Each film-coated tablet contains: Olanzapine USP 5 mg.
Pharmacology: 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 (5HT2) antagonism. The mechanism of action of olanzapine in the treatment of acute manic or mixed episodes associated with bipolar I disorder is unknown.
Pharmacodynamics: Olanzapine binds with high affinity to the following receptors: serotonin 5HT2A/2C, 5HT6 (Ki=4, 11, and 5 nM, respectively), dopamine D1-4(Ki=11-31 nM), histamine H1 (Ki=7 nM), and adrenergic α1 receptors (Ki=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 (K=57 nM) and muscarinic M1-5 (Ki=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds weakly to GABAA, BZD, and β-adrenergic receptors (Ki>10 μM).
Antagonism at receptors other than dopamine and 5HT2 may explain some of the other therapeutic and side effects of olanzapine. Olanzapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic-like effects. Olanzapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Olanzapine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug.
Pharmacokinetics: Oral Administration, Monotherapy: Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not affect the rate or extent of olanzapine absorption. Pharmacokinetic studies showed that Olanzapine tablets and olanzapine orally disintegrating tablets dosage forms of olanzapine are bioequivalent.
Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 46 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 aracid glycoprotein.
Metabolism and Elimination: Following a single oral dose of 14C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4'-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed.
Direct glucuronidation and cytochrome 450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine.
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 (Child's Pugh Classification A and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine.
Geriatric: The mean elimination half-life of olanzapine was about 1.5 times greater in elderly (≥65 years) than in non-elderly subjects (<65 years). Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity.
Gender: Clearance of olanzapine is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed.
Smoking Status: Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely recommended.
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.
Adolescents (ages 13 to 17 years): 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 indicated for the treatment of schizophrenia.
Olanzapine is effective in maintaining the clinical improvement during continuing therapy in patients who have shown initial treatment response.
Olanzapine is indicated for short-term treatment of acute manic episode associated with Bipolar I Disorder.
Olanzapine is indicated for preventing recurrence of manic, mixed or depressive episodes in Bipolar I Disorder.
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, when dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.
Short-term (3-4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day. The safety of doses above 20 mg/day has not been evaluated in study.
Maintenance Monotherapy: The benefit of maintaining bipolar I patients on monotherapy with oral ZONIA-5 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 study. The physician who elects to use ZONIA-5 for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
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.
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 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with bipolar I disorder (manic or mixed) was demonstrated based on a flexible dose range of 2.5 to 20 mg/day, with a mean modal dose of 10.7 mg/day (mean dose of 8.9 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.
Maintenance Treatment: The efficacy of ZONIA-5 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. 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.
Human Experience: In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced levels of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias, delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension.
Management of Overdose: The possibility of multiple drug involvement should be considered in case of acute overdosage, establish and maintain an airway & 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 Cmax and AUC of oral olanzapine by about 60%. As peak olanzapine levels are not typically obtained until about 6 hours.
Do not take Olanzapine Tablets if the patient has had an allergic reaction to Olanzapine or any of the ingredients listed at the end of this information. Signs of allergic reaction may include a skin rash, itching, shortness of breath or swelling of the face, lips or tongue.
Elderly Patients with Dementia-Related Psychosis: Increased risk of death and increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack).
Suicide: The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drug therapy; when using in combination with fluoxetine.
Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring.
Hyperglycemia: In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking olanzapine. Patients taking olanzapine should be monitored for symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during, treatment.
Hyperlipidemia: Undesirable alterations in lipids have been observed. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during treatment.
Weight Gain: Potential consequences of weight gain should be considered. Patients should receive regular monitoring of weight.
Tardive Dyskinesia: Discontinue if clinically appropriate.
Orthostatic Hypotension: Orthostatic hypotension associated with dizziness. tachycardia, bradycardia and, in some patients, syncope, may occur especially during initial dose titration. Use caution in patients with cardiovascular disease, cerebrovascular disease, and those conditions that could affect hemodynamic responses.
Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including Olanzapine. Patients with a history of a clinically significant low white blood cell count (WBC) or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of Olanzapine should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold.
Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery.
Hyperprolactinemia: May elevate prolactin levels.
Use in Combination with Fluoxetine, Lithium or Valproate.
Laboratory Tests: Monitor fasting blood glucose and lipid profiles at the beginning of, and periodically during, treatment.
Agitation or hostile, angry behavior; Changes in emotions or behavior, like a very depressed mood; Restlessness or need to keep moving; Stiffness, spasms; Tremors or trembling.
Rare or Less common:
Changes in vision, inability to control eye movements; Confusion; Difficulty breathing; Difficulty concentrating; Difficulty in speaking or swallowing; Excessive thirst and/or hunger; Fainting spells, loss of balance; Fast heartbeat (palpitations); Frequently needing to urinate; Inability to control muscle movements in the face, hands, arms, or legs; Menstrual changes; Painful erections; Seizures (convulsions); Skin rash; Swelling of face or legs; Uncontrollable tongue or chewing movements, smacking lips or puffing cheeks; Unusual tiredness or weakness.
Less common or rare:
Blurred or unclear vision; Changes in sexual desire; Excessive drainage from eyes; Excessive watering or drooling of mouth; Joint pain; Nausea or vomiting; Sensitivity of skin to sunlight; Tingling sensation in your hands, feet or other area of your body; Trouble in controlling urine.
Constipation, Dizziness; especially on standing from a standing from a sitting or lying position; Drowsiness; Dry mouth; Lowered blood pressure; Runny nose, Weight gain.
Diazepam: May potentiate orthostatic hypotension.
Alcohol: May potentiate orthostatic hypotension.
Carbamazepine: Increased clearance of olanzapine.
Fluvoxamine: May increase olanzapine levels.
CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs and alcohol.
Antihypertensive Agents: Enhanced antihypertensive effect.
Levodopa and Dopamine Agonists: May antagonize levodopa/dopamine agonists.
Other Concomitant Drug Therapy: When using olanzapine in combination with lithium or valproate.
Store at temperatures not exceeding 30°C. Protect from light & moisture.
Shelf Life: 24 Months from the date of manufacturing.
N05AH03 - olanzapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics