ZYPREXA VELOTAB 5 MG

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Patient leaflet in accordance with the Pharmacists' Regulations (Preparations) - 1986

This medicine is to be supplied by a doctor’s prescription only

Zyprexa Velotab

5 mg

Orodispersible tablets

Composition:

Each orodispersible tablet contains:

olanzapine 5 mg

Zyprexa Velotab

10 mg

Orodispersible tablets

Composition:

Each orodispersible tablet contains:

olanzapine 10 mg

Inactive ingredients and allergens: See Chapter 6 “Additional information” and Section “Important

information regarding some of the ingredients of this medicine” in Chapter 2.

Read the entire leaflet carefully before you start using this medicine. This leaflet contains

concise information about this medicine. If you have any further questions, refer to the doctor or

pharmacist.

This medicine has been prescribed to treat your illness. Do not pass it on to others. It may harm

them even if it seems to you that their illness is similar.

Vital information about this medicine:

Antipsychotics (like Zyprexa Velotab) can increase the risk of death in elderly people who are

experiencing confusion, memory loss, and loss of touch with reality (dementia-related

psychosis). This medicine is not intended for adult patients who suffer from dementia-related

psychosis.

Zyprexa

Velotab

is intended for adults over 18 years of age.

1.

WHAT IS THIS MEDICINE INTENDED FOR?

Zyprexa Velotab is an antipsychotic agent for the treatment of schizophrenic patients and

symptoms of psychotic disorders.

In addition, it is intended for the treatment of bipolar affective disorder (BIPOLAR I).

Therapeutic group:

Atypical antipsychotic medicines.

The symptoms of schizophrenia include hearing voices, seeing things that do not exist,

believing in things that are not true, suspicion and disconnection.

The symptoms of bipolar I disorder include intermittent periods of depression and uplifted

mood or nervousness, increased activity and restlessness, racing thoughts, rapid speech,

changes in appetite, impulsive behavior, and 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.

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2.

BEFORE USING THIS MEDICINE:

Do not use this medicine if:

you are sensitive to olanzapine or to any of the other ingredients that this medicine

contains.

For specific information on the contraindications of lithium or valproate, refer to the

Contraindications section of the package inserts included in the packs of those products.

Special warnings regarding the use of this medicine:

Zyprexa Velotab interferes with the body's ability to reduce temperature. Situations in which

there may be an increase in body temperature and dehydration, such as increased physical

activity or frequent stays in hot places, should be avoided. Be sure to drink fluids to prevent

dehydration.

Zyprexa Velotab may cause low blood pressure upon transition from a lying to sitting

position. The symptoms include: dizziness, slow or rapid heart rate, and even fainting in

some patients. This side effect usually occurs at the beginning of treatment.

Zyprexa Velotab can cause drowsiness, low blood pressure upon transition from a

lying to sitting position, and motor and sensory instability that can lead to falls

resulting in fractures and other injuries. Use with caution and consider the risks against

the benefits in patients with underlying conditions or who are taking medicines that may

increase the risk of falls.

Weight gain has been observed in patients taking Zyprexa Velotab. Weight should be

monitored regularly.

Blood sugar and lipid levels should be monitored since Zyprexa Velotab may cause an

increase in these parameters.

In patients with a medical history of low levels of white blood cells, blood count tests should

be regularly performed during the first months of treatment for follow up. Zyprexa Velotab

may cause a decrease in the levels of white blood cells. Discontinuation of Zyprexa Velotab

treatment should be considered upon appearance of the first symptom of this condition.

Patients with reduced levels of white blood cells must be monitored for symptoms indicating

infection or fever. If any of these are experienced, immediately discontinue the treatment with

Zyprexa Velotab.

Taking Zyprexa Velotab is not recommended for elderly patients suffering from dementia

due to the probability of severe side effects: falls, drowsiness, peripheral edema, abnormal

walking, urinary incontinence, extreme tiredness, weight gain, weakness, fever, pneumonia,

dry mouth, visual hallucinations, stroke and death.

Patients with schizophrenia and bipolar disorders are at a greater risk of attempted suicide.

Therefore, these patients must be closely monitored while being treated with Zyprexa

Velotab.

