1. Name Of The Medicinal Product
ZYPREXA*
2. Qualitative And Quantitative Composition
Each vial contains 10 mg olanzapine. After reconstitution each ml of the solution contains 5 mg olanzapine.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for solution for injection.
Yellow lyophilised powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Adults
ZYPREXA powder for solution for injection is indicated for the rapid control of agitation and disturbed behaviours in patients with schizophrenia or manic episode, when oral therapy is not appropriate. Treatment with ZYPREXA powder for solution for injection should be discontinued and the use of oral olanzapine should be initiated, as soon as clinically appropriate.
4.2 Posology And Method Of Administration
Adults
For intramuscular use. Do not administer intravenously or subcutaneously. ZYPREXA powder for solution for injection is intended for short-term use only, for up to a maximum of three consecutive days.
The maximum daily dose of olanzapine (including all formulations of olanzapine) is 20 mg.
The recommended initial dose for olanzapine injection is 10 mg, administered as a single intramuscular injection. A lower dose (5 mg or 7.5 mg) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.4). A second injection, 5-10 mg, may be administered 2 hours after the first injection, on the basis of individual clinical status.
Not more than three injections should be given in any 24-hour period and the maximum daily dose of olanzapine of 20 mg (including all formulations) should not be exceeded.
ZYPREXA powder for solution for injection should be reconstituted in accordance with the recommendation in section 6.6.
For further information on continued treatment with oral olanzapine (5 to 20 mg daily), see the Summary of Product Characteristics for ZYPREXA coated tablets or ZYPREXA VELOTAB orodispersible tablets.
Paediatric population
There is no experience in children. ZYPREXA powder for solution for injection is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.
Elderly
The recommended starting dose in elderly patients (>60 years) is 2.5-5 mg. Depending on the patient's clinical status (see section 4.4), a second injection, 2.5-5 mg, may be administered 2 hours after the first injection. Not more than 3 injections should be given in any 24-hour period and the maximum daily dose of 20 mg (including all formulations) of olanzapine should not be exceeded.
Renal and/or hepatic impairment
A lower starting dose (5 mg) should be considered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh class A or B), the starting dose should be 5 mg and only increased with caution.
Gender
The dose and dose range need not be routinely altered for female patients relative to male patients.
Smokers
The dose and dose range need not be routinely altered for non-smokers relative to smokers.
When more than one factor is present which might result in slower metabolism (female gender, geriatric age, non-smoking status), consideration should be given to decreasing the dose. Additional injections, when indicated, should be conservative in such patients.
(See sections 4.5 and 5.2.)
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients. Patients with known risk of narrow-angle glaucoma.
4.4 Special Warnings And Precautions For Use
The efficacy of IM olanzapine has not been established in patients with agitation and disturbed behaviours related to conditions other than schizophrenia or manic episode.
Unstable medical conditions
IM olanzapine should not be administered to patients with unstable medical conditions, such as acute myocardial infarction, unstable angina pectoris, severe hypotension and/or bradycardia, sick sinus syndrome, or following heart surgery. If the patient's medical history with regard to these unstable medical conditions cannot be determined, the risks and benefits of IM olanzapine should be considered in relation to other alternative treatments.
Concomitant use of benzodiazepines and other medicinal products
Special caution is necessary in patients who have received treatment with other medicinal products having haemodynamic properties similar to those of intramuscular olanzapine including other antipsychotics (oral and/or intramuscular) and benzodiazepines (see section 4.5). Temporal association of treatment with IM olanzapine with hypotension, bradycardia, respiratory depression and death has been very rarely (< 0.01%) reported, particularly in patients who have received benzodiazepines and/or other antipsychotics (see section 4.8).
Simultaneous injection of intramuscular olanzapine and parenteral benzodiazepine is not recommended due to the potential for excessive sedation, cardiorespiratory depression and in very rare cases, death (see sections 4.5 and 6.2). If the patient is considered to need parenteral benzodiazepine treatment, this should not be given until at least one hour after IM olanzapine administration. If the patient has received parenteral benzodiazepine, IM olanzapine administration should only be considered after careful evaluation of clinical status, and the patient should be closely monitored for excessive sedation and cardiorespiratory depression.
Hypotension
It is extremely important that patients receiving intramuscular olanzapine should be closely observed for hypotension, including postural hypotension, bradyarrhythmia, and/or hypoventilation, particularly for the first 4 hours following injection and close observation should be continued after this period if clinically indicated. Blood pressure, pulse, respiratory rate and level of consciousness should be observed regularly and remedial treatment provided if required. Patients should remain recumbent if dizzy or drowsy after injection until examination indicates that they are not experiencing hypotension, including postural hypotension, bradyarrhythmia, and/or hypoventilation.
The safety and efficacy of IM olanzapine has not been evaluated in patients with alcohol or drug intoxication (either with prescribed or illicit drugs) (see section 4.5).
Dementia-related psychosis and/or behavioural disturbances
Olanzapine is not approved for the treatment of dementia-related psychosis and/or behavioural disturbances and is not recommended for use in this particular group of patients because of an increase in mortality and the risk of cerebrovascular accident. In placebo-controlled clinical trials (6-12 weeks duration) of elderly patients (mean age 78 years) with dementia-related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated patients compared to patients treated with placebo (3.5% vs. 1.5%, respectively). The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to increased mortality include age > 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was higher in olanzapine-treated than in placebo-treated patients independent of these risk factors.
