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Zyprexa

Zyprexa(olanzapine) – Lilly

BOXED WARNING

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death; most deaths appeared to be cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Not approved for the treatment of patients with dementia-related psychosis. When used with fluoxetine, refer to the Boxed Warning section of the PI for Symbyax.

OTHER BRAND NAMES

Zyprexa Zydis (Lilly)

THERAPEUTIC CLASS

Thienobenzodiazepine

INDICATIONS

(PO) Treatment of schizophrenia, acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder in adults and adolescents 13-17 yrs. Adjunct to lithium or valproate for the treatment of manic or mixed episodes associated with bipolar I disorder in adults. In combination with fluoxetine for the treatment of depressive episodes associated with bipolar I disorder and of treatment-resistant depression in adults. (IM) Treatment of acute agitation associated with schizophrenia and bipolar I mania in adults.

ADULT DOSAGE

Adults: (PO) Schizophrenia: Initial/Usual: 5-10mg qd. Target dose: 10mg/day. Adjust dose by increments/decrements of 5mg qd at intervals of not <1 week. Max: 20mg/day. Maint: 10-20mg/day. Bipolar I Disorder (Manic or Mixed Episodes): Initial: 10mg or 15mg qd. Adjust dose by increments/decrements of 5mg qd at intervals of not <24 hrs. Maint: 5-20mg/day. Max: 20mg/day. With Lithium or Valproate: Initial/Usual: 10mg qd. Max: 20mg/day. Depressive Episodes Associated with Bipolar I Disorder/Resistant Depression in Combination with Fluoxetine: Initial: 5mg with 20mg fluoxetine qpm. Adjust dose based on efficacy and tolerability. Usual: 5-12.5mg with 20-50mg fluoxetine (depressive episodes associated with Bipolar I disorder) or 5-20mg with 20-50mg fluoxetine (resistant depression). Max: 18mg with 75mg fluoxetine. (IM) Agitation: Usual: 10mg. Range: 2.5-10mg. Assess for orthostatic hypotension prior to subsequent dosing. Max: 3 doses of 10mg q2-4h. May initiate PO therapy in a range of 5-20mg/day when clinically appropriate. Elderly: 5mg/inj. See PI for dosing in special populations.

PEDIATRIC DOSAGE

Pediatrics: 13-17 yrs: (PO) Schizophrenia/Bipolar I Disorder (Manic or Mixed Episodes): Initial: 2.5mg or 5mg qd. Target dose: 10mg/day. Adjust dose by increments/decrements of 2.5mg or 5mg. Max: 20mg/day. Maint: use lowest dose to maintain remission.

HOW SUPPLIED

Inj: 10mg [vial]; Tab: 2.5mg, 5mg, 7.5mg, 10mg, 15mg, 20mg; Tab, Disintegrating: (Zydis) 5mg, 10mg, 15mg, 20mg

WARNINGS/PRECAUTIONS

May cause hyperglycemia; caution in patients with diabetes mellitus or borderline increased blood glucose levels, and monitor for worsening of glucose control. Supervision should accompany therapy in patients at high risk of attempted suicide. Neuroleptic malignant syndrome (NMS) reported; d/c if symptoms occur and instill intensive symptomatic treatment and monitoring. Tardive dyskinesia (TD) reported; d/c if signs/symptoms develop unless treatment is required despite the presence of syndrome. Hyperlipidemia, weight gain, and hyperprolactinemia reported. May cause orthostatic hypotension; caution with cardiovascular disease (CVD), cerebrovascular disease and conditions that would predispose to hypotension. May cause esophageal dysmotility and aspiration, and disruption of body temperature regulation. Not approved for use in patients with Alzheimer's disease. Seizures reported; caution in patients with history of seizures or with conditions that lower the seizure threshold (eg, Alzheimer's dementia). Leukopenia, neutropenia, and agranulocytosis reported; d/c at 1st sign of clinically significant decline in WBC without causative factors or if severe neutropenia (absolute neutrophil count <1000/mm3) develops. May cause cognitive and motor impairment. Caution in patients with clinically significant prostatic hypertrophy, narrow-angle glaucoma, history of paralytic ileus or related conditions, hepatic impairment, and in elderly.

ADVERSE REACTIONS

Postural hypotension, constipation, dry mouth, weight gain, somnolence, dizziness, personality disorder, akathisia, asthenia, dyspepsia, tremor, increased appetite, abdominal pain, headache, insomnia.

DRUG INTERACTIONS

May potentiate orthostatic hypotension with diazepam and alcohol. May enhance effects of certain antihypertensives. Increased clearance with carbamazepine, omeprazole, and rifampin (CYP1A2 inducers). Caution with other CNS-acting drugs, drugs whose effects can induce hypotension, bradycardia, or respiratory/CNS depression, and in patients being treated with potentially hepatotoxic drugs. May antagonize effects of levodopa and dopamine agonists. Decreased clearance with fluoxetine (CYP2D6) and fluvoxamine (CYP1A2 inhibitor); consider lower dose with fluvoxamine. Caution when prescribing with anticholinergic drugs; may contribute to elevation in core body temperature. (IM) Not recommended with parenteral benzodiazepines. Increased somnolence with IM lorazepam. (PO) Decreased levels with activated charcoal.

PREGNANCY

Category C, not for use in nursing.

MECHANISM OF ACTION

Thienobenzodiazepine; not established. Proposed that efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism.

PHARMACOKINETICS

Absorption: (PO) Well-absorbed, Tmax=6 hrs; (IM) Rapid, Tmax=15-45 min. Distribution: Found in breast milk. (PO) Vd=1000L; plasma protein binding (93%). Metabolism: Via CYP450 mediated oxidation and direct glucuronidation; 10-N-glucuronide and 4'-N-desmethyl olanzapine (major metabolites). Elimination: (PO) Urine (57%, 7% unchanged), feces (30%); T1/2=21-54 hrs.

ASSESSMENT

Assess for CVD, cerebrovascular disease, risk of hypotension, history of seizures or conditions that could lower the seizure threshold, prostatic hypertrophy, narrow-angle glaucoma, history of paralytic ileus, hepatic impairment, history of drug abuse, risk factors/history of drug induced leukopenia/neutropenia, clinically significant low WBC, pregnancy/nursing status, and possible drug interactions. Assess for dementia-related psychosis and Alzheimer's disease in the elderly. Obtain baseline lipid panel, CBC, and FBG levels.

MONITORING

Monitor for signs/symptoms of NMS, TD, and other adverse effects. Monitor FBG, lipid levels, CBC, and weight of patient periodically. In patients with clinically significant neutropenia, monitor for fever or other symptoms/signs of infection. Periodically reassess to determine the need for maintenance treatment.

PATIENT COUNSELING

Advise of benefits/risks of therapy. Counsel about signs and symptoms of NMS. Inform of potential risk of hyperglycemia-related adverse events. Medication may cause hyperlipidemia and weight gain. Inform that medication may cause orthostatic hypotension; instruct to contact physician if dizziness, fast or slow heart beat, or fainting occurs. Inform that medication may impair judgment, thinking, or motor skills; instruct to use caution when operating hazardous machinery. Instruct to avoid overheating and dehydration. Instruct to avoid alcohol. Inform that orally disintegrating tab contains phenylalanine. Notify physician if taking, planning to take, or have stopped taking any prescription or over-the-counter products, including herbal supplements. Notify physician if pregnant or plan to become pregnant during treatment. Advise to avoid breastfeeding during therapy.

ADMINISTRATION/STORAGE

Administration: Oral/IM routes. (Inj) Do not administer IV or SQ. Inj slowly, deep into the muscle mass. See PI for proper reconstitution procedures. (Zydis) After opening sachet, peel back foil on blister. Do not push tab through foil. Upon opening the blister, remove tab and place entire tab in the mouth using dry hands. Storage: Tab, Zydis, and Inj (Before Reconstitution): 20-25°C (68-77°F); excursions permitted between 15-30oC (59-86oF). Reconstituted Inj: 20-25°C (68-77°F) for up to 1 hr; excursions permitted between 15-30oC (59-86oF). Tab/Zydis: Protect from light and moisture. Inj: Protect from light. Do not freeze.


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    Zyprexa

    Zyprexa

    Pronunciation Generic Name: olanzapine (oral) (oh LANZ a peen)

    Brand Name: ZyPREXA, ZyPREXA Zydis

    OverviewSide EffectsDosageInteractionsFor ProfessionalsMore…

    What is olanzapine?

    Olanzapine is an antipsychotic medication that affects chemicals in the brain.

    Olanzapine is used to treat the symptoms of psychotic conditions such as schizophrenia and bipolar disorder (manic depression) in adults and children who are at least 13 years old.

    Olanzapine is sometimes used together with other antipsychotic medications or antidepressants.

    Olanzapine may also be used for purposes not listed in this medication guide.

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

    Olanzapine is not for use in psychotic conditions related to dementia. Olanzapine may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions.

    You may gain weight or have high cholesterol and triglycerides (types of fat) while taking this medicine, especially if you are a teenager. Your blood may need to be tested often. Visit your doctor regularly.

    Video: Treatment for Depression Treatments for depression are getting better everyday and there are things you can start doing right away.

    Olanzapine can cause high blood sugar (hyperglycemia). If you are diabetic, check your blood sugar levels on a regular basis while you are taking olanzapine.

    Olanzapine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

    Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

    Avoid drinking alcohol while taking olanzapine.

    Avoid becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise. It is easier to become dangerously overheated and dehydrated while you are taking olanzapine.

    What should I discuss with my healthcare provider before taking olanzapine?

    Olanzapine is not for use in psychotic conditions related to dementia. Olanzapine may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions.

    You should not take olanzapine if you are allergic to it.

    To make sure you can safely take olanzapine, tell your doctor if you have any of these other conditions:

    • liver disease;

    • heart disease, high or low blood pressure;
    • a history of low white blood cell (WBC) counts;
    • high cholesterol or triglycerides;
    • a history of heart failure, heart attack, or stroke;
    • a history of breast cancer;
    • seizures or epilepsy;
    • diabetes;
    • an enlarged prostate or difficulty urinating;
    • bowel problems; or
    • narrow-angle glaucoma.

    FDA pregnancy category C. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

    Taking antipsychotic medication during the last 3 months of pregnancy may cause problems in the newborn, such as withdrawal symptoms, breathing problems, feeding problems, fussiness, tremors, and limp or stiff muscles. However, you may have withdrawal symptoms or other problems if you stop taking your medicine during pregnancy. If you become pregnant while taking olanzapine, do not stop taking it without your doctor’s advice.

    Olanzapine can pass into breast milk and may harm a nursing baby. You should not breast-feed while using olanzapine.

    The olanzapine orally disintegrating tablet (Zyprexa Zydis) may contain phenylalanine. Talk to your doctor before using this form of olanzapine if you have phenylketonuria (PKU).

    How should I take olanzapine?

    Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results.

    Olanzapine can be taken with or without food.

    Olanzapine is usually taken once a day. Olanzapine may be only part of a complete program of treatment that also includes counseling and other psychological support programs. Follow your doctor’s instructions.

    Call your doctor if your symptoms do not improve, or if they get worse while using olanzapine. Do not stop taking olanzapine suddenly without first talking to your doctor, even if you feel fine. You may have serious side effects if you stop taking olanzapine suddenly.

    To take olanzapine orally disintegrating tablets (Zyprexa Zydis):

    • Keep the tablet in its blister pack until you are ready to take it. Open the package and peel back the foil from the tablet blister. Do not push a tablet through the foil or you may damage the tablet.

    • Using dry hands, remove the tablet and place it in your mouth. It will begin to dissolve right away.
    • Do not swallow the tablet whole. Allow it to dissolve in your mouth without chewing.
    • Swallow several times as the tablet dissolves. If desired, you may drink liquid to help swallow the dissolved tablet.

    Olanzapine can cause high blood sugar (hyperglycemia). If you are diabetic, check your blood sugar levels on a regular basis while you are taking olanzapine.

    You may gain weight or have high cholesterol and triglycerides (types of fat) while taking this medicine, especially if you are a teenager. Your blood may need to be tested often. Visit your doctor regularly.

    If you are taking a combination of drugs, use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor’s advice.

    Store at room temperature away from moisture, heat, and light.

    See also: Zyprexa dosage (in more detail)

    What happens if I miss a dose?

    Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

    What happens if I overdose?

    Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include drowsiness, agitation, aggression, slurred speech, confusion, increased heart rate, jerky or uncontrolled muscle movements, trouble breathing, or fainting.

    What should I avoid while taking olanzapine?

    Olanzapine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

    Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

    Drinking alcohol can increase sleepiness caused by olanzapine.

    Avoid becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise. It is easier to become dangerously overheated and dehydrated while you are taking olanzapine.

    Olanzapine side effects

    Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

    Stop using olanzapine and call your doctor at once if you have any of these serious side effects:

    • very stiff (rigid) muscles, high fever, tremors, sweating, confusion, fast or uneven heartbeats, slow heart rate, feeling like you might pass out;

    • twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs;
    • trouble speaking or swallowing;
    • dry mouth, thirst, feeling very hot (with or without sweating), urinating less than usual or not at all;
    • high blood sugar (increased thirst, loss of appetite, fruity breath odor, increased urination, drowsiness, dry skin, nausea, and vomiting);
    • sudden numbness or weakness, confusion, or problems with vision, speech, or balance;
    • fever, chills, body aches, flu symptoms, sores in your mouth and throat;
    • swelling in your hands or feet;
    • changes in personality, unusual thoughts or behavior, hallucinations, or thoughts about hurting yourself; or
    • upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

    Less serious side effects may include:

    • weight gain (more likely in teenagers), increased appetite;

    • headache, dizziness, drowsiness, feeling tired or restless;
    • memory problems;
    • stomach pain, constipation, loss of bladder control;
    • back pain, pain in your arms or legs;
    • numbness or tingly feeling;
    • breast swelling or discharge (in women or men); or
    • missed menstrual periods.

    This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    See also: Zyprexa side effects (in more detail)

    What other drugs will affect olanzapine?

    Before using olanzapine, tell your doctor if you regularly use other medicines that can make you sleepy or slow your breathing (such as cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to the side effects of olanzapine.

