Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3640
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Zyprexa (Tablet)
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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 5mg QD are recommended. Efficacy in schizophrenia was demonstrated in a dose range of 10 to 15 mg/day in clinical trials. However, doses above 10 mg/day were not demonstrated to be more efficacious than the 10 mg/day dose. An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment. The safety of doses above 20 mg/day has not been evaluated in clinical trials. 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���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 ZYPREXA 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.<br/>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 ZYPREXA 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 ZYPREXA 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. Dosing in Special Populations���See Dosing in Special Populations under DOSAGE AND ADMINISTRATION, Schizophrenia.<br/>Administration of ZYPREXA ZYDIS (olanzapine orally disintegrating tablets): After opening sachet, peel back foil on blister. Do not push tablet through foil. Immediately upon opening the blister, using dry hands, remove tablet and place entire ZYPREXA ZYDIS in the mouth. Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without liquid.<br/>Agitation Associated with Schizophrenia and Bipolar I Mania: Usual Dose for Agitated Patients with Schizophrenia or Bipolar Mania���The efficacy of intramuscular olanzapine for injection in controlling agitation in these disorders was demonstrated in a dose range of 2.5 mg to 10 mg. The recommended dose in these patients is 10 mg. A lower dose of 5 or 7.5 mg may be considered when clinical factors warrant . If agitation warranting additional intramuscular doses persists following the initial dose, subsequent doses up to 10 mg may be given. However, the efficacy of repeated doses of intramuscular olanzapine for injection in agitated patients has not been systematically evaluated in controlled clinical trials. Also, the safety of total daily doses greater than 30 mg, or 10 mg injections given more frequently than 2 hours after the initial dose, and 4 hours after the second dose have not been evaluated in clinical trials. Maximal dosing of intramuscular olanzapine (e.g., three doses of 10 mg administered 2���4 hours apart) may be associated with a substantial occurrence of significant orthostatic hypotension . Thus, it is recommended that patients requiring subsequent intramuscular injections be assessed for orthostatic hypotension prior to the administration of any subsequent doses of intramuscular olanzapine for injection. The administration of an additional dose to a patient with a clinically significant postural change in systolic blood pressure is not recommended. If ongoing olanzapine therapy is clinically indicated, oral olanzapine may be initiated in a range of 5���20 mg/day as soon as clinically appropriate . Intramuscular Dosing in Special Populations���A dose of 5 mg per injection should be considered for geriatric patients or when other clinical factors warrant. A lower dose of 2.5 mg per injection should be considered for patients who otherwise might be debilitated, be predisposed to hypotensive reactions, or be more pharmacodynamically sensitive to olanzapine .<br/>Administration of ZYPREXA IntraMuscular: ZYPREXA IntraMuscular is intended for intramuscular use only. Do not administer intravenously or subcutaneously. Inject slowly, deep into the muscle mass. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.<br/>Directions for preparation of ZYPREXA IntraMuscular with Sterile Water for Injection: Dissolve the contents of the vial using 2.1 mL of Sterile Water for Injection to provide a solution containing approximately 5 mg/mL of olanzapine. The resulting solution should appear clear and yellow. ZYPREXA IntraMuscular reconstituted with Sterile Water for Injection should be used immediately (within 1 hour) after reconstitution. Discard any unused portion. The following table provides injection volumes for delivering various doses of intramuscular olanzapine for injection reconstituted with Sterile Water for Injection.<br/>Physical Incompatibility Information: ZYPREXA IntraMuscular should be reconstituted only with Sterile Water for Injection. ZYPREXA IntraMuscular should not be combined in a syringe with diazepam injection because precipitation occurs when these products are mixed. Lorazepam injection should not be used to reconstitute ZYPREXA IntraMuscular as this combination results in a delayed reconstitution time. ZYPREXA IntraMuscular should not be combined in a syringe with haloperidol injection because the resulting low pH has been shown to degrade olanzapine over time.