Caution should be exercised in patients who have suffered or are currently suffering from

urinary retention, prostate enlargement, constipation or a history of intestinal obstruction, as

the use of Zyprexa Velotab in these patients may cause symptoms such as constipation, dry

mouth and tachycardia. From experience gained after marketing the drug, it was found that

the risk of serious side effects (including deaths) increased when combining Zyprexa

Velotab with anticholinergic drugs.

Before treatment with Zyprexa Velotab tell your doctor if you:

suffer or have previously suffered from cardiac dysfunction.

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suffer or have previously suffered from a stroke or "mini stroke” (temporary symptoms of

stroke).

suffer from problems with the liver, gastrointestinal system (such as bowel obstruction).

suffer from Alzheimer's disease, breast cancer.

experience suicidal thoughts or harming yourself. In this case you should contact a doctor or

Emergency Room immediately.

suffer or have previously suffered from enlargement of the prostate gland.

suffer or have previously suffered from seizures, diabetes or high blood glucose levels, high

or low blood pressure, high blood levels of cholesterol or triglycerides.

exercises a lot or stay in hot places often.

have a history of drug abuse.

are sensitive to a certain type of food or medicine.

suffer from phenylketonuria – Zyprexa Velotab contains phenylalanine (aspartame).

suffer from any other medical condition.

Smoking:

If you smoke - inform your doctor prior to beginning treatment with this medicine.

Tests and follow-up;

At the beginning and during treatment, blood glucose levels should be monitored, especially

if you have diabetes or borderline glucose levels (fasting levels of 100-126 mg/dL)

You should monitor the levels of fats (cholesterol and triglycerides) in the blood, especially in

patients with impaired blood lipid levels or risk factors of developing such disorders. Blood

tests for blood lipids should be performed at the beginning and during treatment even if you

do not have any symptoms.

Weight gain is a common side effect of treatment with Zyprexa Velotab. This should be

taken into account prior to beginning the treatment and weight should be routinely monitored.

In patients with a history of low white blood cell levels, white blood cell levels should be

monitored during the first months of treatment. Discontinuation of treatment with Zyprexa

Velotab should be considered upon appearance of the first significant symptom indicating

reduced white blood cell levels.

Drug interactions:

If you are taking or have recently taken other medicines, including over-the-counter

medications and food supplements, inform your doctor or pharmacist. Especially if you

are taking:

Diazepam: co-administration of Zyprexa Velotab and diazepam may cause low blood

pressure upon transition from a lying to sitting position (orthostatic hypotension).

Medicines affecting the CYP1A2 enzyme, such as carbamazepine, fluvoxamine,

omeprazole and rifampicin – may affect the levels of olanzapine in the blood.

Medicines containing activated charcoal – may reduce the absorption of olanzapine.

Medicines affecting the central nervous system such as sedatives, antidepressants and

sleep medications, anti-epileptic medicines – care should be taken upon concomitant

administration of these medicines and olanzapine.

Medicines used to reduce high blood pressure – olanzapine may enhance the blood

pressure lowering effect upon concomitant administration with these medicines.

Medicines that mimic the action of dopamine (such as Levodopa, a drug for the

treatment of Parkinson's disease) - olanzapine may inhibit the activity of these

medicines.

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Anticholinergic drugs - their combination with Zyprexa Velotab may increase the risk of

serious gastrointestinal side effects resulting from decreased gastrointestinal motility.

Use of this medicine and food

Zyprexa Velotab may be taken with or without food.

Use of this medicine and alcohol consumption:

Avoid alcohol consumption while using Zyprexa Velotab. Drinking alcohol while taking Zyprexa

Velotab may make you more sleepy compared to taking Zyprexa Velotab without alcohol.

Pregnancy, breastfeeding and fertility:

Pregnancy

Consult a doctor or pharmacist before taking this medicine.

Consult a doctor if you are pregnant or planning to get pregnant. It is not known whether

Zyprexa Velotab harms the fetus. Newborns may develop a withdrawal syndrome if the mother

has taken the medicine during the last trimester (last 3 months) of pregnancy. The withdrawal

syndrome includes the following symptoms: restlessness, tremor, muscle stiffness/weakness,

drowsiness, irritability, respiratory and feeding problems. If your child develops one or more of

the above symptoms, contact the doctor.

