence, gastritis, gastroenteritis, gingivitis, melena, mouth ulceration, nausea and vomiting, oral moniliasis, periodontal abscess, rectal hemorrhage, stomatitis, tongue edema, taste perversion, and tooth caries have also been reported. Aphthous stomatitis, enteritis, eructation, esophageal ulcer, glossitis, ileus, intestinal obstruction, and tongue discoloration have been reported rarely. Isolated cases of olanzapine-induced acute pancreatitis have been reported during postmarketing use.

Nausea and dry mouth have been reported to be dose related.

A 65 year old man developed fecal incontinence following initiation of treatment with olanzapine 2.5 mg daily. This effect continued until the patient's next scheduled exam, at approximately 20 days after initiation of therapy, at which point olanzapine was discontinued. Fecal incontinence resolved within approximately 24 hours. No organic cause for fecal incontinence was determined, rectal exam was negative, sigmoidoscopy results were normal, and lab tests were all within normal limits.

Hepatic

Placebo-controlled clinical trials reported a 2% discontinuation rate due to increases in SGPT with olanzapine compared to 0% for placebo.

A 78 year old woman diagnosed with acute depression with psychotic features developed fever, malaise, arthralgia, upper abdominal pain, anorexia, and nausea approximately 13 days after initiating therapy with olanzapine 10 mg per day. Concomitant medications included calcium, vitamin D, multivitamin, and occasional acetaminophen. The patient had no history of liver disease, intravenous drug use, alcohol use, or blood transfusions. Physical examination revealed dry mucous membranes and a palpable, firm, tender liver. Lab results revealed a slight increase in leukocyte count and an increase in aspartate aminotransferase, alanine aminotransferase, total bilirubin, and alkaline phosphatase levels. All serologic tests were negative. Symptoms resolved and liver function test decreased with 4 days, and patient was completely recovered with all lab tests within normal limits within 4 weeks of onset.

Hepatic side effects have rarely included hepatitis, liver fatty deposit, and cholestatic or mixed liver injury. Transient and moderate, asymptomatic elevations in liver function tests have been reported.

Respiratory

An increased risk of mortality, possibly due to an infection, such as pneumonia, has been reported with the use of atypical antipsychotic agents, including olanzapine, in the treatment of behavioral disorders in the elderly patient with dementia.

Collective data gathered from 17 placebo-controlled clinical studies (n=5106) involving the use of atypical antipsychotic agents, including olanzapine, for the treatment of behavioral disorders in the elderly patient with dementia showed a risk of death 1.6 to 1.7 times greater in the drug treated patient than in the placebo treated patient. The average length of duration for the trials was 10 weeks with the cause of death in the majority of cases, though not all, reported as either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Olanzapine is not approved by the FDA for use in the treatment of behavioral disorders in elderly patients with dementia.

Respiratory side effects have frequently included rhinitis, increased cough, pharyngitis, and dyspnea. Apnea, asthma, epistaxis, hemoptysis, hyperventilation, hypoxia, laryngitis, and voice alterations have also been reported. Atelectasis, hiccup, hypoventilation, lung edema, and stridor have been reported rarely. Postmarketing reports have included pneumonia and lower respiratory tract infection which may be fatal.

Endocrine

Endocrine side effects have included hyperprolactinemia, hyperglycemia, and diabetes mellitus. Diabetic ketoacidosis (may be fatal) and goiter have been reported rarely.

A study of U.S. military veterans with schizophrenia has reported that patients on olanzapine had 1.27 times as many cases of diabetes when compared to patients taking decades old drugs for psychosis including haloperidol, thioridazine, and others.

Over an eight year period that ended in 2002, 288 cases of olanzapine-associated diabetes have been reported, 75 of which resulted in severe illness and 23 in death. One group of investigators suggests that olanzapine may precipitate or unmask diabetes in susceptible patients. One study on olanzapine-associated diabetes concluded that the number of reports, temporal relationship to the start of olanzapine therapy, relatively young age, and improvement on drug withdrawal suggests that olanzapine may precipitate or unmask diabetes in susceptible patients.

Additional studies have confirmed that patients receiving atypical antipsychotics (i.e., clozapine, risperidone, olanzapine, quetiapine, ziprasidone) are at an increased risk of developing hyperglycemia and/or diabetes mellitus.

Hyperprolactinemia in some patients may cause sexual dysfunction, menstrual irregularities, and osteoporosis. In addition, as many as one-third of human breast cancers may be prolactin-dependent in vitro.

Hematologic

Hematologic side effects have rarely included anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocytopenia, normocytic anemia, neutropenia, leukopenia, agranulocytosis, eosinophilia, agranulocytosis, and thrombocythemia.

Ocular

Ocular side effects have frequently included amblyopia, abnormal vision, and conjunctivitis. Abnormality of accommodation, blepharitis, cataract, diplopia, dry eyes, eye hemorrhage, eye inflammation, eye pain, ocular muscle abnormality have also been reported. Glaucoma, corneal lesion, keratoconjunctivitis, macular hypopigmentation, miosis, mydriasis, esotropia, and pigment deposits in the lens have been reported rarely. One possible case of olanzapine-induced oculogyric crisis and another case of bilateral eyelid edema have also been reported. At least one case of blepharoclonus has also been associated with olanzapine.

Other

Other side effects have frequently included asthenia, accidental injury, back pain, fever, chest pain, dental pain, peripheral edema, edema, and flu syndrome. Enlarged abdomen, chills, face edema, intentional injury, malaise, moniliasis, neck pain, neck rigidity, pelvic pain, photosensitivity reaction, ear pain, tinnitus, and deafness have also been reported. Chills and fever, hangover effect, and sudden death have been reported rarely. In addition, rare cases of withdrawal syndrome following discontinuation of olanzapine have been reported. One possible case of increased serum creatine kinase, without neuromalignant syndrome, has been reported.

In one reported case of withdrawal, symptoms included shaking, body aches, nausea, headache, reduced sleep, piloerection, blurred vision, fearfulness, nightmares, depression, restlessness in the arms and legs, and unformed auditory hallucinations.

Placebo-controlled clinical trials involving patients receiving olanzapine with either valproate or lithium for the treatment of bipolar mania reported a discontinuation rate of 1% due to peripheral edema.

A 34 year old white female with a history of bipolar disorder was diagnosed with bilateral 2-plus pitting edema in the ankles and dorsum of the feet approximately 10 days after initiating therapy with olanzapine 10 mg daily. Concomitant therapy included long-term routine use of bupropion and diazepam. All lab tests and clinical findings were found to be within normal limits. Olanzapine was discontinued and the edema resolved. Approximately 2 weeks after discontinuation, olanzapine 10 mg daily was resumed upon patients request, and again within approximately 10 days the bilateral edema recurred. Olanzapine was discontinued immediately, and the edema resolved within approximately 10 days.

Hypersensitivity

Hypersensitivity side effects have rarely included hypersensitivity syndrome.

In one reported case of hypersensitivity syndrome, the patient presented with a severe, generalized pruritic skin eruption, fever, eosinophilia, and toxic hepatitis 60 days after ingestion of olanzapine.

Genitourinary

A 35 year old male with no prior history of mental illness nor history of psychotropic medication use developed priapism within approximately 14 hours after a single dose of olanzapine 10 mg for the treatment of schizoaffective disorder. The patient reported the condition to his clinician approximately 48 hours later. Several treatment options were tried before eventual detumescence of the penis occurred. The patient was reported to have permanent impotence as a result of his prolonged priapism.

A 27 year old female receiving valproate (6 month duration) for bipolar disorder reported painful swelling of the clitoris of 3 day duration following approximately 4 weeks of treatment with olanzapine 5 mg daily for mania. The patient was positive for intermittent, 2 to 3 times a month for 2 years, alcohol and cannabis use. The patient had no history of clitoral priapism or clitoral related pathology, routine physical and laboratory investigations were normal. Clitoral swelling resolved within approximately 2 days of discontinuation of olanzapine therapy.

Genitourinary side effects have included urinary incontinence, and urinary tract infection in 2% of patients. Dysmenorrhea and vaginitis have been reported in 2% of female patients. Amenorrhea, decreased menstruation, lactation, increased menstruation, menorrhagia, metrorrhagia, premenstrual syndrome, enlarged uterine fibroids, and vaginal hemorrhage have also been reported in female patients. Impotence and abnormal ejaculation have been reported in male patients. Breast pain, cystitis, dysuria, glycosuria, gynecomastia, hematuria, polyuria, pyuria, urinary retention, urinary urgency, urination impairment, albuminuria, mastitis, and oliguria have also been reported. Priapism, which required treatment in some cases, has been reported occasionally.

Musculoskeletal

Musculoskeletal side effects have included extremity pain (other than joint pain) and joint pain in 5% of patients. Joint stiffness and twitching have been reported frequently. Arthritis, arthrosis, leg cramps, and myasthenia have also been reported. Bone pain, bursitis, myopathy, osteoporosis, rheumatoid arthritis, and rhabdomyolysis have been reported rarely.

Dermatologic

A 26-year-old male receiving treatment with olanzapine 20 mg daily for approximately 2 years developed progressively increasing slate gray pigmentation of the dorsal aspect of both hands over a period of 4 months. Past medical history was insignificant, and negative for previous dermatologic disorders. All serum blood levels were within normal limits. Drug-induced acral melanosis was determined based on lab and clinical findings, with olanzapine as the offending agent due to temporal association.

Eruptive xanthomas was diagnosed via biopsy in a 31 year old male, 21 year old male, and a 50 year old Filipino female following approximately 4 to 8 weeks of treatment with olanzapine. Personal history was negative for diabetes mellitus or glucose intolerance in all cases; however, one case was positive for familial history of diabetes mellitus. Upon clinical evaluation, all patients were found to be positive for severe hyperglycemia and hypertriglyceridemia. Following initiation of appropriate treatment for diabetes mellitus and hypertriglyceridemia, the 31 year old male was found to be compliant with treatment, experienced normalization of serum glucose and triglycerides, and resolution of xanthomas despite continuation of olanzapine therapy; the 21 year old male was found to be noncompliant with treatment, continued to experience hypertriglyceridemia, and continued to exhibit persistent eruptive xanthomas; the 50 year old female was unavailable for follow-up.

Dermatologic side effects have frequently included ecchymosis, sweating, acne, and dry skin. Alopecia, contact dermatitis, eczema, maculopapular rash, pruritus, seborrhea, skin discoloration, skin ulcer, urticaria, and vesiculobullous rash have also been reported. Hirsutism, papular rash, and eruptive xanthomas have been reported rarely. One case of hyperpigmentation has been reported.

Psychiatric

Psychiatric side effects have frequently included depression, euphoria, delusions, manic reaction, and schizophrenic reaction. Obsessive-compulsive symptoms and suicide attempt have also been reported.

General

In general, clinical placebo-controlled trials have reported no difference in the incidence of discontinuation due to side effects in patients receiving olanzapine versus placebo for the treatment of schizophrenia or monotherapy for bipolar mania. However, clinical studies involving valproate or lithium monotherapy for treatment of bipolar mania reported a 2% discontinuation rate due to side effects as compared to 11% when olanzapine was added.

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