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dailymed-instance:descripti... |
ZYPREXA (olanzapine) is a psychotropic agent that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. The molecular formula is CHNS, which corresponds to a molecular weight of 312.44. The chemical structure is: Olanzapine is a yellow crystalline solid, which is practically insoluble in water. ZYPREXA tablets are intended for oral administration only. Each tablet contains olanzapine equivalent to 2.5 mg (8��mol), 5 mg (16��mol), 7.5 mg (24��mol), 10 mg (32��mol), 15 mg (48��mol), or 20 mg (64��mol). Inactive ingredients are carnauba wax, crospovidone, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, and other inactive ingredients. The color coating contains Titanium Dioxide (all strengths), FD&C Blue No. 2 Aluminum Lake (15 mg), or Synthetic Red Iron Oxide (20 mg). The 2.5, 5, 7.5, and 10 mg tablets are imprinted with edible ink which contains FD&C Blue No. 2 Aluminum Lake. ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) is intended for oral administration only. Each orally disintegrating tablet contains olanzapine equivalent to 5 mg (16��mol), 10 mg (32��mol), 15 mg (48��mol) or 20 mg (64��mol). It begins disintegrating in the mouth within seconds, allowing its contents to be subsequently swallowed with or without liquid. ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) also contains the following inactive ingredients: gelatin, mannitol, aspartame, sodium methyl paraben and sodium propyl paraben. ZYPREXA IntraMuscular (olanzapine for injection) is intended for intramuscular use only. Each vial provides for the administration of 10 mg (32��mol) olanzapine with inactive ingredients 50 mg lactose monohydrate and 3.5 mg tartaric acid. Hydrochloric acid and/or sodium hydroxide may have been added during manufacturing to adjust pH.
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dailymed-instance:clinicalP... |
Pharmacodynamics: Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors: serotonin 5HT, 5HT, (K=4, 11, and 5 nM, respectively), dopamine D(K=11���31 nM), histamine H(K=7 nM), and adrenergic��receptors (K=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT(K=57 nM) and muscarinic M(K=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds weakly to GABA, BZD, and��adrenergic receptors (K>10��M). 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) antagonism. The mechanism of action of olanzapine in the treatment of acute manic episodes associated with Bipolar I Disorder is unknown. Antagonism at receptors other than dopamine and 5HTmay explain some of the other therapeutic and side effects of olanzapine. Olanzapine's antagonism of muscarinic Mreceptors may explain its anticholinergic���like effects. Olanzapine's antagonism of histamine Hreceptors may explain the somnolence observed with this drug. Olanzapine's antagonism of adrenergic��receptors may explain the orthostatic hypotension observed with this drug.<br/>Pharmacokinetics:<br/>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. Pharmacokinetic studies showed that ZYPREXA tablets and ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) dosage forms of olanzapine are bioequivalent. Olanzapine displays linear kinetics over the clinical dosing range. Its half���life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr). Administration of olanzapine once daily leads to steady���state concentrations in about one 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 (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 over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and�����acid glycoprotein. Metabolism and Elimination���Following a single oral dose ofC 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 P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin���containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be a minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.<br/>Intramuscular Administration: ZYPREXA IntraMuscular results in rapid absorption with peak plasma concentrations occurring within 15 to 45 minutes. Based upon a pharmacokinetic study in healthy volunteers, a 5 mg dose of intramuscular olanzapine for injection produces, on average, a maximum plasma concentration approximately 5 times higher than the maximum plasma concentration produced by a 5 mg dose of oral olanzapine. Area under the curve achieved after an intramuscular dose is similar to that achieved after oral administrationof the same dose. The half���life observed after intramuscular administration is similar to that observed after oral dosing. The pharmacokinetics are linear over the clinical dosing range. Metabolic profiles after intramuscular administration are qualitatively similar to metabolic profiles after oral administration.<br/>Special Populations: For specific information about the pharmacology of lithium or valproate, refer to the CLINICAL PHARMACOLOGY section of the package inserts for these other products.
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ZYPREXA is contraindicated in patients with a known hypersensitivity to the product. For specific information about the contraindications of lithium or valproate, refer to the CONTRAINDICATIONS section of the package inserts for these other products.
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dailymed-instance:supply |
The ZYPREXA 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets are white, round, and imprinted in blue ink with LILLY and tablet number. The 15 mg tablets are elliptical, blue, and debossed with LILLY and tablet number. The 20 mg tablets are elliptical, pink, and debossed with LILLY and tablet number. The tablets are available as follows: ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) are yellow, round, and debossed with the tablet strength. The tablets are available as follows: ZYPREXA is a registered trademark of Eli Lilly and Company. ZYDIS is a registered trademark of Catalent Pharma Solutions. ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) is manufactured for Eli Lilly and Company by Catalent Pharma Solutions, United Kingdom, SN5 8RU. ZYPREXA IntraMuscular is available in:NDC 0002���7597���01 (No. VL7597)���10 mg vial (1s) Store ZYPREXA tablets, ZYPREXA ZYDIS, and ZYPREXA IntraMuscular vials (before reconstitution) at controlled room temperature, 20��to 25��C (68��to 77��F) [see USP]. Reconstituted ZYPREXA IntraMuscular may be stored at controlled room temperature, 20��to 25��C (68��to 77��F) [see USP] for up to 1 hour if necessary. Discard any unused portion of reconstituted ZYPREXA IntraMuscular. The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20��to 25��C (68��to 77��F); that results in a mean kinetic temperature calculated to be not more than 25��C; and that allows for excursions between 15��and 30��C (59��and 86��F) that are experienced in pharmacies, hospitals, and warehouses. Protect ZYPREXA tablets and ZYPREXA ZYDIS from light and moisture. Protect ZYPREXA IntraMuscular from light, do not freeze.
