OLANZAPINE- olanzapine_tablet, film coated

The mechanism of action of olanzapine, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (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 Antagonism at receptors other than dopamine and 5HT 2 1 Oral Administration, Monotherapy 14 Specific Populations Renal Impairment Hepatic Impairment Geriatric [see Dosage and Administration ( 2 )] Gender Smoking Status Race Combined Effects [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 is 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 13-17): 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 13-17): 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: 1. 6 Oral olanzapine 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 13-17), efficacy was established in one 6-week trial [see Clinical Studies ( 14. 1 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 dyslipidema. 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. 5 Monotherapy [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 dyslipidema. 5 Adjunctive Therapy to Lithium or Valproate [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. 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.

Schizophrenia in adults ( 2. 1 Oral: Start at 5‑10 mg once daily; Target: 10 mg/day within several days Schizophrenia in adolescents ( 2. 1 Oral: Start at 2. 5‑5 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. 5-5 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 and Fluoxetine in Combination: 2. 5 Adults Dose Selection Dosing in Special Populations [see Warnings and Precautions ( 5. 3 Maintenance Treatment [see Clinical Studies ( 14. 1 Adolescents Dose Selection [see Clinical Studies ( 14. 1 Maintenance Treatment Adults Dose Selection for Monotherapy [see Clinical Studies ( 14. 2 Maintenance Monotherapy [see Clinical Studies ( 14. 2 Dose Selection for Adjunctive Treatment Antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials [see Clinical Studies ( 14. 2 Adolescents Dose Selection [see Clinical Studies ( 14. 2 Maintenance Treatment When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Adults Children and Adolescents (10-17 years of age) Table 1: Approximate Dose Correspondence Between Symbyaxa and the Combination of Olanzapine 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 Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of olanzapine and fluoxetine. 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 physician should periodically reexamine the need for continued pharmacotherapy. When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. The starting dose of oral olanzapine 2. 5-5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modification may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. 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.

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) en dash 6. 3 Manic or Mixed Episodes, Bipolar I Disorder (Adults) en dash 6. 1 Manic or Mixed Episodes, Bipolar I Disorder (Adolescents) en dash 6. 3 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 Macleods Pharma USA, Inc. , at 1-888-943-3210 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 Incidence of Adverse Reactions in Short-Term, Placebo-Controlled and 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 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 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: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Oral Olanzapine Body System/Adverse Reaction Percentage of Patients Reporting Event Olanzapine Placebo Body as a Whole Accidental injury 12 8 Asthenia 10 9 Fever 6 2 Back pain 5 2 Chest pain 3 1 Cardiovascular System Postural hypotension 3 1 Tachycardia 3 1 Hypertension 2 1 Digestive System Dry mouth 9 5 Constipation 9 4 Dyspepsia 7 5 Vomiting 4 3 Increased appetite 3 2 Hemic and Lymphatic System Ecchymosis 5 3 Metabolic and Nutritional Disorders Weight gain 5 3 Peripheral edema 3 1 Musculoskeletal System Extremity pain (other than joint) 5 3 Joint pain 5 3 Nervous System Somnolence 29 13 Insomnia 12 11 Dizziness 11 4 Abnormal gait 6 1 Tremor 4 3 Akathisia 3 2 Hypertonia 3 2 Articulation impairment 2 1 Respiratory System Rhinitis 7 6 Cough increased 6 3 Pharyngitis 4 3 Special Senses Amblyopia 3 2 Urogenital System Urinary incontinence 2 1 Urinary tract infection 2 1 Dose Dependency of Adverse Reactions [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 Olanzapine Olanzapine Olanzapine Table 13: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Adjunct to Lithium or Valproate Trials em dash Bipolar I Disorder (Manic or Mixed Episodes) 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: 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 (N=229) Placebo with lithium or valproate (N=115) Body as a Whole Asthenia Back pain Accidental injury Chest pain Cardiovascular System Hypertension Digestive System Dry mouth Increased appetite Thirst Constipation Increased salivation Metabolic and Nutritional Disorders Weight gain Peripheral edema Edema Nervous System Somnolence Tremor Depression Dizziness Speech disorder Amnesia Paresthesia Apathy Confusion Euphoria Incoordination Respiratory System Pharyngitis Dyspnea Skin and Appendages Sweating Acne Dry skin Special Senses Amblyopia Abnormal vision Urogenital System Dysmenorrhea a Vaginitis a a 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 Percentage of Patients Reporting Event Placebo Olanzapine Olanzapine Olanzapine Parkinsonism a 15 14 12 14 Akathisia b 23 16 19 27 a b a b c d e a b c d e 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 Percentage of Patients Reporting Event Placebo Olanzapine Categories a (N=89) (N=179) Dystonic events Parkinsonism events Akathisia events Dyskinetic events Nonspecific events Any extrapyramidal event a Dystonia, Class Effect: Other Adverse Reactions Observed During the Clinical Trial Evaluation of Oral Olanzapine 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 Table 21: Treatment-Emergent Adverse Reactions of >=5% Incidence among Adolescents (13-17 Years Old) with Schizophrenia or Bipolar I Disorder (Manic or Mixed Episodes) Adverse Reactions Percentage of Patients Reporting Event 6 Week Trial 3 Week Trial Olanzapine Placebo Olanzapine Placebo Sedation a Weight increased Headache Increased appetite Dizziness Abdominal pain b Pain in extremity Fatigue Dry mouth a b Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term (3-6 weeks), Placebo-Controlled Trials Table 22: Treatment-Emergent Adverse Reactions of >=2% Incidence among Adolescents (13-17 Years Old) (Combined Incidence from Short-Term, Placebo-Controlled Clinical Trials of Schizophrenia or Bipolar I Disorder [Manic or Mixed Episodes]) Adverse Reaction Percentage of Patients Reporting Event Olanzapine Placebo 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 Vital Signs and Laboratory Studies Vital Sign Changes [see Warnings and Precautions ( 5 Laboratory Changes Olanzapine Monotherapy in Adults: 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. [see Warnings and Precautions ( 5. 15 Olanzapine Monotherapy in Adolescents: ECG 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.

