OLANZAPINE- olanzapine tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
OLANZAPINE (UNII: N7U69T4SZR) (OLANZAPINE - UNII:N7U69T4SZR)
Available from:
REMEDYREPACK INC.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Oral olanzapine 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 to 17), efficacy was established in one 6-week trial [see Clinical Studies (14.1)] . 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 [see Warnings and Precautions (5.5)] . Monotherapy — Oral olanzapine 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
Product summary:
Olanzapine tablets, USP 2.5 mg, 5 mg, 7.5 mg, and 10 mg are white, round, unscored, film-coated tablets, debossed with tablet number on one side and plain on the other side. Olanzapine tablets, USP 15 mg are blue, elliptical, unscored, film-coated tablets, debossed with tablet number on one side and plain on the other side. Olanzapine tablets, USP 20 mg are pink, elliptical, unscored, film-coated tablets, debossed with tablet number on one side and plain on the other side. The tablets are available as follows: Store olanzapine tablets at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses. Protect olanzapine tablets from light and moisture.
Authorization status:
Abbreviated New Drug Application
Authorization number:
70518-2299-0

OLANZAPINE- olanzapine tablet

REMEDYREPACK INC.

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Medication Guide

Olanzapine (oh lan' za peen) Tablets, USP

Read the Medication Guide that comes with olanzapine tablets before you start taking them 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 olanzapine tablets.

What is the most important information I should know about olanzapine tablets?

Olanzapine tablets 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). Olanzapine tablets are 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 olanzapine tablets and during

treatment. In people who do not have diabetes, sometimes high blood sugar goes away when olanzapine

tablets are stopped. People with diabetes and some people who did not have diabetes before taking

olanzapine tablets need to take medicine for high blood sugar even after they stop taking olanzapine tablets.

If you have diabetes, follow your doctor's instructions about how often to check your blood sugar while

taking olanzapine tablets.

Call your doctor if you have any of these symptoms of high blood sugar (hyperglycemia) while taking

olanzapine tablets:

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 olanzapine tablets, 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 olanzapine tablets and during

treatment.

4. Weight gain. Weight gain is very common in people who take olanzapine tablets. 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 olanzapine is used in

combination with fluoxetine. Some people may gain a lot of weight while taking olanzapine tablets, 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 are olanzapine tablets?

Olanzapine tablets are 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.

Olanzapine tablets have not been approved for use in children under 13 years of age. Olanzapine 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 olanzapine tablets?

Olanzapine tablets may not be right for you. Before starting olanzapine tablets, 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

breast cancer

thoughts of suicide or hurting yourself

any other medical condition

are pregnant or plan to become pregnant. It is not known if olanzapine tablets will harm your unborn

baby.

are breast-feeding or plan to breast-feed. Olanzapine can pass into your breast milk and may harm

your baby. You should not breast-feed while taking olanzapine tablets. Talk to your doctor about the

best way to feed your baby if you take olanzapine tablets.

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. Olanzapine tablets 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

olanzapine tablets with your other medicines. Do not start or stop any medicine while taking olanzapine

tablets without talking to your doctor first.

How should I take olanzapine tablets?

Take olanzapine tablets exactly as prescribed. Your doctor may need to change (adjust) the dose of

olanzapine tablets until it is right for you.

If you miss a dose of olanzapine tablets, 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 olanzapine tablets at the same time.

To prevent serious side effects, do not stop taking olanzapine tablets suddenly. If you need to stop

taking olanzapine tablets, your doctor can tell you how to safely stop taking them.

If you take too much olanzapine tablets, call your doctor or poison control center at 1-800-222-1222

right away, or get emergency treatment.

Olanzapine tablets can be taken with or without food.

Olanzapine tablets are usually taken one time each day.

Call your doctor if you do not think you are getting better or have any concerns about your condition

while taking olanzapine tablets.

What should I avoid while taking olanzapine tablets?

Olanzapine tablets 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 olanzapine tablets affect you.

Avoid drinking alcohol while taking olanzapine tablets. Drinking alcohol while you take olanzapine

tablets may make you sleepier than if you take olanzapine tablets alone.

What are the possible side effects of olanzapine tablets?

Serious side effects may happen when you take olanzapine tablets, including:

See "What is the most important information I should know about olanzapine tablets?", 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). Olanzapine tablets are 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 olanzapine tablets. 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

olanzapine tablets. 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 olanzapine tablets. It may also start after you stop taking olanzapine tablets.

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 olanzapine tablets.

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 olanzapine tablets 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 to 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 olanzapine tablets. 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 olanzapine tablets?

Store olanzapine tablets at room temperature, between 68° to 77°F (20° to 25°C).

Keep olanzapine tablets away from light.

Keep olanzapine tablets dry and away from moisture.

Keep olanzapine tablets and all medicines out of the reach of children.

General information about olanzapine tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use

olanzapine tablets for a condition for which it was not prescribed. Do not give olanzapine tablets to other

people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about olanzapine tablets. If you would

like more information, talk with your doctor. You can ask your doctor or pharmacist for information about

olanzapine tablets that was written for healthcare professionals. For more information about olanzapine

tablets call 1-888-848-3593.

What are the ingredients in olanzapine tablets?

Active ingredient: olanzapine, USP

Inactive ingredients: crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate,

microcrystalline cellulose.

Film coating: Opadry ® 03A18286 (Hypromellose, Titanium Dioxide and Sodium Lauryl Sulfate), Opadry

® 03A605003 (Hypromellose, Titanium Dioxide, FD&C Blue #2/Indigo Carmine Aluminum Lake and

FD&C Yellow #6/ Sunset Yellow FCF Aluminum Lake) or Opadry ® 03A640001 (Hypromellose, Titanium

Dioxide, Talc and Iron Oxide Red).

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:

Virtus Pharmaceuticals, LLC

Langhorne, PA 19047, USA

1-888-848-3593

Manufactured by:

Qilu Pharmaceutical Co., Ltd.

Jinan, 250101, China

Revised: 08/2018

340311000380

Revised: 9/2019

Document Id: 922a035c-4542-5959-e053-2995a90abecc

34391-3

Set id: 257f93a6-82c3-4d67-b829-930f51a110b1

Version: 1

Effective Time: 20190909

REMEDYREPACK INC.

OLANZAPINE- olanzapine tablet

REMEDYREPACK INC.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use OLANZAPINE TABLETS safely and

effectively. See Full Prescribing Information for OLANZAPINE TABLETS.

OLANZAPINE tablets, for oral use

Initial U.S. Approval: 1996

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED

PSYCHOSIS

See full prescribing information for complete boxed warning.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased

risk of death. Olanzapine is not approved for the treatment of patients with dementia-related

psychosis. (5.1, 5.14, 17.2)

When using olanzapine and fluoxetine in combination, also refer to the Boxed Warning section of the

package insert for Symbyax.

INDICATIONS AND USAGE

Olanzapine is an atypical antipsychotic indicated:

As oral formulation for the:

Treatment of schizophrenia. (1.1)

Adults: Efficacy was established in three clinical trials in patients with schizophrenia: two 6-week trials and one

maintenance trial. (14.1)

Adolescents (ages 13 to 17): Efficacy was established in one 6-week trial in patients with schizophrenia (14.1). The

increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to

consider prescribing other drugs first in adolescents. (1.1)

Acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I

disorder. (1.2)

Adults: Efficacy was established in three clinical trials in patients with manic or mixed episodes of bipolar I disorder:

two 3- to 4-week trials and one maintenance trial. (14.2)

Adolescents (ages 13 to 17): Efficacy was established in one 3-week trial in patients with manic or mixed episodes

associated with bipolar I disorder (14.2). The increased potential (in adolescents compared with adults) for weight

gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents. (1.2)

Medication therapy for pediatric patients with schizophrenia or bipolar I disorder should be undertaken only after a

thorough diagnostic evaluation and with careful consideration of the potential risks. (1.3)

Adjunct to valproate or lithium in the treatment of manic or mixed episodes associated with bipolar I disorder. (1.2)

Efficacy was established in two 6-week clinical trials in adults (14.2). Maintenance efficacy has not been

systematically evaluated.

As Olanzapine and Fluoxetine in Combination for the:

Treatment of depressive episodes associated with bipolar I disorder. (1.5)

Efficacy was established with Symbyax (olanzapine and fluoxetine in combination); refer to the product label for

Symbyax.

Treatment of treatment resistant depression. ( 1.6)

Efficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product

label for Symbyax.

DOSAGE AND ADMINISTRATION

Schizophrenia in adults (2.1)

Oral: Start at 5 to 10 mg once daily; Target: 10 mg/day within

several days

Schizophrenia in adolescents (2.1)

Oral: Start at 2.5 to 5 mg once daily; Target: 10 mg/day

Bipolar I Disorder (manic or mixed episodes) in adults

(2.2)

Oral: Start at 10 or 15 mg once daily

Bipolar I Disorder (manic or mixed episodes) in

adolescents (2.2)

Oral: Start at 2.5 to 5 mg once daily; Target: 10 mg/day

Bipolar

Disorder

(manic

mixed

episodes)

with

lithium or valproate in adults (2.2)

Oral: Start at 10 mg once daily

Depressive Episodes associated with Bipolar I Disorder

in adults (2.5)

Oral

combination

with

fluoxetine:

Start

oral

olanzapine and 20 mg of fluoxetine once daily

Depressive Episodes associated with Bipolar I Disorder

in children and adolescents (2.5)

Oral

combination

with

fluoxetine:

Start

oral

olanzapine and 20 mg of fluoxetine once daily

Treatment Resistant Depression in adults ( 2.6)

Oral

combination

with

fluoxetine:

Start

oral

olanzapine and 20 mg of fluoxetine once daily

Lower starting dose recommended in debilitated or pharmacodynamically sensitive patients or patients with

predisposition to hypotensive reactions, or with potential for slowed metabolism. (2.1)

Olanzapine may be given without regard to meals. (2.1)

Olanzapine and Fluoxetine in Combination:

Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. (

2.5, 2.6)

Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder or

treatment resistant depression. ( 2.5, 2.6)

Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults. (

2.5, 2.6)

Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children

and adolescents ages 10 to 17. (2.5)

DOSAGE FORMS AND STRENGTHS

Tablets (not scored): 2.5, 5, 7.5, 10, 15, 20 mg (3)

CONTRAINDICATIONS

None with olanzapine monotherapy.