    Tell your doctor about all other medicines you use, especially:

    • heart or blood pressure medication;

    • carbamazepine (Carbatrol, Tegretol);
    • diazepam (Valium);
    • fluoxetine and olanzapine (Symbyax);
    • fluvoxamine (Luvox);
    • omeprazole (Prilosec);
    • rifampin (Rifater, Rifadin, Rifamate); or
    • a medication to treat Parkinson’s disease including levodopa (Sinemet, Larodopa, Atamet), selegiline (Eldepryl, Emsam, Zelapar), pramipexole (Mirapex), ropinirole (Requip), and others.

    This list is not complete and other drugs may interact with olanzapine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

    Next Page → Side Effects

    More Zyprexa resources

    • Side Effects
    • Recommended Dosage
    • Pregnancy Warnings
    • Drug Images
    • Drug Interactions
    • Support Group
    • 101 Reviews - Add your own review/rating
    • Generic Availability
    • Zyprexa Consumer Overview
    • Zyprexa Advanced Consumer (Micromedex) – Includes Dosage Information
    • Zyprexa Prescribing Information (FDA)
    • Zyprexa MedFacts Consumer Leaflet (Wolters Kluwer)
    • Olanzapine Professional Patient Advice (Wolters Kluwer)
    • Olanzapine Monograph (AHFS DI)
    • Zyprexa Relprevv Advanced Consumer (Micromedex) – Includes Dosage Information
    • Zyprexa Relprevv MedFacts Consumer Leaflet (Wolters Kluwer)
    • Zyprexa Relprevv Consumer Overview
    • Zyprexa Relprevv Prescribing Information (FDA)
    • Zyprexa Zydis orally disintegrating tablets MedFacts Consumer Leaflet (Wolters Kluwer)
    • olanzapine MedFacts Consumer Leaflet (Wolters Kluwer)

    Compare Zyprexa with other medications

    • Anorexia
    • Anorexia Nervosa
    • Asperger Syndrome
    • Bipolar Disorder
    • Body Dysmorphic Disorder
    • Borderline Personality Disorder
    • Depression
    • Insomnia
    • Obsessive Compulsive Disorder
    • Paranoid Disorder
    • Schizoaffective Disorder
    • Schizophrenia
    • Tourette’s Syndrome

    Where can I get more information?

    • Your pharmacist can provide more information about olanzapine.

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    ZyPREXA

    ZyPREXA

    Pronunciation Generic Name: olanzapine (injection) (oh LAN za peen)

    Brand Name: ZyPREXA, ZyPREXA Relprevv

    OverviewSide EffectsInteractionsFor ProfessionalsMore…

    What is olanzapine injection?

    Olanzapine is an antipsychotic medication that affects chemicals in the brain.

    Olanzapine injection is used to treat adults who are in an agitated state due to schizophrenia or bipolar disorder (manic depression). Olanzapine injection is not for daily use to treat any psychotic condition.

    Olanzapine injection may also be used for purposes not listed in this medication guide.

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

    You should not receive this medication if you are allergic to olanzapine.

    If possible before you receive olanzapine injection, tell your doctor if you have heart disease, congestive heart failure, a heart rhythm disorder, a history of heart attack or stroke, or if you are also using a sedative such as Valium.

    Video: Treatment for Depression Treatments for depression are getting better everyday and there are things you can start doing right away.

    You may need to stop breast-feeding for a short time after receiving an olanzapine injection. Follow your doctor’s instructions.

    In an emergency situation it may not be possible before you are treated to tell your caregivers about your health conditions or if you are pregnant or breast feeding. Make sure any doctor caring for you afterward knows that you have received this medicine.

    Olanzapine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

    What should I discuss with my healthcare provider before receiving olanzapine injection?

    Olanzapine is not for use in psychotic conditions related to dementia. Olanzapine may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions.

    You should not receive this medication if you are allergic to olanzapine.

    If possible before you receive olanzapine injection, tell your doctor if you have:

    • heart disease;

    • congestive heart failure;
    • a heart rhythm disorder;
    • a history of heart attack or stroke; or
    • if you are also using a sedative such as Valium.

    FDA pregnancy category C. It is not known whether olanzapine injection will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

    Olanzapine can pass into breast milk and may harm a nursing baby. You may need to stop breast-feeding for a short time after receiving an olanzapine injection. Follow your doctor’s instructions.

    In an emergency situation, it may not be possible before you are treated with olanzapine to tell your caregivers if you are pregnant or breast feeding. Make sure any doctor caring for your pregnancy or your baby knows you have received this medicine.

    How is olanzapine injection given?

    Olanzapine is injected into a muscle. You will receive this injection in a clinic or hospital setting.

    An olanzapine injection is usually given only once. If you still have symptoms after 2 hours, your caregivers may use a second or third dose.

    What happens if I miss a dose?

    Since olanzapine injection is given by a healthcare professional in an emergency setting, you are not likely to miss a dose.

    What happens if I overdose?

    Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

    What should I avoid after receiving olanzapine injection?

    Olanzapine may impair your thinking or reactions. Be careful if you do anything that requires you to be alert.

    Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

    Drinking alcohol can increase sleepiness caused by olanzapine.

    Olanzapine injection side effects

    Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

    Tell your caregivers at once if you have a serious side effect such as:

    • fast or slow heart rate;

    • feeling like you might pass out;
    • twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs; or
    • being unable to sit still.

    Less serious side effects may include:

    • dizziness, drowsiness;

    • weakness;
    • tremors or shaking;
    • nausea; or
    • pain where the injection was given.

    This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    See also: ZyPREXA side effects (in more detail)

    What other drugs will affect olanzapine injection?

    Tell your doctor about all other medicines you use, especially:

    • blood pressure medication;

    • alprazolam (Xanax)
    • diazepam (Valium);
    • clonazepam (Klonopin);
    • lorazepam (Ativan);
    • temazepam (Restoril); or
    • if you take olanzapine by mouth (Zyprexa, Symbyax, or Zyprexa Zydis).

    This list is not complete and other drugs may interact with olanzapine injection. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

    Next Page → Side Effects

    More ZyPREXA resources

    • Side Effects
    • Pregnancy Warnings
    • Drug Images
    • Drug Interactions
    • Support Group
    • 101 Reviews - Add your own review/rating
    • Generic Availability

    Compare ZyPREXA with other medications

    • Anorexia
    • Anorexia Nervosa
    • Asperger Syndrome
    • Bipolar Disorder
    • Body Dysmorphic Disorder
    • Borderline Personality Disorder
    • Depression
    • Insomnia
    • Obsessive Compulsive Disorder
    • Paranoid Disorder
    • Schizoaffective Disorder
    • Schizophrenia
    • Tourette’s Syndrome

    Where can I get more information?

    • Your doctor or pharmacist can provide more information about olanzapine injection.

    Post a Comment

    Your email is kept private. Required fields are marked *

    You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>

    Zyprexa

    Zyprexa

    Pronunciation Generic Name: olanzapine (Oral route)

    oh-LAN-za-peen

    OverviewSide EffectsInteractionsFor ProfessionalsMore… Oral route(Tablet;Tablet, Disintegrating) Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo. Although the causes of death in clinical trials were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that antipsychotic drugs may increase mortality. It is unclear from these studies to what extent the mortality findings may be attributed to the antipsychotic drug as opposed to patient characteristics. Olanzapine is not approved for the treatment of patients with dementia-related psychosis .

    Commonly used brand name(s)

    In the U.S.

    • Zyprexa
    • Zyprexa Zydis

    Available Dosage Forms:

    • Tablet
    • Tablet, Disintegrating

    Therapeutic Class: Antipsychotic

    Chemical Class: Thienobenzodiazepine

    Uses For Zyprexa

    Olanzapine is used to treat nervous, emotional, and mental conditions (e.g., schizophrenia). It may also be used alone or with other medicines (e.g., lithium or valproate) to treat bipolar disorder (manic-depressive illness) or mania that is part of bipolar disorder. This medicine should not be used to treat behavioral problems in older adult patients who have dementia or Alzheimer’s disease.

    This medicine is available only with your doctor’s prescription.

    Before Using Zyprexa

    In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

    Allergies

    Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

    Pediatric

    Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of olanzapine in teenagers 13 to 17 years of age. However, safety and efficacy of olanzapine in children younger than 13 years of age have not been established.

    Geriatric

    Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of olanzapine in the elderly. However, elderly patients are more likely to have dementia or age-related liver, kidney, or heart problems, which may require caution or an adjustment in the dose for patients receiving olanzapine.

    Pregnancy

    Pregnancy Category Explanation
    All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

    Breast Feeding

    There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

    Interactions with Medicines

    Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

    Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

    • Levomethadyl
    • Metoclopramide

    Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

    • Clomipramine
    • Hydromorphone
    • Lithium
    • Milnacipran
    • Mirtazapine
    • Tetrabenazine
    • Tramadol

    Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

    • Betel Nut
    • Carbamazepine
    • Ciprofloxacin
    • Fluvoxamine
    • Haloperidol
    • Valproic Acid

    Interactions with Food/Tobacco/Alcohol

    Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

    Other Medical Problems

    The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

    • Blood vessel disease or circulation problems or
    • Dehydration or
    • Heart attack or stroke, history of or
    • Heart disease or
    • Heart failure or
    • Heart rhythm problems or
    • Hypotension (low blood pressure) or
    • Hypovolemia (low blood volume)—May cause side effects to become worse.
    • Breast cancer, prolactin-dependent or
    • Glaucoma, narrow-angle or
    • Hyperlipidemia (high cholesterol or fat in the blood) or
    • Hyperprolactinemia (high prolactin in the blood) or
    • Liver disease or
    • Paralytic ileus (severe intestinal problem), history of or
    • Prostatic hypertrophy (enlarged prostate) or
    • Seizures, history of—Use with caution. This medicine may make these conditions worse.
    • Diabetes or
    • Hyperglycemia (high blood sugar)—This medicine may raise your blood sugar levels.
    • Phenylketonuria (PKU, a genetic disease of metabolism)—The orally disintegrating tablet (Zyprexa® Zydis®) contains phenylalanine, which can make this condition worse.

    Proper Use of olanzapine

    This section provides information on the proper use of a number of products that contain olanzapine. It may not be specific to Zyprexa. Please read with care.

    Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

    This medicine should come with a medication guide. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions. Ask your pharmacist for the medication guide if you do not have one.

    If you are using the orally disintegrating tablet (Zyprexa® Zydis®), make sure your hands are dry before you handle the tablet. Do not open the blister pack that contains the tablet until you are ready to take it. Remove the tablet from the blister pack by peeling back the foil, then taking the tablet out. Do not push the tablet through the foil. Place the tablet in your mouth. It should melt quickly. After the tablet has melted, swallow or take a sip of water.

    You may take this medicine with or without food.

    Tell your doctor if you smoke tobacco. You might need a different amount of this medicine if you smoke.

    Dosing

    The dose of this medicine will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

    The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

    • For oral dosage form (orally disintegrating tablets, regular tablets):
      • For treatment of schizophrenia:
        • Adults—At first, 5 to 10 milligrams (mg) once a day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 20 mg per day.
        • Teenagers and children 13 to 17 years of age—At first, 2.5 or 5 milligrams (mg) once a day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 20 mg per day.
        • Children younger than 13 years of age—Use and dose must be determined by your doctor.
      • For treatment of bipolar disorder:
        • Adults—At first, 5 to 15 milligrams (mg) once a day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 20 mg per day.
        • Teenagers and children 13 to 17 years of age—At first, 2.5 or 5 milligrams (mg) once a day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 20 mg per day.
        • Children younger than 13 years of age—Use and dose must be determined by your doctor.
      • For treatment of mania with bipolar disorder:
        • Adults—At first, 10 to 15 milligrams (mg) once a day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 20 mg per day.
        • Teenagers and children 13 to 17 years of age—At first, 2.5 or 5 milligrams (mg) once a day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 20 mg per day.
        • Children younger than 13 years of age—Use and dose must be determined by your doctor.

    Missed Dose

    If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

    Storage

    Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

    Keep out of the reach of children.

    Do not keep outdated medicine or medicine no longer needed.

    Ask your healthcare professional how you should dispose of any medicine you do not use.

    Precautions While Using Zyprexa

    It is very important that your doctor check your or your child’s progress at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for unwanted effects.

    For some patients, this medicine can increase thoughts of suicide. Tell your doctor right away if you or your child start to feel more depressed and have thoughts about hurting yourself. Report any unusual thoughts or behaviors that trouble you, especially if they are new or are getting worse quickly. Make sure the doctor knows if you or your child have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell the doctor if you have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. Let the doctor know if you or anyone in your family has bipolar disorder (manic-depressive illness) or has tried to commit suicide.

    This medicine may increase the amount of sugar in your blood. Check with your doctor right away if you have increased thirst or increased urination. If you or your child have diabetes, you may notice a change in the results of your urine or blood sugar tests. If you have any questions, check with your doctor.

    This medicine may increase your cholesterol and fats in the blood. If this condition occurs, your doctor may give you or your child some medicines that can lower the amount of cholesterol and fats in the blood.

    This medicine may increase your weight. Your doctor may need to check your or your child’s weight on a regular basis while you are using this medicine.

    Stop taking this medicine and check with your doctor right away if you or your child have any of the following symptoms while using this medicine: convulsions (seizures), difficulty with breathing, a fast heartbeat, a high fever, high or low blood pressure, increased sweating, loss of bladder control, severe muscle stiffness, unusually pale skin, or tiredness. These could be symptoms of a serious condition called neuroleptic malignant syndrome (NMS).

    This medicine may cause tardive dyskinesia (a movement disorder). Check with your doctor right away if you or your child have any of the following symptoms while taking this medicine: lip smacking or puckering, puffing of the cheeks, rapid or worm-like movements of the tongue, uncontrolled chewing movements, or uncontrolled movements of the arms and legs.

    Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying or sitting position. Getting up slowly may help. If this problem continues or gets worse, check with your doctor.

    This medicine can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. If you can, avoid people with infections. Check with your doctor immediately if you or your child think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.

    Olanzapine may cause drowsiness, trouble with thinking, trouble with controlling body movements, or trouble with your vision. Make sure you know how you react to this medicine before you drive, use machines, or do other jobs that require you to be alert, well-coordinated, or able to think or see well.

    This medicine may add to the effects of alcohol and other central nervous system (CNS) depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicines for allergies or colds; sedatives, tranquilizers, or sleeping medicines; prescription pain medicines or narcotics; medicines for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any CNS depressants while you are taking this medicine.

    This medicine may make it more difficult for your body to cool down. It might reduce how much you sweat. Your body could get too hot if you do not sweat enough. If your body gets too hot, you might feel dizzy, weak, tired, or confused. You might vomit or have an upset stomach. Do not get too hot while you are exercising. Avoid places that are very hot. Call your doctor if you are too hot and can not cool down.

    Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines) and herbal or vitamin supplements.

    Zyprexa Side Effects

    Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

    Check with your doctor immediately if any of the following side effects occur:

    More common

    • Bloating or swelling of the face, arms, hands, lower legs, or feet
    • blurred vision
    • change in vision
    • change in walking and balance
    • clumsiness or unsteadiness
    • difficulty with speaking
    • difficulty with swallowing
    • drooling
    • impaired vision
    • inability to sit still
    • loss of balance control
    • mask-like face
    • muscle trembling, jerking, or stiffness
    • need to keep moving
    • rapid weight gain
    • restlessness
    • shakiness in the legs, arms, hands, or feet
    • shuffling walk
    • slowed movements
    • slurred speech
    • stiffness of the arms and legs
    • tic-like (jerky) movements of the head, face, mouth, and neck
    • tingling of the hands or feet
    • trembling or shaking of the fingers, hands, or feet
    • twisting movements of the body
    • uncontrolled movements, especially of the face, neck, and back
    • unusual weight gain or loss

    Less common

    • Bladder pain
    • bloody or cloudy urine
    • bruising
    • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
    • chest pain
    • difficult or labored breathing
    • difficult, burning, or painful urination
    • dizziness
    • excessive muscle tone
    • frequent urge to urinate
    • headache
    • inability to move the eyes
    • increased blinking or spasms of the eyelid
    • itching of the vagina or genital area
    • lack of coordination
    • large, flat, blue, or purplish patches in the skin
    • loss of bladder control
    • loss of memory
    • lower back or side pain
    • muscle tension or tightness
    • nervousness
    • pain during sexual intercourse
    • pounding in the ears
    • problems with memory
    • rhythmic movement of the muscles
    • shortness of breath
    • slow, fast, pounding, or irregular heartbeat or pulse
    • speaking is less clear than usual
    • sticking out the tongue
    • thick, white vaginal discharge with no odor or with a mild odor
    • tightness in the chest
    • trouble with breathing, speaking, or swallowing
    • twitching
    • uncontrolled twisting movements of the neck, trunk, arms, or legs
    • unusual or incomplete body or facial movements
    • weakness of the arms and legs
    • wheezing

    Get emergency help immediately if any of the following symptoms of overdose occur:

    Symptoms of overdose

    • Anxiety
    • attacking, assaulting, or using force
    • change in consciousness
    • change in patterns and rhythms of speech
    • confusion as to time, place, or person
    • convulsions (seizures)
    • dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly
    • drowsiness
    • dry mouth
    • fainting
    • hallucinations
    • heart stops beating
    • high fever
    • high or low blood pressure
    • holding false beliefs that cannot be changed by fact
    • increased sweating
    • irregular, fast or slow, or shallow breathing
    • irritability
    • lightheadedness
    • loss of consciousness
    • mood or mental changes
    • no breathing
    • no pulse or blood pressure
    • pale or blue lips, fingernails, or skin
    • rapid breathing
    • relaxed and calm
    • severe muscle stiffness
    • shaking or trembling
    • sleepiness
    • trouble with sleeping
    • unconscious
    • unusual excitement, nervousness, or restlessness
    • unusual tiredness or weakness
    • unusually pale skin

    Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

    More common

    • Acid or sour stomach
    • back pain
    • belching
    • change in personality
    • difficulty having a bowel movement (stool)
    • discouragement
    • feeling sad or empty
    • fever
    • heartburn
    • increased appetite
    • increased cough
    • indigestion
    • lack of appetite
    • lack or loss of strength
    • loss of interest or pleasure
    • runny nose
    • sleeplessness
    • sneezing
    • stomach discomfort, upset, or pain
    • stuffy nose
    • thirst
    • trouble with concentrating
    • unable to sleep
    • watering of the mouth
    • weight gain

    Less common

    • Blemishes on the skin
    • body aches or pain
    • chills
    • cold sweats
    • congestion
    • cough
    • dry skin
    • dryness or soreness of the throat
    • false or unusual sense of well-being
    • joint pain
    • heavy menstrual bleeding (periods)
    • hoarseness
    • lack of feeling or emotion
    • leg cramps
    • pain in the arms or legs
    • pimples
    • sweating
    • tender, swollen glands in the neck
    • uncaring feelings
    • voice change
    • vomiting

    Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

    See also: Zyprexa side effects (in more detail)

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    Zyprexa

    Zyprexa

    Pronunciation Generic Name: olanzapine (oh-LAN-za-peen)

    Brand Name: Zyprexa

    Zyprexa is an antipsychotic. It may increase the risk of death when used to treat mental problems caused by dementia in elderly patients. Most of the deaths were linked to heart problems or infection. Zyprexa is not approved to treat mental problems caused by dementia.

    OverviewSide EffectsDosageInteractionsFor ProfessionalsMore…

    Zyprexa is used for:

    Treating schizophrenia or bipolar disorder. It is also used along with another medicine (fluoxetine) to treat certain types of depression. It may also be used for other conditions as determined by your doctor.

    Zyprexa is an atypical antipsychotic. Exactly how it works is not known. It is thought to affect certain substances in the brain.

    Do NOT use Zyprexa if:

    • you are allergic to any ingredient in Zyprexa

    Contact your doctor or health care provider right away if any of these apply to you.

    Video: Treatment for Depression Treatments for depression are getting better everyday and there are things you can start doing right away.

    Before using Zyprexa:

    Some medical conditions may interact with Zyprexa. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

    • if you are pregnant, planning to become pregnant, or are breast-feeding
    • if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
    • if you have allergies to medicines, foods, or other substances
    • if you have a history of seizures, heart problems (eg, heart failure; fast, slow, or irregular heartbeat), an abnormal electrocardiogram (ECG), a heart attack, a stroke or “mini-stroke,” blood vessel problems, high blood cholesterol levels, high or low blood pressure, or low white blood cell levels
    • if you have a history of liver problems, stomach or bowel problems (eg, decreased muscle movement), enlarged prostate, narrow-angle glaucoma, neuroleptic malignant syndrome (NMS), aspiration pneumonia, or suicidal thoughts or attempts
    • if you have Alzheimer disease, bowel blockage, dementia, or trouble swallowing
    • if you have diabetes or are very overweight, or if a family member has had diabetes
    • if you have had high blood prolactin levels or a history of certain types of cancer (eg, breast, pancreas, pituitary), or if you are at risk of breast cancer
    • if you are dehydrated or have low blood volume, drink alcohol, smoke, or you will be exposed to high temperatures

    Some MEDICINES MAY INTERACT with Zyprexa. Tell your health care provider if you are taking any other medicines, especially any of the following:

    • Tramadol because the risk of seizures may be increased
    • Alpha-blockers (eg, doxazosin), diazepam, or medicines for high blood pressure because the risk of low blood pressure and fainting may be increased
    • Anticholinergics (eg, scopolamine), benzodiazepines (eg, lorazepam), or fluvoxamine because they may increase the risk of Zyprexa’s side effects
    • Carbamazepine, HIV protease inhibitors (eg, ritonavir), omeprazole, or rifampin because they may decrease Zyprexa’s effectiveness
    • Dopamine receptor agonists (eg, pramipexole) or levodopa because their effectiveness may be decreased by Zyprexa

    This may not be a complete list of all interactions that may occur. Ask your health care provider if Zyprexa may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

    How to use Zyprexa:

    Use Zyprexa as directed by your doctor. Check the label on the medicine for exact dosing instructions.

    • Zyprexa comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Zyprexa refilled.
    • Take Zyprexa by mouth with or without food.
    • Drinking extra fluids while you are taking Zyprexa is recommended. Check with your doctor for instructions.
    • Continue to take Zyprexa even if you feel well. Do not miss any doses.
    • If you miss a dose of Zyprexa, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

    Ask your health care provider any questions you may have about how to use Zyprexa.

    Important safety information:

    • Zyprexa may cause dizziness, drowsiness, or decreased vision. These effects may be worse if you take it with alcohol or certain medicines. Use Zyprexa with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.
    • Do not drink alcohol while you are taking Zyprexa.
    • Talk with your doctor before you use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are taking Zyprexa; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.
    • Zyprexa may cause dizziness, lightheadedness, or fainting; alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects.
    • Do not suddenly stop taking Zyprexa without checking with your doctor.
    • Do not become overheated or dehydrated in hot weather or while you are being active; heatstroke may occur.
    • If vomiting or diarrhea occurs, you will need to take care not to become dehydrated. Contact your doctor right away if you think you may be dehydrated.
    • Zyprexa may raise your blood sugar. High blood sugar may make you feel confused, drowsy, or thirsty. It can also make you flush, breathe faster, or have a fruit-like breath odor. If these symptoms occur, tell your doctor right away.
    • Zyprexa may lower the ability of your body to fight infection. Avoid contact with people who have colds or infections. Tell your doctor if you notice signs of infection like fever, sore throat, rash, or chills.
    • NMS is a possibly fatal syndrome that can be caused by Zyprexa. Symptoms may include fever; stiff muscles; confusion; abnormal thinking; fast or irregular heartbeat; and sweating. Contact your doctor at once if you have any of these symptoms.
    • Some patients who take Zyprexa may develop muscle movements that they cannot control. This is more likely to happen in elderly patients, especially women. The chance that this will happen or that it will become permanent is greater in those who take Zyprexa in higher doses or for a long time. Muscle problems may also occur after short-term treatment with low doses. Tell your doctor at once if you have muscle problems with your arms; legs; or your tongue, face, mouth, or jaw (eg, tongue sticking out, puffing of cheeks, mouth puckering, chewing movements) while taking Zyprexa.
    • Some patients have experienced weight gain while using Zyprexa. You may need to have regular weight checks while you use Zyprexa.
    • Lab tests, including fasting blood glucose, cholesterol, complete blood cell counts, and liver function, may be performed while you take Zyprexa. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.
    • Use Zyprexa with caution in the ELDERLY; they may be more sensitive to its effects, especially uncontrolled muscle movements.
    • Caution is advised when using Zyprexa in CHILDREN; they may be more sensitive to its effects, especially drowsiness, increased cholesterol and lipid levels, increased levels of prolactin (a hormone), and weight gain. Children may need regular weight checks while they take Zyprexa.
    • Zyprexa should be used with extreme caution in CHILDREN younger than 13 years old; safety and effectiveness in these children have not been confirmed.
    • PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of taking Zyprexa while you are pregnant. Taking Zyprexa during the third trimester may result in uncontrolled muscle movements or withdrawal symptoms in the newborn. Discuss any questions or concerns with your doctor. Zyprexa is found in breast milk. Do not breast-feed while taking Zyprexa.

    Possible side effects of Zyprexa:

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

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

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

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

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

    If OVERDOSE is suspected:

    Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include abnormal thinking; aggression; agitation; chest pain; coma; confusion; difficult or slurred speech; fainting; fast or irregular heartbeat; fever; mental or mood changes; seizure; severe drowsiness, dizziness, or weakness; severe or persistent headache; slow or shallow breathing; stiff muscles; sweating; uncontrolled muscle movements.

    Proper storage of Zyprexa: Store Zyprexa at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Keep Zyprexa out of the reach of children and away from pets.

    General information:

    • If you have any questions about Zyprexa, please talk with your doctor, pharmacist, or other health care provider.
    • Zyprexa is to be used only by the patient for whom it is prescribed. Do not share it with other people.
    • If your symptoms do not improve or if they become worse, check with your doctor.
    • Check with your pharmacist about how to dispose of unused medicine.

    This information should not be used to decide whether or not to take Zyprexa or any other medicine. Only your health care provider has the knowledge and training to decide which medicines are right for you. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Zyprexa. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Zyprexa. This information is not specific medical advice and does not replace information you receive from your health care provider. You must talk with your healthcare provider for complete information about the risks and benefits of using Zyprexa.

    Issue Date: March 6, 2013 Database Edition 13.1.1.003 Copyright © 2013 Wolters Kluwer Health, Inc.

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    Zyprexa

    Zyprexa

    Pronunciation Generic Name: olanzapine

    Dosage Form: tablets, orally disintegrating tablets, injection

    For ProfessionalsSide EffectsInteractionsMore…

    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, 5.13) and Patient Counseling Information (17.2)].

    When using Zyprexa and fluoxetine in combination, also refer to the Boxed Warning section of the package insert for Symbyax.

    Indications and Usage for Zyprexa

    Schizophrenia

    Oral Zyprexa is indicated for acute and maintenance treatment of Schizophrenia in adults.

    Bipolar I Disorder (Manic or Mixed Episodes)

    Monotherapy — Oral Zyprexa is indicated for acute treatment of manic or mixed episodes associated with Bipolar I Disorder (monotherapy and in combination with lithium or valproate) and maintenance treatment of Bipolar I Disorder (monotherapy) in adults.

    Combination Therapy — The combination of oral Zyprexa with lithium or valproate is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults [see Clinical Studies (14.2)].

    Zyprexa IntraMuscular: Agitation Associated with Schizophrenia and Bipolar I Mania

    Zyprexa IntraMuscular is indicated for the treatment of acute agitation associated with Schizophrenia and Bipolar I Mania. “Psychomotor agitation” is defined in DSM-IV as “excessive motor activity associated with a feeling of inner tension.” Patients experiencing agitation often manifest behaviors that interfere with their diagnosis and care, e.g., threatening behaviors, escalating or urgently distressing behavior, or self-exhausting behavior, leading clinicians to the use of intramuscular antipsychotic medications to achieve immediate control of the agitation [see Clinical Studies (14.3)].

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

    When using Zyprexa and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

    Oral Zyprexa and fluoxetine in combination is indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder in adult patients.

    Zyprexa monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

    Zyprexa and Fluoxetine in Combination: Treatment Resistant Depression

    When using Zyprexa and fluoxetine in combination, also refer to the Indications and Usage section of the package insert for Symbyax.

    Oral Zyprexa and fluoxetine in combination is indicated for the acute treatment of 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).

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

    Zyprexa Dosage and Administration

    Schizophrenia

    Usual Dose — 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 Specific 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 (5.13), Drug Interactions (7), and Clinical Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients.