Breastfeeding

The drug passes into breast milk. Talk to your doctor about the best way to feed your baby if

you are taking Zyprexa.

Fertility

Treatment with Zyprexa

Velotab may cause an increase in blood prolactin levels, which can

lead to reversible infertility in women of childbearing potential.

Driving and using machines:

The use of this medicine may cause drowsiness and affect your decision-making skills, sharp

thinking or quick response, and therefore requires caution when driving a vehicle, operating

dangerous machinery and any activity that requires alertness. Avoid any activity such as these

until you understand how Zyprexa Velotab affects you.

Important information about some of the ingredients of this medicine:

Zyprexa Velotab 5/10 mg contains aspartame 0.6/0.8 mg (respectively) in each soluble tablet.

Aspartame is a source of phenylalanine. It may harm a patient who has phenylketonuria, a rare

genetic disorder in which phenylalanine accumulates, resulting in the body not being able to

clear it properly.

Zyprexa Velotab contains parahydroxybenzoate - may cause allergic reactions (possible late reactions).

3.

HOW TO USE THIS MEDICINE?

Always use according to the doctor's instructions. You must check with the doctor or

pharmacist if you are not sure about the dose and manner of treatment with the drug.

The dosage and manner of treatment will be determined only by the doctor. Your doctor

may need to change the dose until he finds the right dose for you.

Do not exceed the recommended dose.

Make sure your hands are dry. Separate one unit from the blister package and carefully

peel off the cover. Do not push the tablet. The tablet should be removed and placed in

the mouth in its entirety immediately after peeling the cover. The tablet dissolves in the

saliva quickly, so it can be easily swallowed with or without a drink.

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There is no information on the preparation when it is crushed or split. Therefore, do not

chew, crush or split the tablet!

There is no information on the preparation when used with a nasogastric tube.

Use this medicine at regular time intervals as determined by your doctor.

If you have accidentally taken a higher dose you may feel drowsy, experience

impaired speech, aggressiveness or restlessness, rapid heart rate and reduced levels of

consciousness.

If you have taken an overdose or if a child has accidentally swallowed the medicine, go

immediately to a hospital Emergency Room and bring the medicine package with you.

If you forgot to take the medicine at the required time, take the medicine as soon as

you remember. If it is close to the time of taking the next dose, skip this dose and take

the dose at the usual time. Do not take a double dose.

Persist with the treatment as recommended by the doctor.

Even if there is an improvement in your health, do not discontinue treatment with this

medicine without consulting the doctor or pharmacist.

To avoid serious side effects, do not stop taking Zyprexa abruptly. If you need to

stop taking Zyprexa, your doctor will instruct you on how to do it.

Do not take medicines in the dark! Check the label and the dose each time you

take a medicine. Wear glasses if you need them.

If you have any further questions regarding the use of the medicine, consult the

doctor or pharmacist.

4.

SIDE EFFECTS

As with any medicine, the use of Zyprexa Velotab may cause side effects in some users. Do not

be alarmed by reading the list of side effects. You may not experience any of them.

Zyprexa Velotab may cause serious side effects:

Increased risk of death in elderly patients who are experiencing confusion, memory loss,

and loss of touch with reality (dementia-related psychosis). Zyprexa Velotab is not

intended for use in elderly patients with dementia.

Increase in blood glucose levels (hyperglycemia) may occur in patients with diabetes

and in patients who do not have diabetes. Increase in blood glucose levels may cause:

ketoacidosis - increased level of acid in the blood due to build-up of ketones

coma

death

Your doctor should perform blood tests to regularly monitor your blood glucose levels

before and during treatment with Zyprexa Velotab. Patients who do not have diabetes

may experience an increase in blood glucose levels when they stop taking Zyprexa

Velotab. Patients with diabetes and some patients who did not have diabetes at the start

of treatment with Zyprexa Velotab should take medication to lower their blood glucose

even after stopping treatment with Zyprexa Velotab.

