OLANZAPINE_- olanzapine_tablet, orally disintegrating

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 (5HT 2 Olanzapine binds with high affinity to the following receptors: serotonin 5HT 2A/2C 6 i 1-4 i 1 i 1 i 3 i 1-5 i A i 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 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 1,000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1,100 ng/mL, binding primarily to albumin and alpha 1 Metabolism and Elimination Following a single oral dose of 14 Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro in vivo 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 nonelderly subjects (< 65 years). Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity [see Dosage and Administration ( 2 Gender Clearance of olanzapine is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed. Smoking Status Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely recommended. Race In vivo 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.

Olanzapine orally disintegrating tablets are an atypical antipsychotic indicated: As oral formulation for the: Treatment of schizophrenia. 1 Adults Efficacy was established in three clinical trials in patients with schizophrenia: two 6-week trials and one maintenance trial. 1 Adolescents (ages 13 to 17) Efficacy was established in one 6-week trial in patients with schizophrenia ( 14. 1 Acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. 2 Adults Efficacy was established in three clinical trials in patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one maintenance trial. 2 Adolescents (ages 13 to 17) Efficacy was established in one 3-week trial in patients with manic or mixed episodes associated with bipolar I disorder ( 14. 2 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. 3 Adjunct to valproate or lithium in the treatment of manic or mixed episodes associated with bipolar I disorder. 2 Efficacy was established in two 6-week clinical trials in adults ( 14. 2 As Olanzapine and Fluoxetine in Combination for the: Treatment of depressive episodes associated with bipolar I disorder. 5 Efficacy was established with Symbyax (olanzapine and fluoxetine in combination); refer to the product label for Symbyax. Treatment of treatment resistant depression. 6 Efficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax. Olanzapine orally disintegrating tablets are indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia (ages 13 to 17), efficacy was established in one 6-week trial [see Clinical Studies ( 14. When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Warnings and Precautions ( 5. Monotherapy Olanzapine orally disintegrating tablets are indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial. In adolescent patients with manic or mixed episodes associated with bipolar I disorder (ages 13 to 17), efficacy was established in one 3-week trial [see Clinical Studies ( 14. 2 When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. 5 Adjunctive Therapy to Lithium or Valproate Olanzapine orally disintegrating tablets are indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials [see Clinical Studies ( 14. 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. 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. 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.

Schizophrenia in adults ( 2. 1 Oral: Start at 5 mg to 10 mg once daily; Target: 10 mg/day within several days Schizophrenia in adolescents ( 2. 1 Oral: Start at 2. 5 mg to 5 mg once daily; Bipolar I Disorder (manic or mixed episodes) in adults ( 2. 2 Oral: Start at 10 mg or 15 mg once daily Bipolar I Disorder (manic or mixed episodes) in adolescents ( 2. 2 Oral: Start at 2. 5 mg to 5 mg once daily; Bipolar I Disorder (manic or mixed episodes) with lithium or valproate in adults ( 2. 2 Oral: Start at 10 mg once daily Agitation associated with Schizophrenia and Bipolar I Mania in adults (2. 4) IM: 10 mg (5 mg or 7. 5 mg when clinically warranted) Depressive Episodes associated with Bipolar I Disorder in adults ( 2. 5 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 ( 2. 5 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 ( 2. 6 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. 1 Olanzapine may be given without regard to meals. 1 Olanzapine and Fluoxetine in Combination: Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. 6 Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder or treatment resistant depression. 6 Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults. 6 Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17. 5 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 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. , 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. , nonsmoking female patients >= 65 years of age), or who may be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions ( 5. Maintenance Treatment The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients who had been stable on olanzapine for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial [see Clinical Studies ( 14. Adolescents Dose Selection Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2. 