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Maintenance Monotherapy — The benefit of maintaining bipolar patients on monotherapy with oral OLANZAPINE after achieving a responder status for an average duration of two weeks was demonstrated in a controlled trial.
Combination Therapy — The combination of oral OLANZAPINE with lithium or valproate is indicated for the short-term treatment of acute mixed or manic episodes associated with Bipolar I Disorder.
DOSAGE AND ADMINISTRATION:
Schizophrenia: Usual Dose — Oral Olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady state for Olanzapine would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.
Dosing in Special Populations — The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of Olanzapine (e.g., nonsmoking female patients over 65 years of age), or who may be more pharmacodynamically sensitive to Olanzapine. When indicated, dose escalation should be performed with caution in these patients.
Maintenance Treatment — While there is no body of evidence available to answer the question of how long the patient treated with Olanzapine should remain on it, the effectiveness of oral Olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients who had been stable on OLANZAPINE for approximately 8 weeks and were then followed for a period of up to 8 months has been demonstrated in a placebo-controlled trial. Patients should be periodically reassessed to determine the need for maintenance treatment with appropriate dose.
Bipolar Disorder
Usual Monotherapy Dose — Oral Olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 or 15 mg. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials. 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 in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials.
Maintenance Monotherapy — The benefit of maintaining bipolar patients on monotherapy with oral OLANZAPINE at a dose of 5 to 20 mg/day, after achieving a responder status for an average duration of two weeks, was demonstrated in a controlled trial. The physician who elects to use OLANZAPINE for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Bipolar Mania Usual Dose in Combination with Lithium or Valproate — When administered in combination with lithium or valproate, oral Olanzapine dosing should generally begin with 10 mg once-a-day without regard to meals.
Short-term (6 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials.
Mechanism of action: 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 episodes associated with Bipolar I Disorder is unknown.
CONTRAINDICATIONS:
OLANZAPINE is contraindicated in patients with a known hypersensitivity to the product.
DESCRIPTION: Olanzapine is a psychotropic agent that belongs to the thienobenzodiazepine class.
CLINICAL PHARMACOLOGY:
Pharmacodynamics Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors: serotonin 5HT2A/2C , 5HT6 , dopamine
Pharmacokinetics
Oral Administration: 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.
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).
Plasma concentrations, half-life, and clearance of Olanzapine may vary between individuals on the basis of smoking status, gender, and age (see Special Populations).
Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins.
Metabolism and Elimination —Approximately 57% and 30% of the dose was recovered in the urine and feces. 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 P450 (CYP) mediated oxidation are the primary metabolic pathways for Olanzapine.
Special 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.
Hepatic Impairment —The effect of impaired liver function revealed little on the pharmacokinetics of Olanzapine.
Age —Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity.
Smoking Status — Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely recommended.
Clinical Efficacy Data
Schizophrenia
The efficacy of oral Olanzapine in the treatment of schizophrenia was established in 2 short-term (6-week) controlled trials of inpatients who met DSM III-R criteria for schizophrenia. A single haloperidol arm was included as a comparative treatment in one of the two trials, but this trial did not compare these two 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, two 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 two 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 two 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.
Examination of population subsets (race and gender) did not reveal any differential responsiveness on the basis of these subgroupings.
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.
Bipolar Disorder
Monotherapy — The efficacy of oral Olanzapine in the treatment of acute manic or mixed episodes was established in 2 short-term (one 3-week and one 4-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course.
The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow:
(1) In one 3-week placebo-controlled trial (n=67) which involved a dose range of Olanzapine (5-20 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 (5-20 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 disorder who had responded during an initial open-label treatment phase for about two 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.
Combination Therapy — The efficacy of oral Olanzapine with concomitant lithium or valproate in the treatment of acute manic episodes was established in two controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course. The results of the trials follow:
(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 5-20 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 g/mL to 125 g/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. Olanzapine (in a dose range of 5-20 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 g/mL to 125 g/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.
WARNINGS:
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. OLANZAPINE is not approved for the treatment of patients with dementia-related psychosis.
In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in Olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of Olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with Olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis.
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including Olanzapine.
Neuroleptic Malignant Syndrome (NMS) — A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including Olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
Tardive Dyskinesia — A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Chronic antipsychotic treatment should generally be reserved for patients (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on Olanzapine, drug discontinuation should be considered. However, some patients may require treatment with Olanzapine despite the presence of the syndrome.
