Olanzapine: Package Insert and Label Information (Page 4 of 8)

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 [see Patient Counseling Information (17.8) ].

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 [see Patient Counseling Information (17.9) ].

5.14 Use in Patients with Concomitant Illness

Clinical experience with olanzapine in patients with certain concomitant systemic illnesses is limited [see Clinical Pharmacology (12.3) ].

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 significantly 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 [see Boxed Warning, Warnings and Precautions (5.1), and Patient Counseling Information (17.2)].

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 [see Warnings and Precautions (5.8) ].

5.15 Hyperprolactinemia

As with other drugs that antagonize dopamine D₂ receptors, olanzapine elevates prolactin levels, and a modest 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 [see Nonclinical Toxicology (13.1) ]. 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) [see Use in Specific Populations (8.4) ].

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.

5.16 Use in Combination with Fluoxetine, Lithium or Valproate

When using olanzapine and fluoxetine in combination, the prescriber should also refer to the Warnings and Precautions section of the package insert for olanzapine and fluoxetine in combination.

When using olanzapine in combination with lithium or valproate, the prescriber should refer to the Warnings and Precautions sections of the package inserts for lithium or valproate. [See Drug Interactions (7)].

5.17 Laboratory Tests

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see Warnings and Precautions (5.4, 5.5) and Patient Counseling Information (17.4, 17.5)].

6 ADVERSE REACTIONS

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

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 is derived from a clinical trial database for olanzapine consisting of 8661 adult patients with approximately 4165 patient-years of exposure to olanzapine. 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; and (4) 5788 patients from 88 additional oral olanzapine clinical trials as of December 31, 2001. 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 Events in Short-Term, Placebo-Controlled and Combination Trials

The following findings are based on premarketing trials of 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.

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 events (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 events (2% for olanzapine vs. 2% 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 Events in Short-Term, Placebo-Controlled Trials

The most commonly observed adverse events 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

* 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 disorder *	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

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 events that occurred in 2% or more of patients treated with 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

* Denominator used was for females only (olanzapine, N = 128; placebo, N = 51).
		Percentage of Patients Reporting Event
Body System/Adverse Reaction		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
Vaginitis *		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.

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

Akathisia *	23	16	19	27
* Percentage of patients with a Barnes Akathisia Scale global score ≥ 2. † Percentage of patients with a Simpson-Angus Scale total score > 3.
	Percentage of Patients Reporting Event
	Placebo	Olanzapine 5 ± 2.5 mg/day	Olanzapine 10 ± 2.5 mg/day	Olanzapine 15 ± 2.5 mg/day
Parkinsonism †	15	14	12	14

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse events 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

* Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis. † Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor. ‡ Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia. § Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia. ¶ 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 events *	1	3	2	3
Parkinsonism events †	10	8	14	20
Akathisia events ‡	1	5	11	10
Dyskinetic events §	4	0	2	1
Residual events ¶	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 17: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in Placebo-Controlled Clinical Trials of Oral Olanzapine in Schizophrenia and Bipolar I Disorder – Adolescents

	Percentage of Patients Reporting Event
Categoriesa	Placebo (N = 89)	Olanzapine (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

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

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 events using data from a schizophrenia trial involving fixed dosage ranges of olanzapine. It enumerates the percentage of patients with treatment-emergent adverse events for the three 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 events for which there was a trend.

Table 20: Percentage of Patients from a Schizophrenia Trial with Treatment-Emergent Adverse Reactions for the Three Dose Range Groups and Placebo

	Percentage of Patients Reporting Event
Adverse 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 per mL (female) or > 18.77 ng per 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.

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

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

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

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

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

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 Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term (3-6 weeks), Placebo-Controlled Trials

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

Table 22: Treatment-Emergent Adverse Reactions of ≥ 2% Incidence among Adolescents (13 to 17 Years Old)

(Combined Incidence from Short-Term, Placebo-Controlled Clinical Trials of Schizophrenia or Bipolar I Disorder [Manic or Mixed Episodes])

Percentage of Patients Reporting Event

	Olanzapine	Placebo
Adverse Reaction	(N = 179)	(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

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.