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Olanzapine is a thienobenzodiazepine derivative and an atypical or second-generation antipsychotic agent.

Its chemical structure contains a thienobenzodiazepine core, and has a methyl group attached to the piperazine ring.

The second-generation antipsychotics were introduced in the 90s and quickly gained traction due to their impressive efficacy, reduced risk for extrapyramidal side effects and reduced susceptibility to drug-drug interactions.

Olanzapine was discovered by scientists at Eli Lilly and approved to be marketed in the US in 1996.

Olanzapine was initially used Oral and

Intramuscular for the chronic treatment of schizophrenia in patients over 13 years old and other psychiatric disorders such as bipolar I disorder including mixed or manic episodes.

Olanzapine is also indicated, in combination with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder in adults.

As well, olanzapine is indicated, in combination with fluoxetine for the treatment of episodes of depression associated with bipolar disorder type and treatment-resistant depression in patients over 10 years old.

Olanzapine is also approved for the management of psychomotor agitation associated with schizophrenia and bipolar I mania.

Schizophrenia is a complex biochemical brain disorder that affects the person's ability to differentiate reality.

It is usually observed as the presence of delusions, hallucinations, social withdrawal and disturbed thinking.

Bipolar disorder is a mental health condition defined by periods of extreme mood disturbances.

It is categorized in different types from which type is known to involve episodes of severe mania and often depression while type 2 presents less severe forms of mania.

Olanzapine is also indicated in combination with samidorphan for the treatment of bipolar I disorder, either as an adjunct to lithium or valproate or as monotherapy for the acute treatment of manic or mixed episodes or as maintenance therapy, and for the treatment of schizophrenia in adults.

The effect of olanzapine in the

D2 receptor is reported to produce the positive effects of this drug such as a decrease in hallucinations, delusions, disorganized speech, disorganized thought, and disorganized behavior.

On the other hand, its effect on the serotonin 5HT2A receptor prevents the onset of anhedonia, flat affect, alogia, avolition and poor attention.

Based on the specific mechanism of action, olanzapine presents a higher affinity for the dopamine D2 receptor when compared to the rest of the dopamine receptor isotypes.

This characteristic significantly reduces the presence of side effects.

Clinical trials for the original use of olanzapine demonstrated significant effectiveness in the treatment of schizophrenia and bipolar disorder in adults and acute manic or mixed episodes associated with bipolar disorder in adolescents.

The effect of olanzapine on dopamine and serotonin receptors has been suggested to reduce chemotherapy-induced nausea and vomiting as those receptors are suggested to be involved in this process.

For this effect, several clinical trials have been conducted and it has been shown that olanzapine can produce a significant increase in total control of nausea and vomiting.

In a high-level study of the effect of olanzapine for this condition, a complete response on the delay phase was observed in 84% of the individual and control of emesis of over 80% despite the phase.

5-hydroxytryptamine receptor 2A Antagonist D dopamine receptor Antagonist D(1A) dopamine receptor Antagonist + 15 more targets.

Olanzapine presents a linear pharmacokinetic profile and, after daily administration, it reaches steady-state in about a week.

Under the administration of a normal dosage of olanzapine, the steady-state plasma concentration does not seem to exceed 150 ng/ml with an AUC of 333 ng/h/ml. 7, 10 The absorption of olanzapine is not affected by the concomitant administration of food.

The pharmacokinetic profile of olanzapine is characterized by reaching peak plasma concentration of 156.9 ng/ml approximately 6 hours after oral administration.

The volume of distribution of olanzapine is reported to be of 1000 liters which indicate a large distribution throughout the body.

Olanzapine is greatly metabolized in the liver, which represents around 40% of the administered dose, mainly by the activity of glucuronide enzymes and by the cytochrome P450 system.

From the

CYP system, the main metabolic enzymes are CYP1A2 and CYP2D6.

As part of the phase

I metabolism, the major circulating metabolites of olanzapine, accounting for approximate 50-60% of this phase, are the 10-N-glucuronide and the 4'-N-desmethyl olanzapine which are clinically inactive and formed by the activity of CYP1A2.

On the other hand, CYP2D6 catalyzes the formation of 2-OH olanzapine and the flavin-containing monooxygenase (FMO3) is responsible for N-oxide olanzapine.

On the phase

II metabolism of olanzapine, UGT1A4 is the key player by generating direct conjugation forms of olanzapine.

Hover over products below to view reaction partners Olanzapine 7-hydroxyolanzapine 4'-N-desmethylolanzapine 2-hydroxymethylolanzapine Olanzapine 10-N-glucuronide N-oxide olanzapine.

Olanzapine is mainly eliminated through metabolism and hence, only 7% of the eliminated drug can be found as the unchanged form.

It is mainly excreted in the urine which represents around 53% of the excreted dose followed by the feces that represent about 30%.

Olanzapine presents a half-life ranging between 21-54 hours with an average half-life of 30 hours.

The mean clearance rate of olanzapine is of 29.4 L/hour however, some studies have reported an apparent clearance of 25 L/h.

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The toxicity symptoms of olanzapine are known to include somnolence, mydriasis, blurred vision, respiratory depression, hypotension, extrapyramidal symptoms and anticholinergic effects.

The overdosage effects in children are generally associated with more significant side effects.

The maximum registered dosage of olanzapine in clinical trials was of 300 mg and it was reported to present drowsiness and slurred speech.

However, on post-marketing surveillance, a wide range of symptoms have been presented including agitation, dysarthria, tachycardia, extrapyramidal symptoms, and reduced consciousness.

One case of overdosage-driven death was reported after ingestion of 450 mg of olanzapine.

In the cases of acute overdosage, the establishment of adequate oxygenation and ventilation, gastric lavage and administration of activated charcoal with a laxative is recommended.

In carcinogenesis studies, olanzapine was showed to present an increase in the incidence of liver hemangiomas and hemangiosarcomas as well as mammary gland adenomas, and adenocarcinomas.

On fertility studies, there was solely found impairment in male mating performance and delays in ovulation.

There is no evidence of mutagenic, genotoxic potential not adverse events on fertility.

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.