    Maintenance Treatment — While there is no body of evidence available to answer the question of how long the patient treated with olanzapine should remain on it, 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 a period of up to 8 months has been demonstrated in a placebo-controlled trial [see Clinical Studies (14.1)]. Patients should be periodically reassessed to determine the need for maintenance treatment with appropriate dose. The physician who elects to use Zyprexa for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

    Bipolar I Disorder (Manic or Mixed Episodes)

    Usual Monotherapy Dose — 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 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.

    Usual Dose in Combination with Lithium or Valproate — When administered in combination with lithium or valproate, oral olanzapine dosing should generally begin with 10 mg once-a-day without regard to meals.

    Short-term (6 weeks) 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.

    Dosing in Specific PopulationsDosage and Administration (2.1).

    Administration of Zyprexa ZYDIS (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 ZYDIS in the mouth. Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without liquid.

    Zyprexa IntraMuscular: Agitation Associated with Schizophrenia and Bipolar I Mania

    Usual Dose for Agitated Patients with Schizophrenia or Bipolar I Mania — The efficacy of intramuscular olanzapine for injection in controlling agitation in these disorders was demonstrated in a dose range of 2.5 mg to 10 mg. The recommended dose in these patients is 10 mg. A lower dose of 5 or 7.5 mg may be considered when clinical factors warrant [see Clinical Studies (14.3)]. If agitation warranting additional intramuscular doses persists following the initial dose, subsequent doses up to 10 mg may be given. However, the efficacy of repeated doses of intramuscular olanzapine for injection in agitated patients has not been systematically evaluated in controlled clinical trials. Also, the safety of total daily doses greater than 30 mg, or 10 mg injections given more frequently than 2 hours after the initial dose, and 4 hours after the second dose have not been evaluated in clinical trials. Maximal dosing of intramuscular olanzapine (e.g., 3 doses of 10 mg administered 2-4 hours apart) may be associated with a substantial occurrence of significant orthostatic hypotension [see Warnings and Precautions (5.8)]. Thus, it is recommended that patients requiring subsequent intramuscular injections be assessed for orthostatic hypotension prior to the administration of any subsequent doses of intramuscular olanzapine for injection. The administration of an additional dose to a patient with a clinically significant postural change in systolic blood pressure is not recommended.

    If ongoing olanzapine therapy is clinically indicated, oral olanzapine may be initiated in a range of 5-20 mg/day as soon as clinically appropriate [see Dosage and Administration (2.1, 2.2)].

    Intramuscular Dosing in Specific Populations — A dose of 5 mg/injection should be considered for geriatric patients or when other clinical factors warrant. A lower dose of 2.5 mg/injection should be considered for patients who otherwise might be debilitated, be predisposed to hypotensive reactions, or be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions (5.13), Drug Interactions (7), and Clinical Pharmacology (12.3)].

    Administration of Zyprexa IntraMuscular — Zyprexa IntraMuscular is intended for intramuscular use only. Do not administer intravenously or subcutaneously. Inject slowly, deep into the muscle mass.

    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

    Directions for Preparation of Zyprexa IntraMuscular with Sterile Water for Injection — Dissolve the contents of the vial using 2.1 mL of Sterile Water for Injection to provide a solution containing approximately 5 mg/mL of olanzapine. The resulting solution should appear clear and yellow. Zyprexa IntraMuscular reconstituted with Sterile Water for Injection should be used immediately (within 1 hour) after reconstitution. Discard any unused portion.

    The following table provides injection volumes for delivering various doses of intramuscular olanzapine for injection reconstituted with Sterile Water for Injection.

    Dose, mg Olanzapine Volume of Injection, mL
    10 Withdraw total contents of vial
    7.5 1.5
    5 1
    2.5 0.5

    Physical Incompatibility Information — Zyprexa IntraMuscular should be reconstituted only with Sterile Water for Injection. Zyprexa IntraMuscular should not be combined in a syringe with diazepam injection because precipitation occurs when these products are mixed. Lorazepam injection should not be used to reconstitute Zyprexa IntraMuscular as this combination results in a delayed reconstitution time. Zyprexa IntraMuscular should not be combined in a syringe with haloperidol injection because the resulting low pH has been shown to degrade olanzapine over time.

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

    When using Zyprexa 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 12.5 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with Zyprexa and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg.

    Safety and efficacy of Zyprexa and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of Zyprexa 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 Zyprexa 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 Symbyaxa and the Combination of Zyprexa and Fluoxetine
    a Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of Zyprexa and fluoxetine.

    For

    Symbyax

    (mg/day)

    Use in Combination
    Zyprexa

    (mg/day)

    Fluoxetine

    (mg/day)

    3 mg olanzapine/25 mg fluoxetine 2.5 20
    6 mg olanzapine/25 mg fluoxetine 5 20
    12 mg olanzapine/25 mg fluoxetine 10+2.5 20
    6 mg olanzapine/50 mg fluoxetine 5 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 Zyprexa 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.

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

    Zyprexa monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

    Zyprexa and Fluoxetine in Combination: Treatment Resistant Depression

    When using Zyprexa 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 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 Zyprexa 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 Zyprexa 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.

    Zyprexa 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).

    Zyprexa and Fluoxetine in Combination: Dosing in Specific Populations

    The starting dose of oral olanzapine 2.5-5 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. Zyprexa and fluoxetine in combination have not been systematically studied in patients over 65 years of age or in patients <18 years of age [see Warnings and Precautions (5.13), Drug Interactions (7), and Clinical Pharmacology (12.3)].

    Dosage Forms and Strengths

    The Zyprexa 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets are white, round, and imprinted in blue ink with LILLY and tablet number. The 15 mg tablets are elliptical, blue, and debossed with LILLY and tablet number. The 20 mg tablets are elliptical, pink, and debossed with LILLY and tablet number. Tablets are not scored. The tablets are available as follows:

    TABLET STRENGTH
    2.5 mg 5 mg 7.5 mg 10 mg 15 mg 20 mg
    Tablet No. 4112 4115 4116 4117 4415 4420
    Identification LILLY LILLY LILLY LILLY LILLY LILLY
    4112 4115 4116 4117 4415 4420

    Zyprexa ZYDIS (olanzapine orally disintegrating tablets) are yellow, round, and debossed with the tablet strength. Tablets are not scored. The tablets are available as follows:

    TABLET STRENGTH
    Zyprexa ZYDIS Tablets 5 mg 10 mg 15 mg 20 mg
    Tablet No. 4453 4454 4455 4456
    Debossed 5 10 15 20

    Zyprexa IntraMuscular is available in 10 mg vial (1s).

    Contraindications

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

    Warnings and Precautions

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

    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, Warnings and Precautions (5.13), 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)].

    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.

    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)].

    Hyperglycemia

    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, non-fasting 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 [see Patient Counseling Information (17.4)].

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

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

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

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

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

    Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies
    a Not Applicable.

      Up to 12 weeks exposure At least 48 weeks exposure
    Laboratory Analyte Category Change (at least once)

    from Baseline

    Treatment Arm N Patients N Patients
    Fasting

    Glucose

    Normal to High

    (<100 mg/dL to ≥126 mg/dL)

    Olanzapine 543 2.2% 345 12.8%
    Placebo 293 3.4% NAa NAa    
    Borderline to High

    (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)

    Olanzapine 178 17.4% 127 26.0%  
    Placebo 96 11.5% NAa NAa    

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

    Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 18 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with Schizophrenia (6 weeks) or Bipolar I Disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121). Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

    Table 3: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies
    a Not Applicable.

      Up to 12 weeks exposure At least 24 weeks exposure
    Laboratory Analyte Category Change (at least once)

    from Baseline

    Treatment Arm N Patients N Patients
    Fasting

    Glucose

    Normal to High

    (<100 mg/dL to ≥126 mg/dL)

    Olanzapine 124 0% 108 0.9%
    Placebo 53 1.9% NAa NAa    
    Borderline to High

    (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)

    Olanzapine 14 14.3% 13 23.1%  
    Placebo 13 0% NAa NAa    

    Hyperlipidemia

    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 (17.5)].

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

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

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

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

    Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies
    a Not Applicable.

      Up to 12 weeks exposure At least 48 weeks exposure
    Laboratory Analyte Category Change (at least once)

    from Baseline

    Treatment Arm

    N

    Patients

    N

    Patients

    Fasting

    Triglycerides

    Increase by ≥50 mg/dL Olanzapine 745 39.6% 487 61.4%
    Placebo 402 26.1% NAa NAa    
    Normal to High

    (<150 mg/dL to ≥200 mg/dL)

    Olanzapine 457 9.2% 293 32.4%  
    Placebo 251 4.4% NAa NAa    
    Borderline to High

    (≥150 mg/dL and <200 mg/dL to ≥200 mg/dL)

    Olanzapine 135 39.3% 75 70.7%  
    Placebo 65 20.0% NAa NAa    
     
    Fasting Total

    Cholesterol

    Increase by ≥40 mg/dL Olanzapine 745 21.6% 489 32.9%
    Placebo 402 9.5% NAa NAa    
    Normal to High

    (<200 mg/dL to ≥240 mg/dL)

    Olanzapine 392 2.8% 283 14.8%  
    Placebo 207 2.4% NAa NAa    
    Borderline to High

    (≥200 mg/dL and <240 mg/dL to ≥240 mg/dL)

    Olanzapine 222 23.0% 125 55.2%  
    Placebo 112 12.5% NAa NAa    
     
    Fasting LDL

    Cholesterol

    Increase by ≥30 mg/dL Olanzapine 536 23.7% 483 39.8%
    Placebo 304 14.1% NAa NAa    
    Normal to High

    (<100 mg/dL to ≥160 mg/dL)

    Olanzapine 154 0% 123 7.3%  
    Placebo 82 1.2% NAa NAa    
    Borderline to High

    (≥100 mg/dL and <160 mg/dL to ≥160 mg/dL)

    Olanzapine 302 10.6% 284 31.0%  
    Placebo 173 8.1% NAa NAa    

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

    Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 18 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescents, including those with Schizophrenia (6 weeks) or Bipolar I Disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

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

    Table 5: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies
    a Not Applicable.

      Up to 6 weeks exposure At least 24 weeks exposure
    Laboratory Analyte Category Change (at least once)

    from Baseline

    Treatment Arm

    N

    Patients

    N

    Patients

    Fasting

    Triglycerides

    Increase by ≥50 mg/dL Olanzapine 138 37.0% 122 45.9%
    Placebo 66 15.2% NAa NAa    
    Normal to High

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

    Olanzapine 67 26.9% 66 36.4%  
    Placebo 28 10.7% NAa NAa    
    Borderline to High

    (≥90 mg/dL and ≤130 mg/dL to >130 mg/dL)

    Olanzapine 37 59.5% 31 64.5%  
    Placebo 17 35.3% NAa NAa    
     
    Fasting Total

    Cholesterol

    Increase by ≥40 mg/dL Olanzapine 138 14.5% 122 14.8%
    Placebo 66 4.5% NAa NAa    
    Normal to High

    (<170 mg/dL to ≥200 mg/dL)

    Olanzapine 87 6.9% 78 7.7%  
    Placebo 43 2.3% NAa NAa    
    Borderline to High

    (≥170 mg/dL and <200 mg/dL to ≥200 mg/dL)

    Olanzapine 36 38.9% 33 57.6%  
    Placebo 13 7.7% NAa NAa    
     
    Fasting LDL

    Cholesterol

    Increase by ≥30 mg/dL Olanzapine 137 17.5% 121 22.3%
    Placebo 63 11.1% NAa NAa    
    Normal to High

    (<110 mg/dL to ≥130 mg/dL)

    Olanzapine 98 5.1% 92 10.9%  
    Placebo 44 4.5% NAa NAa    
    Borderline to High

    (≥110 mg/dL and <130 mg/dL to ≥130 mg/dL)

    Olanzapine 29 48.3% 21 47.6%  
    Placebo 9 0% NAa NAa    

    Weight Gain

    Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight [see Patient Counseling Information (17.6)].

    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 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 of 12 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients.

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

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

    Table 6: Weight Gain with Olanzapine Use in Adults
    Amount Gained

    kg (lb)

    6 Weeks

    (N=7465)

    (%)

    6 Months

    (N=4162)

    (%)

    12 Months

    (N=1345)

    (%)

    24 Months

    (N=474)

    (%)

    36 Months

    (N=147)

    (%)

    ≤0 26.2 24.3 20.8 23.2 17.0
    0 to ≤5 (0-11 lb) 57.0 36.0 26.0 23.4 25.2
    >5 to ≤10 (11-22 lb) 14.9 24.6 24.2 24.1 18.4
    >10 to ≤15 (22-33 lb) 1.8 10.9 14.9 11.4 17.0
    >15 to ≤20 (33-44 lb) 0.1 3.1 8.6 9.3 11.6
    >20 to ≤25 (44-55 lb) 0 0.9 3.3 5.1 4.1
    >25 to ≤30 (55-66 lb) 0 0.2 1.4 2.3 4.8
    >30 (>66 lb) 0 0.1 0.8 1.2 2

    Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 18 years. Mean increase in weight in adolescents was greater than in adults. In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

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

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

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

    Table 8: Weight Gain with Olanzapine Use in Adolescents
    Amount Gained

    kg (lb)

    6 Weeks

    (N=243)

    (%)

    6 Months

    (N=191)

    (%)

    ≤0 2.9 2.1
    0 to ≤5 (0-11 lb) 47.3 24.6
    >5 to ≤10 (11-22 lb) 42.4 26.7
    >10 to ≤15 (22-33 lb) 5.8 22.0
    >15 to ≤20 (33-44 lb) 0.8 12.6
    >20 to ≤25 (44-55 lb) 0.8 9.4
    >25 to ≤30 (55-66 lb) 0 2.1
    >30 to ≤35 (66-77 lb) 0 0
    >35 to ≤40 (77-88 lb) 0 0
    >40 (>88 lb) 0 0.5

    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.

    Orthostatic Hypotension

    Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonistic properties [see Patient Counseling Information (17.7)].

    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.