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WARNING: Increased Mortality in Elderly Patients with Dementia���Related Psychosis���Elderly patients with dementia���related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo���controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug���treated patients of between 1.6 to 1.7 times that seen in placebo���treated patients. Over the course of a typical 10���week controlled trial, the rate of death in drug���treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. ZYPREXA (olanzapine) is not approved for the treatment of patients with dementia���related psychosis (see WARNINGS).
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dailymed-ingredient:Carnauba_wax,
dailymed-ingredient:Cellulose_microcrystalline,
dailymed-ingredient:Crospovidone,
dailymed-ingredient:FD&C_Blue_No._2_aluminum_lake,
dailymed-ingredient:Hydroxypropyl_cellulose,
dailymed-ingredient:Hypromellose,
dailymed-ingredient:Ink_(edible),
dailymed-ingredient:Lactose,
dailymed-ingredient:Magnesium_stearate,
dailymed-ingredient:Titanium_dioxide
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dailymed-instance:possibleD... |
diseasome-diseases:1025,
diseasome-diseases:1032,
diseasome-diseases:130,
diseasome-diseases:1377,
diseasome-diseases:1460,
diseasome-diseases:1547,
diseasome-diseases:2216,
diseasome-diseases:3423,
diseasome-diseases:347,
diseasome-diseases:3841,
diseasome-diseases:3852,
diseasome-diseases:54,
diseasome-diseases:852,
diseasome-diseases:94
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dailymed-instance:precautio... |
General: Hemodynamic Effects���Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose���titration period, probably reflecting its�����adrenergic antagonistic properties. Hypotension, bradycardia with or without hypotension, tachycardia, and syncope were also reported during the clinical trials with intramuscular olanzapine for injection. In an open���label clinical pharmacology study in non���agitated patients with schizophrenia in which the safety and tolerability of intramuscular olanzapine were evaluated under a maximal dosing regimen (three 10 mg doses administered 4 hours apart), approximately one���third of these patients experienced a significant orthostatic decrease in systolic blood pressure (i.e., decrease���30 mmHg) . Syncope was reported in 0.6% (15/2500) of olanzapine���treated patients in phase 2���3 oral olanzapine studies and in 0.3% (2/722) of olanzapine���treated patients with agitation in the intramuscular olanzapine for injection studies. Three normal volunteers in phase 1 studies with intramuscular olanzapine experienced hypotension, bradycardia, and sinus pauses of up to 6 seconds that spontaneously resolved (in 2 cases the events occurred on intramuscular olanzapine, and in 1 case, on oral olanzapine). The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs. 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. For intramuscular olanzapine for injection therapy, patients should remain recumbent if drowsy or dizzy after injection until examination has indicated that they are not experiencing postural hypotension, bradycardia, and/or hypoventilation. 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 bradycardiamight 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 (see Drug Interactions). Concomitant administration of intramuscular olanzapine and parenteral benzodiazepine has not been studied and is therefore not recommended. If use of intramuscular olanzapine in combination with parenteral benzodiazepines is considered,careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended. Seizures���During premarketing testing, 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 Dreceptors, olanzapine elevates prolactin levels, and a modest elevation persists during chronic administration. Tissue culture experiments indicate that approximately one���third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer of this type. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin���elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats (see Carcinogenesis). However, neither clinical studies nor epidemiologic studies have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive. Transaminase Elevations���In placebo���controlled studies, clinically significant ALT (SGPT) elevations (���3 times the upper limit of the normal range) were observed in 2% (6/243) of patients exposed to olanzapine compared to none (0/115) of the placebo patients. None of these patients experienced jaundice. In two of these patients, liver enzymes decreased toward normal despite continued treatment and in two others, enzymes decreased upondiscontinuation of olanzapine. In the remaining two patients, one, seropositive for hepatitis C, had persistent enzyme elevation for four months after discontinuation, and the other had insufficient follow���up to determine if enzymes normalized. Within the larger premarketing database of about 2400 patients with baseline SGPT���90 IU/L, 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. Rare postmarketing reports of hepatitis have been received. Very rare cases of cholestatic or mixed liver injury have also been reported in the postmarketing period. Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre���existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs. Periodic assessment of transaminases is recommended in patients with significant hepatic disease (see Laboratory Tests). Potential for Cognitive and Motor Impairment���Somnolence was a commonly reported adverse event associated with olanzapine treatment, occurring at an incidence of 26% in olanzapine patients compared to 15% in placebo patients. This adverse event was also dose related. Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing database. 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. In premarketing clinical trials with olanzapine, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse events possibly related to cholinergic antagonism. Such adverse events were not often the basis for discontinuations from olanzapine, but olanzapine should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma, or a history of paralytic ileus. In five placebo���controlled studies of olanzapine in elderly patients with dementia���related psychosis (n=1184), the following treatment���emergent adverse events 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 events was significantly greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia���related psychosis treated with olanzapine are at an increased risk of death compared to placebo. 