When using olanzapine and fluoxetine in combination, also refer to the Contraindications section of the package insert

for Symbyax

. (4)

When using olanzapine in combination with lithium or valproate, refer to the Contraindications section of the package

inserts for those products. (4)

WARNINGS AND PRECAUTIONS

Elderly Patients with Dementia-Related Psychosis: Increased risk of death and increased incidence of cerebrovascular

adverse events (e.g., stroke, transient ischemic attack). (5.1)

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; when using in combination with fluoxetine, also refer to the Boxed

Warning and Warnings and Precautions sections of the package insert for Symbyax. (5.2)

Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. (5.3)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue if DRESS is suspected. (5.4)

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes including

hyperglycemia, dyslipidemia, and weight gain. (5.5)

Hyperglycemia and Diabetes Mellitus: In some cases extreme and associated with ketoacidosis or hyperosmolar

coma or death, has been reported in patients taking olanzapine. Patients taking olanzapine should be monitored for

symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during,

treatment. (5.5)

Dyslipidemia: Undesirable alterations in lipids have been observed. Appropriate clinical monitoring is

recommended, including fasting blood lipid testing at the beginning of, and periodically during, treatment. (5.5)

Weight Gain: Potential consequences of weight gain should be considered. Patients should receive regular

monitoring of weight. (5.5)

Tardive Dyskinesia: Discontinue if clinically appropriate. (5.6)

Orthostatic Hypotension: Orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some

patients, syncope, may occur especially during initial dose titration. Use caution in patients with cardiovascular disease,

cerebrovascular disease, and those conditions that could affect hemodynamic responses. (5.7)

Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including olanzapine. Patients

with a history of a clinically significant low white blood cell count (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 olanzapine should be considered at the first sign of a clinically significant decline in WBC in the absence of other

causative factors. (5.9)

Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure

threshold. (5.11)

Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution

when operating machinery. (5.12)

Hyperprolactinemia: May elevate prolactin levels. (5.15)

Use in Combination with Fluoxetine, Lithium or Valproate: Also refer to the package inserts for Symbyax, lithium, or

valproate. (5.16)

Laboratory Tests: Monitor fasting blood glucose and lipid profiles at the beginning of, and periodically during, treatment.

(5.17)

ADVERSE REACTIONS

Most common adverse reactions (≥ 5% and at least twice that for placebo) associated with:

Oral Olanzapine Monotherapy:

Schizophrenia (Adults) – postural hypotension, constipation, weight gain, dizziness, personality disorder, akathisia (6.1)

Schizophrenia (Adolescents) – sedation, weight increased, headache, increased appetite, dizziness, abdominal pain, pain

in extremity, fatigue, dry mouth (6.3)

Manic or Mixed Episodes, Bipolar I Disorder (Adults) – asthenia, dry mouth, constipation, increased appetite,

somnolence, dizziness, tremor (6.1)

Manic or Mixed Episodes, Bipolar I Disorder (Adolescents) – sedation, weight increased, increased appetite, headache,

fatigue, dizziness, dry mouth, abdominal pain, pain in extremity (6.3)

Combination of Olanzapine and Lithium or Valproate:

Manic or Mixed Episodes, Bipolar I Disorder (Adults) – dry mouth, weight gain, increased appetite, dizziness, back pain,

constipation, speech disorder, increased salivation, amnesia, paresthesia (6.1)

Olanzapine and Fluoxetine in Combination: Also refer to the Adverse Reactions section of the package insert for

Symbyax. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Virtus Pharmaceuticals, LLC at 1-888-848-3593 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

Diazepam: May potentiate orthostatic hypotension. (7.1, 7.2)

Alcohol: May potentiate orthostatic hypotension. (7.1)

Carbamazepine: Increased clearance of olanzapine. (7.1)

Fluvoxamine: May increase olanzapine levels. (7.1)

Olanzapine and Fluoxetine in Combination: Also refer to the Drug Interactions section of the package insert for

Symbyax. (7.1)

CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs and alcohol.

(7.2)

Antihypertensive Agents: Enhanced antihypertensive effect. (7.2)

Levodopa and Dopamine Agonists: May antagonize levodopa/dopamine agonists. (7.2)

Other Concomitant Drug Therapy: When using olanzapine in combination with lithium or valproate, refer to the Drug

Interactions sections of the package insert for those products. (7.2)

USE IN SPECIFIC POPULATIONS

Pregnancy: Olanzapine should be used during pregnancy only if the potential benefit justifies the potential risk to the

fetus. (8.1)

Nursing Mothers: Breast-feeding is not recommended. (8.3)

Pediatric Use: Safety and effectiveness of olanzapine in children <13 years of age have not been established. Safety

and effectiveness of olanzapine and fluoxetine in combination in children <10 years of age have not been established.

(8.4)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 9/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-

RELATED PSYCHOSIS

1 INDICATIONS AND USAGE

1.1 Schizophrenia

1.2 Bipolar I Disorder (Manic or Mixed Episodes)

1.3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder

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

Disorder

1.6 Olanzapine and Fluoxetine in Combination: Treatment Resistant Depression

2 DOSAGE AND ADMINISTRATION

2.1 Schizophrenia

2.2 Bipolar I Disorder (Manic or Mixed Episodes)

2.5 Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I

Disorder

2.6 Olanzapine and Fluoxetine in Combination: Treatment Resistant Depression

2.7 Olanzapine and Fluoxetine in Combination: Dosing in Special Populations

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Elderly Patients with Dementia-Related Psychosis

5.2 Suicide

5.3 Neuroleptic Malignant Syndrome (NMS)

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

5.5 Metabolic Changes

5.6 Tardive Dyskinesia

5.7 Orthostatic Hypotension

5.8 Falls

5.9 Leukopenia, Neutropenia, and Agranulocytosis

5.10 Dysphagia

5.11 Seizures

5.12 Potential for Cognitive and Motor Impairment

5.13 Body Temperature Regulation

5.14 Use in Patients with Concomitant Illness

5.15 Hyperprolactinemia

5.16 Use in Combination with Fluoxetine, Lithium, or Valproate

5.17 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Extrapyramidal Symptoms

6.3 Other Adverse Reactions

6.4 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Potential for Other Drugs to Affect Olanzapine

7.2 Potential for Olanzapine to Affect Other Drugs

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

9 DRUG ABUSE AND DEPENDENCE

9.3 Dependence

10 OVERDOSAGE

10.1 Human Experience

10.2 Management of Overdose

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Schizophrenia

14.2 Bipolar I Disorder (Manic or Mixed Episodes)

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION

17.1 Information on Medication Guide

17.2 Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular

Adverse Events (CVAE), Including Stroke

17.3 Neuroleptic Malignant Syndrome (NMS)

17.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

17.5 Hyperglycemia and Diabetes Mellitus

17.6 Dyslipidemia

17.7 Weight Gain

17.8 Orthostatic Hypotension

17.9 Potential for Cognitive and Motor Impairment

17.10 Body Temperature Regulation

17.11 Concomitant Medication

17.12 Alcohol

17.14 Use in Specific Populations

17.15 Need for Comprehensive Treatment Program in Pediatric Patients

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH

DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an

increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of

10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in

drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated

patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-

treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either

cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with

conventional antipsychotic drugs may increase mortality. The extent to which the findings

of increased mortality in observational studies may be attributed to the antipsychotic drug

as opposed to some characteristic(s) of the patients is not clear. Olanzapine is not approved

for the treatment of patients with dementia-related psychosis [see Warnings and Precautions

(5.1, 5.14) and Patient Counseling Information (17.2)] .

When using olanzapine and fluoxetine in combination, also refer to the Boxed Warning

section of the package insert for Symbyax.

1 INDICATIONS AND USAGE

1.1 Schizophrenia

Oral olanzapine 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 to 17), efficacy was established in one 6-week trial [see

Clinical Studies (14.1)] .

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 [see Warnings and

Precautions (5.5)] .

1.2 Bipolar I Disorder (Manic or Mixed Episodes)

Monotherapy — Oral olanzapine 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 to 17), efficacy was established in one 3-

week trial [see Clinical Studies (14.2)] .

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 [see Warnings and

Precautions (5.5)] .

Adjunctive Therapy to Lithium or Valproate — Oral olanzapine 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 [see Clinical Studies (14.2)] .

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.

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

Dis order

Oral olanzapine and fluoxetine in combination is indicated for the treatment of depressive episodes

associated with bipolar I disorder, based on clinical studies. When using olanzapine and fluoxetine in

combination, refer to the Clinical Studies section of the package insert for Symbyax.

Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with

bipolar I disorder.

1.6 Olanzapine and Fluoxetine in Combination: Treatment Resistant Depression

Oral olanzapine 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 olanzapine and fluoxetine in combination, refer to the Clinical Studies section of

the package insert for Symbyax.

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

2 DOSAGE AND ADMINISTRATION

2.1 Schizophrenia

Adults

Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to

meals, generally beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several

days. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1

week, since steady state for olanzapine would not be achieved for approximately 1 week in the typical

patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are

recommended.

Efficacy in schizophrenia was demonstrated in a dose range of 10 to 15 mg/day in clinical trials.

However, doses above 10 mg/day were not demonstrated to be more efficacious than the 10 mg/day

dose. An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or

greater) is recommended only after clinical assessment. Olanzapine is not indicated for use in doses

above 20 mg/day.