5 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 to 20 mg/day in clinical trials, with a mean modal dose of 12. 5 mg/day (mean dose of 11. When dosage adjustments are necessary, dose increments/decrements of 2. 5 or 5 mg are recommended. The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies ( 14. 1 Maintenance Treatment The efficacy of olanzapine for the maintenance treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment. Adults Dose Selection for Monotherapy Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 or 15 mg. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials. Short-term (3 to 4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials [see Clinical Studies ( 14. Maintenance Monotherapy The benefit of maintaining bipolar I patients on monotherapy with oral olanzapine at a dose of 5 to 20 mg/day, after achieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial [see Clinical Studies ( 14. Dose Selection for Adjunctive Treatment When administered as adjunctive treatment to lithium or valproate, oral olanzapine dosing should generally begin with 10 mg once-a-day without regard to meals. Antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials [see Clinical Studies ( 14. 5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with bipolar I disorder (manic or mixed episodes) was demonstrated based on a flexible dose range of 2. 5 to 20 mg/day in clinical trials, with a mean modal dose of 10. 7 mg/day (mean dose of 8. 2 Maintenance Treatment The efficacy of olanzapine for the maintenance treatment of bipolar I disorder in the adolescent population has not been evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Using dry hands, remove tablet and place entire olanzapine orally disintegrating tablets in the mouth. Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without liquid. When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Adults Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 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 to 17 years of age) Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 2. 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in pediatric clinical studies. Safety and efficacy of olanzapine and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. Table 1 Approximate Dose Correspondence Between Symbyax a a For Symbyax (mg/day) Use in Combination Olanzapine (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 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. Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg. Safety and efficacy of olanzapine in combination with fluoxetine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Table 1 above demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax. While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that treatment resistant depression (major depressive disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment. Olanzapine monotherapy is not indicated for treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode). The starting dose of oral olanzapine 2. 5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modification may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Olanzapine and fluoxetine in combination have not been systematically studied in patients over 65 years of age or in patients under 10 years of age [see Warnings and Precautions ( 5.

Most common adverse reactions (>= 5% and at least twice that for placebo) associated with: Oral Olanzapine Monotherapy: Schizophrenia (Adults) Postural hypotension, constipation, weight gain, dizziness, personality disorder, akathisia. 1 Schizophrenia (Adolescents) Sedation, weight increased, headache, increased appetite, dizziness, abdominal pain, pain in extremity, fatigue, dry mouth. 1 Manic or Mixed Episodes, Bipolar I Disorder (Adults) Asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor. 1 Manic or Mixed Episodes, Bipolar I Disorder (Adolescents) Sedation, weight increased, increased appetite, headache, fatigue, dizziness, dry mouth, abdominal pain, pain in extremity. 1 Combination of Olanzapine and Lithium or Valproate: Manic or Mixed Episodes, Bipolar I Disorder (Adults) Dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia. 1 Olanzapine and Fluoxetine in Combination: 6 To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www. gov/medwatch. When using olanzapine and fluoxetine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Clinical Trials in Adults The information below for olanzapine is derived from a clinical trial database for olanzapine consisting of 10,504 adult patients with approximately 4,765 patient-years of exposure to olanzapine. This database includes: (1) 2500 patients who participated in multiple-dose oral olanzapine premarketing trials in schizophrenia and Alzheimer's disease representing approximately 1122 patient-years of exposure as of February 14, 1995; (2) 182 patients who participated in oral olanzapine premarketing bipolar I disorder (manic or mixed episodes) trials representing approximately 66 patient-years of exposure; (3) 191 patients who participated in an oral olanzapine trial of patients having various psychiatric symptoms in association with Alzheimer's disease representing approximately 29 patient-years of exposure; (4) 5788 additional patients from 88 oral olanzapine clinical trials as of December 31, 2001; and (5) 1843 additional patients from 41 olanzapine clinical trials as of October 31, 2011. 