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 displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr). Administration of olanzapine once daily leads to steady-state concentrations in about 1 week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age. Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and alpha 1 Metabolism and Elimination 14 Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro in vivo Specific Populations Renal Impairment Hepatic Impairment Geriatric [see Dosage and Administration (2)]. Gender Smoking Status Race In vivo Combined Effects [see Dosage and Administration (2)].

Olanzapine orally disintegrating tablets are atypical antipsychotic indicated: 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 O lanzapine 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. 1)] [see Warnings and Precautions (5. 5)] Monotherapy [ see Clinical Studies (14. 2)] [see Warnings and Precautions (5. 5) [see Clinical Studies (14. 2)] 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. Olanzapine and fluoxetine in combination are 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. 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.

Schizophrenia in adults (2. 1) Oral: Start at 5 to 10 mg once daily; Target: 10 mg/day within several days Schizophrenia in adolescents ( 2. 1 Oral: Start at 2. 5 to 5 mg once daily; Target: 10 mg/day Bipolar I Disorder (manic or mixed episodes) in adults (2. 2) Oral: Start at 10 or 15 mg once daily Bipolar I Disorder (manic or mixed episodes) in adolescents (2. 2) Oral: Start at 2. 5 to 5 mg once daily; Target: 10 mg/day Bipolar I Disorder (manic or mixed episodes) with lithium or valproate in adults (2. 2) Oral: Start at 10 mg once daily 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 Dosing in Special Populations [see Warnings and Precautions (5. 14), Drug Interactions (7), and Clinical Pharmacology (12. 3)] [see Clinical Studies (14. 1)] Adolescents Dose Selection [see Clinical Studies (14. 1)] Maintenance Treatment Adults Dose Selection for Monotherapy [see Clinical Studies (14. Maintenance Monotherapy [ see Clinical Studies (14. 2) Dose Selection for Adjunctive Treatment [see Clinical Studies (14. 2)] Adolescents [see Clinical Studies (14. 2)] Maintenance Treatment Peel back foil on blister. Do not push tablet through foil. Immediately upon opening the blister, 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. When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Adults Children and Adolescents (10 to 17 years of age) 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 and Fluoxetine 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 a 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. 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. 14) , Drug Interactions (7) Clinical Pharmacology (12.

When using olanzapine and fluoxetine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. Most common adverse reactions (>=5% and at least twice that for placebo) associated with: Oral Olanzapine Monotherapy: Schizophrenia (Adults) 6. 1 Schizophrenia (Adolescents) 6. 1 Manic or Mixed Episodes, Bipolar I Disorder (Adults) 6. 1 Manic or Mixed Episodes, Bipolar I Disorder (Adolescents) (6. 1) Combination of Olanzapine and Lithium or Valproate: Manic or Mixed Episodes, Bipolar I Disorder (Adults) 6. 1 Olanzapine and Fluoxetine in Combination: 6 To report SUSPECTED ADVERSE REACTIONS, contact Jubilant Cadista Pharmaceuticals Inc. at 1-800-313-4623 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Clinical Trials in Adults The information below for olanzapine is derived from a clinical trial database for olanzapine consisting of 10,504 adult patients with approximately 4765 patient-years of exposure to olanzapine. 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; Also included below is information from the premarketing 6-week clinical study database for olanzapine in combination with lithium or valproate, consisting of 224 patients who participated in bipolar I disorder (manic or mixed episodes) trials with approximately 22 patient-years of exposure. The conditions and duration of treatment with olanzapine varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analytes, ECGs, chest x-rays, and results of ophthalmologic examinations. Certain portions of the discussion below relating to objective or numeric safety parameters, namely, dose-dependent adverse reactions, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia and have not been duplicated for bipolar I disorder (manic or mixed episodes) or agitation. However, this information is also generally applicable to bipolar I disorder (manic or mixed episodes) and agitation. Adverse reactions during exposure were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized reaction categories. In the tables and tabulations that follow, MedDRA and COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. The reported reactions do not include those reaction terms that were so general as to be uninformative. Reactions listed elsewhere in labeling may not be repeated below. It is important to emphasize that, although the reactions occurred during treatment with olanzapine, they were not necessarily caused by it. The entire label should be read to gain a complete understanding of the safety profile of olanzapine. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing 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 Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy 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 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 em dash SCHIZOPHRENIA Adverse Reaction Percentage of Patients Reporting Event Olanzapine Placebo Postural hypotension 5 2 Constipation 9 3 Weight gain 6 1 Dizziness 11 4 Personality disorder a 8 4 Akathisia 5 1 a 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) Adverse Reaction Percentage of Patients Reporting Event Olanzapine Placebo 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 Olanzapine Placebo 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 [see Warnings and Precautions (5. 15) Perce n tag e of Patients Reporting Event Adverse Reaction 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 Adverse Reaction Percentage of Patients Reporting Event Olanzapine with lithium or valproate Placebo with lithium or valproate 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 Body System/Adverse Reaction Percentage of Patients Reporting Event Olanzapine with lithium or valproate Placebo with lithium or valproate Body as a Whole 18 Cardiovascular System Digestive System Metabolic and Nutritional Disorders Nervous System Respiratory System Skin and Appendages Special Senses Urogenital System a a a Extrapyramidal Symptoms Percentage of Patients Reporting Event Placebo Olanzapine Olanzapine Olanzapine Parkinsonism a 15 14 12 14 Akathisia b 23 16 19 27 a b Percentage of Patients Reporting Event Placebo (N=68) Olanzapine Olanzapine Olanzapine 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 a b c d e 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 a Dystonia, Class Effect: Infrequent: 1 Rare: 1 I nfrequent: Infrequent: Rare: I nfrequent: Metabolic and Nutritional Disorders Frequent: Infrequent: Rare: Infrequent: Rare: Respiratory System Infrequent: Rare: Infrequent: Infrequent: Rare: Infrequent: 2 2 2 2 2 2 1 2 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) 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 a b 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 a b c [see Warnings and Precautions (5)] [see Warnings and Precautions (5. 15)] Olanzapine Monotherapy in Adolescents: [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.

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. ( 4 When using olanzapine and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax registered 4 When using olanzapine in combination with lithium or valproate, refer to the Contraindications section of the package inserts for those products.

Pregnancy: 8. 1 Pediatric Use: 8. 4 Pregnancy Exposure Registry (see Clinical Considerations). (see Clinical Considerations). 2 see Data 2 2 2 2 Risk Summary (see Clinical Considerations). Infertility 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. [see Dosage and Administration (2. 2)] [see Warnings and Precautions (5. 17) and Adverse Reactions (6. 1)] [see Indications and Usage (1. 2)] [see Patient Counseling Information (17)] 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=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 [see Boxed Warning, Warnings and Precautions (5. 1), and Patient Counseling Information (17)]. [see Boxed Warning, Dosage and Administration (2. 1), and Warnings and Precautions (5.

The risks of using olanzapine in combination with other drugs have not been extensively evaluated in systematic studies. Diazepam: 7. 2 Alcohol: 7. 1 Carbamazepine: 7. 1 Fluvoxamine: 7. 1 Olanzapine and Fluoxetine in Combination: 7. 1 CNS Acting Drugs: 7. 2 Antihypertensive Agents: 7. 2 Levodopa and Dopamine Agonists: 7. 2 Other Concomitant Drug Therapy: 7. 2 Diazepam [ see Drug Interactions (7. 2) Cimetidine and Antacids Inducers of CYP1A2 Alcohol [see Drug Interactions (7. Inhibitors of CYP1A2 Fluvoxamine: max Inhibitors of CYP2D6 Fluoxetine: Warfarin [ see Drug Interactions (7. 2) Inducers of CYP1A2 or Glucuronyl Transferase Charcoal max Anticholinergic Drugs [see Warnings and Precautions (5. CNS Acting Drugs Antihypertensive Agents Levodopa and Dopamine Agonists Lithium [see Warnings and Precautions (5. Valproate [see Warnings and Precautions (5. Effect of Olanzapine on Drug Metabolizing Enzymes In vitro Imipramine Warfarin [see Drug Interactions (7. Diazepam [see Drug Interactions (7. Alcohol [see Drug Interactions (7. Biperiden Theophylline.