If you have diabetes, your doctor will tell you how often to perform blood tests for blood

glucose levels while taking Zyprexa Velotab.

Consult a doctor if you experience symptoms of high blood glucose levels:

increased thirst

frequent urination

increased appetite

weakness and fatigue

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nausea

confusion or fruity breath odor

Increase in lipid levels (cholesterol and triglyceride) in the blood may occur in

patients who are being treated with Zyprexa Velotab. Your doctor must perform blood

tests for cholesterol and lipid levels at the beginning and during treatment even if you do

not have any symptoms.

Weight gain is very common in patients who are taking Zyprexa Velotab. Some patients

experience extreme weight gain. Consult your doctor regarding weight maintenance such

as a healthy diet and exercise.

Increased frequency of stroke or "mini stroke” - Transient Ischemic Attack (TIA) in

elderly people with dementia-related psychosis (elderly people who are experiencing

loss of touch with reality due to confusion and memory loss). Zyprexa Velotab is not

approved for use in these patients.

Neuroleptic malignant syndrome - a rare but serious condition which may occur in

patients who are taking antipsychotic medicines, including Zyprexa Velotab. Neuroleptic

malignant syndrome may cause death and requires hospitalization. Refer to the doctor

immediately if you experience:

high fever

increased sweating

stiff muscles

confusion

changes in your breathing, heart rate, and blood pressure.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). This side effect

may include: rash, fever, swollen and mixed glands of other internal organs such as: liver,

kidneys, lungs and heart. This side effect can sometimes lead to death, so tell your

doctor immediately if you experience any of these symptoms.

Tardive dyskinesia - a condition that causes involuntary movements, mainly of the face

or tongue. This side effect may continue even after you stop taking Zyprexa Velotab.

This side effect may also start after you stop taking Zyprexa Velotab. Tell your doctor if

you are having involuntary body movements.

Drop in blood pressure when changing position including symptoms such as

dizziness, fast or slow heart rate, or fainting. This side effect occurs mainly at the

beginning of taking this medicine.

10. Difficulty swallowing which may cause food or beverages to penetrate into your lungs.

11. Seizures - tell your doctor if you experience seizures while using Zyprexa Velotab.

12. Problems regulating body temperature - you may experience an increase in body

temperature, for example when you exercise or when you are in a very hot place. It is

important to drink water to prevent dehydration. See your doctor immediately if you become

very ill and have symptoms of dehydration:

excessive sweating or lack of sweat

dry mouth

feel very hot

increased thirst

urine retention

Additional side effects

Very common side effects:

Weakness (lack of energy), dry mouth, constipation, indigestion, drowsiness, dizziness,

accidental injury, sleep disorders, parkinsonism.

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Common side effects:

Fever, tremors, back pain, chest pain, pain in your limbs, joint pain, increased heart rate, high

blood pressure, vomiting, physical restlessness, increased appetite, behavioral changes,

increased triglyceride levels in the blood, weight gain, drop in blood pressure in the transition

from lying to sitting, subcutaneous bleeding manifested as patches on the skin, peripheral

edema, abnormal gait, stiff muscles, speech impediment, runny nose, cough, lazy eye,

inflammation of the esophagus, sleepiness, urinary incontinence, urinary tract infection,

increased prolactin levels, increased blood levels of alkaline phosphatase, discharge of milk

from the breasts, enlarged breasts in men, memory impairment, paresthesia, uplifted mood

(euphoria), shortness of breath, dry skin, acne, visual impairment, menstrual pain and vaginal

inflammation in women, hard stools or rarely passing stools.

Uncommon side effects:

Chills, facial edema, sensitivity to sunlight, attempted suicide, stroke, vasodilatation, nausea,

vomiting, tongue edema, reduced white blood cell levels, reduced blood platelet levels, high

blood levels of bilirubin, low blood levels of proteins, coordination problems, impaired speech,

reduced libido, lack of sensitivity, nose bleeding, hair loss, dry eyes, changes in visual

accommodation, impotence, changes in the menstrual cycle (such as no menstruation,

decrease/increase in menstrual bleeding, heavy menstrual bleeding), urine retention, urinary

frequency and urgency, large urine volume, breast pain, dystonia (spasm of the neck muscles,

difficulties swallowing, difficulties breathing, tongue protrusion), abdominal distension and death

due to diabetes.