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 . Olanzapine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risk of orthostatic hypotension with olanzapine, caution should be observed in cardiac patients (see Hemodynamic Effects). For specific information about the precautions of lithium or valproate, refer to the PRECAUTIONS section of the package inserts for these other products.<br/>Information for Patients: Physicians are advised to discuss the following issues with patients for whom they prescribe olanzapine: Hyperglycemia���Patients should be advised of the potential risk of hyperglycemia���related adverse events. Patients should be monitored regularly for worsening of glucose control. Weight Gain���Patients should be counseled that olanzapine is associated with weight gain. Patients should have their weight monitored regularly. Orthostatic Hypotension���Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol (see Drug Interactions). Interference with Cognitive and Motor Performance���Because 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. Pregnancy���Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with olanzapine. Nursing���Patients should be advised not to breast���feed an infant if they are taking olanzapine. Concomitant Medication���Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over���the���counter drugs, since there is a potential for interactions. Alcohol���Patients should be advised to avoid alcohol while taking olanzapine. Heat Exposure and Dehydration���Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Phenylketonurics���ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) contains phenylalanine (0.34, 0.45, 0.67, or 0.90 mg per 5, 10, 15, or 20 mg tablet, respectively).<br/>Laboratory Tests: Periodic assessment of transaminases is recommended in patients with significant hepatic disease (see Transaminase Elevations).<br/>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. Effect of Olanzapine on Other Drugs���In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes. 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���Studies in vitro using human liver microsomes determined that olanzapine has little potential to inhibit the major metabolic pathway, glucuronidation, of valproate. Further, valproate has little effect on the metabolism of olanzapine in vitro. 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. Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine, and warfarin. Multiple doses of olanzapine did not influence the kinetics of diazepam and its active metabolite N���desmethyldiazepam, ethanol, or biperiden. However, 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. Lorazepam���Administration of intramuscular lorazepam (2 mg) 1 hour after intramuscular olanzapine for injection (5 mg) did not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. However, this co���administration of intramuscular lorazepam and intramuscular olanzapine for injection added to the somnolence observed with either drug alone (see Hemodynamic Effects).<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis���Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78���week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8���5 times the maximum recommended human daily oral dose on a mg/mbasis) and 0.25, 2, 8 mg/kg/day (equivalent to 0.06���2 times the maximum recommended human daily oral dose on a mg/mbasis). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25, 1, 4, 8 mg/kg/day (females) (equivalent to 0.13���2 and 0.13���4 times the maximum recommended human daily oral dose on a mg/mbasis, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in one mouse study in female mice dosed at 8 mg/kg/day (2 times the maximum recommended human daily oral dose on a mg/mbasis). These tumors were not increased in another mouse study in females dosed at 10 or 30/20 mg/kg/day (2���5 times the maximum recommended human daily oral dose on a mg/mbasis); in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at���2 mg/kg/day and in female rats dosed at���4 mg/kg/day (0.5 and 2 times the maximum recommended human daily oral dose on a mg/mbasis, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4���fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumors in rodents is unknown . Mutagenesis���No evidence of mutagenic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters. Impairment of Fertility���In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the maximum recommended human daily oral dose on a mg/mbasis, respectively). Discontinuance of olanzapine treatment reversed the effects on male mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the maximum recommended human daily oral dose on a mg/mbasis). Diestrous was prolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the maximum recommended human daily oral dose on a mg/mbasis); therefore olanzapine may produce a delay in ovulation.<br/>Pregnancy:<br/>Pregnancy Category C: In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the maximum recommended human daily oral dose on a mg/mbasis, respectively) no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the maximum recommended human daily oral dose on a mg/mbasis). Gestation was prolonged at 10 mg/kg/day (5 times the maximum recommended human daily oral dose on a mg/mbasis). In an oral rabbit teratology study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the maximum recommended human daily oral dose on a mg/mbasis). 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. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Labor and Delivery: Parturition in rats was not affected by olanzapine. The effect of olanzapine on labor and delivery in humans is unknown.<br/>Nursing Mothers: 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.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: 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. 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 .