Dosing in Special Populations — The recommended starting dose is 5 mg in patients who are

debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of

factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥ 65 years

of age), or who may be more pharmacodynamically sensitive to olanzapine [see Warnings

and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)] . When indicated, dose

escalation should be performed with caution in these patients.

Maintenance Treatment — The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining

treatment response in schizophrenic patients who had been stable on olanzapine for approximately 8

weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial [see

Clinical Studies (14.1)] . The physician who elects to use olanzapine for extended periods should

periodically reevaluate the long-term usefulness of the drug for the individual patient.

Adolescents

Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to

meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in

adolescents with schizophrenia was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in

clinical trials, with a mean modal dose of 12.5 mg/day (mean dose of 11.1 mg/day). When dosage

adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.

The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see

Clinical Studies (14.1)].

Maintenance Treatment — The efficacy of olanzapine for the maintenance treatment of schizophrenia in

the adolescent population has not been systematically evaluated; however, maintenance efficacy can be

extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult

and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond

the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically

reassessed to determine the need for maintenance treatment.

2.2 Bipolar I Disorder (Manic or Mixed Episodes)

Adults

Dose Selection for Monotherapy — Oral olanzapine should be administered on a once-a-day schedule

without regard to meals, generally beginning with 10 or 15 mg. Dosage adjustments, if indicated, should

generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-

controlled trials. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are

recommended.

Short-term (3 to 4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in

clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials [see Clinical

Studies (14.2)] .

Maintenance Monotherapy — The benefit of maintaining bipolar I patients on monotherapy with oral

olanzapine at a dose of 5 to 20 mg/day, after achieving a responder status for an average duration of 2

weeks, was demonstrated in a controlled trial [see Clinical Studies (14.2)] . The physician who elects to

use olanzapine for extended periods should periodically reevaluate the long-term usefulness of the

drug for the individual patient.

Dose Selection for Adjunctive Treatment — When administered as adjunctive treatment to lithium or

valproate, oral olanzapine dosing should generally begin with 10 mg once-a-day without regard to

meals.

Antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials [see Clinical

Studies (14.2)] . The safety of doses above 20 mg/day has not been evaluated in clinical trials.

Adolescents

Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to

meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in

adolescents with bipolar I disorder (manic or mixed episodes) was demonstrated based on a flexible

dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 10.7 mg/day (mean dose of

8.9 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are

recommended.

The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see

Clinical Studies (14.2)] .

Maintenance Treatment — The efficacy of olanzapine for the maintenance treatment of bipolar I

disorder in the adolescent population has not been evaluated; however, maintenance efficacy can be

extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult

and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond

the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically

reassessed to determine the need for maintenance treatment.

2.5 Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I

Dis order

When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the

package insert for Symbyax.

Adults

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening,

without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine.

Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges

of oral olanzapine 5 to 12.5 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated

with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 12

mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg

fluoxetine has not been evaluated in clinical studies.

Children and Adolescents (10 to 17 years of age)

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening,

without regard to meals, generally beginning with 2.5 mg of oral olanzapine and 20 mg of fluoxetine.

Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Safety of co-

administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in

pediatric clinical studies.

Safety and efficacy of olanzapine and fluoxetine in combination was determined in clinical trials

supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is

dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per

day. The following table demonstrates the appropriate individual component doses of olanzapine and

fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual

components according to efficacy and tolerability.

Table 1: Approximate Dose Correspondence Between Symbyax

and the Combination of

Olanzapine and Fluoxetine

For

Symbyax

(mg/day)

Use in Combination

Olanzapine(mg/day)

Fluoxetine

(mg/day)

3 mg olanzapine/25 mg fluoxetine

a

Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of olanzapine and fluoxetine.

6 mg olanzapine/25 mg fluoxetine

12 mg olanzapine/25 mg fluoxetine

10+2.5

6 mg olanzapine/50 mg fluoxetine

40+10

12 mg olanzapine/50 mg fluoxetine

10+2.5

40+10

While there is no body of evidence to answer the question of how long a patient treated with olanzapine

and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder,

including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring

chronic treatment. The physician should periodically reexamine the need for continued

pharmacotherapy.

Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with

bipolar I disorder.

2.6 Olanzapine and Fluoxetine in Combination: Treatment Resistant Depression

When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the

package insert for Symbyax.

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening,

without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine.

Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges

of oral olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated

with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 18

mg and fluoxetine 25 to 50 mg.

Safety and efficacy of olanzapine in combination with fluoxetine was determined in clinical trials

supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is

dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per

day. Table 1 above demonstrates the appropriate individual component doses of olanzapine and

fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual

components according to efficacy and tolerability.

While there is no body of evidence to answer the question of how long a patient treated with olanzapine

and fluoxetine in combination should remain on it, it is generally accepted that treatment resistant

depression (major depressive disorder in adult patients who do not respond to 2 separate trials of

different antidepressants of adequate dose and duration in the current episode) is a chronic illness

requiring chronic treatment. The physician should periodically reexamine the need for continued

pharmacotherapy.

Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been

evaluated in clinical studies.

Olanzapine monotherapy is not indicated for treatment of treatment resistant depression (major

depressive disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in

the current episode).

2.7 Olanzapine and Fluoxetine in Combination: Dosing in Special Populations

The starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with

a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a

combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female

gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive

to olanzapine. Dosing modification may be necessary in patients who exhibit a combination of factors

that may slow metabolism. When indicated, dose escalation should be performed with caution in these

patients. Olanzapine and fluoxetine in combination have not been systematically studied in patients over

65 years of age or in patients under 10 years of age [see Warnings and Precautions (5.14), Drug

Interactions (7), and Clinical Pharmacology (12.3)] .

3 DOSAGE FORMS AND STRENGTHS

Olanzapine tablets, USP 2.5 mg, 5 mg, 7.5 mg, and 10 mg are white, round, unscored, film-coated tablets,

debossed with tablet number on one side and plain on the other side. Olanzapine tablets, USP 15 mg are

blue, elliptical, unscored, film-coated tablets, debossed with tablet number on one side and plain on the

other side. Olanzapine tablets, USP 20 mg are pink, elliptical, unscored, film-coated tablets, debossed

with tablet number on one side and plain on the other side. The tablets are available as follows:

TABLET

STRENGTH

Tablet No.

2.5 mg

5 mg

7.5 mg

10 mg

15 mg

20 mg

Identification

4 CONTRAINDICATIONS

None with olanzapine monotherapy.

When using olanzapine 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.

5 WARNINGS AND PRECAUTIONS

When using olanzapine 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. Olanzapine is not approved for the

treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and

Precautions (5.14), and Patient Counseling Information (17.2)] .

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 [see Boxed Warning and Patient Counseling Information (17.2)] .

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 [see Patient Counseling Information (17.3)] .

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 [see Patient Counseling Information (17.4)] .

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 to 126 mg/dL, nonfasting 140 to 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 [see

Patient Counseling Information (17.5)] .

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 HbA

increase from baseline of 0.04% (median exposure 21 days),

compared to a mean HbA

decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4 to 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

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

2.2%

12.8%

Placebo

3.4%

Borderline to High

(≥100 mg/dL and

<126 mg/dL to ≥126 mg/dL)

Olanzapine

17.4%

26.0%

Placebo

11.5%

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 to 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

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

0.9%

Placebo

1.9%

Borderline to High

(≥100 mg/dL and

<126 mg/dL to ≥126 mg/dL)

Olanzapine

14.3%

23.1%

Placebo

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 [see

Patient Counseling Information (17.6)].

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 to 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

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

39.6%

61.4%

Placebo

26.1%

Normal to High

(<150 mg/dL to ≥200 mg/dL)

Olanzapine

9.2%

32.4%

Placebo

4.4%

Borderline to High

(≥150 mg/dL and <200 mg/dL

to ≥200 mg/dL)

Olanzapine

39.3%

70.7%

Placebo

20.0%

Fasting Total

Cholesterol

Increase by ≥40 mg/dL

Olanzapine

21.6%

32.9%

Placebo

9.5%

Normal to High

(<200 mg/dL to ≥240 mg/dL)

Olanzapine

2.8%

14.8%

Placebo

2.4%

Borderline to High

(≥200 mg/dL and <240 mg/dL

to ≥240 mg/dL)

Olanzapine

23.0%

55.2%

Placebo

12.5%

Fasting LDL

Cholesterol

Increase by ≥30 mg/dL

Olanzapine

23.7%

39.8%

Placebo

14.1%

Normal to High (<100 mg/dL

to ≥160 mg/dL)

Olanzapine

7.3%

Placebo

1.2%

Borderline to High

(≥100 mg/dL and <160 mg/dL

to ≥160 mg/dL)

Olanzapine

10.6%

Placebo

8.1%

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

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

37.0%

45.9%

Placebo

15.2%

Normal to High

(<90 mg/dL to >130 mg/dL)

Olanzapine

26.9%

36.4%

Placebo

10.7%

Borderline to High (≥90

mg/dL and ≤130 mg/dL to

>130 mg/dL)

Olanzapine

59.5%

64.5%

Placebo

35.3%

Fasting Total

Cholesterol

Increase by ≥40 mg/dL

Olanzapine

14.5%

14.8%

Placebo

4.5%

Normal to High

(<170 mg/dL to ≥200

mg/dL)

Olanzapine

6.9%

7.7%

Placebo

2.3%

Borderline to High

(≥170 mg/dL and

<200 mg/dL to ≥200

mg/dL)

Olanzapine

38.9%

57.6%

Placebo

7.7%

Fasting LDL

Cholesterol

Increase by ≥30 mg/dL

Olanzapine

17.5%

22.3%

Placebo

11.1%

Normal to High

(<110 mg/dL to ≥130

mg/dL)

Olanzapine

5.1%

10.9%

Placebo

4.5%

Borderline to High

(≥110 mg/dL and

<130 mg/dL to ≥130 mg/dL)

Olanzapine

48.3%

47.6%

Placebo

Weight Gain

Potential consequences of weight gain should be considered prior to starting olanzapine. Patients

receiving olanzapine should receive regular monitoring of weight [see Patient Counseling Information

(17.7)] .