None with olanzapine tablets monotherapy. None with olanzapine monotherapy.

When using olanzapine and fluoxetine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax. · Pregnancy: 8. 1 · Nursing Mothers: 8. 3 · 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 Teratogenic Effects, Pregnancy Category C 2 2 2 2 Placental transfer of olanzapine occurs in rat pups. There are no adequate and well-controlled trials with olanzapine in pregnant females. Seven pregnancies were observed during clinical trials with olanzapine, including 2 resulting in normal births, 1 resulting in neonatal death due to a cardiovascular defect, 3 therapeutic abortions, and 1 spontaneous abortion. Nonteratogenic Effects Olanzapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The effect of olanzapine on labor and delivery in humans is unknown. Parturition in rats was not affected by olanzapine. In a study in lactating, healthy women, olanzapine was excreted in breast milk. Mean infant dose at steady state was estimated to be 1. 8% of the maternal olanzapine dose. It is recommended that women receiving olanzapine should not breast-feed. 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. 3 see Indications and Usage ( 1. 2 see Patient Counseling Information ( 17. 14 )] 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. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient [see Boxed Warning , Dosage and Administration ( 2. 1 ), and Warnings and Precautions ( 5.

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. 2 )] Inhibitors of CYP1A2 Fluvoxamine: max Inhibitors of CYP2D6 Fluoxetine: Warfarin [see Drug Interactions ( 7. 2 )] Inducers of CYP1A2 or Glucuronyl Transferase Charcoal max CNS Acting Drugs Antihypertensive Agents Levodopa and Dopamine Agonists Lithium [see Warnings and Precautions ( 5. 16 Valproate [see Warnings and Precautions ( 5. 16 Effect of Olanzapine on Drug Metabolizing Enzymes vitro Imipramine Warfarin [see Drug Interactions ( 7. 1 )] Diazepam [see Drug Interactions ( 7. 1 )] Alcohol [see Drug Interactions ( 7. 1 )] 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. Eli Lilly and Company has received reports of fatality in association with overdose of olanzapine alone. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine. For current information on the management of olanzapine overdose, contact a certified poison control center (1-800-222-1222 or www. The possibility of multiple drug involvement should be considered. In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation, which may include intubation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The administration of activated charcoal (1 g) reduced the C max.
NONCLINICAL TOXICOLOGY
Carcinogenesis 2 2 2 2 2 2 [see Warnings and Precautions ( 5. 15 Mutagenesis 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 maximum recommended human daily oral dose on a 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. 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 Adjunct to Lithium or Valproate Adolescents Acute Monotherapy.
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