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Human Experience: 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 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. Eli Lilly and Company has received reports of fatality in association with overdose of olanzapine alone. In one 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.<br/>Overdosage Management: 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 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.
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Olanzapine
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Zyprexa (Tablet)
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The information below is derived from a clinical trial database for olanzapine consisting of 8661 patients with approximately 4165 patient���years of exposure to oral olanzapine and 722 patients with exposure to intramuscular olanzapine for injection. 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 mania 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 patients from 88 additional oral olanzapine clinical trials as of December 31, 2001; and (5) 722 patients who participated in intramuscular olanzapine for injection premarketing trials in agitated patients with schizophrenia, Bipolar I Disorder (manic or mixed episodes), or dementia. In addition, 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 mania trials with approximately 22 patient���years of exposure, is included below. 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 events, 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 events, 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 mania or agitation. However, this information is also generally applicable to bipolar mania and agitation. Adverse events 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 events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard COSTART dictionary terminology has been used initially toclassify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment���emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. The reported events do not include those event terms that were so general as to be uninformative. Events listed elsewhere in labeling maynot be repeated below. It is important to emphasize that, although the events 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 physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse event incidence in the population studied. Incidence of Adverse Events in Short-Term, Placebo-Controlled and Combination Trials The following findings are based on premarketing trials of (1) oral olanzapine for schizophrenia, bipolar mania, a subsequent trial of patients having various psychiatric symptoms in association with Alzheimer's disease, and premarketing combination trials, and (2) intramuscular olanzapine for injection in agitated patients with schizophrenia or bipolar mania. Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials Schizophrenia���Overall, there was no difference in the incidence of discontinuation due to adverse events (5% for oral olanzapine vs 6% for placebo). However, discontinuations due to increases in SGPT were considered to be drug related (2% for oral olanzapine vs 0% for placebo) . Bipolar Mania Monotherapy���Overall, there was no difference in the incidence of discontinuation due to adverse events (2% for oral olanzapine vs 2% for placebo). Agitation���Overall, there was no difference in the incidence of discontinuation due to adverse events (0.4% for intramuscular olanzapine for injection vs 0% for placebo). Adverse Events Associated with Discontinuation of Treatment in Short-Term Combination Trials Bipolar Mania Combination Therapy���In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse events were 11% for the combination of oral olanzapine with lithium or valproate compared to 2% for patients who remained on lithium or valproate monotherapy. Discontinuations with the combination of oral olanzapine and lithium or valproate that occurred in more than 1 patient were: somnolence (3%), weight gain (1%), and peripheral edema (1%). Commonly Observed Adverse Events in Short-Term, Placebo-Controlled Trials The most commonly observed adverse events 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: There was one adverse event (somnolence) observed at an incidence of 5% or greater among intramuscular olanzapine for injection���treated patients and not observed at an equivalent incidence among placebo���treated patients (olanzapine incidence at least twice that for placebo) during the placebo���controlled premarketing studies. The incidence of somnolence during the 24 hour IM treatment period in clinical trials in agitated patients with schizophrenia or bipolar mania was 6% for intramuscular olanzapine for injection and 3% for placebo. Adverse Events Occurring at an Incidence of 2% or More Among Oral Olanzapine-Treated Patients in Short-Term, Placebo-Controlled Trials Table 4 enumerates the incidence, rounded to the nearest percent, of treatment���emergent adverse events 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. Commonly Observed Adverse Events in Short-Term Combination Trials In the bipolar mania combination placebo���controlled trials, the most commonly observed adverse events associated with the combination of olanzapine and lithium or valproate (incidence of���5% and at least twice placebo) were: Adverse Events Occurring at an Incidence of 2% or More Among Oral Olanzapine-Treated Patients in Short-Term Combination Trials Table 5 enumerates the incidence, rounded to the nearest percent, of treatment���emergent adverse events 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. For specific information about the adverse reactions observed with lithium or valproate, refer to the ADVERSE REACTIONS section of the package inserts for these other products. Adverse Events Occurring at an Incidence of 1% or More Among Intramuscular Olanzapine for Injection-Treated Patients in Short-Term, Placebo-Controlled Trials Table 6 enumerates the incidence, rounded to the nearest percent, of treatment���emergent adverse events that occurred in 1% or more of patients treated with intramuscular olanzapine for injection (dose range of 2.5���10 mg/injection) and with incidence greater than placebo who participated in the short���term, placebo���controlled trials in agitated patients with schizophrenia or bipolar mania. Dose Dependency of Adverse Events in