OLANZEX ORO

tablet olanzapine: 10 mg 10 mg 1 time per day 5-20 mg 1 time per day 15 mg 1 time per day 10 mg 1 time per day 5-20 mg 1 time per day Renal failure Subject at risk of prolongation of the QT interval The information provided on drug interactions results from the synthesis of the sources consulted by the Vidal scientific team.

They do not systematically reflect the information contained in the SPCs.

They are intended for practical purposes for health professionals.

The absence of an AMI in the Vidal database must never be interpreted as proof of safety. name: OLANZAPINE ARROW 15 mg Cpr orodisp Plq/28 cip13:3400930157220 conservation: Cip: 3400930157220 Storage conditions: Before opening: < 25° for 24 months (Store away from light, Store in its packaging, Store away from humidity) status: Marketed.

Olanzapine is an atypical antipsychotic indicated

As oral formulation for the: Treatment of schizophrenia.

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

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

The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents.

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

Efficacy was established in three clinical trials in patients with manic or mixed episodes of bipolar I disorder: two 3.

• to 4-week trials and one maintenance trial.

Adolescents (ages 13-17): Efficacy was established in one 3-week trial in patients with manic or mixed episodes associated with bipolar I disorder.

Medication therapy for pediatric patients with schizophrenia or bipolar I disorder should be undertaken only after a thorough diagnostic evaluation and with careful consideration of the potential risks.

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

Efficacy was established in two 6-week clinical trials in adults.

Maintenance efficacy has not been systematically evaluated.

As Olanzapine and Fluoxetine in Combination for the: Treatment of depressive episodes associated with bipolar I disorder.

Efficacy was established with

Symbyax (olanzapine and fluoxetine in combination); refer to the product label for Symbyax.

Treatment of treatment resistant depression.

Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax. 1.1 Schizophrenia Oral olanzapine is indicated for the treatment of schizophrenia.

Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial.

In adolescent patients with schizophrenia (ages 13-17), efficacy was established in one 6-week trial.

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia.

Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents. 1.2 Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy — Oral olanzapine is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder.

Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3.

• to 4-week trials and one monotherapy maintenance trial.

In adolescent patients with manic or mixed episodes associated with bipolar I disorder (ages 13-17), efficacy was established in one 3-week trial.

Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents.

Adjunctive Therapy to Lithium or

Valproate — Oral olanzapine is indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate.

The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials. 1.3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder Pediatric schizophrenia and bipolar I disorder are serious mental disorders; however, diagnosis can be challenging.

For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms.

It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment.

Medication treatment for both pediatric schizophrenia and bipolar I disorder should be part of a total treatment program that often includes psychological, educational and social interventions. 1.5 Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder Oral olanzapine and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar I disorder, based on clinical studies.

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

Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder. 1.6 Olanzapine and Fluoxetine in Combination: Treatment Resistant Depression Oral olanzapine and fluoxetine in combination is indicated for the treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode), based on clinical studies in adult patients.

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

The mechanism of action of olanzapine, in the listed indications is unclear.

However, the efficacy of olanzapine in schizophrenia could be mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism. 12.2 Pharmacodynamics Olanzapine binds with high affinity to the following receptors: serotonin 5HT 2A/2C, 5HT 6 (K i =4, 11, and 5 nM, respectively), dopamine D 1-4 (K i =11-31 nM), histamine H 1 (K i =7 nM), and adrenergic α 1 receptors (K i =19 nM).

Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT 3 (K i =57 nM) and muscarinic M 1-5 (K i =73, 96, 132, 32, and 48 nM, respectively).

Olanzapine binds with low affinity to GABA A, BZD, and β-adrenergic receptors (K i >10 μM). 12.3 Pharmacokinetics Oral Administration, Monotherapy — Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose.

It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation.

Food does not affect the rate or extent of olanzapine absorption.

Pharmacokinetic studies showed that olanzapine tablets and olanzapine orally disintegrating tablets dosage forms of olanzapine are bioequivalent.

Olanzapine displays linear kinetics over the clinical dosing range.

Its half-life ranges from to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 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 to 1100 ng/mL, binding primarily to albumin and α 1 -acid glycoprotein.

Metabolism and

Elimination — Following a single oral dose of 14 C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized.

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

In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites.

After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4′-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine.

Both metabolites lack pharmacological activity at the concentrations observed.

Direct glucuronidation and cytochrome

P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine.

In vitro studies suggest that

CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation.

CYP2D6 mediated oxidation appears to be a minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.

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.

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 nonelderly subjects (<65 years).

Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity.

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.

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.

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.

Adolescents (ages 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.

Olanzapine is an antipsychotic agent, an antimanic and mood-regulating treatment with a broad pharmacological profile across a number of receptors.