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)

10.9

14.9

11.4

17.0

>15 to ≤20 (33-44 lb)

11.6

>20 to ≤25 (44-55 lb)

>25 to ≤30 (55-66 lb)

>30 (>66 lb)

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%

(median exposure to

7% = 4 weeks)

9.8%

(median exposure to

7% = 8 weeks)

Percentage of patients who gained at

least 15% of baseline body weight

7.1%

(median exposure to

15% = 19 weeks)

2.7% (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

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)

22.0

>15 to ≤20 (33-44 lb)

12.6

>20 to ≤25 (44-55 lb)

>25 to ≤30 (55-66 lb)

>30 to ≤35 (66-77 lb)

>35 to ≤40 (77-88 lb)

>40 (>88 lb)

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 α

adrenergic antagonistic properties [see Patient Counseling Information (17.8)] .

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 [see Dosage and Administration (2)] . A more gradual titration to the

target dose should be considered if hypotension occurs.

Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in phase 2 to 3 oral olanzapine

studies. 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.

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 [see Drug Interactions (7)] .

5.8 Falls

Olanzapine 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 olanzapine. 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 olanzapine

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/mm

) should discontinue olanzapine 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 [see Patient Counseling Information (17.9)] .

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 (17.10)] .

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 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 (5.7)] .

5.15 Hyperprolactinemia

As with other drugs that antagonize dopamine D

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 [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 events

[49/3240] of females), sexual function-related events

(2% [150/8136] of females and males), and

breast-related events

(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 events

(1% [2/168] of

females), sexual function-related events

(0.7% [3/454] of females and males), and breast-related events

(2% [3/168] of females, 2% [7/286] of males) [see Use in Specific Populations (8.4)] .

Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and

oligomenorrhea.

Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction,

decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

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 olanzapine and fluoxetine in combination, the prescriber should also refer to the Warnings

and Precautions section of the package insert for Symbyax. 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 (5.5) and Patient Counseling Information (17.5, 17.6)] .

6 ADVERSE REACTIONS

When using olanzapine 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. 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. 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 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

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).

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term Combination Trials

Bipolar I Disorder (Manic or Mixed Episodes), Olanzapine as Adjunct to Lithium or Valproate — In a

study of patients who were already tolerating either lithium or valproate as monotherapy,

discontinuation rates due to adverse reactions were 11% for the combination of oral olanzapine with

lithium or valproate compared to 2% for patients who remained on lithium or valproate monotherapy.

Discontinuations with the combination of oral olanzapine and lithium or valproate that occurred in more

than 1 patient were: somnolence (3%), weight gain (1%), and peripheral edema (1%).

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

The most commonly observed adverse reactions associated with the use of oral olanzapine (incidence

of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients

(olanzapine incidence at least twice that for placebo) were:

Table 9: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral

Olanzapine in 6-Week Trials — SCHIZOPHRENIA

Percentage of Patients Reporting Event

Adverse Reaction

Olanzapine

(N=248)

Placebo

(N=118)

Postural hypotension

Constipation

Weight gain

Dizziness

Personality disorder

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

Akathisia

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)

Percentage of Patients Reporting Event

Adverse Reaction

Olanzapine

(N=125)

Placebo

(N=129)

Asthenia

Dry mouth

Constipation

Dyspepsia

Increased appetite

Somnolence

Dizziness

Tremor

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

Asthenia

Fever

Back pain

Chest pain

Cardiovascular System

Postural hypotension

Tachycardia

Hypertension

Digestive System

Dry mouth

Constipation

Dyspepsia

Vomiting

Increased appetite

Hemic and Lymphatic System

Ecchymosis

Metabolic and Nutritional Disorders

Weight gain

Peripheral edema

Musculoskeletal System

Extremity pain (other than joint)

Joint pain

Nervous System

Somnolence

Insomnia

Dizziness

Abnormal gait

Tremor

Akathisia

Hypertonia

Articulation impairment

Respiratory System

Rhinitis

Cough increased

Pharyngitis

Special Senses

Amblyopia

Urogenital System

Urinary incontinence

Urinary tract infection

Dose Dependency of Adverse Reactions

A dose group difference has been observed for fatigue, dizziness, weight gain and prolactin elevation.

In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and

40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder,

incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with

significant differences between 10 vs 40 and 20 vs 40 mg/day. The incidence of dizziness (10 mg/day:

2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 vs 40

mg. Dose group differences were also noted for weight gain and prolactin elevation [see Warnings and

Precautions (5.5, 5.15)] .

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

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

Dry mouth

Nausea

Somnolence

Tremor

Commonly Observed Adverse Reactions in Short-Term Trials of Oral Olanzapine as Adjunct to Lithium or

Valproate

In the bipolar I disorder (manic or mixed episodes) adjunct placebo-controlled trials, the most

commonly observed adverse reactions associated with the combination of olanzapine and lithium or

valproate (incidence of ≥5% and at least twice placebo) were:

Table 13: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral

Olanzapine in 6-Week Adjunct to Lithium or Valproate Trials — Bipolar I Disorder (Manic or

Mixed Episodes)

Adverse Reaction

Percentage of Patients Reporting Event

Olanzapine with

Lithium or Valproate

(N=229)

Placebo with Lithium

or Valproate

(N=115)

Dry mouth

Weight gain

Increased appetite

Dizziness

Back pain

Constipation

Speech disorder

Increased salivation

Amnesia

Paresthesia

Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in

Short-Term Trials of Olanzapine as Adjunct to Lithium or Valproate

Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse

reactions that occurred in 2% or more of patients treated with the combination of olanzapine (doses ≥5

mg/day) and lithium or valproate and with incidence greater than lithium or valproate alone who

participated in the acute phase of placebo-controlled combination trials.

Table 14: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-

Controlled Clinical Trials of Oral Olanzapine as Adjunct to Lithium or Valproate

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

Back pain

Accidental injury

Chest pain

Cardiovascular System

Hypertension

Digestive System

Dry mouth

Increased appetite

Thirst

Constipation

Increased salivation

Metabolic and Nutritional Disorders

Weight gain

Peripheral edema

Edema

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

Nervous System

Somnolence

Tremor

Depression

Dizziness

Speech disorder

Amnesia

Paresthesia

Apathy

Confusion

Euphoria

Incoordination

Respiratory System

Pharyngitis

Dyspnea

Skin and Appendages

Sweating

Acne

Dry skin

Special Senses

Amblyopia

Abnormal vision

Urogenital System

Dysmenorrhea

Vaginitis

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.

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

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

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

Parkinsonism

Akathisia

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

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

Parkinsonism events

Akathisia events

Dyskinetic events

Residual events

Any extrapyramidal event

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

Categories are based on Standard MedDRA Queries (SMQ) for extrapyramidal symptoms as defined

in MedDRA version 12.0.

Categories

Percentage of Patients Reporting Event

Placebo

(N=89)

Olanzapine

(N=179)

Dystonic events

Parkinsonism events

Akathisia events

Dyskinetic events

Nonspecific events

Any extrapyramidal event

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

a

(<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 Infrequent: chills, face edema, photosensitivity reaction, suicide attempt

; Rare:

chills and fever, hangover effect, sudden death

Cardiovascular System Infrequent: cerebrovascular accident, vasodilatation.

Digestive System Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus,

intestinal obstruction, liver fatty deposit.

Hemic and Lymphatic System Infrequent: thrombocytopenia.

Metabolic and Nutritional Disorders Frequent: alkaline phosphatase increased; Infrequent:

bilirubinemia, hypoproteinemia.

Musculoskeletal System Rare: osteoporosis.

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

Respiratory System Infrequent: epistaxis; Rare: lung edema.

Skin and Appendages Infrequent: alopecia.

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

Urogenital System Infrequent: amenorrhea

, breast pain, decreased menstruation, impotence

increased menstruation

, menorrhagia

, metrorrhagia

, polyuria

, urinary frequency, urinary retention,

urinary urgency, urination impaired.

These terms represent serious adverse events but do not meet the definition for adverse drug

reactions. They are included here because of their seriousness.

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)

Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy,

sedation, somnolence.

Patients with the following MedDRA terms were counted in this category: abdominal pain, abdominal

pain lower, abdominal pain upper.

Sedation

Weight increased

Headache

Increased appetite

Dizziness

Abdominal pain

Pain in extremity

Fatigue

Dry mouth

Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in

Short-Term (3 to 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])

Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy,

sedation, somnolence.

The terms alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic enzyme

were combined under liver enzymes.

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)

Sedation

Weight increased

Increased appetite

Headache

Fatigue

Dizziness

Dry mouth

Pain in extremity

Constipation

Nasopharyngitis

Diarrhea

Restlessness

Liver enzymes increased

Dyspepsia

Epistaxis

Respiratory tract infection

Sinusitis

Arthralgia

Musculoskeletal stiffness

Vital Signs and Laboratory Studies

Vital Sign Changes— Oral olanzapine was associated with orthostatic hypotension and tachycardia in

clinical trials [see Warnings and Precautions (5)].

Laboratory Changes

Olanzapine Monotherapy in Adults: An assessment of the premarketing experience for olanzapine

revealed an association with asymptomatic increases in ALT, AST, and GGT. Within the original

premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT

elevations to >200 IU/L was 2% (50/2381). None of these patients experienced jaundice or other

symptoms attributable to liver impairment and most had transient changes that tended to normalize while

olanzapine treatment was continued.

In placebo-controlled olanzapine monotherapy studies in adults, clinically significant ALT elevations

(change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in

5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patients exposed to

placebo. ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients,

compared to 0.3% (4/1196) of placebo-treated patients. ALT values returned to normal, or were

decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine

or discontinued olanzapine. No patient with elevated ALT values experienced jaundice, liver failure, or

met the criteria for Hy's Rule.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult

patients treated with oral olanzapine, high GGT levels were recorded in ≥1% (88/5245) of patients.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with

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 (5.15)] , with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with

an increase in CPK.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult

patients treated with oral olanzapine, elevated uric acid was recorded in ≥3% (171/4641) of patients.

Olanzapine Monotherapy in Adolescents: In placebo-controlled clinical trials of adolescent patients with

schizophrenia or bipolar I disorder (manic or mixed episodes), greater frequencies for the following

treatment-emergent findings, at anytime, were observed in laboratory analytes compared to placebo:

elevated ALT (≥3X ULN in patients with ALT at baseline <3X ULN), (12% vs 2%); elevated AST

(28% vs 4%); low total bilirubin (22% vs 7%); elevated GGT (10% vs 1%); and elevated prolactin (47%

vs 7%).

In placebo-controlled olanzapine monotherapy studies in adolescents, clinically significant ALT

elevations (change from <3 times ULN at baseline to ≥3 times ULN) were observed in 12% (22/192) of

patients exposed to olanzapine compared to 2% (2/109) of patients exposed to placebo. ALT elevations

≥5 times ULN were observed in 4% (8/192) of olanzapine-treated patients, compared to 1% (1/109) of

placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the

majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No

adolescent patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for

Hy's Rule.

ECG Changes — In pooled studies of adults as well as pooled studies of adolescents, there were no

significant differences between olanzapine and placebo in the proportions of patients experiencing

potentially important changes in ECG parameters, including QT, QTc (Fridericia corrected), and PR

intervals. Olanzapine use was associated with a mean increase in heart rate compared to placebo (adults:

+2.4 beats per minute vs no change with placebo; adolescents: +6.3 beats per minute vs -5.1 beats per

minute with placebo). This increase in heart rate may be related to olanzapine's potential for inducing

orthostatic changes [see Warnings and Precautions (5.7)] .

6.4 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of olanzapine. 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 olanzapine 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, stuttering

, 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.

Stuttering was studied in oral formulations.

7 DRUG INTERACTIONS

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

systematic studies.

7.1 Potential for Other Drugs to Affect Olanzapine

Diazepam — The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension

observed with olanzapine [see Drug Interactions (7.2)] .

Cimetidine and Antacids — Single doses of cimetidine (800 mg) or aluminum- and magnesium-

containing antacids did not affect the oral bioavailability of olanzapine.

Inducers of CYP1A2 — Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in

the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer

of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in

olanzapine clearance.

Alcohol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics.

The co-administration of alcohol (i.e., ethanol) with olanzapine potentiated the orthostatic hypotension

observed with olanzapine [see Drug Interactions (7.2)] .

Inhibitors of CYP1A2

Fluvoxamine: Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a

mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in

male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of

olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine.

Inhibitors of CYP2D6

Fluoxetine: Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%)

increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine

clearance. The magnitude of the impact of this factor is small in comparison to the overall variability

between individuals, and therefore dose modification is not routinely recommended. When using

olanzapine and fluoxetine in combination, also refer to the Drug Interactions section of the package

insert for Symbyax.

Warfarin — Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics [see Drug

Interactions (7.2)] .

Inducers of CYP1A2 or Glucuronyl Transferase — Omeprazole and rifampin may cause an increase in

olanzapine clearance.

Charcoal — The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral

olanzapine by about 60%. As peak olanzapine levels are not typically obtained until about 6 hours after

dosing, charcoal may be a useful treatment for olanzapine overdose.

7.2 Potential for Olanzapine to Affect Other Drugs

CNS Acting Drugs — Given the primary CNS effects of olanzapine, caution should be used when

olanzapine is taken in combination with other centrally acting drugs and alcohol.

Antihypertensive Agents — Olanzapine, because of its potential for inducing hypotension, may enhance

the effects of certain antihypertensive agents.

Levodopa and Dopamine Agonists — Olanzapine may antagonize the effects of levodopa and dopamine

agonists.

Lithium — Multiple doses of olanzapine (10 mg for 8 days) did not influence the kinetics of lithium.

Therefore, concomitant olanzapine administration does not require dosage adjustment of lithium [see

Warnings and Precautions (5.16)] .

Valproate — Olanzapine (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations

of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of

valproate [see Warnings and Precautions (5.16)] .

Effect of Olanzapine on Drug Metabolizing Enzymes — In vitro studies utilizing human liver

microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19,

CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions

mediated by these enzymes.

Imipramine — Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active

metabolite desipramine.

Warfarin — Single doses of olanzapine did not affect the pharmacokinetics of warfarin [see Drug

Interactions (7.1)] .

Diazepam — Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite N-

desmethyldiazepam. However, diazepam co-administered with olanzapine increased the orthostatic

hypotension observed with either drug given alone [see Drug Interactions (7.1)] .

Alcohol — Multiple doses of olanzapine did not influence the kinetics of ethanol [see Drug Interactions

Alcohol — Multiple doses of olanzapine did not influence the kinetics of ethanol [see Drug Interactions

(7.1)] .

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

Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its

metabolites.

8 USE IN SPECIFIC POPULATIONS

When using olanzapine and fluoxetine in combination, also refer to the Use in Specific Populations

section of the package insert for Symbyax.

8.1 Pregnancy

Teratogenic Effects, Pregnancy Category C — In oral reproduction studies in rats at doses up to 18

mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the maximum recommended human

daily oral dose on a mg/m

basis, respectively) no evidence of teratogenicity was observed. In an oral

rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a

dose of 18 mg/kg/day (9 times the maximum recommended human daily oral dose on a mg/m

basis).

Gestation was prolonged at 10 mg/kg/day (5 times the maximum recommended human daily oral dose on

a mg/m

basis). In an oral rabbit teratology study, fetal toxicity (manifested as increased resorptions and

decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the maximum

recommended human daily oral dose on a mg/m

basis). Because animal reproduction studies are not

always predictive of human response, this drug should be used during pregnancy only if the potential

benefit justifies the potential risk to the fetus.

Placental transfer of olanzapine occurs in rat pups.

There are no adequate and well-controlled trials with olanzapine in pregnant females. Seven

pregnancies were observed during clinical trials with olanzapine, including 2 resulting in normal births,

1 resulting in neonatal death due to a cardiovascular defect, 3 therapeutic abortions, and 1 spontaneous

abortion.

Nonteratogenic Effects — Neonates exposed to antipsychotic drugs (including olanzapine), during the

third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following

delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory

distress and feeding disorder in these neonates. These complications have varied in severity; while in

some cases symptoms have been self-limited, in other cases neonates have required intensive care unit

support and prolonged hospitalization.

Olanzapine should be used during pregnancy only if the potential benefit justifies the potential risk to

the fetus.

8.2 Labor and Delivery

The effect of olanzapine on labor and delivery in humans is unknown. Parturition in rats was not affected

by olanzapine.

8.3 Nursing Mothers

In a study in lactating, healthy women, olanzapine was excreted in breast milk. Mean infant dose at steady

state was estimated to be 1.8% of the maternal olanzapine dose. It is recommended that women receiving

olanzapine should not breast-feed.

8.4 Pediatric Use

The safety and effectiveness of oral olanzapine in the treatment of schizophrenia and manic or mixed

episodes associated with bipolar I disorder were established in short-term studies in adolescents (ages

13 to 17 years). Use of olanzapine in adolescents is supported by evidence from adequate and well-

controlled studies of olanzapine in which 268 adolescents received olanzapine in a range of 2.5 to 20

mg/day [see Clinical Studies (14.1, 14.2)] . Recommended starting dose for adolescents is lower than that

for adults [see Dosage and Administration (2.1, 2.2)] . Compared to patients from adult clinical trials,

adolescents were likely to gain more weight, experience increased sedation, and have greater increases

in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels [see

Warnings and Precautions (5.5, 5.15, 5.17) and Adverse Reactions (6.3)] . 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 [see Indications and Usage (1.1, 1.2)] .

Safety and effectiveness of olanzapine in children <13 years of age have not been established [see

Patient Counseling Information (17.14)] .

Safety and efficacy of olanzapine and fluoxetine in combination in children and adolescents (10 to 17

years of age) have been established for the acute treatment of depressive episodes associated with

bipolar I disorder.

Safety and effectiveness of olanzapine and fluoxetine in combination in children <10 years of age have

not been established.

8.5 Geriatric Use

Of the 2500 patients in premarketing clinical studies with oral olanzapine, 11% (263) were 65 years of

age or over. In patients with schizophrenia, there was no indication of any different tolerability of

olanzapine in the elderly compared to younger patients. Studies in elderly patients with dementia-related

psychosis have suggested that there may be a different tolerability profile in this population compared

to younger patients with schizophrenia. Elderly patients with dementia-related psychosis treated with

olanzapine are at an increased risk of death compared to placebo. In placebo-controlled studies of

olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of

cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with

olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of

patients with dementia-related psychosis. Also, the presence of factors that might decrease

pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to

consideration of a lower starting dose for any geriatric patient [see Boxed Warning, Dosage and

Administration (2.1), and Warnings and Precautions (5.1)] .

Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of

patients ≥65 years of age to determine whether they respond differently from younger patients.

9 DRUG ABUSE AND DEPENDENCE

9.3 Dependence

In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to

have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats

have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats

administered oral doses up to 15 times the maximum recommended human daily oral dose (20 mg) and

rhesus monkeys administered oral doses up to 8 times the maximum recommended human daily oral dose

on a mg/m

basis.

Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or

physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking

behavior, these observations were not systematic, and it is not possible to predict on the basis of this

limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once

marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such

patients should be observed closely for signs of misuse or abuse of olanzapine (e.g., development of

tolerance, increases in dose, drug-seeking behavior).

10 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 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.

11 DESCRIPTION

Olanzapine, USP is an atypical antipsychotic that belongs to the thienobenzodiazepine class. The

chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10 H-thieno[2,3- b] [1,5]benzodiazepine.

The molecular formula is C

S, which corresponds to a molecular weight of 312.44. The

chemical structure is:

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

Olanzapine tablets, USP are intended for oral administration only.

Each tablet contains olanzapine equivalent to 2.5 mg (8 micromol), 5 mg (16 micromol), 7.5 mg (24

micromol), 10 mg (32 micromol), 15 mg (48 micromol), or 20 mg (64 micromol). Inactive ingredients

are crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline

cellulose, Opadry

03A18286 (Hypromellose, Titanium Dioxide and Sodium Lauryl Sulfate) for 2.5

mg, 5 mg, 7.5 mg and 10 mg tablets, Opadry

03A605003 (Hypromellose, Titanium Dioxide, FD&C

Blue #2/Indigo Carmine Aluminum Lake and FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake) for

15 mg tablets and Opadry

03A640001 (Hypromellose, Titanium Dioxide, Talc and Iron Oxide Red)

for 20 mg tablets.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of olanzapine, as with other drugs having efficacy in schizophrenia, is

unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through

a combination of dopamine and serotonin type 2 (5HT

) antagonism. The mechanism of action of

olanzapine in the treatment of acute manic or mixed episodes associated with bipolar I disorder is

unknown.

12.2 Pharmacodynamics

Olanzapine binds with high affinity to the following receptors: serotonin 5HT

, 5HT

(K =4, 11,

and 5 nM, respectively), dopamine D

(K =11-31 nM), histamine H

(K =7 nM), and adrenergic α

receptors (K =19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT

2A/2C

(K =57 nM) and muscarinic M

(K =73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds

weakly to GABA

, BZD, and β-adrenergic receptors (K >10 μM).

Antagonism at receptors other than dopamine and 5HT

may explain some of the other therapeutic and

side effects of olanzapine. Olanzapine's antagonism of muscarinic M

receptors may explain its

anticholinergic-like effects. Olanzapine's antagonism of histamine H

receptors may explain the

somnolence observed with this drug. Olanzapine's antagonism of adrenergic α

receptors may explain

the orthostatic hypotension observed with this drug.

12.3 Pharmacokinetics

Oral Administration, Monotherapy — Olanzapine is well absorbed and reaches peak concentrations in

approximately 6 hours following an oral dose. It is eliminated extensively by first pass metabolism, with

approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not

affect the rate or extent of olanzapine absorption.

Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54

hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr

(5th to 95th percentile; mean of 25 L/hr).

Administration of olanzapine once daily leads to steady-state concentrations in about 1 week that are

approximately twice the concentrations after single doses. Plasma concentrations, half-life, and

clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age.

Olanzapine is extensively distributed throughout the body, with a volume of distribution of

approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100

ng/mL, binding primarily to albumin and α

-acid glycoprotein.

Metabolism and Elimination — Following a single oral dose of

C labeled olanzapine, 7% of the dose

of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly

metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces,

respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity,

indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites

were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4´-N-

desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites

lack pharmacological activity at the concentrations observed.

Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic

pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin-containing

monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be

a minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who

are deficient in this enzyme.

Specific Populations

Renal Impairment — Because olanzapine is highly metabolized before excretion and only 7% of the

drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact on the

pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in

patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon

the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The

effect of renal impairment on metabolite elimination has not been studied.

Hepatic Impairment — Although the presence of hepatic impairment may be expected to reduce the

clearance of olanzapine, a study of the effect of impaired liver function in subjects (n=6) with clinically

clearance of olanzapine, a study of the effect of impaired liver function in subjects (n=6) with clinically

significant (Childs Pugh Classification A and B) cirrhosis revealed little effect on the pharmacokinetics

of olanzapine.

Geriatric — In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was

about 1.5 times greater in elderly (≥65 years) than in nonelderly subjects (<65 years). Caution should be

used in dosing the elderly, especially if there are other factors that might additively influence drug

metabolism and/or pharmacodynamic sensitivity [see Dosage and Administration (2)] .

Gender — Clearance of olanzapine is approximately 30% lower in women than in men. There were,

however, no apparent differences between men and women in effectiveness or adverse effects. Dosage

modifications based on gender should not be needed.

Smoking Status — Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although

dosage modifications are not routinely recommended.

Race — In vivo studies have shown that exposures are similar among Japanese, Chinese and

Caucasians, especially after normalization for body weight differences. Dosage modifications for race

are, therefore, not recommended.

Combined Effects — The combined effects of age, smoking, and gender could lead to substantial

pharmacokinetic differences in populations. The clearance in young smoking males, for example, may

be 3 times higher than that in elderly nonsmoking females. Dosing modification may be necessary in

patients who exhibit a combination of factors that may result in slower metabolism of olanzapine [see

Dosage and Administration (2)] .

Adolescents (ages 13 to 17 years) — In clinical studies, most adolescents were nonsmokers and this

population had a lower average body weight, which resulted in higher average olanzapine exposure

compared to adults.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis — Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was

administered to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8 to 5

times the maximum recommended human daily oral dose on a mg/m

basis) and 0.25, 2, 8 mg/kg/day

(equivalent to 0.06 to 2 times the maximum recommended human daily oral dose on a mg/m

basis). Rats

were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25, 1, 4, 8 mg/kg/day

(females) (equivalent to 0.13 to 2 and 0.13 to 4 times the maximum recommended human daily oral dose

on a mg/m

basis, respectively). The incidence of liver hemangiomas and hemangiosarcomas was

significantly increased in 1 mouse study in female mice dosed at 8 mg/kg/day (2 times the maximum

recommended human daily oral dose on a mg/m

basis). These tumors were not increased in another

mouse study in females dosed at 10 or 30/20 mg/kg/day (2 to 5 times the maximum recommended human

daily oral dose on a mg/m

basis); in this study, there was a high incidence of early mortalities in males

of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was

significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4 mg/kg/day

(0.5 and 2 times the maximum recommended human daily oral dose on a mg/m

basis, respectively).

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin

levels were not measured during the olanzapine carcinogenicity studies; however, measurements during

subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats

at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been

found in rodents after chronic administration of other antipsychotic drugs and is considered to be

prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumors

in rodents is unknown [see Warnings and Precautions (5.15)] .

Mutagenesis — No evidence of genotoxic potential for olanzapine was found in the Ames reverse

mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster

ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in

mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters.

Impairment of Fertility — In an oral fertility and reproductive performance study in rats, male mating

performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was

decreased at a dose of 3 mg/kg/day (11 and 1.5 times the maximum recommended human daily oral dose

on a mg/m

basis, respectively). Discontinuance of olanzapine treatment reversed the effects on male

mating performance. In female rats, the precoital period was increased and the mating index reduced at 5

mg/kg/day (2.5 times the maximum recommended human daily oral dose on a mg/m

basis). Diestrous

was prolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the maximum recommended human daily

oral dose on a mg/m

basis); therefore olanzapine may produce a delay in ovulation.

13.2 Animal Toxicology and/or Pharmacology

In animal studies with olanzapine, the principal hematologic findings were reversible peripheral

cytopenias in individual dogs dosed at 10 mg/kg (17 times the maximum recommended human daily oral

dose on a mg/m

basis), dose-related decreases in lymphocytes and neutrophils in mice, and

lymphopenia in rats. A few dogs treated with 10 mg/kg developed reversible neutropenia and/or

reversible hemolytic anemia between 1 and 10 months of treatment. Dose-related decreases in

lymphocytes and neutrophils were seen in mice given doses of 10 mg/kg (equal to 2 times the maximum

recommended human daily oral dose on a mg/m

basis) in studies of 3 months' duration. Nonspecific

lymphopenia, consistent with decreased body weight gain, occurred in rats receiving 22.5 mg/kg (11

times the maximum recommended human daily oral dose on a mg/m

basis) for 3 months or 16 mg/kg (8

times the maximum recommended human daily oral dose on a mg/m

basis) for 6 or 12 months. No

evidence of bone marrow cytotoxicity was found in any of the species examined. Bone marrows were

normocellular or hypercellular, indicating that the reductions in circulating blood cells were probably

due to peripheral (non-marrow) factors.

14 CLINICAL STUDIES

When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the

package insert for Symbyax.

14.1 Schizophrenia

Adults

The efficacy of oral olanzapine in the treatment of schizophrenia was established in 2 short-term (6-

week) controlled trials of adult inpatients who met DSM III-R criteria for schizophrenia. A single

haloperidol arm was included as a comparative treatment in 1 of the 2 trials, but this trial did not

compare these 2 drugs on the full range of clinically relevant doses for both.

Several instruments were used for assessing psychiatric signs and symptoms in these studies, among

them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology

traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis

cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought

content) is considered a particularly useful subset for assessing actively psychotic schizophrenic

patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression

of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical

state of the patient. In addition, 2 more recently developed scales were employed; these included the 30-

item Positive and Negative Symptoms Scale (PANSS), in which are embedded the 18 items of the BPRS,

and the Scale for Assessing Negative Symptoms (SANS). The trial summaries below focus on the

following outcomes: PANSS total and/or BPRS total; BPRS psychosis cluster; PANSS negative

subscale or SANS; and CGI Severity. The results of the trials follow:

(1) In a 6-week, placebo-controlled trial (n=149) involving 2 fixed olanzapine doses of 1 and 10 mg/day

(once daily schedule), olanzapine, at 10 mg/day (but not at 1 mg/day), was superior to placebo on the

PANSS total score (also on the extracted BPRS total), on the BPRS psychosis cluster, on the PANSS

Negative subscale, and on CGI Severity.