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 have been received. 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 2 2 2 2 2 2 [see Warnings and Precautions (5. 15)] Mutagenesis in vivo in vivo Impairment of Fertility 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: (1) In a 6-week, placebo-controlled trial (n=149) involving 2 fixed olanzapine doses of 1 and 10 mg/day (once daily schedule), olanzapine, at 10 mg/day (but not at 1 mg/day), was superior to placebo on the PANSS total score (also on the extracted BPRS total), on the BPRS psychosis cluster, on the PANSS Negative subscale, and on CGI Severity. (2) In a 6-week, placebo-controlled trial (n=253) involving 3 fixed dose ranges of olanzapine (5 +/- 2. 5 mg/day, 10 +/- 2. 5 mg/day, and 15 +/- 2. 5 mg/day) on a once daily schedule, the 2 highest olanzapine dose groups (actual mean doses of 12 and 16 mg/day, respectively) were superior to placebo on BPRS total score, BPRS psychosis cluster, and CGI severity score; the highest olanzapine dose group was superior to placebo on the SANS. There was no clear advantage for the high-dose group over the medium-dose group. (3) 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. 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. Adults Monotherapy The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow: (1) In one 3-week placebo-controlled trial (n=67) which involved a dose range of olanzapine (5 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. (2) 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. (3) In another trial, 361 patients meeting DSM-IV criteria for a manic or mixed episode of bipolar I disorder who had responded during an initial open-label treatment phase for about 2 weeks, on average, to olanzapine 5 to 20 mg/day were randomized to either continuation of olanzapine at their same dose (n=225) or to placebo (n=136), for observation of relapse. Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and 50% of the placebo group had discontinued by day 23 of double-blind treatment. Response during the open-label phase was defined by having a decrease of the Y-MRS total score to <=12 and HAM-D 21 to <=8. Relapse during the double-blind phase was defined as an increase of the Y-MRS or HAM-D 21 total score to >=15, or being hospitalized for either mania or depression. In the randomized phase, patients receiving continued olanzapine experienced a significantly longer time to relapse. Adjunct to Lithium or Valproate (1) In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS >=16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5 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. (2) In a second 6-week placebo-controlled combination trial, 169 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS >=16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. The primary rating instrument used for assessing manic symptoms in this trial was the Adolescent Structured Young-Mania Rating Scale (Y-MRS) total score. In this flexible-dose trial, olanzapine 2. 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. 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.
Medication Guide
Olanzapine Orally Disintegrating Tablets Read the Medication Guide that comes with olanzapine orally disintegrating tablets before you start taking them and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor or pharmacist if there is something you do not understand or you want to learn more about olanzapine orally disintegrating tablets. What is the most important information I should know about olanzapine orally disintegrating tablets? Olanzapine orally disintegrating tablets may cause serious side effects, including: Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). High blood sugar (hyperglycemia). High fat levels in your blood (increased cholesterol and triglycerides), especially in teenagers age 13 to 17 or when used in combination with fluoxetine in children age 10 to 17. Weight gain, especially in teenagers age 13 to 17 or when used in combination with fluoxetine in children age 10 to 17. These serious side effects are described below. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). High blood sugar (hyperglycemia). a build up of acid in your blood due to ketones (ketoacidosis) coma death Your doctor should do tests to check your blood sugar before you start taking olanzapine orally disintegrating tablets and during treatment. In people who do not have diabetes, sometimes high blood sugar goes away when olanzapine orally disintegrating tablets are stopped. People with diabetes and some people who did not have diabetes before taking olanzapine orally disintegrating tablets need to take medicine for high blood sugar even after they stop taking olanzapine orally disintegrating tablets. Call your doctor feel very thirsty need to urinate more than usual feel very hungry feel weak or tired feel sick to your stomach feel confused or your breath smells fruity 3. High fat levels in your blood (cholesterol and triglycerides). 4. Weight gain. What are olanzapine orally disintegrating tablets? Olanzapine orally disintegrating tablets are prescription medicine used to treat: schizophrenia in people age 13 or older. bipolar disorder, including: manic or mixed episodes that happen with bipolar I disorder in people age 13 or older. manic or mixed episodes that happen with bipolar I disorder, when used with the medicine lithium or valproate, in adults. long-term treatment of bipolar I disorder in adults. episodes of depression that happen with bipolar I disorder, when used with the medicine fluoxetine (Prozac registered episodes of depression that do not get better after 2 other medicines, also called treatment resistant depression, when used with the medicine fluoxetine (Prozac), in adults. Olanzapine orally disintegrating tablets have not been approved for use in children under 13 years of age. Olanzapine orally disintegrating tablets in combination with fluoxetine has not been approved for use in children under 10 years of age. What should I tell my doctor before