In preclinical studies, olanzapine showed affinity for certain receptors (Ki < 100 nM) such as serotonergic 5HT2A/2C, 5HT3, 5HT6, dopamine D1, D2, D3, D4, D5, muscarinic cholinergic m1-m5, α1 adrenergic, and histamine H1 receptors.

Animal behavioral studies have shown antagonism of the 5HT, dopaminergic and cholinergic systems, supporting the receptor binding profile. in vitro that olanzapine had greater affinity for serotonin 5HT2 receptors than for dopamine D2 receptors, and greater activity in vivo on 5HT2 models compared to D2 models.

It has been demonstrated by electrophysiological studies that olanzapine selectively reduces transmission at the level of dopaminergic neurons of the mesolimbic system (A10) while the effect observed on the striatal system (A9) involved in motor activity is limited.

Olanzapine reduces the conditioned avoidance response, a test which may indicate antipsychotic activity, at doses lower than those responsible for inducing catalepsy, an effect which may indicate the occurrence of motor adverse effects.

Unlike other antipsychotic agents, olanzapine increases the response to an "anxiolysis" test.

syndrome NUTRITION, METABOLISM ENT, STOMATOLOGY PSYCHIATRY CARDIOVASCULAR SYSTEM DIGESTIVE SYSTEM MUSCULO-SKELETAL SYSTEM NERVOUS SYSTEM RESPIRATORY SYSTEM TOXICOLOGY UROLOGY, NEPHROLOGY.

In premarketing trials involving more than 3100 patients and/or normal subjects, accidental or intentional acute overdosage of olanzapine was identified in 67 patients.

In the patient taking the largest identified amount, 300 mg, the only symptoms reported were drowsiness and slurred speech.

In the limited number of patients who were evaluated in hospitals, including the patient taking 300 mg, there were no observations indicating an adverse change in laboratory analytes or ECG.

Vital signs were usually within normal limits following overdoses.

In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases.

In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma.

Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and 1 patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension.

Eli Lilly and

Company has received reports of fatality in association with overdose of olanzapine alone.

In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine. 10.2 Management of Overdose There is no specific antidote to an overdose of olanzapine.

The possibility of multiple drug involvement should be considered.

Establish and maintain an airway and ensure adequate oxygenation and ventilation.

Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

Center for the most up to date information on the management of overdosage.

For specific information about overdosage with lithium or valproate, refer to the Overdosage section of the prescribing information for those products.

For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax prescribing information.

None with olanzapine monotherapy.

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

For specific information about the contraindications of lithium or valproate, refer to the Contraindications section of the package inserts for these other products.

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

When using olanzapine in combination with lithium or valproate, refer to the Contraindications section of the package inserts for those products.

Schizophrenia in adults Oral

Start at 5 mg to 10 mg once daily; Target: 10 mg/day within several days Schizophrenia in adolescents Oral: Start at 2.5 mg to 5 mg once daily; Target: 10 mg/day Bipolar I Disorder (manic or mixed episodes) in adults Oral: Start at 10 mg or 15 mg once daily Bipolar I Disorder (manic or mixed episodes) in adolescents Oral: Start at 2.5 mg to 5 mg once daily; Target: 10 mg/day Bipolar I Disorder (manic or mixed episodes) with lithium or valproate in adults Oral: Start at 10 mg once daily Depressive Episodes associated with Bipolar I Disorder in adults Oral in combination with fluoxetine: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily Depressive Episodes associated with Bipolar I Disorder in children and adolescents Oral in combination with fluoxetine: Start at 2.5 mg of oral olanzapine and 20 mg of fluoxetine once daily Treatment Resistant Depression in adults Oral in combination with fluoxetine: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily Lower starting dose recommended in debilitated or pharmacodynamically sensitive patients or patients with predisposition to hypotensive reactions, or with potential for slowed metabolism.

Olanzapine may be given without regard to meals.

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

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

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

Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages to 17. 2.1 Schizophrenia Adults Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 mg 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 mg/day to 15 mg/day in clinical trials.

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

An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment.

Olanzapine is not indicated for use in doses above 20 mg/day. Dosing in Special Populations — The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine.

When indicated, dose escalation should be performed with caution in these patients.

Treatment — The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients who had been stable on olanzapine for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial.

The healthcare provider who elects to use olanzapine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 mg or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with schizophrenia was demonstrated based on a flexible dose range of 2.5 mg/day to 20 mg/day in clinical trials, with a mean modal dose of 12.5 mg/day (mean dose of 11.1 mg/day).

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

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

Treatment — The efficacy of olanzapine for the maintenance treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients.

Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission.

Patients should be periodically reassessed to determine the need for maintenance treatment. 2.2 Bipolar I Disorder (Manic or Mixed Episodes) Adults Dose Selection for Monotherapy — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 mg 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.

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.