    Hypotension, bradycardia with or without hypotension, tachycardia, and syncope were also reported during the clinical trials with intramuscular olanzapine for injection. In an open-label clinical pharmacology study in non-agitated patients with Schizophrenia in which the safety and tolerability of intramuscular olanzapine were evaluated under a maximal dosing regimen (three 10 mg doses administered 4 hours apart), approximately one-third of these patients experienced a significant orthostatic decrease in systolic blood pressure (i.e., decrease ≥30 mmHg) [see Dosage and Administration (2.4)]. Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in phase 2-3 oral olanzapine studies and in 0.3% (2/722) of olanzapine-treated patients with agitation in the intramuscular olanzapine for injection studies. Three normal volunteers in phase 1 studies with intramuscular olanzapine experienced hypotension, bradycardia, and sinus pauses of up to 6 seconds that spontaneously resolved (in 2 cases the reactions occurred on intramuscular olanzapine, and in 1 case, on oral olanzapine). The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs. For intramuscular olanzapine for injection therapy, patients should remain recumbent if drowsy or dizzy after injection until examination has indicated that they are not experiencing postural hypotension, bradycardia, and/or hypoventilation.

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

    Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7)]. Concomitant administration of intramuscular olanzapine and parenteral benzodiazepine has not been studied and is therefore not recommended. If use of intramuscular olanzapine in combination with parenteral benzodiazepines is considered, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended.

    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.

    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.

    Potential for Cognitive and Motor Impairment

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

    Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely [see Patient Counseling Information (17.8)].

    Body Temperature Regulation

    Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing olanzapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration. [See Patient Counseling Information (17.9)].

    Use in Patients with Concomitant Illness

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

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

    In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following treatment-emergent adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was significantly greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1), and Patient Counseling Information (17.2)].

    Olanzapine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risk of orthostatic hypotension with olanzapine, caution should be observed in cardiac patients [see Warnings and Precautions (5.8)].

    Hyperprolactinemia

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

    Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

    In clinical studies, elevated plasma prolactin concentrations were observed in 34% of adults treated with olanzapine compared to 13.1% of placebo-treated patients. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations such as galactorrhea (14/8136; 0.2%), gynecomastia (8/4896; 0.2% of males), and breast enlargement (2/3240; 0.06% of females) were reported.

    In placebo-controlled olanzapine monotherapy studies in adolescent patients with Schizophrenia or Bipolar I Disorder (manic or mixed episodes), elevated prolactin concentrations compared to baseline occurred in 47.4% of olanzapine-treated patients compared to 6.8% of placebo-treated patients. In long-term clinical trials of olanzapine in adolescents, gynecomastia occurred in 2.4% of males (7/286) and galactorrhea occurred in 1.8% of females (3/168) [see Use in Specific Populations (8.4)].

    Use in Combination with Fluoxetine, Lithium, or Valproate

    [See Drug Interactions (7)].

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

    Laboratory Tests

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

    Adverse Reactions

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

    Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

    Clinical Trials in Adults

    The information below for olanzapine is derived from a clinical trial database for olanzapine consisting of 8661 adult patients with approximately 4165 patient-years of exposure to oral olanzapine and 722 patients with exposure to intramuscular olanzapine for injection. This database includes: (1) 2500 patients who participated in multiple-dose oral olanzapine premarketing trials in Schizophrenia and Alzheimer’s disease representing approximately 1122 patient-years of exposure as of February 14, 1995; (2) 182 patients who participated in oral olanzapine premarketing Bipolar I Disorder (manic or mixed episodes) trials representing approximately 66 patient-years of exposure; (3) 191 patients who participated in an oral olanzapine trial of patients having various psychiatric symptoms in association with Alzheimer’s disease representing approximately 29 patient-years of exposure; (4) 5788 patients from 88 additional oral olanzapine clinical trials as of December 31, 2001; and (5) 722 patients who participated in intramuscular olanzapine for injection premarketing trials in agitated patients with Schizophrenia, Bipolar I Disorder (manic or mixed episodes), or dementia. In addition, information from the premarketing 6-week clinical study database for olanzapine in combination with lithium or valproate, consisting of 224 patients who participated in Bipolar I Disorder (manic or mixed episodes) trials with approximately 22 patient-years of exposure, is included below.

    The conditions and duration of treatment with olanzapine varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analytes, ECGs, chest x-rays, and results of ophthalmologic examinations.

    Certain portions of the discussion below relating to objective or numeric safety parameters, namely, dose-dependent adverse reactions, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with Schizophrenia and have not been duplicated for Bipolar I Disorder (manic or mixed episodes) or agitation. However, this information is also generally applicable to Bipolar I Disorder (manic or mixed episodes) and agitation.

    Adverse reactions during exposure were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized reaction categories. In the tables and tabulations that follow, MedDRA and COSTART Dictionary terminology has been used to classify reported adverse reactions.

    The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. The reported reactions do not include those reaction terms that were so general as to be uninformative. Reactions listed elsewhere in labeling may not be repeated below. It is important to emphasize that, although the reactions occurred during treatment with olanzapine, they were not necessarily caused by it. The entire label should be read to gain a complete understanding of the safety profile of olanzapine.

    The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactions incidence in the population studied.

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

    The following findings are based on premarketing trials of (1) oral olanzapine for Schizophrenia, Bipolar I Disorder (manic or mixed episodes), a subsequent trial of patients having various psychiatric symptoms in association with Alzheimer’s disease, and premarketing combination trials, and (2) intramuscular olanzapine for injection in agitated patients with Schizophrenia or Bipolar I Mania.

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

    Schizophrenia — Overall, there was no difference in the incidence of discontinuation due to adverse reactions (5% for oral olanzapine vs 6% for placebo). However, discontinuations due to increases in ALT were considered to be drug related (2% for oral olanzapine vs 0% for placebo).

    Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy — Overall, there was no difference in the incidence of discontinuation due to adverse reactions (2% for oral olanzapine vs 2% for placebo).

    Agitation — Overall, there was no difference in the incidence of discontinuation due to adverse reactions (0.4% for intramuscular olanzapine for injection vs 0% for placebo).

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

    Bipolar I Disorder (Manic or Mixed Episodes), Olanzapine in Combination with Lithium or Valproate — In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 11% for the combination of oral olanzapine with lithium or valproate compared to 2% for patients who remained on lithium or valproate monotherapy. Discontinuations with the combination of oral olanzapine and lithium or valproate that occurred in more than 1 patient were: somnolence (3%), weight gain (1%), and peripheral edema (1%).

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

    The most commonly observed adverse reactions associated with the use of oral olanzapine (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) were:

    Table 9: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Trials — SCHIZOPHRENIA
    a Personality disorder is the COSTART term for designating non-aggressive objectionable behavior.

    Adverse Reaction Percentage of Patients Reporting Event
    Olanzapine

    (N=248)

    Placebo

    (N=118)

    Postural hypotension 5 2
    Constipation 9 3
    Weight gain 6 1
    Dizziness 11 4
    Personality disordera 8 4
    Akathisia 5 1
    Table 10: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 3-Week and 4-Week Trials — Bipolar I Disorder (Manic or Mixed Episodes)
    Adverse Reaction Percentage of Patients Reporting Event
    Olanzapine

    (N=125)

    Placebo

    (N=129)

    Asthenia 15 6
    Dry mouth 22 7
    Constipation 11 5
    Dyspepsia 11 5
    Increased appetite 6 3
    Somnolence 35 13
    Dizziness 18 6
    Tremor 6 3

    Olanzapine Intramuscular — There was 1 adverse reaction (somnolence) observed at an incidence of 5% or greater among intramuscular olanzapine for injection-treated patients and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) during the placebo-controlled premarketing studies. The incidence of somnolence during the 24 hour IM treatment period in clinical trials in agitated patients with Schizophrenia or Bipolar I Mania was 6% for intramuscular olanzapine for injection and 3% for placebo.

    Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term, Placebo-Controlled Trials

    Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with oral olanzapine (doses ≥2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of placebo-controlled trials.

    Table 11: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Oral Olanzapine
    Body System/Adverse Reaction Percentage of Patients Reporting Event
    Olanzapine

    (N=532)

    Placebo

    (N=294)

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

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

    In the Bipolar I Disorder (manic or mixed episodes) combination placebo-controlled trials, the most commonly observed adverse reactions associated with the combination of olanzapine and lithium or valproate (incidence of ≥5% and at least twice placebo) were:

    Table 12: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Combination Trials — Bipolar I Disorder (Manic or Mixed Episodes)
    Adverse Reaction Percentage of Patients Reporting Event
    Olanzapine with lithium or valproate

    (N=229)

    Placebo with lithium or valproate

    (N=115)

    Dry mouth 32 9
    Weight gain 26 7
    Increased appetite 24 8
    Dizziness 14 7
    Back pain 8 4
    Constipation 8 4
    Speech disorder 7 1
    Increased salivation 6 2
    Amnesia 5 2
    Paresthesia 5 2

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

    Table 13 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with the combination of olanzapine (doses ≥5 mg/day) and lithium or valproate and with incidence greater than lithium or valproate alone who participated in the acute phase of placebo-controlled combination trials.

    Table 13: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials of Oral Olanzapine in Combination with Lithium or Valproate
    a Denominator used was for females only (olanzapine, N=128; placebo, N=51).

    Body System/Adverse Reaction Percentage of Patients Reporting Event
    Olanzapine with lithium or valproate

    (N=229)

    Placebo with lithium or valproate

    (N=115)

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

    For specific information about the adverse reactions observed with lithium or valproate, refer to the Adverse Reactions section of the package inserts for these other products.

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

    Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 1% or more of patients treated with intramuscular olanzapine for injection (dose range of 2.5-10 mg/injection) and with incidence greater than placebo who participated in the short-term, placebo-controlled trials in agitated patients with Schizophrenia or Bipolar I Mania.

    Table 14: Treatment-Emergent Adverse Reactions: Incidence in Short-Term (24 Hour), Placebo-Controlled Clinical Trials with Intramuscular Olanzapine for Injection in Agitated Patients with Schizophrenia or Bipolar I Mania
    Body System/Adverse Reaction Percentage of Patients Reporting Event
    Olanzapine

    (N=415)

    Placebo

    (N=150)

    Body as a Whole
    Asthenia 2 1
    Cardiovascular System
    Hypotension 2 0
    Postural hypotension 1 0
    Nervous System
    Somnolence 6 3
    Dizziness 4 2
    Tremor 1 0

    Additional Findings Observed in Clinical Trials

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

    Extrapyramidal Symptoms: The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of Schizophrenia in a 6-week trial.

    Table 15: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase
    a Percentage of patients with a Simpson-Angus Scale total score >3.

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

    Percentage of Patients Reporting Event
    Placebo Olanzapine

    5 ± 2.5 mg/day

    Olanzapine

    10 ± 2.5 mg/day

    Olanzapine

    15 ± 2.5 mg/day

    Parkinsonisma 15 14 12 14
    Akathisiab 23 16 19 27

    The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of Schizophrenia in a 6-week trial.

    Table 16: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase
    a Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis.

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

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

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

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

    Percentage of Patients Reporting Event
    Placebo

    (N=68)

    Olanzapine

    5 ± 2.5 mg/day

    (N=65)

    Olanzapine

    10 ± 2.5 mg/day

    (N=64)

    Olanzapine

    15 ± 2.5 mg/day

    (N=69)

    Dystonic eventsa 1 3 2 3
    Parkinsonism eventsb 10 8 14 20
    Akathisia eventsc 1 5 11 10
    Dyskinetic eventsd 4 0 2 1
    Residual eventse 1 2 5 1
    Any extrapyramidal event 16 15 25 32

    The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during controlled clinical trials comparing fixed doses of intramuscular olanzapine for injection with placebo in agitation. Patients in each dose group could receive up to 3 injections during the trials [see Clinical Studies (14.3)]. Patient assessments were conducted during the 24 hours following the initial dose of intramuscular olanzapine for injection. There were no statistically significant differences from placebo.

    Table 17: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dose, Placebo-Controlled Clinical Trial of Intramuscular Olanzapine for Injection in Agitated Patients with Schizophrenia
    a Percentage of patients with a Simpson-Angus Scale total score >3.

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

    Percentage of Patients Reporting Event
    Placebo Olanzapine

    IM

    2.5 mg

    Olanzapine

    IM

    5 mg

    Olanzapine

    IM

    7.5 mg

    Olanzapine

    IM

    10 mg

    Parkinsonisma 0 0 0 0 3
    Akathisiab 0 0 5 0 0

    The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions in the same controlled clinical trial comparing fixed doses of intramuscular olanzapine for injection with placebo in agitated patients with Schizophrenia.

    Table 18: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dose, Placebo-Controlled Clinical Trial of Intramuscular Olanzapine for Injection in Agitated Patients with Schizophrenia
    a Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis.

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

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

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

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

    Percentage of Patients Reporting Event
    Placebo

    (N=45)

    Olanzapine

    IM

    2.5 mg

    (N=48)

    Olanzapine

    IM

    5 mg

    (N=45)

    Olanzapine

    IM

    7.5 mg

    (N=46)

    Olanzapine

    IM

    10 mg

    (N=46)

    Dystonic eventsa 0 0 0 0 0
    Parkinsonism eventsb 0 4 2 0 0
    Akathisia eventsc 0 2 0 0 0
    Dyskinetic eventsd 0 0 0 0 0
    Residual eventse 0 0 0 0 0
    Any extrapyramidal events 0 4 2 0 0

    Dystonia, Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use.

    Other Adverse Reactions: The following table addresses dose relatedness for other adverse reactions using data from a Schizophrenia trial involving fixed dosage ranges of oral olanzapine. It enumerates the percentage of patients with treatment-emergent adverse reactions for the 3 fixed-dose range groups and placebo. The data were analyzed using the Cochran-Armitage test, excluding the placebo group, and the table includes only those adverse reactions for which there was a trend.

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

    (N=68)

    Olanzapine

    5 ± 2.5 mg/day

    (N=65)

    Olanzapine

    10 ± 2.5 mg/day

    (N=64)

    Olanzapine

    15 ± 2.5 mg/day

    (N=69)

    Asthenia 15 8 9 20
    Dry mouth 4 3 5 13
    Nausea 9 0 2 9
    Somnolence 16 20 30 39
    Tremor 3 0 5 7

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

    In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in patients with Schizophrenia or Schizoaffective Disorder, differences among 3 dose groups were observed for the following safety outcomes: weight gain, prolactin elevation, fatigue and dizziness. Mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day. Incidence of treatment-emergent prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) with significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day; fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) with significant differences between 10 vs 40 and 20 vs 40 mg/day; and dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) with significant differences between 20 vs 40 mg, was observed.

    Other Adverse Reactions Observed During the Clinical Trial Evaluation of Oral Olanzapine

    Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 mg/day) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

     
    Body as a WholeInfrequent: chills, face edema, photosensitivity reaction, suicide attempt1; Rare: chills and fever, hangover effect, sudden death1.
     