PRECAUTIONS:
General
Hemodynamic Effects — Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period. For oral Olanzapine therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg QD. A more gradual titration to the target dose should be considered if hypotension occurs.
Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk.
Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression.
Seizures —Seizures occurred in 0.9% (22/2500) of Olanzapine-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. Olanzapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
Hyperprolactinemia — As with other drugs that antagonize dopamine D2 receptors, Olanzapine elevates prolactin levels, and a modest elevation persists during chronic administration.
Transaminase Elevations — The incidence of SGPT elevation to >200 IU/L was 2% (50/2381). Again, none of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while Olanzapine treatment was continued. Among 2500 patients in oral Olanzapine clinical trials, about 1% (23/2500) discontinued treatment due to transaminase increases.
Potential for Cognitive and Motor Impairment — Since Olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Olanzapine therapy does not affect them adversely.
Body Temperature Regulation — Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Olanzapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
Dysphagia — Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
Suicide — The possibility of a suicide attempt is inherent in schizophrenia and in bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for Olanzapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Use in Patients with Concomitant Illness — Clinical experience with Olanzapine in patients with certain concomitant systemic illnesses is limited.
Olanzapine exhibits in vitro muscarinic receptor affinity. Olanzapine should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma, or a history of paralytic ileus.
Laboratory Tests: Periodic assessment of transaminases is recommended in patients with significant hepatic disease.
Pregnancy
Pregnancy Category C
Nursing Mothers: It is recommended that women receiving Olanzapine should not breast-feed.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Geriatric Use: Olanzapine is not approved for the treatment of patients with dementia-related psychosis. If the prescriber elects to treat elderly patients with dementia-related psychosis, vigilance should be exercised. 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.
Drug Interactions:
The risks of using Olanzapine in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of Olanzapine, caution should be used when Olanzapine is taken in combination with other centrally acting drugs and alcohol.
Because of its potential for inducing hypotension, Olanzapine may enhance the effects of certain antihypertensive agents.
Olanzapine may antagonize the effects of levodopa and dopamine agonists.
The Effect of Other Drugs on Olanzapine — Agents that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and rifampin, may cause an increase in Olanzapine clearance. Inhibitors of CYP1A2 could potentially inhibit Olanzapine clearance. Although Olanzapine is metabolized by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably alter Olanzapine clearance. Therefore, a dosage increase (for induction) or a dosage decrease (for inhibition) may need to be considered with specific drugs.
Charcoal — 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 after dosing, charcoal may be a useful treatment for Olanzapine overdose.
Cimetidine and Antacids — Single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids did not affect the oral bioavailability of Olanzapine.
Carbamazepine — Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of Olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in Olanzapine clearance.
Ethanol — Ethanol (45 mg/70 kg single dose) did not have an effect on Olanzapine pharmacokinetics.
Fluoxetine — Fluoxetine (60 mg single dose or 60 mg daily for 8 days) causes a small (mean 16%) increase in the maximum concentration of Olanzapine and a small (mean 16%) decrease in Olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended.
Fluvoxamine — Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of Olanzapine. This results in a mean increase in Olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in Olanzapine AUC is 52% and 108%, respectively. Lower doses of Olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine.
Warfarin — Warfarin (20 mg single dose) did not affect Olanzapine pharmacokinetics.
Lithium — Multiple doses of Olanzapine (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant Olanzapine administration does not require dosage adjustment of lithium.
Valproate —In vivo administration of Olanzapine (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations of valproate. Therefore, concomitant Olanzapine administration does not require dosage adjustment of valproate.
The co-administration of either diazepam or ethanol with Olanzapine potentiated the orthostatic hypotension observed with Olanzapine. Multiple doses of Olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.
SIDE EFFECTS:
Body as a Whole — Frequent: dental pain and flu syndrome; Infrequent: abdomen enlarged, chills, face edema, intentional injury, malaise, moniliasis, neck pain, neck rigidity, pelvic pain, photosensitivity reaction, and suicide attempt; Rare: chills and fever, hangover effect, and sudden death.
Cardiovascular System — Frequent: hypotension; Infrequent: atrial fibrillation, bradycardia, cerebrovascular accident, congestive heart failure, heart arrest, hemorrhage, migraine, pallor, palpitation, vasodilatation, and ventricular extrasystoles; Rare: arteritis, heart failure, and pulmonary embolus.