Rare side effects:

Hangover effect, intestinal obstruction, fatty liver, osteoporosis, coma, pulmonary edema,

dilated pupils, sudden death.

Side effects of unknown frequency:

Allergic reaction [such as: anaphylactic reaction, swelling of the face or throat (angioedema),

itching, rash], diabetes-related coma, diabetic ketoacidosis, side effects that may occur when

stopping treatment (nausea, vomiting and sweating), jaundice, pancreatitis and hepatitis, liver

injury, increased salivation, restless legs syndrome, neutropenia (reduced number of a certain

type of white blood cells), painful and prolonged erection (priapism), painful muscle injury

(rhabdomyolysis), venous thrombosis, stuttering.

If you experience any side effect, if any side effect gets worse, or if you suffer from a

side effect not mentioned in the leaflet, you should consult the doctor.

Reporting side effects

Side effects can be reported to the Ministry of Health by clicking on the link “Reporting

side effects due to drug treatment” that can be found on the Home Page of the Ministry of

Health’s website (www.health.gov.il), which refers to an online form for reporting side effects, or

https://sideeffects.health.gov.il

by entering the following link:

5.

HOW TO STORE THIS MEDICINE?

Avoid poisoning! This medicine and any other medicine should be kept in a closed place out

of the sight and reach of children and/or infants in order to avoid poisoning. Do not induce

vomiting without an explicit instruction from the doctor.

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Do not use the medicine after the expiry date (exp. date) appearing on the package. The

expiry date refers to the last day of that month.

Storage conditions: store at a temperature below 25

6.

ADDITIONAL INFORMATION:

In addition to the active ingredient, Zyprexa Velotab tablets also contain:

Gelatin, mannitol, aspartame, sodium methyl parahydroxybenzoate, sodium propyl

parahydroxybenzoate and purified water.

Zyprexa Velotab 5 mg tablets: contain 0.60 mg aspartame/tablet.

Zyprexa Velotab 10 mg tablets: contain 0.80 mg aspartame/tablet.

What does the medicine look like and what are the contents of the package:

Packs of 14, 28 yellow round tablets.

Not all pack sizes may be marketed.

License holder and address: Eli Lilly Israel Ltd., 4 HaSheizaf Street, P.O.B 4246, Ra’anana

4366411

Manufacturer and address: Lilly S.A., Alcobendas (Madrid), Spain.

Revised in June 2020.

Registration numbers in the National Drug Registry of the Ministry of Health:

Zyprexa Velotab 5 mg: 130-75-30740-00

Zyprexa Velotab 10 mg: 130-76-30741-00

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ZYPREXA

ZYPREXA® VELOTAB®

1

DOSAGE FORMS AND STRENGTHS

ZYPREXA 5 mg, 7.5 mg, and 10 mg tablets

ZYPREXA Velotab 5 mg and 10 mg orodispersible tablets (orally disintegrating tablets)

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. ZYPREXA (olanzapine) is

not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions

(5.1, Use in specific populations (8.5)].

2

INDICATIONS AND USAGE

Zyprexa tablets and velotabs: Acute and maintenance treatment of schizophrenia. Zyprexa is indicated for the

management of the manifestations of psychotic disorders. Zyprexa is indicated for the short-term treatment of acute manic

episodes associated with Bipolar I Disorder. Prevention of recurrence in Bipolar Disorder: In patients whose manic

episode has responded to olanzapine treatment Zyprexa is indicated for the prevention of recurrence in patients with

Bipolar Disorder. Combination therapy in Bipolar I Disorder: The combination of Zyprexa with lithium or valproate is

indicated for the short-term treatment of acute manic episodes associated with Bipolar I Disorder.

3

DOSAGE AND ADMINISTRATION

Both Zyprexa tablets and Zyprexa velotab should not be crushed or split. There is no data to support the administration of

those products through a gastric tube.

3.1

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

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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 ZYPREXA 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 ZYPREXA for extended periods should periodically reevaluate the long-term usefulness of the drug for

the individual patient.

3.2

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 (3-4 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 ZYPREXA 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 ZYPREXA 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.

3.3

Administration of ZYPREXA Velotab (olanzapine orally disintegrating tablets)

After opening sachet, peel back foil on blister. Do not push tablet through foil. Immediately upon opening the

blister, using dry hands, remove tablet and place entire ZYPREXA Velotab in the mouth. Tablet disintegration occurs

rapidly in saliva so it can be easily swallowed with or without liquid.

disorder.

4

CONTRAINDICATIONS

Hypersensitivity to the active substance or to any of the excipients listed in section 11.

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

5.1

Elderly Patients with Dementia-Related Psychosis

Increased Mortality — Elderly patients with dementia-related psychosis treated with antipsychotic drugs

are at an increased risk of death. ZYPREXA is not approved for the treatment of patients with dementia-related

psychosis [see Boxed Warning,Use in Specific Populations (8.5)].

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].

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5.2

Suicide

The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of

high-risk patients should accompany drug therapy. Prescriptions for olanzapine should be written for the smallest quantity

of tablets consistent with good patient management, in order to reduce the risk of overdose.

5.3

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been

reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS

are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood

pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine

phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to

exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection,

etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in

the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous

system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not

essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any

concomitant serious medical problems for which specific treatments are available. There is no general agreement about

specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug

therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been

reported.

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure. DRESS

may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or

lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis.

DRESS is sometimes fatal. Discontinue olanzapine if DRESS is suspected.

5.5

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia,

and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapine’s

specific metabolic profile is presented below.

Hyperglycemia and Diabetes Mellitus

Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis

of diabetes mellitus, or having borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting

140-200 mg/dL). Patients taking olanzapine should be monitored regularly for worsening of glucose control. Patients

starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and

periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of

hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of

hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases,

hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required

continuation of anti-diabetic treatment despite discontinuation of the suspect drug

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has

been reported in patients treated with atypical antipsychotics including olanzapine. Assessment of the relationship

between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased

background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the

general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related

adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the

association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and

olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with

olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of

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serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was

15.0 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase

compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in

fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies

with a median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in

fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL). The difference in mean changes between

olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (patients diagnosed

with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline

random glucose level

200 mg/dL, and/or a baseline fasting glucose level

126 mg/dL). Olanzapine-treated patients had

a greater mean HbA1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA1c

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

In an analysis of 8 placebo-controlled studies (median treatment exposure 4-5 weeks), 6.1% of olanzapine-treated

subjects (N=855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599). Table 2

shows short-term and long-term changes in fasting glucose levels from adult olanzapine monotherapy studies.

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

Up to 12 weeks

exposure

At least 48

weeks exposure

Laboratory

Analyte

Category Change (at least once)

from Baseline

Treatment

Arm

N

Patient

s

N

Patient

s

Normal to High

Olanzapine

2.2%

12.8%

Fasting

(<100 mg/dL to

126 mg/dL)

Placebo

3.4%

Glucose

Borderline to High

Olanzapine

17.4%

26.0%

100 mg/dL and <126 mg/dL to

126 mg/dL)

Placebo

11.5%

Not Applicable.

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487). In analyses

of patients who completed 9-12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels

continued to increase over time.

Dyslipidemia

Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline

and periodic follow-up lipid evaluations in patients using olanzapine, is recommended.

Clinically significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed

with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled olanzapine monotherapy studies with

treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total

cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL, respectively, compared to

decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and

10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed

between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total

cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline,

where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients

treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol,

LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting

HDL cholesterol of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean nonfasting total

cholesterol did not increase further after approximately 4-6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides

from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-

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term studies (at least 48 weeks) as compared with short-term studies. Table 3 shows categorical changes in fasting lipids

values.

Table 3: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies

Up to 12 weeks

exposure

At least 48

weeks exposure

Laboratory

Analyte

Category Change (at least once)

from Baseline

Treatment

Arm

N

Patient

s

N

Patient

s

Increase by

50 mg/dL

Olanzapine

39.6%

61.4%

Placebo

26.1%

Fasting

Normal to High

Olanzapine

9.2%

32.4%

Triglycerides

(<150 mg/dL to

200 mg/dL)

Placebo

4.4%

Borderline to High

Olanzapine

39.3%

70.7%

150 mg/dL and <200 mg/dL to

200 mg/dL)

Placebo

20.0%

Increase by

40 mg/dL

Olanzapine

21.6%

32.9%

Placebo

9.5%

Fasting Total

Normal to High

Olanzapine

2.8%

14.8%

Cholesterol

(<200 mg/dL to

240 mg/dL)

Placebo

2.4%

Borderline to High

Olanzapine

23.0%

55.2%

200 mg/dL and <240 mg/dL to

240 mg/dL)

Placebo

12.5%

Increase by

30 mg/dL

Olanzapine

23.7%

39.8%

Placebo

14.1%

Fasting LDL

Normal to High

Olanzapine

7.3%

Cholesterol

(<100 mg/dL to

160 mg/dL)

Placebo

1.2%

Borderline to High

Olanzapine

10.6%

31.0%

100 mg/dL and <160 mg/dL to

160 mg/dL)

Placebo

8.1%

Not Applicable.

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.

Weight Gain

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

olanzapine should receive regular monitoring of weight.

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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 4 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 4: Weight Gain with Olanzapine Use in Adults

6 Weeks

6 Months

12 Months

24 Months

36 Months

Amount Gained

(N=7465)

(N=4162)

(N=1345)

(N=474)

(N=147)

kg (lb)

(%)

(%)

(%)

(%)

(%)

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.

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.

Tardive dyskinesia, 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.

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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

-adrenergic antagonistic

properties.

From an analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients

treated with oral olanzapine, orthostatic hypotension was recorded in ≥20% (1277/6030) of patients.

For oral olanzapine therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating

therapy with 5 mg QD [see Dosage and Administration (2)]. A more gradual titration to the target dose should be

considered if hypotension occurs. 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

ZYPREXA may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls

and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate

these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-

term antipsychotic therapy.

5.9

Leukopenia, Neutropenia, and Agranulocytosis

Class Effect — In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been

reported temporally related to antipsychotic agents, including ZYPREXA. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history

of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced

leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of

therapy and discontinuation of ZYPREXA should be considered at the first sign of a clinically significant decline in WBC in

the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of

infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil

count <1000/mm

) should discontinue ZYPREXA and have their WBC followed until recovery.

5.10

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is

a common cause of morbidity and mortality in patients with advanced Alzheimer’s disease. Olanzapine is not approved for

the treatment of patients with Alzheimer’s disease.

5.11

Seizures

During premarketing testing, seizures occurred in 0.9% (22/2500) of olanzapine-treated patients. There were

confounding factors that may have contributed to the occurrence of seizures in many of these cases. Olanzapine should

be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g.,

Alzheimer’s dementia. Olanzapine is not approved for the treatment of patients with Alzheimer’s disease. Conditions that

lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.12

Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse reaction associated with olanzapine treatment, occurring at an

incidence of 26% in olanzapine patients compared to 15% in placebo patients. This adverse reaction was also dose

related. Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing database.

Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about

operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not

affect them adversely.

5.13

Body Temperature Regulation

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Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents.

Appropriate care is advised when prescribing olanzapine for patients who will be experiencing conditions which may

contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving

concomitant medication with anticholinergic activity, or being subject to dehydration.

5.14

Anticholinergic (antimuscarinic) Effects

Olanzapine exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology 12.2].. In premarketing clinical

trials, Zyprexa 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, but Zyprexa should be used

with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic

hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post marketing experience, the risk for

severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see

Drug Interactions (7.1)].

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 and Warnings and Precautions (5.1)].

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

(2% [49/3240] of females), sexual function-related events

[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.

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5.16

Use in Combination with Lithium or Valproate

When using ZYPREXA in combination with lithium or valproate, the prescriber should refer to the Warnings and

Precautions sections of the package inserts for lithium or valproate [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)].

6

ADVERSE REACTIONS

6.1

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the

clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or

predict the rates observed in practice.

Clinical Trials in Adults

The information below for olanzapine is derived from a clinical trial database for olanzapine consisting of 10,504

adult patients with approximately 4765 patient-years of exposure to olanzapine plus 722 patients with exposure to

intramuscular olanzapine for injection. This database includes: (1) 2500 patients who participated in multiple-dose oral

olanzapine premarketing trials in schizophrenia and Alzheimer’s disease representing approximately 1122 patient-years of

exposure as of February 14, 1995; (2) 182 patients who participated in oral olanzapine premarketing bipolar I disorder

(manic or mixed episodes) trials representing approximately 66 patient-years of exposure; (3) 191 patients who

participated in an oral olanzapine trial of patients having various psychiatric symptoms in association with Alzheimer’s

disease representing approximately 29 patient-years of exposure; (4) 5788 additional patients from 88 oral olanzapine

clinical trials as of December 31, 2001; (5) 1843 additional patients from 41 olanzapine clinical trials as of October 31,

2011; and (6) 722 patients who participated in intramuscular olanzapine for injection premarketing trials in agitated

patients with schizophrenia, bipolar I disorder (manic or mixed episodes), or dementia. Also included below is ,

information from the premarketing 6-week clinical study database for olanzapine in combination with lithium or valproate,

consisting of 224 patients who participated in bipolar I disorder (manic or mixed episodes) trials with approximately 22

patient-years of exposure.

The conditions and duration of treatment with olanzapine varied greatly and included (in overlapping categories)

open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and

short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse reactions, results of physical

examinations, vital signs, weights, laboratory analytes, ECGs, chest x-rays, and results of ophthalmologic examinations.

Certain portions of the discussion below relating to objective or numeric safety parameters, namely, dose-

dependent adverse reactions, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from

studies in patients with schizophrenia and have not been duplicated for bipolar I disorder (manic or mixed episodes) or

agitation. However, this information is also generally applicable to bipolar I disorder (manic or mixed episodes) and

agitation.

Adverse reactions during exposure were obtained by spontaneous report and recorded by clinical investigators

using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the

proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller

number of standardized reaction categories. In the tables and tabulations that follow, MedDRA and COSTART Dictionary

terminology has been used to classify reported adverse reactions.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least

once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it

occurred for the first time or worsened while receiving therapy following baseline evaluation. The reported reactions do not

include those reaction terms that were so general as to be uninformative. Reactions listed elsewhere in labeling may not

be repeated below. It is important to emphasize that, although the reactions occurred during treatment with olanzapine,

they were not necessarily caused by it. The entire label should be read to gain a complete understanding of the safety

profile of olanzapine.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the

incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from

those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from

other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide

the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the

adverse reactions incidence in the population studied.

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Incidence of Adverse Reactions in Short-Term, Placebo-Controlled and Combination Trials

The following findings are based on premarketing trials of (1) oral olanzapine for schizophrenia, bipolar I disorder

(manic or mixed episodes), a subsequent trial of patients having various psychiatric symptoms in association with

Alzheimer’s disease, and premarketing combination trials, and (2) intramuscular olanzapine for injection in agitated

patients with schizophrenia or bipolar I mania.

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials

Schizophrenia — Overall, there was no difference in the incidence of discontinuation due to adverse reactions (5%

for oral olanzapine vs. 6% for placebo). However, discontinuations due to increases in ALT were considered to be drug

related (2% for oral olanzapine vs. 0% for placebo).

Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy — Overall, there was no difference in the incidence of

discontinuation due to adverse reactions (2% for oral olanzapine vs. 2% for placebo).

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 5: Common Treatment-Emergent Adverse Reactions Associated with the

Use of Oral Olanzapine in 6-Week Trials — SCHIZOPHRENIA

Percentage of Patients Reporting Event

Olanzapine

Placebo

Adverse Reaction

(N=248)

(N=118)

Postural hypotension

Constipation

Weight gain

Dizziness

Personality disorder

Akathisia

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

Table 6: 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

Olanzapine

Placebo

Adverse Reaction

(N=125)

(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