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 healthcare provider with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactions incidence in the population studied. Incidence of Adverse Reactions in Short-Term, Placebo-Controlled and Combination Trials The following findings are based on premarketing trials of oral olanzapine for schizophrenia, bipolar I disorder (manic or mixed episodes), a subsequent trial of patients having various psychiatric symptoms in association with Alzheimer's disease, and premarketing combination trials. Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials Schizophrenia Overall, there was no difference in the incidence of discontinuation due to adverse reactions (5% for oral olanzapine vs. 6% for placebo). However, discontinuations due to increases in ALT were considered to be drug related (2% for oral olanzapine vs. 0% for placebo). Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy Overall, there was no difference in the incidence of discontinuation due to adverse reactions (2% for oral olanzapine vs. 2% for placebo). Adverse Reactions Associated with Discontinuation of Treatment in Short-Term Combination Trials Bipolar I Disorder (Manic or Mixed Episodes), Olanzapine as Adjunct to Lithium or Valproate In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 11% for the combination of oral olanzapine with lithium or valproate compared to 2% for patients who remained on lithium or valproate monotherapy. Discontinuations with the combination of oral olanzapine and lithium or valproate that occurred in more than 1 patient were: somnolence (3%), weight gain (1%), and peripheral edema (1%). Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials The most commonly observed adverse reactions associated with the use of oral olanzapine (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) were: Table 9 Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Trials-SCHIZOPHRENIA a Percentage of Patients Reporting Event Adverse Reaction Olanzapine (N=248) Placebo (N=118) Postural hypotension a 5 2 Table 10 Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 3-Week and 4-Week Trials em dash Bipolar I Disorder (Manic or Mixed Episodes) Percentage of Patients Reporting Event Adverse Reaction 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 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 Percentage of Patients Reporting Event Body System / Adverse Reaction Olanzapine ( N = 532 ) Placebo ( N = 294 ) Body as a Whole Cardiovascular System Digestive System Hemic and Lymphatic System Metabolic and Nutritional Disorders Musculoskeletal System Nervous System Respiratory System Special Senses Urogenital System Dose Dependency of Adverse Reactions A dose group difference has been observed for fatigue, dizziness, weight gain and prolactin elevation. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of fatigue (10 mg/day: 1. 5%; 20 mg/day: 2. 1%; 40 mg/day: 6. 6%) was observed with significant differences between 10 vs. 40 and 20 vs. The incidence of dizziness (10 mg/day: 2. 6%; 20 mg/day: 1. 6%; 40 mg/day: 6. 6%) was observed with significant differences between 20 vs. Dose group differences were also noted for weight gain and prolactin elevation [see Warnings and Precautions ( 5. 15 The following table addresses dose relatedness for other adverse reactions using data from a schizophrenia trial involving fixed dosage ranges of oral olanzapine. It enumerates the percentage of patients with treatment-emergent adverse reactions for the 3 fixed-dose range groups and placebo. The data were analyzed using the Cochran-Armitage test, excluding the placebo group, and the table includes only those adverse reactions for which there was a trend. Table 12 Percentage of Patients from a Schizophrenia Trial with Treatment-Emergent Adverse Reactions for the 3 Dose Range Groups and Placebo Adverse Reaction Percentage of Patients Reporting Event Placebo (N=68) Olanzapine 5 +/- 2. 5 mg/day (N=65) Olanzapine 10 +/- 2. 5 mg/day (N=64) Olanzapine 15 +/- 2. 5 mg/day (N=69) Asthenia 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 Commonly Observed Adverse Reactions in Short-Term Trials of Oral Olanzapine as Adjunct to Lithium or Valproate In the bipolar I disorder (manic or mixed episodes) adjunct placebo-controlled trials, the most commonly observed adverse reactions associated with the combination of olanzapine and lithium or valproate (incidence of >= 5% and at least twice placebo) were: Table 13 Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Adjunct to Lithium or Valproate Trials-Bipolar I Disorder (Manic or Mixed Episodes) Adverse Reaction Percentage of Patients Reporting Event Olanzapine with lithium or valproate (N=229) Placebo with lithium or valproate (N=115) Dry mouth 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 as Adjunct to Lithium or Valproate Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with the combination of olanzapine (doses >= 5 mg/day) and lithium or valproate and with incidence greater than lithium or valproate alone who participated in the acute phase of placebo-controlled combination trials. Table 14 Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials of Oral Olanzapine as Adjunct to Lithium or Valproate a Percentage of Patients Reporting Event Body System/Adverse Reaction 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 Dysmenorrhea a 2 0 Vaginitis a 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. Extrapyramidal Symptoms The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial. Table 16 Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia em dash Acute Phase a b Percentage of Patients Reporting Event Placebo Olanzapine 5 +/- 2. 5 mg/day Olanzapine 10 +/- 2. 5 mg/day Olanzapine 15 +/- 2. 5 mg/day Parkinsonism a 15 14 12 14 Akathisia b 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 17 Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia em dash Acute Phase a b c d e Percentage of Patients Reporting Event Placebo (N=68) Olanzapine 5 +/- 2. 5 mg/day (N=69) Dystonic events a 1 3 2 3 Parkinsonism events b 10 8 14 20 Akathisia events c 1 5 11 10 Dyskinetic events d 4 0 2 1 Residual events e 1 2 5 1 Any extrapyramidal event 16 15 25 32 The following table enumerates the percentage of adolescent patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy (dose range: 2. 5 to 20 mg/day). Table 18 Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in Placebo-Controlled Clinical Trials of Oral Olanzapine in Schizophrenia and Bipolar I Disorder em dash Adolescents a Categories a Percentage of Patients Reporting Event Placebo (N=89) Olanzapine (N=179) Dystonic events 0 1 Parkinsonism events 2 1 Akathisia events 4 6 Dyskinetic events 0 1 Nonspecific events 0 4 Any extrapyramidal event 6 10 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 Other Adverse Reactions Observed During the Clinical Trial Evaluation of Oral Olanzapine Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses >=1 mg/day) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Body as a Whole Infrequent: 1 ; Rare: 1. Cardiovascular System Infrequent: Digestive System Infrequent: Rare: Hemic and Lymphatic System Infrequent: Metabolic and Nutritional Disorders Frequent: Infrequent Musculoskeletal System Rare: Nervous System Infrequent: Rare: Respiratory System Infrequent: Rare: Skin and Appendages Infrequent: Special Senses Infrequent: Rare: Urogenital System Infrequent: 2 2 2 2 2 2 1 2 Clinical Trials in Adolescent Patients (age 13 to 17 years) Commonly Observed Adverse Reactions in Oral Olanzapine Short-Term, Placebo-Controlled Trials Adverse reactions in adolescent patients treated with oral olanzapine (doses >=2. 5 mg) reported with an incidence of 5% or more and reported at least twice as frequently as placebo-treated patients are listed in Table 21. Table 21 Treatment-Emergent Adverse Reactions of >=5% Incidence among Adolescents (13 to 17 Years Old) with Schizophrenia or Bipolar I Disorder (Manic or Mixed Episodes) a b 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) Sedation a 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 pain b 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 to 6 weeks), Placebo-Controlled Trials Adverse reactions in adolescent patients treated with oral olanzapine (doses >=2. 5 mg) reported with an incidence of 2% or more and greater than placebo are listed in Table 22. Table 22 Treatment-Emergent Adverse Reactions of >=2% Incidence among Adolescents (13 to 17 Years Old) (Combined Incidence from Short-Term, Placebo-Controlled Clinical Trials of Schizophrenia or Bipolar I Disorder [Manic or Mixed Episodes]) a b c Adverse Reaction Percentage of Patients Reporting Event Olanzapine (N=179) Placebo (N=89) Sedation a 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 increased b 8 1 Dyspepsia 3 1 Epistaxis 3 0 Respiratory tract infection c 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. Laboratory Changes Olanzapine Monotherapy in Adults An assessment of the premarketing experience for olanzapine revealed an association with asymptomatic increases in ALT, AST, and GGT. Within the original premarketing database of about 2400 adult patients with baseline ALT <= 90 IU/L, the incidence of ALT elevations to > 200 IU/L was 2% (50/2381). None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued. In placebo-controlled olanzapine monotherapy studies in adults, clinically significant ALT elevations (change from < 3 times the upper limit of normal [ULN] at baseline to >= 3 times ULN) were observed in 5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patients exposed to placebo. ALT elevations >= 5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0. 3% (4/1196) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule. From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, high GGT levels were recorded in >=1% (88/5245) of patients. Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with preexisting conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs. Olanzapine administration was also associated with increases in serum prolactin [see Warnings and Precautions ( 5. 