(2) In a 6-week, placebo-controlled trial (n=253) involving 3 fixed dose ranges of olanzapine (5 ± 2.5

mg/day, 10 ± 2.5 mg/day, and 15 ± 2.5 mg/day) on a once daily schedule, the 2 highest olanzapine dose

groups (actual mean doses of 12 and 16 mg/day, respectively) were superior to placebo on BPRS total

score, BPRS psychosis cluster, and CGI severity score; the highest olanzapine dose group was

superior to placebo on the SANS. There was no clear advantage for the high-dose group over the

medium-dose group.

(3) In a longer-term trial, adult outpatients (n=326) who predominantly met DSM-IV criteria for

schizophrenia and who remained stable on olanzapine during open-label treatment for at least 8 weeks

were randomized to continuation on their current olanzapine doses (ranging from 10 to 20 mg/day) or to

placebo. The follow-up period to observe patients for relapse, defined in terms of increases in BPRS

positive symptoms or hospitalization, was planned for 12 months, however, criteria were met for

stopping the trial early due to an excess of placebo relapses compared to olanzapine relapses, and

olanzapine was superior to placebo on time to relapse, the primary outcome for this study. Thus,

olanzapine was more effective than placebo at maintaining efficacy in patients stabilized for

approximately 8 weeks and followed for an observation period of up to 8 months.

Examination of population subsets (race and gender) did not reveal any differential responsiveness on

the basis of these subgroupings.

Adolescents

The efficacy of oral olanzapine in the acute treatment of schizophrenia in adolescents (ages 13 to 17

years) was established in a 6-week double-blind, placebo-controlled, randomized trial of inpatients and

outpatients with schizophrenia (n=107) who met diagnostic criteria according to DSM-IV-TR and

confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged

Children-Present and Lifetime Version (K-SADS-PL).

The primary rating instrument used for assessing psychiatric signs and symptoms in this trial was the

Anchored Version of the Brief Psychiatric Rating Scale for Children (BPRS-C) total score.

In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 12.5 mg/day, mean dose of 11.1

mg/day) was more effective than placebo in the treatment of adolescents diagnosed with schizophrenia,

as supported by the statistically significantly greater mean reduction in BPRS-C total score for patients

in the olanzapine treatment group than in the placebo group.

While there is no body of evidence available to answer the question of how long the adolescent patient

treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data

along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. It is

generally recommended that responding patients be continued beyond the acute response, but at the

lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the

need for maintenance treatment.

14.2 Bipolar I Disorder (Manic or Mixed Episodes)

Adults

Monotherapy — The efficacy of oral olanzapine in the treatment of manic or mixed episodes was

established in 2 short-term (one 3-week and one 4-week) placebo-controlled trials in adult patients who

met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included

patients with or without psychotic features and with or without a rapid-cycling course.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania

Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic

symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased

activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range

from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change

from baseline in the Y-MRS total score. The results of the trials follow:

(1) In one 3-week placebo-controlled trial (n=67) which involved a dose range of olanzapine (5 to 20

mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-

MRS total score. In an identically designed trial conducted simultaneously with the first trial, olanzapine

demonstrated a similar treatment difference, but possibly due to sample size and site variability, was not

shown to be superior to placebo on this outcome.

(2) In a 4-week placebo-controlled trial (n=115) which involved a dose range of olanzapine (5 to 20

mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-

MRS total score.

(3) In another trial, 361 patients meeting DSM-IV criteria for a manic or mixed episode of bipolar I

disorder who had responded during an initial open-label treatment phase for about 2 weeks, on average,

to olanzapine 5 to 20 mg/day were randomized to either continuation of olanzapine at their same dose

(n=225) or to placebo (n=136), for observation of relapse. Approximately 50% of the patients had

discontinued from the olanzapine group by day 59 and 50% of the placebo group had discontinued by

day 23 of double-blind treatment. Response during the open-label phase was defined by having a

decrease of the Y-MRS total score to ≤12 and HAM-D 21 to ≤8. Relapse during the double-blind phase

was defined as an increase of the Y-MRS or HAM-D 21 total score to ≥15, or being hospitalized for

either mania or depression. In the randomized phase, patients receiving continued olanzapine

experienced a significantly longer time to relapse.

Adjunct to Lithium or Valproate — The efficacy of oral olanzapine with concomitant lithium or

valproate in the treatment of manic or mixed episodes was established in 2 controlled trials in patients

who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials

included patients with or without psychotic features and with or without a rapid-cycling course. The

results of the trials follow:

(1) In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy

with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either

olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5 to 20

mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of

0.6 mEq/L to 1.2 mEq/L or 50 mcg/mL to 125 mcg/mL, respectively) was superior to lithium or

valproate alone in the reduction of Y-MRS total score.

(2) In a second 6-week placebo-controlled combination trial, 169 outpatients on lithium or valproate

(2) In a second 6-week placebo-controlled combination trial, 169 outpatients on lithium or valproate

therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to

receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose

range of 5 to 20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a

therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 mcg/mL to 125 mcg/mL, respectively) was superior

to lithium or valproate alone in the reduction of Y-MRS total score.

Adoles cents

Acute Monotherapy — The efficacy of oral olanzapine in the treatment of acute manic or mixed

episodes in adolescents (ages 13 to 17 years) was established in a 3-week, double-blind, placebo-

controlled, randomized trial of adolescent inpatients and outpatients who met the diagnostic criteria for

manic or mixed episodes associated with bipolar I disorder (with or without psychotic features)

according to the DSM-IV-TR (n=161). Diagnosis was confirmed by the K-SADS-PL.

The primary rating instrument used for assessing manic symptoms in this trial was the Adolescent

Structured Young-Mania Rating Scale (Y-MRS) total score.

In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 10.7 mg/day, mean dose of 8.9

mg/day) was more effective than placebo in the treatment of adolescents with manic or mixed episodes

associated with bipolar I disorder, as supported by the statistically significantly greater mean reduction

in Y-MRS total score for patients in the olanzapine treatment group than in the placebo group.

While there is no body of evidence available to answer the question of how long the adolescent patient

treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data

along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. It is

generally recommended that responding patients be continued beyond the acute response, but at the

lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the

need for maintenance treatment.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Olanzapine tablets, USP 2.5 mg, 5 mg, 7.5 mg, and 10 mg are white, round, unscored, film-coated tablets,

debossed with tablet number on one side and plain on the other side. Olanzapine tablets, USP 15 mg are

blue, elliptical, unscored, film-coated tablets, debossed with tablet number on one side and plain on the

other side. Olanzapine tablets, USP 20 mg are pink, elliptical, unscored, film-coated tablets, debossed

with tablet number on one side and plain on the other side. The tablets are available as follows:

TABLET

STRENGTH

2.5 mg

5 mg

7.5 mg

10 mg

15 mg

20 mg

Identification

NDC codes:

Bottle 30

NDC 69543-

380-30

NDC 69543-

381-30

NDC 69543-

382-30

NDC 69543-

383-30

NDC 69543-

384-30

NDC 69543-

385-30

Bottle 90

NDC 69543-

380-90

NDC 69543-

381-90

NDC 69543-

382-90

NDC 69543-

383-90

NDC 69543-

384-90

NDC 69543-

385-90

16.2 Storage and Handling

Store olanzapine tablets at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. The USP

defines controlled room temperature as a temperature maintained thermostatically that encompasses the

usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic

temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C

(59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses.

Protect olanzapine tablets from light and moisture.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Medication Guide for the oral formulations.

Patients should be advised of the following issues and asked to alert their prescriber if these occur

while taking olanzapine as monotherapy or in combination with fluoxetine. If you do not think you are

getting better or have any concerns about your condition while taking olanzapine, call your doctor.

When using olanzapine and fluoxetine in combination, also refer to the Patient Counseling Information

section of the package insert for Symbyax.

17.1 Information on Medication Guide

Prescribers or other health professionals should inform patients, their families, and their caregivers

about the potential benefits and potential risks associated with treatment with olanzapine, and should

counsel them in its appropriate use. A patient Medication Guide is available for olanzapine. Prescribers

or other health professionals should instruct patients, their families, and their caregivers to read the

Medication Guide and should assist them in understanding its contents. Patients should be given the

opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they

may have. When using olanzapine and fluoxetine in combination, also refer to the Medication Guide for

Symbyax.

17.2 Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular

Adverse Events (CVAE), Including Stroke

Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated

with antipsychotic drugs are at an increased risk of death. Patients and caregivers should be advised that

elderly patients with dementia-related psychosis treated with olanzapine had a significantly higher

incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with

placebo.

Olanzapine is not approved for elderly patients with dementia-related psychosis [see Boxed Warning and

Warnings and Precautions (5.1)] .

17.3 Neuroleptic Malignant Syndrome (NMS)

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes

referred to as NMS has been reported in association with administration of antipsychotic drugs,

including olanzapine. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental

status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia,

diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)] .

17.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Patients should be advised to report to their health care provider at the earliest onset of any signs and

symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms

(DRESS) [see Warnings and Precautions (5.4)] .

17.5 Hyperglycemia and Diabetes Mellitus

Patients should be advised of the potential risk of hyperglycemia-related adverse reactions. Patients

should be monitored regularly for worsening of glucose control. Patients who have diabetes should

follow their doctor's instructions about how often to check their blood sugar while taking olanzapine

[see Warnings and Precautions (5.5)] .

17.6 Dyslipidemia

Patients should be counseled that dyslipidemia has occurred during treatment with olanzapine. Patients

should have their lipid profile monitored regularly [see Warnings and Precautions (5.5)] .

17.7 Weight Gain

Patients should be counseled that weight gain has occurred during treatment with olanzapine. Patients

should have their weight monitored regularly [see Warnings and Precautions (5.5)] .

17.8 Orthostatic Hypotension

Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial

dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic

effect of olanzapine, e.g., diazepam or alcohol [see Warnings and Precautions (5.7) and Drug

Interactions (7)] . Patients should be advised to change positions carefully to help prevent orthostatic

hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised

to call their doctor if they experience any of the following signs and symptoms associated with

orthostatic hypotension: dizziness, fast or slow heartbeat, or fainting.

17.9 Potential for Cognitive and Motor Impairment

Because 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 Warnings and Precautions (5.12)] .

17.10 Body Temperature Regulation

Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients

should be advised to call their doctor right away if they become severely ill and have some or all of

these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling

thirsty, not able to produce urine [see Warnings and Precautions (5.13)] .

17.11 Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, Symbyax. Patients

should also be advised to inform their physicians if they are taking, plan to take, or have stopped taking

any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for

interactions [see Drug Interactions (7)] .

17.12 Alcohol

Patients should be advised to avoid alcohol while taking olanzapine [see Drug Interactions (7)] .

17.14 Use in Specific Populations

Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to

become pregnant during therapy with olanzapine [see Use in Specific Populations (8.1)] .

Nursing Mothers — Patients should be advised not to breast-feed an infant if they are taking olanzapine

[see Use in Specific Populations (8.3)] .

Pediatric Use — Olanzapine is indicated for treatment of schizophrenia and manic or mixed episodes

associated with bipolar I disorder in adolescents 13 to 17 years of age. Compared to patients from adult

clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have

greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin, and hepatic

aminotransferase levels. Patients should be counseled about the potential long-term risks associated

with olanzapine and advised that these risks may lead them to consider other drugs first [see Indications

and Usage (1.1, 1.2)]. Safety and effectiveness of olanzapine in patients under 13 years of age have not

been established. Safety and efficacy of olanzapine and fluoxetine in combination in patients 10 to 17

years of age have been established for the acute treatment of depressive episodes associated with

bipolar I disorder. Safety and effectiveness of olanzapine and fluoxetine in combination in patients <10

years of age have not been established [see Warnings and Precautions (5.5) and Use in Specific

Populations (8.4)].

17.15 Need for Comprehensive Treatment Program in Pediatric Patients

Olanzapine is indicated as an integral part of a total treatment program for pediatric patients with

schizophrenia and bipolar disorder that may include other measures (psychological, educational, social)

for patients with the disorder. Effectiveness and safety of olanzapine have not been established in

pediatric patients less than 13 years of age. Atypical antipsychotics are not intended for use in the

pediatric patient who exhibits symptoms secondary to environmental factors and/or other primary

psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is

often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the

physician's assessment of the chronicity and severity of the patient's symptoms [see Indications and

Usage (1.3)].

Symbyax

is a registered trademark of Eli Lilly and Company

Distributed by:

Virtus Pharmaceuticals, LLC

Langhorne, PA 19047, USA

1-888-848-3593

Manufactured by:

Qilu Pharmaceutical Co., Ltd.

Jinan, 250101, China

Revised: 08/2018

34040047211C

Medication Guide

Olanzapine (oh lan' za peen) Tablets, USP

Read the Medication Guide that comes with olanzapine tablets before you start taking them 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 olanzapine tablets.

What is the most important information I should know about olanzapine tablets?

Olanzapine tablets 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). Olanzapine tablets are 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 olanzapine tablets and

during treatment. In people who do not have diabetes, sometimes high blood sugar goes away when

olanzapine tablets are stopped. People with diabetes and some people who did not have diabetes before

taking olanzapine tablets need to take medicine for high blood sugar even after they stop taking

olanzapine tablets.

If you have diabetes, follow your doctor's instructions about how often to check your blood sugar

while taking olanzapine tablets.

Call your doctor if you have any of these symptoms of high blood sugar (hyperglycemia) while taking

olanzapine tablets:

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 olanzapine tablets, 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 olanzapine

tablets and during treatment.

4. Weight gain. Weight gain is very common in people who take olanzapine tablets. 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 olanzapine is used in

combination with fluoxetine. Some people may gain a lot of weight while taking olanzapine tablets, 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 are olanzapine tablets?

Olanzapine tablets are 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.

Olanzapine tablets have not been approved for use in children under 13 years of age. Olanzapine 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 olanzapine tablets?

Olanzapine tablets may not be right for you. Before starting olanzapine tablets, 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

breast cancer

thoughts of suicide or hurting yourself

any other medical condition

are pregnant or plan to become pregnant. It is not known if olanzapine tablets will harm your unborn

baby.

are breast-feeding or plan to breast-feed. Olanzapine can pass into your breast milk and may harm

your baby. You should not breast-feed while taking olanzapine tablets. Talk to your doctor about the

best way to feed your baby if you take olanzapine tablets.

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. Olanzapine tablets 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 olanzapine tablets with your other medicines. Do not start or stop any medicine while

taking olanzapine tablets without talking to your doctor first.

How should I take olanzapine tablets?

Take olanzapine tablets exactly as prescribed. Your doctor may need to change (adjust) the dose of

olanzapine tablets until it is right for you.

If you miss a dose of olanzapine tablets, 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 olanzapine tablets at the same time.

To prevent serious side effects, do not stop taking olanzapine tablets suddenly. If you need to

stop taking olanzapine tablets, your doctor can tell you how to safely stop taking them.

If you take too much olanzapine tablets, call your doctor or poison control center at 1-800-

222-1222 right away, or get emergency treatment.

Olanzapine tablets can be taken with or without food.

Olanzapine tablets are usually taken one time each day.

Call your doctor if you do not think you are getting better or have any concerns about your condition

while taking olanzapine tablets.

What should I avoid while taking olanzapine tablets?

Olanzapine tablets 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 olanzapine tablets affect you.

Avoid drinking alcohol while taking olanzapine tablets. Drinking alcohol while you take olanzapine

tablets may make you sleepier than if you take olanzapine tablets alone.

What are the possible side effects of olanzapine tablets?

Serious side effects may happen when you take olanzapine tablets, including:

See "What is the most important information I should know about olanzapine tablets?", 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). Olanzapine tablets are 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 olanzapine tablets. 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

olanzapine tablets. 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 olanzapine tablets. It may also start after you stop taking olanzapine

tablets. 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 olanzapine tablets.

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 olanzapine tablets 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 to 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 olanzapine tablets. 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 olanzapine tablets?

Store olanzapine tablets at room temperature, between 68° to 77°F (20° to 25°C).

Keep olanzapine tablets away from light.

Keep olanzapine tablets dry and away from moisture.

Keep olanzapine tablets and all medicines out of the reach of children.

General information about olanzapine tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use olanzapine tablets for a condition for which it was not prescribed. Do not give olanzapine tablets to

other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about olanzapine tablets. If you

would like more information, talk with your doctor. You can ask your doctor or pharmacist for

information about olanzapine tablets that was written for healthcare professionals. For more information

about olanzapine tablets call 1-888-848-3593.

What are the ingredients in olanzapine tablets?

Active ingredient: olanzapine, USP

Inactive ingredients: crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium

stearate, microcrystalline cellulose.

Film coating: Opadry

03A18286 (Hypromellose, Titanium Dioxide and Sodium Lauryl Sulfate),

Opadry

03A605003 (Hypromellose, Titanium Dioxide, FD&C Blue #2/Indigo Carmine Aluminum

Lake and FD&C Yellow #6/ Sunset Yellow FCF Aluminum Lake) or Opadry

03A640001

(Hypromellose, Titanium Dioxide, Talc and Iron Oxide Red).

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:

Virtus Pharmaceuticals, LLC

Langhorne, PA 19047, USA

1-888-848-3593

Manufactured by:

Qilu Pharmaceutical Co., Ltd.

Jinan, 250101, China

Revised: 08/2018

340311000380

PRINCIPAL DISPLAY PANEL

DRUG: Olanzapine

GENERIC: Olanzapine

DOSAGE: TABLET

ADMINSTRATION: ORAL

NDC: 70518-2299-0

COLOR: white

SHAPE: ROUND

SCORE: No score

SIZE: 10 mm

IMPRINT: 14

PACKAGING: 30 in 1 BLISTER PACK

ACTIVE INGREDIENT(S):

OLANZAPINE 10mg in 1

INACTIVE INGREDIENT(S):

CROSPOVIDONE, UNSPECIFIED

TITANIUM DIOXIDE

HYPROMELLOSE 2910 (6 MPA.S)

MICROCRYSTALLINE CELLULOSE

HYDROXYPROPYL CELLULOSE, UNSPECIFIED

LACTOSE MONOHYDRATE

MAGNESIUM STEARATE

SODIUM LAURYL SULFATE

OLANZAPINE

olanzapine tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:70 518 -229 9 (NDC:6 9 543-38 3)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

O LANZAPINE (UNII: N7U6 9 T4SZR) (OLANZAPINE - UNII:N7U6 9 T4SZR)

OLANZAPINE

10 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CRO SPO VIDO NE, UNSPECIFIED (UNII: 2S78 30 E56 1)

HYDRO XYPRO PYL CELLULO SE, UNSPECIFIED (UNII: 9 XZ8 H6 N6 OH)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

HYPRO MELLO SE 2 9 10 ( 6 MPA.S) (UNII: 0 WZ8 WG20 P6 )

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

REMEDYREPACK INC.

Product Characteristics

Color

white

S core

no sco re

S hap e

ROUND (Bico nvex)

S iz e

10 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:70 518 -229 9 -

30 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 4/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 4319

0 9 /0 4/20 19

Labeler -

REMEDYREPACK INC. (829572556)

Revised: 9/2019

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