Short-Term, Placebo-Controlled Trials Extrapyramidal Symptoms���The following table enumerates the percentage of patients with treatment���emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia. The following table enumerates the percentage of patients with treatment���emergent extrapyramidal symptoms as assessed by spontaneously reported adverse events during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia. The following table enumerates the percentage of patients with treatment���emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during controlled clinical trials comparing fixed doses of intramuscular olanzapine for injection with placebo in agitation. Patients in each dose group could receive up to three injections during the trials . Patient assessments were conducted during the 24 hours following the initial dose of intramuscular olanzapine for injection. There wereno statistically significant differences from placebo. The following table enumerates the percentage of patients with treatment���emergent extrapyramidal symptoms as assessed by spontaneously reported adverse events in the same controlled clinical trial comparing fixed doses of intramuscular olanzapine for injection with placebo in agitated patients with schizophrenia. There were no statistically significant differences from placebo. Dystonia, Class Effect���Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use. Other Adverse Events���The following table addresses dose relatedness for other adverse events using data from a schizophrenia trial involving fixed dosage ranges of oral olanzapine. It enumerates the percentage of patients with treatment���emergent adverse events for the three 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 events for which there was a statistically significant trend. Additional Findings In a single 8���week randomized, double���blind, fixed���dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of olanzapine in patients with schizophrenia or schizoaffective disorder, statistically significant differences among 3 dose groups were observed for the following safety outcomes: weight gain, prolactin elevation, fatigue and dizziness. Mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day. Incidence of treatment���emergent prolactin elevation>24.2 ng/mL (female) or>18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) with significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day; fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) with significant differences between 10 vs 40 and 20 vs 40 mg/day; and dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) with significant differences between 20 vs 40 mg, was observed. Additional Findings Observed in Clinical Trials The following findings are based on clinical trials. Vital Sign Changes���Oral olanzapine was associated with orthostatic hypotension and tachycardia in clinical trials. Intramuscular olanzapine for injection was associated with bradycardia, hypotension, and tachycardia in clinical trials . Laboratory Changes���An assessment of the premarketing experience for olanzapine revealed an association with asymptomatic increases in SGPT, SGOT, and GGT . Olanzapine administration was also associated with increases in serum prolactin , with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK. Given the concern about neutropenia associated with other psychotropic compounds and the finding of leukopenia associated with the administration of olanzapine in several animal models , careful attention was given to examination of hematologic parameters in premarketing studies with olanzapine. There was no indication of a risk of clinically significant neutropenia associated with olanzapine treatment in the premarketing database for this drug. ECG Changes���Between���group comparisons for pooled placebo���controlled trials revealed no statistically significant olanzapine/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. Olanzapine use was associated with a mean increase in heart rate of 2.4 beats per minute compared to no change among placebo patients. This slight tendency to tachycardia may be related to olanzapine's potential for inducing orthostatic changes . Other Adverse Events Observed During the Clinical Trial Evaluation of Olanzapine Following is a list of terms that reflect treatment���emergent adverse events reported by patients treated with oral olanzapine (at multiple doses���1 mg/day) in clinical trials (8661 patients, 4165 patient���years of exposure). This listing may not include those events already listed in previous tables or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those events reported only once or twice which did not have a substantial probability of being acutely life���threatening. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo���controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. 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. Following is a list of terms that reflect treatment���emergent adverse events reported by patients treated with intramuscular olanzapine for injection (at one or more doses���2.5 mg/injection) in clinical trials (722 patients). This listing may not include those events already listed in previous tables or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life���threatening. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo���controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients. Body as a Whole���Frequent: injection site pain; Infrequent: abdominal pain and fever. Cardiovascular System���Infrequent: AV block, heart block, and syncope. Digestive System���Infrequent: diarrhea and nausea. Hemic and Lymphatic System���Infrequent: anemia. Metabolic and Nutritional Disorders���Infrequent: creatine phosphokinase increased, dehydration, and hyperkalemia. Musculoskeletal System���Infrequent: twitching. Nervous System���Infrequent: abnormal gait, akathisia, articulation impairment, confusion, and emotional lability. Skin and Appendages���Infrequent: sweating. Postintroduction Reports Adverse events reported since market introduction that were temporally (but not necessarily causally) related to ZYPREXA therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), diabetic coma, jaundice, neutropenia, pancreatitis, priapism, rhabdomyolysis, and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis). Random cholesterol levels of���240 mg/dL and random triglyceride levels of���1000 mg/dL have been reported.