    Cardiovascular SystemInfrequent: cerebrovascular accident, vasodilatation.
     
    Digestive SystemInfrequent: nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit.
     
    Hemic and Lymphatic SystemInfrequent: leukopenia, thrombocytopenia.
     
    Metabolic and Nutritional DisordersInfrequent: alkaline phosphatase increased, bilirubinemia, hypoproteinemia.
     
    Musculoskeletal SystemRare: osteoporosis.
     
    Nervous SystemInfrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma.
     
    Respiratory SystemInfrequent: epistaxis; Rare: lung edema.
     
    Skin and AppendagesInfrequent: alopecia.
     
    Special SensesInfrequent: abnormality of accommodation, dry eyes; Rare: mydriasis.
     
    Urogenital SystemInfrequent: amenorrhea2, breast pain, decreased menstruation, impotence2, increased menstruation2, menorrhagia2, metrorrhagia2, polyuria2, urinary frequency, urinary retention, urinary urgency, urination impaired.

    1 These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

    2 Adjusted for gender.

    Other Adverse Reactions Observed During the Clinical Trial Evaluation of Intramuscular Olanzapine for Injection

    Following is a list of treatment-emergent adverse reactions reported by patients treated with intramuscular olanzapine for injection (at 1 or more doses ≥2.5 mg/injection) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) for which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients.

     
    Body as a WholeFrequent: injection site pain.
     
    Cardiovascular SystemInfrequent: syncope.
     
    Digestive SystemInfrequent: nausea.
     
    Metabolic and Nutritional DisordersInfrequent: creatine phosphokinase increased.

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

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

    Adverse reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg) reported with an incidence of 5% or more and reported at least twice as frequently as placebo-treated patients are listed in Table 20.

    Table 20: Treatment-Emergent Adverse Reactions of ≥5% Incidence among Adolescents (13-17 Years Old) with Schizophrenia or Bipolar I Disorder (Manic or Mixed Episodes)
    a Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence.

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

    Adverse Reactions Percentage of Patients Reporting Event
    6 Week Trial

    % Schizophrenia Patients

    3 Week Trial

    % Bipolar Patients

    Olanzapine

    (N=72)

    Placebo

    (N=35)

    Olanzapine

    (N=107)

    Placebo

    (N=54)

    Sedationa 39 9 48 9
    Weight increased 31 9 29 4
    Headache 17 6 17 17
    Increased appetite 17 9 29 4
    Dizziness 8 3 7 2
    Abdominal painb 6 3 6 7
    Pain in extremity 6 3 5 0
    Fatigue 3 3 14 6
    Dry mouth 4 0 7 0

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

    Adverse reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg) reported with an incidence of 2% or more and greater than placebo are listed in Table 21.

    Table 21: Treatment-Emergent Adverse Reactions of ≥2% Incidence among Adolescents (13-17 Years Old) (Combined Incidence from Short-Term, Placebo-Controlled Clinical Trials of Schizophrenia or Bipolar I Disorder [Manic or Mixed Episodes])
    a Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence.

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

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

    Adverse Reaction Percentage of Patients Reporting Event
    Olanzapine

    (N=179)

    Placebo

    (N=89)

    Sedationa 44 9
    Weight increased 30 6
    Increased appetite 24 6
    Headache 17 12
    Fatigue 9 4
    Dizziness 7 2
    Dry mouth 6 0
    Pain in extremity 5 1
    Constipation 4 0
    Nasopharyngitis 4 2
    Diarrhea 3 0
    Restlessness 3 2
    Liver enzymes increasedb 8 1
    Dyspepsia 3 1
    Epistaxis 3 0
    Respiratory tract infectionc 3 2
    Sinusitis 3 0
    Arthralgia 2 0
    Musculoskeletal stiffness 2 0

    Vital Signs and Laboratory Studies

    Vital Sign Changes — Oral olanzapine was associated with orthostatic hypotension and tachycardia in clinical trials. Intramuscular olanzapine for injection was associated with bradycardia, hypotension, and tachycardia in clinical trials [see Warnings and Precautions (5)].

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

    Within the larger premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT elevation to >200 IU/L was 2% (50/2381). Again, none of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued.

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

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

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

    Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.

    Olanzapine administration was also associated with increases in serum prolactin [see Warnings and Precautions (5.14)], with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK.

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

    Olanzapine Monotherapy in Adolescents: In placebo-controlled clinical trials of adolescent patients with Schizophrenia or Bipolar I Disorder (manic or mixed episodes), greater frequencies for the following treatment-emergent findings, at anytime, were observed in laboratory analytes compared to placebo: elevated ALT (≥3 X ULN in patients with ALT at baseline <3 X ULN), (12.1% vs 2.3%); elevated AST (27.6% vs 3.8%); low total bilirubin (22.1% vs 6.7%); elevated GGT (10.1% vs 1.2%); and elevated prolactin (47.4% vs 6.8%).

    ECG Changes — In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc (Fridericia corrected), and PR intervals. Olanzapine use was associated with a mean increase in heart rate compared to placebo (adults: +2.4 beats per minute vs no change with placebo; adolescents: +6.3 beats per minute vs -5.1 beats per minute with placebo). This increase in heart rate may be related to olanzapine’s potential for inducing orthostatic changes [see Warnings and Precautions (5.8)].

    Postmarketing Experience

    The following adverse reactions have been identified during post-approval use of Zyprexa. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

    Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to Zyprexa therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea or vomiting), jaundice, neutropenia, pancreatitis, priapism, rash, rhabdomyolysis, and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis). Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported.

    Drug Interactions

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

    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 1A2

    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.

    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 Zyprexa 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.

    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.

    Lorazepam (IM) — Administration of intramuscular lorazepam (2 mg) 1 hour after intramuscular olanzapine for injection (5 mg) did not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. However, this co-administration of intramuscular lorazepam and intramuscular olanzapine for injection added to the somnolence observed with either drug alone [see Warnings and Precautions (5.8)].

    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 (5.15)].

    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 (5.15)].

    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 (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.

    USE IN SPECIFIC POPULATIONS

    When using Zyprexa and fluoxetine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax.

    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/m2 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/m2 basis). Gestation was prolonged at 10 mg/kg/day (5 times the maximum recommended human daily oral dose on a mg/m2 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/m2 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.

    Labor and Delivery

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

    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.

    Pediatric Use

    Safety and effectiveness of olanzapine in children and adolescent patients have not been established [see Patient Counseling Information (17.13)].

    Safety and effectiveness of Zyprexa and fluoxetine in combination in children and adolescent patients have not been established.

    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 Zyprexa and fluoxetine in combination did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients.

    Drug Abuse and Dependence

    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 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/m2 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).

    Overdosage

    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.

    Management of Overdose

    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.

    Zyprexa Description

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

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

    Zyprexa tablets are intended for oral administration only.

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

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

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

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

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

    Zyprexa – Clinical Pharmacology

    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 (5HT2) antagonism. The mechanism of action of olanzapine in the treatment of acute manic or mixed episodes associated with Bipolar I Disorder is unknown.

    Pharmacodynamics

    Olanzapine binds with high affinity to the following receptors: serotonin 5HT2A/2C, 5HT6 (Ki=4, 11, and 5 nM, respectively), dopamine D1-4 (Ki=11-31 nM), histamine H1 (Ki=7 nM), and adrenergic α1 receptors (Ki=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 (Ki=57 nM) and muscarinic M1-5 (Ki=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds weakly to GABAA, BZD, and β adrenergic receptors (Ki>10 μM).

    Antagonism at receptors other than dopamine and 5HT2 may explain some of the other therapeutic and side effects of olanzapine. Olanzapine’s antagonism of muscarinic M1-5 receptors may explain its anticholinergic-like effects. Olanzapine’s antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Olanzapine’s antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug.

    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. Pharmacokinetic studies showed that Zyprexa tablets and Zyprexa ZYDIS (olanzapine orally disintegrating tablets) dosage forms of olanzapine are bioequivalent.

    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 α1-acid glycoprotein.

    Metabolism and Elimination — Following a single oral dose of 14C 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.

    Intramuscular Administration — Zyprexa IntraMuscular results in rapid absorption with peak plasma concentrations occurring within 15 to 45 minutes. Based upon a pharmacokinetic study in healthy volunteers, a 5 mg dose of intramuscular olanzapine for injection produces, on average, a maximum plasma concentration approximately 5 times higher than the maximum plasma concentration produced by a 5 mg dose of oral olanzapine. Area under the curve achieved after an intramuscular dose is similar to that achieved after oral administration of the same dose. The half-life observed after intramuscular administration is similar to that observed after oral dosing. The pharmacokinetics are linear over the clinical dosing range. Metabolic profiles after intramuscular administration are qualitatively similar to metabolic profiles after oral administration.

    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 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 non-elderly 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.

    Nonclinical Toxicology

    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 0.8-5 times the maximum recommended human daily oral dose on a mg/m2 basis) and 0.25, 2, 8 mg/kg/day (equivalent to 0.06-2 times the maximum recommended human daily oral dose on a mg/m2 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 0.13-2 and 0.13-4 times the maximum recommended human daily oral dose on a mg/m2 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/m2 basis). These tumors were not increased in another mouse study in females dosed at 10 or 30/20 mg/kg/day (2-5 times the maximum recommended human daily oral dose on a mg/m2 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/m2 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 (5.14)].

    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/m2 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/m2 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/m2 basis); therefore olanzapine may produce a delay in ovulation.

    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/m2 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/m2 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/m2 basis) for 3 months or 16 mg/kg (8 times the maximum recommended human daily oral dose on a mg/m2 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.

    Clinical Studies

    When using Zyprexa and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

    Schizophrenia

    Short-Term Trials

    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.

    Examination of population subsets (race and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

    Longer-Term Trial

    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.

    Bipolar I Disorder (Manic or Mixed Episodes)

    Monotherapy — The efficacy of oral olanzapine in the treatment of acute 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 (5-20 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 (5-20 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.

    Combination Therapy with Lithium or Valproate — The efficacy of oral olanzapine with concomitant lithium or valproate in the treatment of acute 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 5-20 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 μg/mL to 125 μg/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 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 5-20 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 μg/mL to 125 μg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.

    Agitation Associated with Schizophrenia and Bipolar I Mania

    The efficacy of intramuscular olanzapine for injection for the treatment of agitation was established in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated inpatients from 2 diagnostic groups: Schizophrenia and Bipolar I Disorder (manic or mixed episodes). Each of the trials included a single active comparator treatment arm of either haloperidol injection (Schizophrenia studies) or lorazepam injection (Bipolar I Mania study). Patients enrolled in the trials needed to be: (1) judged by the clinical investigators as clinically agitated and clinically appropriate candidates for treatment with intramuscular medication, and (2) exhibiting a level of agitation that met or exceeded a threshold score of ≥14 on the 5 items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness and excitement items) with at least 1 individual item score ≥4 using a 1-7 scoring system (1=absent, 4=moderate, 7=extreme). In the studies, the mean baseline PANSS Excited Component score was 18.4, with scores ranging from 13 to 32 (out of a maximum score of 35), thus suggesting predominantly moderate levels of agitation with some patients experiencing mild or severe levels of agitation. The primary efficacy measure used for assessing agitation signs and symptoms in these trials was the change from baseline in the PANSS Excited Component at 2 hours post-injection. Patients could receive up to 3 injections during the 24 hour IM treatment periods; however, patients could not receive the second injection until after the initial 2 hour period when the primary efficacy measure was assessed. The results of the trials follow:

    (1) In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for Schizophrenia (n=270), 4 fixed intramuscular olanzapine for injection doses of 2.5 mg, 5 mg, 7.5 mg and 10 mg were evaluated. All doses were statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection. However, the effect was larger and more consistent for the 3 highest doses. There were no significant pairwise differences for the 7.5 and 10 mg doses over the 5 mg dose.

    (2) In a second placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for Schizophrenia (n=311), 1 fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.

    (3) In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for Bipolar I Disorder (and currently displaying an acute manic or mixed episode with or without psychotic features) (n=201), 1 fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.

    Examination of population subsets (age, race, and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

    How Supplied/Storage and Handling

    How Supplied

    The Zyprexa 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets are white, round, and imprinted in blue ink with LILLY and tablet number. The 15 mg tablets are elliptical, blue, and debossed with LILLY and tablet number. The 20 mg tablets are elliptical, pink, and debossed with LILLY and tablet number. The tablets are available as follows:

    a Identi-Dose® (unit dose medication, Lilly).

    TABLET STRENGTH
    2.5 mg 5 mg 7.5 mg 10 mg 15 mg 20 mg
    Tablet No. 4112 4115 4116 4117 4415 4420
    Identification LILLY LILLY LILLY LILLY LILLY LILLY
    4112 4115 4116 4117 4415 4420
    NDC Codes:
    Bottles 30 NDC 0002-4112-30 NDC 0002-4115-30 NDC 0002-4116-30 NDC 0002-4117-30 NDC 0002-4415-30 NDC 0002-4420-30
    Blisters – IDa 100 NDC 0002-4112-33 NDC 0002-4115-33 NDC 0002-4116-33 NDC 0002-4117-33 NDC 0002-4415-33 NDC 0002-4420-33
    Bottles 1000 NDC 0002-4112-04 NDC 0002-4115-04 NDC 0002-4116-04 NDC 0002-4117-04 NDC 0002-4415-04 NDC 0002-4420-04

    Zyprexa ZYDIS (olanzapine orally disintegrating tablets) are yellow, round, and debossed with the tablet strength. The tablets are available as follows:

    Zyprexa is a registered trademark of Eli Lilly and Company.

    ZYDIS is a registered trademark of Catalent Pharma Solutions.

    a Zyprexa ZYDIS (olanzapine orally disintegrating tablets) is manufactured for Eli Lilly and Company by Catalent Pharma Solutions, United Kingdom, SN5 8RU.

    TABLET STRENGTH
    Zyprexa ZYDIS Tabletsa 5 mg 10 mg 15 mg 20 mg
    Tablet No. 4453 4454 4455 4456
    Debossed 5 10 15 20
    NDC Codes:
    Dose Pack 30 (Child Resistant) NDC 0002-4453-85 NDC 0002-4454-85 NDC 0002-4455-85 NDC 0002-4456-85

    Zyprexa IntraMuscular is available in:

     
    NDC 0002-7597-01 (No. VL7597) – 10 mg vial (1s)

    Storage and Handling

    Store Zyprexa tablets, Zyprexa ZYDIS, and Zyprexa IntraMuscular vials (before reconstitution) at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. Reconstituted Zyprexa IntraMuscular may be stored at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP] for up to 1 hour if necessary. Discard any unused portion of reconstituted Zyprexa IntraMuscular. 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 Zyprexa tablets and Zyprexa ZYDIS from light and moisture. Protect Zyprexa IntraMuscular from light, do not freeze.

    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 Zyprexa 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 Zyprexa, call your doctor. When using Zyprexa and fluoxetine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.

    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 Zyprexa, and should counsel them in its appropriate use. A patient Medication Guide is available for Zyprexa. 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 Zyprexa and fluoxetine in combination, also refer to the Medication Guide for Symbyax.

    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 increased risk of death. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with Zyprexa had a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo.

    Zyprexa is not approved for elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].

    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 Zyprexa. 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)].

    Hyperglycemia

    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 Zyprexa [see Warnings and Precautions (5.4)].

    Hyperlipidemia

    Patients should be counseled that hyperlipidemia has occurred during treatment with Zyprexa. Patients should have their lipid profile monitored regularly [see Warnings and Precautions (5.5)].

    Weight Gain

    Patients should be counseled that weight gain has occurred during treatment with Zyprexa. Patients should have their weight monitored regularly [see Warnings and Precautions (5.6)].

    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 Zyprexa, e.g., diazepam or alcohol [see Warnings and Precautions (5.8) 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 heart beat, or fainting.

    Potential for Cognitive and Motor Impairment

    Because Zyprexa 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 Zyprexa therapy does not affect them adversely [see Warnings and Precautions (5.11)].

    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 (5.12)].

    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)].

    Alcohol

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

    Phenylketonurics

    Zyprexa ZYDIS (olanzapine orally disintegrating tablets) contains phenylalanine (0.34, 0.45, 0.67, or 0.90 mg per 5, 10, 15, or 20 mg tablet, respectively) [see Description (11)].

    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 Zyprexa [see Use in Specific Populations (8.1)].

    Nursing Mothers — Patients should be advised not to breast-feed an infant if they are taking Zyprexa [see Use in Specific Populations (8.3)].

    Pediatric Use — Zyprexa is not approved for the treatment of Schizophrenia and Bipolar I Disorder (manic or mixed episodes) in children and adolescents. Compared to patients from adult clinical trials, adolescents were more likely to gain more weight and have greater increases in cholesterol and triglycerides. Safety and effectiveness of Zyprexa in patients under 18 years of age have not been established. Safety and effectiveness of Zyprexa and fluoxetine in combination in patients under 18 years of age have not been established [see Warnings and Precautions (5.4, 5.5, 5.6) and Use in Specific Populations (8.4)].

    Literature revised March 19, 2009

    Eli Lilly and Company, Indianapolis, IN 46285, USA

    Copyright © 1997, 2009, Eli Lilly and Company. All rights reserved.

    PV 6242 AMP

    Medication Guide

    Zyprexa® (zy-PREX-a)

    (olanzapine)

    Tablet

    Zyprexa® ZYDIS® (zy-PREX-a ZY-dis)

    (olanzapine)

    Tablet, Orally Disintegrating

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

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

    Zyprexa may be associated with the following serious risks:

    High blood sugar (hyperglycemia): High blood sugar can occur if you have diabetes already or even if you have never had diabetes. In rare cases, this could lead to ketoacidosis (build up of acid in the blood due to ketones), coma, or death. Your doctor should do lab tests to check your blood sugar before you start taking Zyprexa and during treatment. In people who do not have diabetes, sometimes high blood sugar goes away when Zyprexa is stopped. People with diabetes and some people who did not have diabetes before taking Zyprexa need to take medicine for high blood sugar even after they stop taking Zyprexa.

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

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

    • feel very thirsty
    • need to urinate more than usual
    • feel very hungry
    • feel weak or tired
    • feel sick to your stomach
    • feel confused, or your breath smells fruity.

    High cholesterol and triglyceride levels in the blood (fat in the blood): These have been observed in patients treated with Zyprexa, especially in teenagers (13-17 years old). Zyprexa is not approved in patients less than 18 years old. You may not have any symptoms, so your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking Zyprexa and during treatment.

    Increase in weight (weight gain): Weight gain is very commonly seen in patients who take Zyprexa. Teenagers (13-17 years old) are more likely to gain weight and to gain more weight than adults. Zyprexa is not approved in patients less than 18 years old. Some patients may gain a lot of weight while taking Zyprexa, so you and your doctor should check your weight regularly. Talk to your doctor about ways to control weight gain, such as eating a healthy, balanced diet, and exercising.

    What is Zyprexa?

    Zyprexa is a prescription medicine approved for use in adults:

    • to treat schizophrenia.
    • alone or with lithium or valproate for the short-term treatment of manic or mixed episodes that happen with Bipolar I Disorder.
    • for long-term treatment of Bipolar I Disorder.
    • with the medicine fluoxetine (Prozac®), for the short-term treatment of episodes of depression that happen with Bipolar I Disorder.
    • with the medicine fluoxetine (Prozac), for the short-term treatment of episodes of depression that do not respond to 2 other medicines, also called treatment resistant depression.

    It is not known if Zyprexa is safe and works in children under 18 years of age.

    It is not known if Zyprexa taken with fluoxetine (Prozac) is safe and works in children under 18 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. With treatment, some of your symptoms of schizophrenia may improve.

    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. With treatment, some of your symptoms of Bipolar I Disorder may improve.

    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. With treatment, some of your symptoms of treatment resistant depression may improve.

    If you do not think you are getting better, call your doctor.

    What should I tell my doctor before taking Zyprexa?

    Zyprexa may not be right for you. Before starting Zyprexa, tell your doctor about all your medical conditions, including if you have or had any of the following:

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

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

    How should I take Zyprexa?

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

    What should I avoid while taking Zyprexa?

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

    What are the possible side effects of Zyprexa?

    Other possible serious risks:

    • Increased risk of death and increased incidence of stroke or “mini-strokes” called transient ischemic attacks (TIAs) in elderly people with psychosis related to dementia (a brain disorder that lessens the ability to remember, think, and reason). Zyprexa is not approved for these patients.
    • Neuroleptic Malignant Syndrome (NMS): NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including Zyprexa. NMS can cause death and must be treated in a hospital. Call your doctor right away if you become severely ill and have some or all of these symptoms:
      • high fever
      • excessive sweating
      • rigid muscles
      • confusion
      • changes in your breathing, heartbeat, and blood pressure
    • Tardive Dyskinesia: This condition causes body movements that keep happening and that you cannot control. These movements usually affect the face and tongue. Tardive dyskinesia may not go away, even if you stop taking Zyprexa. It may also start after you stop taking Zyprexa. Tell your doctor if you get any body movements that you cannot control.
    • Decreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heart beat, or fainting
    • Difficulty swallowing
    • Seizures
    • 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 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

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

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

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

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

    How should I store Zyprexa?

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

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

    General information about Zyprexa

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

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

    What are the ingredients in Zyprexa?

    Active ingredient: olanzapine

    Inactive ingredients:

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

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

    Medication Guide issued March 19, 2009

    Eli Lilly and Company

    Indianapolis, IN 46285, USA

    www.Zyprexa.com

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

    PV 6920 AMP

    PACKAGE LABEL – Zyprexa 2.5 mg tablet, bottle of 30

    NDC 0002-4112-30

    30 Tablets

    No. 4112

    Zyprexa

    Olanzapine Tablets

    2.5 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 2.5 mg tablet, ID 100

    ID 100

    IDENTI-DOSE®

    NDC 0002-4112-33

    Tablets No. 4112

    Zyprexa®

    Olanzapine Tablets

    2.5 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 2.5 mg tablet, bottle of 1000

    NDC 0002-4112-04

    1000 Tablets

    No. 4112

    Zyprexa®

    Olanzapine Tablets

    2.5 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 2.5 mg tablet, bottle of 7, sample

    7 Tablets

    No. 4112

    Rx only

    FREE SAMPLE

    Zyprexa®

    Olanzapine Tablets

    2.5 mg

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 5 mg tablet, bottle of 30

    NDC 0002-4115-30

    30 Tablets

    No. 4115

    Zyprexa

    Olanzapine Tablets

    5 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 5 mg tablet, ID 100

    ID 100

    IDENTI-DOSE®

    NDC 0002-4115-33

    Tablets No. 4115

    Zyprexa®

    Olanzapine Tablets

    5 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 5 mg tablet, bottle of 1000

    NDC 0002-4115-04

    1000 Tablets

    No. 4115

    Zyprexa®

    Olanzapine Tablets

    5 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 5 mg tablet, bottle of 7, sample

    7 Tablets

    No. 4115

    Rx only

    FREE SAMPLE

    Zyprexa®

    Olanzapine Tablets

    5 mg

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 7.5 mg tablet, bottle of 30

    NDC 0002-4116-30

    30 Tablets

    No. 4116

    Zyprexa

    Olanzapine Tablets

    7.5 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 7.5 mg tablet, ID 100

    ID 100

    IDENTI-DOSE®

    NDC 0002-4116-33

    Tablets No. 4116

    Zyprexa®

    Olanzapine Tablets

    7.5 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 7.5 mg tablet, bottle of 1000

    NDC 0002-4116-04

    1000 Tablets

    No. 4116

    Zyprexa®

    Olanzapine Tablets

    7.5 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 10 mg tablet, bottle of 30

    NDC 0002-4117-30

    30 Tablets

    No. 4117

    Zyprexa

    Olanzapine Tablets

    10 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 10 mg tablet, ID 100

    ID 100

    IDENTI-DOSE®

    NDC 0002-4117-33

    Tablets No. 4117

    Zyprexa®

    Olanzapine Tablets

    10 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 10 mg tablet, bottle of 1000

    NDC 0002-4117-04

    1000 Tablets

    No. 4117

    Zyprexa®

    Olanzapine Tablets

    10 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 10 mg tablet, bottle of 7, sample

    7 Tablets

    No. 4117

    Rx only

    FREE SAMPLE

    Zyprexa®

    Olanzapine Tablets

    10 mg

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 15 mg tablet, bottle of 30

    NDC 0002-4415-30

    30 Tablets

    No. 4415

    Zyprexa

    Olanzapine Tablets

    15 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 15 mg tablet, ID 100

    ID 100

    IDENTI-DOSE®

    NDC 0002-4415-33

    Tablets No. 4415

    Zyprexa®

    Olanzapine Tablets

    15 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 15 mg tablet, bottle of 1000

    NDC 0002-4415-04

    1000 Tablets

    No. 4415

    Zyprexa®

    Olanzapine Tablets

    15 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 15 mg tablet, bottle of 7, sample

    7 Tablets

    No. 4415

    Rx only

    FREE SAMPLE

    Zyprexa®

    Olanzapine Tablets

    15 mg

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 20 mg tablet, bottle of 30

    NDC 0002-4420-30

    30 Tablets

    No. 4420

    Zyprexa

    Olanzapine Tablets

    20 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 20 mg tablet, ID 100

    ID 100

    IDENTI-DOSE®

    NDC 0002-4420-33

    Tablets No. 4420

    Zyprexa®

    Olanzapine Tablets

    20 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 20 mg tablet, bottle of 1000

    NDC 0002-4420-04

    1000 Tablets

    No. 4420

    Zyprexa®

    Olanzapine Tablets

    20 mg

    Rx only

    Medication Guide is to be dispensed to patients.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa 20 mg tablet, bottle of 7, sample

    7 Tablets

    No. 4420

    Rx only

    FREE SAMPLE

    Zyprexa®

    Olanzapine Tablets

    20 mg

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa ZYDIS 5 mg tablet, 30 sachets

    5 mg orally disintegrating tablets

    30 Sachets, No. 4453

    NDC 0002-4453-85

    Rx only

    Medication Guide is to be dispensed to patients.

    Zyprexa ® ZYDIS®

    Olanzapine Orally Disintegrating Tablets

    5 mg

    Phenylketonurics: Contains phenylalanine 0.34 mg per tablet.

    DO NOT OPEN POUCH UNTIL IMMEDIATELY PRIOR TO USE.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa ZYDIS 5 mg tablet, 7 sachets, sample

    5 mg orally disintegrating tablets

    7 Sachets, No. 4453

    Rx only

    FREE SAMPLE

    Medication Guide is to be dispensed to patients.

    Zyprexa® ZYDIS®

    Olanzapine Orally Disintegrating Tablets

    5 mg

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa ZYDIS 10 mg tablet, 30 sachets

    10 mg orally disintegrating tablets

    30 Sachets, No. 4454

    NDC 0002-4454-85

    Rx only

    Medication Guide is to be dispensed to patients.

    Zyprexa® ZYDIS®

    Olanzapine Orally Disintegrating Tablets

    10 mg

    Phenylketonurics: Contains phenylalanine 0.45 mg per tablet.

    DO NOT OPEN POUCH UNTIL IMMEDIATELY PRIOR TO USE.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa ZYDIS 10 mg tablet, 7 sachets, sample

    10 mg orally disintegrating tablets

    7 Sachets, No. 4454

    Rx only

    FREE SAMPLE

    Medication Guide is to be dispensed to patients.

    Zyprexa® ZYDIS®

    Olanzapine Orally Disintegrating Tablets

    10 mg

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa ZYDIS 15 mg tablet, 30 sachets

    15 mg orally disintegrating tablets

    30 Sachets, No. 4455

    NDC 0002-4455-85

    Rx only

    Medication Guide is to be dispensed to patients.

    Zyprexa® ZYDIS®

    Olanzapine Orally Disintegrating Tablets

    15 mg

    Phenylketonurics: Contains phenylalanine 0.67 mg per tablet.

    DO NOT OPEN POUCH UNTIL IMMEDIATELY PRIOR TO USE.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa ZYDIS 15 mg tablet, 7 sachets, sample

    15 mg orally disintegrating tablets

    7 Sachets, No. 4455

    Rx only

    FREE SAMPLE

    Medication Guide is to be dispensed to patients.

    Zyprexa® ZYDIS®

    Olanzapine Orally Disintegrating Tablets

    15 mg

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa ZYDIS 20 mg tablet, 30 sachets

    20 mg orally disintegrating tablets

    30 Sachets, No. 4456

    NDC 0002-4456-85

    Rx only

    Medication Guide is to be dispensed to patients.

    Zyprexa® ZYDIS®

    Olanzapine Orally Disintegrating Tablets

    20 mg

    Phenylketonurics: Contains phenylalanine 0.90 mg per tablet.

    DO NOT OPEN POUCH UNTIL IMMEDIATELY PRIOR TO USE.

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa ZYDIS 20 mg tablet, 7 sachets, sample

    20 mg orally disintegrating tablets

    7 Sachets, No. 4456

    Rx only

    FREE SAMPLE

    Medication Guide is to be dispensed to patients.

    Zyprexa® ZYDIS®

    Olanzapine Orally Disintegrating Tablets

    20 mg

    www.Zyprexa.com

    Lilly

    PACKAGE LABEL – Zyprexa INTRAMUSCULAR 10 mg/vial

    NDC 0002-7597-01

    1 Vial

    No. VL7597

    Zyprexa® IntraMuscular

    Olanzapine for Injection

    Sterile Single Use Vial

    Rx only

    For intramuscular use only.

    10 mg/vial

    www.Zyprexa.com

    Lilly

    Zyprexa 

    olanzapine tablet

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-4112
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Olanzapine (Olanzapine) Olanzapine 2.5 mg
    Inactive Ingredients
    Ingredient Name Strength
    Carnauba wax  
    Crospovidone  
    Hydroxypropyl cellulose  
    Hypromellose  
    Lactose  
    Magnesium stearate  
    Cellulose, Microcrystalline  
    Titanium dioxide  
    POLYETHYLENE GLYCOL  
    POLYSORBATE 80  
    Product Characteristics
    Color white Score no score
    Shape ROUND Size 7mm
    Flavor Imprint Code LILLY;4112
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-4112-30 30 TABLET (30 TABLET) in 1 BOTTLE
    2 NDC:0002-4112-04 1 BOTTLE (1 BOTTLE) in 1 CARTON
    2 1000 TABLET (1000 TABLET) in 1 BOTTLE
    3 NDC:0002-4112-33 100 BLISTER PACK (100 BLISTER PACK) in 1 CARTON
    3 NDC:0002-4112-01 1 TABLET (1 TABLET) in 1 BLISTER PACK
    4 NDC:0002-4112-07 1 BOTTLE (1 BOTTLE) in 1 CARTON
    4 7 TABLET (7 TABLET) in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA020592 06/23/1997
    Zyprexa 

    olanzapine tablet

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-4115
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Olanzapine (Olanzapine) Olanzapine 5 mg
    Inactive Ingredients
    Ingredient Name Strength
    Carnauba wax  
    Crospovidone  
    Hydroxypropyl cellulose  
    Hypromellose  
    Lactose  
    Magnesium stearate  
    Cellulose, Microcrystalline  
    Titanium dioxide  
    POLYETHYLENE GLYCOL  
    POLYSORBATE 80  
    Product Characteristics
    Color white Score no score
    Shape ROUND Size 8mm
    Flavor Imprint Code LILLY;4115
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-4115-30 30 TABLET (30 TABLET) in 1 BOTTLE
    2 NDC:0002-4115-04 1 BOTTLE (1 BOTTLE) in 1 CARTON
    2 1000 TABLET (1000 TABLET) in 1 BOTTLE
    3 NDC:0002-4115-33 100 BLISTER PACK (100 BLISTER PACK) in 1 CARTON
    3 NDC:0002-4115-01 1 TABLET (1 TABLET) in 1 BLISTER PACK
    4 NDC:0002-4115-07 1 BOTTLE (1 BOTTLE) in 1 CARTON
    4 7 TABLET (7 TABLET) in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA020592 10/01/1996
    Zyprexa 

    olanzapine tablet

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-4116
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Olanzapine (Olanzapine) Olanzapine 7.5 mg
    Inactive Ingredients
    Ingredient Name Strength
    Carnauba wax  
    Crospovidone  
    Hydroxypropyl cellulose  
    Hypromellose  
    Lactose  
    Magnesium stearate  
    Cellulose, Microcrystalline  
    Titanium dioxide  
    POLYETHYLENE GLYCOL  
    POLYSORBATE 80  
    Product Characteristics
    Color white Score no score
    Shape ROUND Size 9mm
    Flavor Imprint Code LILLY;4116
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-4116-30 30 TABLET (30 TABLET) in 1 BOTTLE
    2 NDC:0002-4116-04 1 BOTTLE (1 BOTTLE) in 1 CARTON
    2 1000 TABLET (1000 TABLET) in 1 BOTTLE
    3 NDC:0002-4116-33 100 BLISTER PACK (100 BLISTER PACK) in 1 CARTON
    3 NDC:0002-4116-01 1 TABLET (1 TABLET) in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA020592 10/01/1996
    Zyprexa 

    olanzapine tablet

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-4117
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Olanzapine (Olanzapine) Olanzapine 10 mg
    Inactive Ingredients
    Ingredient Name Strength
    Carnauba wax  
    Crospovidone  
    Hydroxypropyl cellulose  
    Hypromellose  
    Lactose  
    Magnesium stearate  
    Cellulose, Microcrystalline  
    Titanium dioxide  
    POLYETHYLENE GLYCOL  
    POLYSORBATE 80  
    Product Characteristics
    Color white Score no score
    Shape ROUND Size 10mm
    Flavor Imprint Code LILLY;4117
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-4117-30 30 TABLET (30 TABLET) in 1 BOTTLE
    2 NDC:0002-4117-04 1 BOTTLE (1 BOTTLE) in 1 CARTON
    2 1000 TABLET (1000 TABLET) in 1 BOTTLE
    3 NDC:0002-4117-33 100 BLISTER PACK (100 BLISTER PACK) in 1 CARTON
    3 NDC:0002-4117-01 1 TABLET (1 TABLET) in 1 BLISTER PACK
    4 NDC:0002-4117-07 1 BOTTLE (1 BOTTLE) in 1 CARTON
    4 7 TABLET (7 TABLET) in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA020592 10/01/1996
    Zyprexa 

    olanzapine tablet

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-4415
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Olanzapine (Olanzapine) Olanzapine 15 mg
    Inactive Ingredients
    Ingredient Name Strength
    Carnauba wax  
    Crospovidone  
    Hydroxypropyl cellulose  
    Hypromellose  
    Lactose  
    Magnesium stearate  
    Cellulose, Microcrystalline  
    Titanium dioxide  
    Triacetin  
    Product Characteristics
    Color blue Score no score
    Shape OVAL (elliptical) Size 12mm
    Flavor Imprint Code LILLY;4415
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-4415-30 30 TABLET (30 TABLET) in 1 BOTTLE
    2 NDC:0002-4415-04 1 BOTTLE (1 BOTTLE) in 1 CARTON
    2 1000 TABLET (1000 TABLET) in 1 BOTTLE
    3 NDC:0002-4415-33 100 BLISTER PACK (100 BLISTER PACK) in 1 CARTON
    3 NDC:0002-4415-01 1 TABLET (1 TABLET) in 1 BLISTER PACK
    4 NDC:0002-4415-07 1 BOTTLE (1 BOTTLE) in 1 CARTON
    4 7 TABLET (7 TABLET) in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA020592 01/10/2000
    Zyprexa 

    olanzapine tablet

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-4420
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Olanzapine (Olanzapine) Olanzapine 20 mg
    Inactive Ingredients
    Ingredient Name Strength
    Carnauba wax  
    Crospovidone  
    Hydroxypropyl cellulose  
    Hypromellose  
    Lactose  
    Magnesium stearate  
    Cellulose, Microcrystalline  
    Titanium dioxide  
    Ferric Oxide Red  
    Polyethylene glycol 4000  
    Product Characteristics
    Color pink Score no score
    Shape OVAL (elliptical) Size 13mm
    Flavor Imprint Code LILLY;4420
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-4420-30 30 TABLET (30 TABLET) in 1 BOTTLE
    2 NDC:0002-4420-04 1 BOTTLE (1 BOTTLE) in 1 CARTON
    2 1000 TABLET (1000 TABLET) in 1 BOTTLE
    3 NDC:0002-4420-33 100 BLISTER PACK (100 BLISTER PACK) in 1 CARTON
    3 NDC:0002-4420-01 1 TABLET (1 TABLET) in 1 BLISTER PACK
    4 NDC:0002-4420-07 1 BOTTLE (1 BOTTLE) in 1 CARTON
    4 7 TABLET (7 TABLET) in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA020592 03/01/2001
    Zyprexa   ZYDIS

    olanzapine tablet, orally disintegrating

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-4453
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Olanzapine (Olanzapine) Olanzapine 5 mg
    Inactive Ingredients
    Ingredient Name Strength
    Gelatin  
    Mannitol  
    Methylparaben Sodium  
    Propylparaben Sodium  
    Aspartame  
    Product Characteristics
    Color yellow Score no score
    Shape ROUND Size 9mm
    Flavor Imprint Code 5
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-4453-85 30 DOSE PACK (30 DOSE PACK) in 1 CARTON
    1 NDC:0002-4453-01 1 BLISTER PACK (1 BLISTER PACK) in 1 DOSE PACK
    1 1 TABLET, ORALLY DISINTEGRATING (1 TABLET) in 1 BLISTER PACK
    2 NDC:0002-4453-07 7 DOSE PACK (7 DOSE PACK) in 1 CARTON
    2 1 BLISTER PACK (1 BLISTER PACK) in 1 DOSE PACK
    2 1 TABLET, ORALLY DISINTEGRATING (1 TABLET) in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021086 06/01/2000
    Zyprexa   ZYDIS

    olanzapine tablet, orally disintegrating

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-4454
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Olanzapine (Olanzapine) Olanzapine 10 mg
    Inactive Ingredients
    Ingredient Name Strength
    Gelatin  
    Mannitol  
    Methylparaben Sodium  
    Propylparaben Sodium  
    Aspartame  
    Product Characteristics
    Color yellow Score no score
    Shape ROUND Size 9mm
    Flavor Imprint Code 10
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-4454-85 30 DOSE PACK (30 DOSE PACK) in 1 CARTON
    1 NDC:0002-4454-01 1 BLISTER PACK (1 BLISTER PACK) in 1 DOSE PACK
    1 1 TABLET, ORALLY DISINTEGRATING (1 TABLET) in 1 BLISTER PACK
    2 NDC:0002-4454-07 7 DOSE PACK (7 DOSE PACK) in 1 CARTON
    2 1 BLISTER PACK (1 BLISTER PACK) in 1 DOSE PACK
    2 1 TABLET, ORALLY DISINTEGRATING (1 TABLET) in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021086 06/01/2000
    Zyprexa   ZYDIS

    olanzapine tablet, orally disintegrating

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-4455
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Olanzapine (Olanzapine) Olanzapine 15 mg
    Inactive Ingredients
    Ingredient Name Strength
    Gelatin  
    Mannitol  
    Methylparaben Sodium  
    Propylparaben Sodium  
    Aspartame  
    Product Characteristics
    Color yellow Score no score
    Shape ROUND Size 9mm
    Flavor Imprint Code 15
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-4455-85 30 DOSE PACK (30 DOSE PACK) in 1 CARTON
    1 NDC:0002-4455-01 1 BLISTER PACK (1 BLISTER PACK) in 1 DOSE PACK
    1 1 TABLET, ORALLY DISINTEGRATING (1 TABLET) in 1 BLISTER PACK
    2 NDC:0002-4455-07 7 DOSE PACK (7 DOSE PACK) in 1 CARTON
    2 1 BLISTER PACK (1 BLISTER PACK) in 1 DOSE PACK
    2 1 TABLET, ORALLY DISINTEGRATING (1 TABLET) in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021086 09/01/2001
    Zyprexa   ZYDIS

    olanzapine tablet, orally disintegrating

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-4456
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Olanzapine (Olanzapine) Olanzapine 20 mg
    Inactive Ingredients
    Ingredient Name Strength
    Gelatin  
    Mannitol  
    Methylparaben Sodium  
    Propylparaben Sodium  
    Aspartame  
    Product Characteristics
    Color yellow Score no score
    Shape ROUND Size 9mm
    Flavor Imprint Code 20
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-4456-85 30 DOSE PACK (30 DOSE PACK) in 1 CARTON
    1 NDC:0002-4456-01 1 BLISTER PACK (1 BLISTER PACK) in 1 DOSE PACK
    1 1 TABLET, ORALLY DISINTEGRATING (1 TABLET) in 1 BLISTER PACK
    2 NDC:0002-4456-07 7 DOSE PACK (7 DOSE PACK) in 1 CARTON
    2 1 BLISTER PACK (1 BLISTER PACK) in 1 DOSE PACK
    2 1 TABLET, ORALLY DISINTEGRATING (1 TABLET) in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021086 09/01/2001
    Zyprexa   INTRAMUSCULAR

    olanzapine injection, powder, for solution

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-7597
    Route of Administration INTRAMUSCULAR DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Olanzapine (Olanzapine) Olanzapine 10 mg  in 2 mL
    Inactive Ingredients
    Ingredient Name Strength
    Lactose monohydrate 50 mg  in 2 mL
    Tartaric acid 3.5 mg  in 2 mL
    Hydrochloric acid  
    Sodium hydroxide  
    Packaging
    # Item Code Package Description
    1 NDC:0002-7597-01 1 VIAL (1 VIAL) in 1 CARTON
    1 2 mL in 1 VIAL
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021253 04/01/2004
    Labeler - Eli Lilly and Company (006421325)
    Establishment
    Name Address ID/FEI Operations
    Eli Lilly S.A. – Irish Branch 986500023 MANUFACTURE, ANALYSIS
    Establishment
    Name Address ID/FEI Operations
    Eli Lilly and Company (Tippecanoe Laboratories) 130890994 ANALYSIS
    Establishment
    Name Address ID/FEI Operations
    Eli Lilly and Company (Indianapolis) 006421325 MANUFACTURE, ANALYSIS
    Establishment
    Name Address ID/FEI Operations
    Lilly del Caribe, Inc. (PR01) 806917345 MANUFACTURE, ANALYSIS
    Establishment
    Name Address ID/FEI Operations
    Catalent Pharma Solutions LLC – PR 961182920 MANUFACTURE
    Establishment
    Name Address ID/FEI Operations
    Catalent UK Swindon ZYDIS LTD 237676320 MANUFACTURE, ANALYSIS
    Establishment
    Name Address ID/FEI Operations
    Sharp Corporation-Conshohocken 002346625 REPACK

    Revised: 03/2009   Eli Lilly and Company

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