taking olanzapine orally disintegrating tablets? Olanzapine orally disintegrating tablets may not be right for you. Before starting olanzapine orally disintegrating tablets, tell your doctor if you have or had: heart problems seizures diabetes or high blood sugar levels (hyperglycemia) high cholesterol or triglyceride levels in your blood liver problems low or high blood pressure strokes or “mini-strokes” also called transient ischemic attacks (TIAs) Alzheimer''s disease narrow-angle glaucoma enlarged prostate in men bowel obstruction phenylketonuria, because olanzapine orally disintegrating tablets contains phenylalanine breast cancer thoughts of suicide or hurting yourself any other medical condition are pregnant or plan to become pregnant. It is not known if olanzapine orally disintegrating tablets will harm your unborn baby. If you become pregnant while receiving olanzapine orally disintegrating tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-andresearch- programs/pregnancyregistry/. are breast-feeding or plan to breast-feed. Olanzapine passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take olanzapine orally disintegrating tablets. Tell your doctor if you exercise a lot or are in hot places often. thoughts of suicide Tell your doctor about all the medicines that you take, How should I take olanzapine orally disintegrating tablets? Take olanzapine orally disintegrating tablets exactly as prescribed. Your doctor may need to change (adjust) the dose of olanzapine orally disintegrating tablets until it is right for you. If you miss a dose of olanzapine orally disintegrating tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, just skip the missed dose and take your next dose at the regular time. Do not take two doses of olanzapine orally disintegrating tablets at the same time. To prevent serious side effects, do not stop taking olanzapine orally disintegrating tablets suddenly. If you need to stop taking olanzapine orally disintegrating tablets, your doctor can tell you how to safely stop taking it. If you take too much olanzapine orally disintegrating tablets, call your doctor or poison control center at 1-800-222-1222 right away, or get emergency treatment. Olanzapine orally disintegrating tablets can be taken with or without food. Olanzapine orally disintegrating tablets are usually taken one time each day. Take olanzapine orally disintegrating tablets as follows: Be sure that your hands are dry. Peel back the foil on the blister. Do not push the tablet through the foil. As soon as you open the blister, remove the tablet and put it into your mouth. The tablet will disintegrate quickly in your saliva so that you can easily swallow it with or without drinking liquid. Call your doctor if you do not think you are getting better or have any concerns about your condition while taking olanzapine orally disintegrating tablets. What should I avoid while taking olanzapine orally disintegrating tablets? Olanzapine orally disintegrating tablets can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how olanzapine orally disintegrating tablets affects you. Avoid drinking alcohol while taking olanzapine orally disintegrating tablets. Drinking alcohol while you take olanzapine may make you sleepier than if you take olanzapine orally disintegrating tablets alone. What are the possible side effects of olanzapine orally disintegrating tablets? Serious side effects may happen when you take olanzapine orally disintegrating tablets, including: See “What is the most important information I should know about olanzapine orally disintegrating tablets?”, which describes the increased risk of death in elderly people with dementia-related psychosis and the risks of high blood sugar, high cholesterol and triglyceride levels, and weight gain. Increased incidence of stroke or “mini-strokes” called transient ischemic attacks (TIAs) in elderly people with dementia-related psychosis Neuroleptic Malignant Syndrome (NMS): high fever Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Tardive Dyskinesia Decreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heartbeat, or fainting. Difficulty swallowing, that can cause food or liquid to get into your lungs. Seizures: Tell your doctor if you have a seizure during treatment with olanzapine orally disintegrating tablets. Problems with control of body temperature: sweating too much or not at all Common side effects of olanzapine orally disintegrating tablets include: Other common side effects in teenagers (13 to 17 years old) include: Tell your doctor about any side effect that bothers you or that does not go away. These are not all the possible side effects with olanzapine orally disintegrating tablets. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store olanzapine orally disintegrating tablets? Store olanzapine orally disintegrating tablets at 20ºC to 25°C (68ºF to 77ºF). Olanzapine orally disintegrating tablets comes in a child-resistant pack. Keep olanzapine orally disintegrating tablets away from light. Keep olanzapine orally disintegrating tablets dry and away from moisture. Keep olanzapine orally disintegrating tablets and all medicines out of the reach of children. General information about olanzapine orally disintegrating tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use olanzapine orally disintegrating tablets for a condition for which it was not prescribed. Do not give olanzapine orally disintegrating tablets to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about olanzapine orally disintegrating tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about olanzapine orally disintegrating tablets that was written for healthcare professionals. For more information about olanzapine orally disintegrating tablets, call 1-800-313-4623. What are the ingredients in olanzapine orally disintegrating tablets? Active ingredient: Inactive ingredients: This Medication Guide has been approved by the U.S. Food and Drug Administration. Rx Only Marketed by: Revision: 10/2024

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