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Increased Mortality in Elderly Patients with Dementia���Related Psychosis���Elderly patients with dementia���related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. ZYPREXA 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, Including Stroke, in Elderly Patients with Dementia���Related Psychosis���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���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. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increasedbackground risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia���related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment���emergent hyperglycemia���related adverse events in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics. Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the two highest serum concentrations was 15.0 mg/dL. Olanzapine Monotherapy in Adults���In an analysis of 5 placebo���controlled adult olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL). The difference in mean changes between olanzapine and placebo was greater in patients with evidence ofglucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse events, patients treated with anti���diabetic agents, patients with a baseline random glucose level���200 mg/dL, and/or a baseline fasting glucose level���126 mg/dL). These patients had a statistically significantly greater mean increase in HbAcompared to placebo. In patients with baseline normal fasting glucose levels (<100 mg/dL), 2.2% (N=543) of those treated with olanzapine were found to have high glucose levels (���126 mg/dL) during olanzapine treatment versus 3.4% (N=293) of those treated with placebo. In patients with baseline borderline fasting glucose levels (���100 mg/dL and<126 mg/dL), 17.4% (N=178) of those treated with olanzapine were found to have high glucose levels (���126 mg/dL) during olanzapine treatment versus 11.5% (N=96) of those treated with placebo. Olanzapine Monotherapy in Adolescents���The safety and efficacy of olanzapine have not been established in patients under the age of 18 years. In an analysis of 3 placebo���controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a statistically significantly greater mean change in fasting glucose levels compared to placebo (2.68 mg/dL versus���2.59 mg/dL). In patients with baseline normal fasting glucose levels (<100 mg/dL), zero out of 124 (0%) of those treated with olanzapine were found to have high glucose levels (���126 mg/dL) during olanzapine treatment versus 1 out of 53 (1.9%) of those treated with placebo. In patients with baseline borderline fasting glucose levels (���100 mg/dL and<126 mg/dL), 2 out of 14 (14.3%) of those treated with olanzapine were found to have high glucose levels (���126 mg/dL) during olanzapine treatment versus zero out of 13 (0%) of those treated with placebo. Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100���126 mg/dL, non���fasting 140���200 mg/dL). Patients taking olanzapine should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti���diabetic treatment despite discontinuation of the suspect drug. Hyperlipidemia���Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and follow���up lipid evaluations in patients using olanzapine, is advised. Significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use. Olanzapine Monotherapy in Adults���In an analysis of 5 placebo���controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine���treated patients had statistically significant increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo���treated patients. For fasting HDL cholesterol, no statistically significant differences were observed between olanzapine���treated patients and placebo���treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse events, patients treated with lipid lowering agents, or patients with high baseline lipid levels. Table 1 shows categorical changes in fasting lipid values. In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL. Olanzapine Monotherapy in Adolescents���The safety and efficacy of olanzapine have not been established in patients under the age of 18 years. In an analysis of 3 placebo���controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar disorder (manic or mixed episodes) (3 weeks), for fasting HDL cholesterol, no statistically significant differences were observed between olanzapine���treated patients and placebo���treated patients. Table 2 shows categorical changes in fasting lipid values in adolescent patients. Weight Gain���Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight. Olanzapine Monotherapy in Adults���In an analysis of 13 placebo���controlled olanzapine monotherapy studies, olanzapine���treated patients gained an average of 2.6 kg, which was statistically significantly different compared to an average 0.3 kg weight loss in placebo���treated patients with a median exposure of 6 weeks; 22.2% of olanzapine���treated patients gained at least 7% of their baseline weight, which was statistically significantly different compared to 3% of placebo���treated patients, with a median exposure of 8 weeks; 4.2% of olanzapine���treated patients gained at least 15% of their baseline weight, which was statistically significantly different compared to 0.3% of placebo���treated patients, with a median exposure of 12 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 0.2% of olanzapine���treated patients and