Monotherapy — The benefit of maintaining bipolar I patients on monotherapy with oral olanzapine at a dose of 5 mg/day to 20 mg/day, after achieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial.

Treatment — When administered as adjunctive treatment to lithium or valproate, oral olanzapine dosing should generally begin with 10 mg once-a-day without regard to meals.

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

Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 mg or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with bipolar I disorder (manic or mixed episodes) was demonstrated based on a flexible dose range of 2.5 mg/day to 20 mg/day in clinical trials, with a mean modal dose of 10.7 mg/day (mean dose of 8.9 mg/day).

Treatment — The efficacy of olanzapine for the maintenance treatment of bipolar I disorder in the adolescent population has not been evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients.

Patients should be periodically reassessed to determine the need for maintenance treatment. 2.3 Administration of Olanzapine Orally Disintegrating Tablets Peel back foil on blister.

Do not push tablet through foil.

Immediately upon opening the blister or the bottle, using dry hands, remove tablet and place entire olanzapine orally disintegrating tablet in the mouth.

Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without liquid. 2.5 Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine.

Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 mg to 12.5 mg and fluoxetine 20 mg to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 mg to 12 mg and fluoxetine 25 mg to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

Children and

Adolescents (10-17 years of age) Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 2.5 mg of oral olanzapine and 20 mg of fluoxetine.

Dosage adjustments, if indicated, can be made according to efficacy and tolerability.

Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in pediatric clinical studies.

Safety and efficacy of olanzapine and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine).

Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax.

Table 1: Approximate Dose Correspondence Between Symbyax a and the Combination of Olanzapine and Fluoxetine a Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of olanzapine and fluoxetine.

Fluoxetine (mg/day) (mg/day) (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 olanzapine and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment.

The healthcare provider should periodically reexamine the need for continued pharmacotherapy.

Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder. 2.6 Olanzapine and Fluoxetine in Combination: Treatment Resistant Depression When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 mg to 20 mg and fluoxetine 20 mg to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combinat.

Olanzapine orally disintegrating tablets, USP are yellow or almost-yellow round tablets supplied as follows: 5 mg tablets: (debossed with “L32” on one side and blank on the other side) Bottles of 30 (NDC 0527-3161-32) 10 mg tablets: (debossed with “L33” on one side and blank on the other side) Bottles of 30 (NDC 0527-3162-32) 15 mg tablets: (debossed with “L35” on one side and blank on the other side) Bottles of 30 (NDC 0527-3163-32) 20 mg tablets: (debossed with “L37” on one side and blank on the other side) Bottles of 30 (NDC 0527-3164-32) 16.2 Storage and Handling Store olanzapine orally disintegrating tablets, USP at 20° to 25°C (68° to 77°F) .

USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses.

Protect olanzapine orally disintegrating tablets from light and moisture.

Store olanzapine orally disintegrating tablets, USP at 20° to 25°C (68° to 77°F) .

USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses.

Protect olanzapine orally disintegrating tablets from light and moisture.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including Olanzapine Tablets, during pregnancy.

Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit Risk Summary Neonates exposed to antipsychotic drugs, including olanzapine, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

Overall available data from published epidemiologic studies of pregnant women exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including olanzapine, during pregnancy.

Olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9.

• and 30 times the daily oral maximum recommended human dose (MRHD), based on mg/m 2 body surface area; some fetal toxicities were observed at these doses.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Disease-associated maternal and embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide.

Schizophrenia and bipolar

I disorder are associated with increased adverse perinatal outcomes, including preterm birth.

It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including olanzapine, during the third trimester of pregnancy.

These symptoms have varied in severity.

Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Placental passage has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy.

The clinical relevance of this finding is unknown.

Published data from observational studies, birth registries, and case reports that have evaluated the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects.

A retrospective cohort study from a

Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

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 daily oral MRHD based on mg/m 2 body surface area, 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 daily oral MRHD based on mg/m 2 body surface area), and gestation was prolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m 2 body surface area).

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 daily oral MRHD based on mg/m 2 body surface area).

Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of olanzapine (D 2 receptor antagonism), treatment with olanzapine may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential.

The safety and effectiveness of oral olanzapine in the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder were established in short-term studies in adolescents (ages to 17 years).

Use of olanzapine in adolescents is supported by evidence from adequate and well-controlled studies of olanzapine in which 268 adolescents received olanzapine in a range of 2.5 mg/day to 20 mg/day.

Recommended starting dose for adolescents is lower than that for adults.

Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels.

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia.

Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents.

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

Safety and efficacy of olanzapine and fluoxetine in combination in children and adolescents (10 to 17 years of age) have been established for the acute treatment of depressive episodes associated with bipolar I disorder.

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

Of the 2500 patients in premarketing clinical studies with oral olanzapine, 11% 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.

In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations.

The rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%).

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.

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