15 , From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, elevated uric acid was recorded in >=3% (171/4641) of patients. Olanzapine Monotherapy in Adolescents In placebo-controlled clinical trials of adolescent patients with schizophrenia or bipolar I disorder (manic or mixed episodes), greater frequencies for the following treatment-emergent findings, at anytime, were observed in laboratory analytes compared to placebo: elevated ALT (>= 3X ULN in patients with ALT at baseline < 3X ULN), (12% vs. 2%); elevated AST (28% vs. 4%); low total bilirubin (22% vs. 7%); elevated GGT (10% vs. 1%); and elevated prolactin (47% vs. In placebo-controlled olanzapine monotherapy studies in adolescents, clinically significant ALT elevations (change from < 3 times ULN at baseline to >= 3 times ULN) were observed in 12% (22/192) of patients exposed to olanzapine compared to 2% (2/109) of patients exposed to placebo. ALT elevations >= 5 times ULN were observed in 4% (8/192) of olanzapine-treated patients, compared to 1% (1/109) of placebo-treated patients. No adolescent patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule. ECG Changes In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc (Fridericia corrected), and PR intervals. Olanzapine use was associated with a mean increase in heart rate compared to placebo (adults: +2. 4 beats per minute vs. no change with placebo; adolescents: +6. 3 beats per minute vs. 1 beats per minute with placebo). This increase in heart rate may be related to olanzapine's potential for inducing orthostatic changes [see Warnings and Precautions ( 5. 7 The following adverse reactions have been identified during post-approval use of olanzapine. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to olanzapine therapy include the following: allergic reaction (e. , anaphylactoid reaction, angioedema, pruritus or urticaria), cholestatic or mixed liver injury, diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea or vomiting), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hepatitis, jaundice, neutropenia, pancreatitis, priapism, rash, restless legs syndrome, rhabdomyolysis, salivary hypersecretion, stuttering 1 1.

None with olanzapine monotherapy. ( 4 When using olanzapine and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax. ( 4 When using olanzapine in combination with lithium or valproate, refer to the Contraindications section of the package inserts for those products. ( 4 None with olanzapine orally disintegrating tablets monotherapy. When using olanzapine orally disintegrating tablets 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.

Pregnancy May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. 1 Pediatric Use Safety and effectiveness of olanzapine in children < 13 years of age have not been established. Safety and effectiveness of olanzapine and fluoxetine in combination in children <10 years of age have not been established. 4 When using olanzapine and fluoxetine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including olanzapine, 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 http://womensmentalhealth. org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including olanzapine, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). (see Clinical Considerations). 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 (see Data). 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. 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. Clinical Considerations 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. Data Human Data 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 9,258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. Animal Data 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 2 2 2 Risk Summary Olanzapine is present in human milk. There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for olanzapine and any potential adverse effects on the breastfed child from olanzapine or from the mother's underlying condition. Clinical Considerations Infants exposed to olanzapine should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements). Infertility Females Based on the pharmacologic action of olanzapine (D 2 [see Warnings and Precautions ( 5. 15 The safety and effectiveness of oral olanzapine in the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder were established in short-term studies in adolescents (ages 13 to 17 years). Use of olanzapine in adolescents is supported by evidence from adequate and well-controlled studies of olanzapine in which 268 adolescents received olanzapine in a range of 2. 5 to 20 mg/day [see Clinical Studies ( 14. 2 [see Dosage and Administration ( 2. 2 [see Warnings and Precautions ( 5. 1 [see Indications and Usage ( 1. 2 Safety and effectiveness of olanzapine in children < 13 years of age have not been established [see Patient Counseling Information ( 17 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% (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. , 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=1,184), 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. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning 5. 1 17 [see Boxed Warning, Dosage and Administration ( 2. 1 Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients >= 65 years of age to determine whether they respond differently from younger patients.