in zero placebo���treated patients. During long���term continuation therapy with olanzapine (238 median days of exposure), 56% of olanzapine patients met the criterion for having gained greater than 7% of their baseline weight. Average weight gain during long���term therapy was 5.4 kg. Table 3 includes data on weight gain with olanzapine pooled from 68 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified. Olanzapine Monotherapy in Adolescents���The safety and efficacy of olanzapine have not been established in patients under the age of 18 years. In an analysis of 4 placebo���controlled olanzapine monotherapy studies of adolescent patients (ages 13 to 17 years), including those with schizophrenia (6 weeks) or bipolar disorder (manic or mixed episodes) (3 weeks), olanzapine���treated patients gained an average of 4.6 kg, which was statistically significantly different compared to an average of 0.3 kg in placebo���treated patients, with a median exposure of 3 weeks; 40.6% of olanzapine���treated patients gained at least 7% of their baseline body weight, which was statistically significantly different compared to 9.8% of placebo���treated patients, with a median exposure of 4 weeks; 7.1% of olanzapine���treated patients gained at least 15% of their baseline weight, compared to 2.7% of placebo���treated patients, with a median exposure of 19 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories, but mean changes in weight were greater in adolescents with BMI categories above normal at baseline. Discontinuation due to weight gain occurred in 1% of olanzapine���treated patients, compared to zero placebo���treated patients. During long���term continuation therapy with olanzapine, 65% of olanzapine���treated patients met the criterion for having gained greater than 7% of their baseline weight. Average weight gain during long���term therapy was 7.4 kg. 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 signsmay include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. 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. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long���term course of the syndrome is unknown. Given these considerations, olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. 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. For specific information about the warnings of lithium or valproate, refer to the WARNINGS section of the package inserts for these other products.
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Schizophrenia: Oral ZYPREXA is indicated for the treatment of schizophrenia. The efficacy of ZYPREXA was established in short���term (6���week) controlled trials of schizophrenic inpatients . The effectiveness of oral ZYPREXA at maintaining a treatment response in schizophrenic patients who had been stable on ZYPREXA for approximately 8 weeks and were then followed for a period of up to 8 months has been demonstrated in a placebo���controlled trial . Nevertheless, the physician who elects to use ZYPREXA for extended periods should periodically re���evaluate the long���term usefulness of the drug for the individual patient .<br/>Bipolar Disorder: Acute Monotherapy���Oral ZYPREXA is indicated for the treatment of acute mixed or manic episodes associated with Bipolar I Disorder. The efficacy of ZYPREXA was established in two placebo���controlled trials (one 3���week and one 4���week) with patients meeting DSM���IV criteria for Bipolar I Disorder who currently displayed an acute manic or mixed episode with or without psychotic features . Maintenance Monotherapy���The benefit of maintaining bipolar patients on monotherapy with oral ZYPREXA after achieving a responder status for an average duration of two weeks was demonstrated in a controlled trial . The physician who elects to use ZYPREXA for extended periods should periodically re���evaluate the long���term usefulness of the drug for the individual patient . Combination Therapy���The combination of oral ZYPREXA with lithium or valproate is indicated for the short���term treatment of acute mixed or manic episodes associated with Bipolar I Disorder. The efficacy of ZYPREXA in combination with lithium or valproate was established in two placebo���controlled (6���week) trials with patients meeting DSM���IV criteria for Bipolar I Disorder who currently displayed an acute manic or mixed episode with or without psychotic features .<br/>Agitation Associated with Schizophrenia and Bipolar I Mania: ZYPREXA IntraMuscular is indicated for the treatment of agitation associated with schizophrenia and bipolar I mania.���Psychomotor agitation���is defined in DSM���IV as���excessive motor activity associated with a feeling of inner tension.���Patients experiencing agitation often manifest behaviors that interfere with their diagnosis and care, e.g., threatening behaviors, escalating or urgently distressing behavior, or self���exhausting behavior, leading clinicians to the use of intramuscular antipsychotic medications to achieve immediate control of the agitation. The efficacy of ZYPREXA IntraMuscular for the treatment of agitation associated with schizophrenia and bipolar I mania was established in 3 short���term (24 hours) placebo���controlled trials in agitated inpatients with schizophrenia or Bipolar I Disorder (manic or mixed episodes) .
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Zyprexa
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