Digestive System — Frequent: flatulence, increased salivation, and thirst; Infrequent: dysphagia, esophagitis, fecal impaction, fecal incontinence, gastritis, gastroenteritis, gingivitis, hepatitis, melena, mouth ulceration, nausea and vomiting, oral moniliasis, periodontal abscess, rectal hemorrhage, stomatitis, tongue edema, and tooth caries; Rare: aphthous stomatitis, enteritis, eructation, esophageal ulcer, glossitis, ileus, intestinal obstruction, liver fatty deposit, and tongue discoloration.
Endocrine System — Infrequent: diabetes mellitus; Rare: diabetic acidosis and goiter.
Hemic and Lymphatic System — Infrequent: anemia, cyanosis, leukocytosis, leukopenia, lymphadenopathy, and thrombocytopenia; Rare: normocytic anemia and thrombocythemia.
Metabolic and Nutritional Disorders — Infrequent: acidosis, alkaline phosphatase increased, bilirubinemia, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, lower extremity edema, and upper extremity edema; Rare: gout, hyperkalemia, hypernatremia, hypoproteinemia, ketosis, and water intoxication.
Musculoskeletal System — Frequent: joint stiffness and twitching; Infrequent: arthritis, arthrosis, leg cramps, and myasthenia; Rare: bone pain, bursitis, myopathy, osteoporosis, and rheumatoid arthritis.
Nervous System — Frequent: abnormal dreams, amnesia, delusions, emotional lability, euphoria, manic reaction, paresthesia, and schizophrenic reaction; Infrequent: akinesia, alcohol misuse, antisocial reaction, ataxia, CNS stimulation, cogwheel rigidity, delirium, dementia, depersonalization, dysarthria, facial paralysis, hypesthesia, hypokinesia, hypotonia, incoordination, libido decreased, libido increased, obsessive compulsive symptoms, phobias, somatization, stimulant misuse, stupor, stuttering, tardive dyskinesia, vertigo, and withdrawal syndrome; Rare: circumoral paresthesia, coma, encephalopathy, neuralgia, neuropathy, nystagmus, paralysis, subarachnoid hemorrhage, and tobacco misuse.
Respiratory System — Frequent: dyspnea; Infrequent: apnea, asthma, epistaxis, hemoptysis, hyperventilation, hypoxia, laryngitis, and voice alteration; Rare: atelectasis, hiccup, hypoventilation, lung edema, and stridor.
Skin and Appendages — Frequent: sweating; Infrequent: alopecia, contact dermatitis, dry skin, eczema, maculopapular rash, pruritus, seborrhea, skin discoloration, skin ulcer, urticaria, and vesiculobullous rash; Rare: hirsutism and pustular rash.
Special Senses — Frequent: conjunctivitis; Infrequent: abnormality of accommodation, blepharitis, cataract, deafness, diplopia, dry eyes, ear pain, eye hemorrhage, eye inflammation, eye pain, ocular muscle abnormality, taste perversion, and tinnitus; Rare: corneal lesion, glaucoma, keratoconjunctivitis, macular hypopigmentation, miosis, mydriasis, and pigment deposits lens.
Urogenital System — Frequent: vaginitis*; Infrequent: abnormal ejaculation*, amenorrhea*, breast pain, cystitis, decreased menstruation*, dysuria, female lactation*, glycosuria, gynecomastia, hematuria, impotence*, increased menstruation*, menorrhagia*, metrorrhagia*, polyuria, premenstrual syndrome*, pyuria, urinary frequency, urinary retention, urinary urgency, urination impaired, uterine fibroids enlarged*, and vaginal hemorrhage*; Rare: albuminuria, breast enlargement, mastitis, and oliguria.
OVERDOSAGE:
Reports of overdose with Olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with over 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 events: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and one patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. In one case of death, the amount of acutely ingested Olanzapine was reported to be possibly as low as 450 mg; however, in another case, a patient was reported to survive an acute Olanzapine ingestion of 1500 mg.
Overdosage Management: 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 possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
There is no specific antidote to Olanzapine. Therefore, appropriate supportive measures should be initiated. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. (Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of Olanzapine-induced alpha blockade.) Close medical supervision and monitoring should continue until the patient recovers.
How Supplied: Pack of 100 tablets in 10 blisters.
STORAGE: Store at 15-30°C.
Reference: PDR 2000, page 1649
USPDI for Professional Health Care, 2004, Page 2123