RECENT MAJOR CHANGES
Warnings and Precautions, Tardive Dyskinesia ( 5.6 10/2019 Warnings and Precautions, Use in Patients with Concomitant Illness ( 5.14 Removed 4/2020 Warnings and Precautions, Anticholinergic (antimuscarinic) Effects ( 5.14 4/2020
DRUG INTERACTIONS
Diazepam May potentiate orthostatic hypotension. 2 Alcohol May potentiate orthostatic hypotension. 1 Carbamazepine Increased clearance of olanzapine. 1 Fluvoxamine May increase olanzapine levels. 1 Olanzapine and Fluoxetine in Combination Also refer to the Drug Interactions section of the package insert for Symbyax. 1 CNS Acting Drugs Caution should be used when taken in combination with other centrally acting drugs and alcohol. 2 Antihypertensive Agents Enhanced antihypertensive effect. 2 Levodopa and Dopamine Agonists May antagonize levodopa/dopamine agonists. 2 Other Concomitant Drug Therapy When using olanzapine in combination with lithium or valproate, refer to the Drug Interactions sections of the package insert for those products. 2 The risks of using olanzapine in combination with other drugs have not been extensively evaluated in systematic studies. Diazepam The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions ( 7. 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 coadministration of alcohol (i. , ethanol) with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions ( 7. 2 Inhibitors of CYP1A2 Fluvoxamine Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine C max Inhibitors of CYP2D6 Fluoxetine Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. When using olanzapine and fluoxetine in combination, also refer to the Drug Interactions section of the package insert for Symbyax. Warfarin Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics [see Drug Interactions ( 7. 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 C max Anticholinergic Drugs Concomitant treatment with olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions ( 5. 14 CNS Acting Drugs Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrally acting drugs and alcohol. Antihypertensive Agents Olanzapine, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents. Levodopa and Dopamine Agonists Olanzapine may antagonize the effects of levodopa and dopamine agonists. Lithium Multiple doses of olanzapine (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant olanzapine administration does not require dosage adjustment of lithium [see Warnings and Precautions ( 5. Valproate Olanzapine (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate [see Warnings and Precautions ( 5. 16 Effect of Olanzapine on Drug Metabolizing Enzymes In vitro 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. 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. 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.

OVERDOSAGE
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. 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. 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. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222). 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.
NONCLINICAL TOXICOLOGY
Carcinogenesis Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3 mg/kg/day, 10 mg/kg/day, 30/20 mg/kg/day (equivalent to 0. 8 times to 5 times the daily oral MRHD based on mg/m 2 2 2 2 2 2 [see Warnings and Precautions ( 5. 15 Mutagenesis No evidence of genotoxic potential for olanzapine was found in the Ames reverse mutation test, in vivo in vivo 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 daily oral MRHD based on mg/m 2 2 2 In animal studies with olanzapine, the principal hematologic findings were reversible peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 times the daily oral MRHD based on mg/m 2 2 2 2.
CLINICAL STUDIES
When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Adults The efficacy of oral olanzapine in the treatment of schizophrenia was established in 2 short-term (6-week) controlled trials of adult inpatients who met DSM III-R criteria for schizophrenia. A single haloperidol arm was included as a comparative treatment in 1 of the 2 trials, but this trial did not compare these 2 drugs on the full range of clinically relevant doses for both. Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, 2 more recently developed scales were employed; these included the 30-item Positive and Negative Symptoms Scale (PANSS), in which are embedded the 18 items of the BPRS, and the Scale for Assessing Negative Symptoms (SANS). The trial summaries below focus on the following outcomes: PANSS total and/or BPRS total; BPRS psychosis cluster; PANSS negative subscale or SANS; and CGI Severity. The results of the trials follow: 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. 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. In a longer-term trial, adult outpatients (n=326) who predominantly met DSM-IV criteria for schizophrenia and who remained stable on olanzapine during open-label treatment for at least 8 weeks were randomized to continuation on their current olanzapine doses (ranging from 10 to 20 mg/day) or to placebo. The follow-up period to observe patients for relapse, defined in terms of increases in BPRS positive symptoms or hospitalization, was planned for 12 months, however, criteria were met for stopping the trial early due to an excess of placebo relapses compared to olanzapine relapses, and olanzapine was superior to placebo on time to relapse, the primary outcome for this study. Thus, olanzapine was more effective than placebo at maintaining efficacy in patients stabilized for approximately 8 weeks and followed for an observation period of up to 8 months. Examination of population subsets (race and gender) did not reveal any differential responsiveness on the basis of these subgroupings. Adolescents The efficacy of oral olanzapine in the acute treatment of schizophrenia in adolescents (ages 13 to 17 years) was established in a 6-week double-blind, placebo-controlled, randomized trial of inpatients and outpatients with schizophrenia (n=107) who met diagnostic criteria according to DSM-IV-TR and confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL). The primary rating instrument used for assessing psychiatric signs and symptoms in this trial was the Anchored Version of the Brief Psychiatric Rating Scale for Children (BPRS-C) total score. In this flexible-dose trial, olanzapine 2. 5 to 20 mg/day (mean modal dose 12. 5 mg/day, mean dose of 11. 1 mg/day) was more effective than placebo in the treatment of adolescents diagnosed with schizophrenia, as supported by the statistically significantly greater mean reduction in BPRS-C total score for patients in the olanzapine treatment group than in the placebo group. While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment. Adults Monotherapy The efficacy of oral olanzapine in the treatment of manic or mixed episodes was established in 2 short-term (one 3-week and one 4-week) placebo-controlled trials in adult patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course. The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow: In one 3-week placebo-controlled trial (n=67) which involved a dose range of olanzapine (5 to 20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the first trial, olanzapine demonstrated a similar treatment difference, but possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome. In a 4-week placebo-controlled trial (n=115) which involved a dose range of olanzapine (5 to 20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. In another trial, 361 patients meeting DSM-IV criteria for a manic or mixed episode of bipolar I disorder who had responded during an initial open-label treatment phase for about 2 weeks, on average, to olanzapine 5 to 20 mg/day were randomized to either continuation of olanzapine at their same dose (n=225) or to placebo (n=136), for observation of relapse. Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and 50% of the placebo group had discontinued by day 23 of double-blind treatment. Response during the open-label phase was defined by having a decrease of the Y-MRS total score to <= 12 and HAM-D 21 to <= 8. Relapse during the double-blind phase was defined as an increase of the Y-MRS or HAM-D 21 total score to >= 15, or being hospitalized for either mania or depression. In the randomized phase, patients receiving continued olanzapine experienced a significantly longer time to relapse. Adjunct to Lithium or Valproate The efficacy of oral olanzapine with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in 2 controlled trials in patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. The results of the trials follow: In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS >= 16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5 to 20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0. 6 mEq/L to 1. 2 mEq/L or 50 mcg/mL to 125 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score. 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. Adolescents Acute Monotherapy The efficacy of oral olanzapine in the treatment of acute manic or mixed episodes in adolescents (ages 13 to 17 years) was established in a 3-week, double-blind, placebo-controlled, randomized trial of adolescent inpatients and outpatients who met the diagnostic criteria for manic or mixed episodes associated with bipolar I disorder (with or without psychotic features) according to the DSM-IV-TR (n=161). Diagnosis was confirmed by the K-SADS-PL. The primary rating instrument used for assessing manic symptoms in this trial was the Adolescent Structured Young-Mania Rating Scale (Y-MRS) total score. 5 to 20 mg/day (mean modal dose 10. 7 mg/day, mean dose of 8. 9 mg/day) was more effective than placebo in the treatment of adolescents with manic or mixed episodes associated with bipolar I disorder, as supported by the statistically significantly greater mean reduction in Y-MRS total score for patients in the olanzapine treatment group than in the placebo group.

Zydus Pharmaceuticals USA Inc.

OLANZAPINE_- olanzapine_tablet, orally disintegrating Product manual source documgent