In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischaemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials.
Parkinson's disease
The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In these trials, patients were initially required to be stable on the lowest effective dose of anti-Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.
Neuroleptic Malignant Syndrome (NMS)
NMS is a potentially life-threatening condition associated with antipsychotic medicinal product. Rare cases reported as NMS have also been received in association with 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 creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.
Hyperglycaemia and diabetes
Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported rarely, including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g., measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually thereafter. Patients treated with any antipsychotic agents, including ZYPREXA, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g., at baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter.
Lipid alterations
Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebo-controlled clinical trials (see section 4.8). Lipid alterations should be managed as clinically appropriate, particularly in dyslipidemic patients and in patients with risk factors for the development of lipids disorders. Patients treated with any antipsychotic agents, including ZYPREXA, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g., at baseline, 12 weeks after starting olanzapine treatment and every 5 years thereafter.
Anticholinergic activity
While olanzapine demonstrated anticholinergic activity in vitro, experience during oral clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.
Hepatic function
Transient, asymptomatic elevations of hepatic aminotransferases, ALT, AST have been seen commonly, especially in early treatment. Caution should be exercised and follow-up organised in patients with elevated ALT and/or AST, 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 medicines. In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment should be discontinued.
Neutropenia
Caution should be exercised in patients with low leucocyte and/or neutrophil counts for any reason, in patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with myeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly (see section 4.8).
Discontinuation of treatment
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported very rarely (<0.01%) when olanzapine is stopped abruptly.
QT interval
In clinical trials with oral administration, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF]
Thromboembolism
Temporal association of olanzapine treatment and venous thromboembolism has been reported uncommonly (
General CNS activity
Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Seizures
Olanzapine should be used cautiously in patients who have a history of seizures or are subject to factors which may lower the seizure threshold. Seizures have been reported to occur rarely in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.
Tardive dyskinesia
In comparator oral studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment-emergent dyskinesia. However, the risk of tardive dyskinesia increases with long-term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.
Postural hypotension
Postural hypotension was infrequently observed in the elderly in oral olanzapine clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.
Sudden cardiac death
In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Paediatric Population
Interaction studies have only been performed in adults.
IM olanzapine has not been studied in patients with alcohol or drug intoxication (see section 4.4).
Caution should be exercised in patients who consume alcohol or receive medicinal products that can induce hypotension, bradycardia, respiratory or central nervous system depression (see section 4.4).
Potential for Interaction, Following Intramuscular Injection
In a single dose intramuscular study of olanzapine 5 mg, administered 1 hour before intramuscular lorazepam 2 mg (metabolised by glucuronidation), the pharmacokinetics of both medicines were unchanged. However, the combination added to the somnolence observed with either medicine alone. Concomitant injection of olanzapine and parenteral benzodiazepine is not recommended (see sections 4.4 and 6.2).
Potential Interactions Affecting Olanzapine
Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.
Induction of CYP1A2
The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been observed. The clinical consequences are likely to be limited, but clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.2).
Inhibition of CYP1A2
Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54% in female non-smokers and 77% in male smokers. The mean increase in olanzapine AUC was 52% and 108%, respectively. A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.
Decreased Bioavailability
Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be taken at least 2 hours before or after olanzapine.
Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine.
Potential for Olanzapine to Affect Other Medicinal Products
Olanzapine may antagonise the effects of direct and indirect dopamine agonists (see section 6.2).
Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g., 1A2, 2D6, 2C9, 2C19, 3A4). Thus, no particular interaction is expected, as verified through in vivo studies, where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2), or diazepam (CYP3A4 and 2C19).
Olanzapine showed no interaction when co-administered with lithium or biperiden.
Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine.
The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson's disease and dementia is not recommended (see section 4.4).
QTc interval
Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval (see section 4.4).
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.
Neonates exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Breast feeding
In a study in breast feeding, healthy women, olanzapine was excreted in breast milk. Mean infant exposure (mg/kg) at steady-state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breast feed an infant if they are taking olanzapine.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. Because olanzapine may cause somnolence and dizziness, patients should be cautioned about operating machinery, including motor vehicles.
4.8 Undesirable Effects
A common (1-10%) undesirable effect associated with the use of intramuscular olanzapine in clinical trials was somnolence.
In post-marketing reports, temporal association of treatment with IM olanzapine with cases of respiratory depression, hypotension or bradycardia, and death have been very rarely reported, mostly in patients who concomitantly received benzodiazepines and/or other antipsychotic medicinal products, or who were treated in excess of olanzapine recommended daily doses (see sections 4.4 and 4.5).
The following table is based on the undesirable effects and laboratory investigations from clinical trials with ZYPREXA powder for solution for injection rather than oral olanzapine.
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The undesirable effects listed below have been observed following administration of oral olanzapine, but may also occur following administration of ZYPREXA powder for solution for injection.
Adults
The most frequently (seen in
The following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (
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1 Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short-term treatment (median duration 47 days), weight gain
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.
3 Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high (
4 Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (
5 Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high (
6In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existing history of individual acute and tardive extrapyramidal movement disorders, it can not be concluded at present that olanzapine produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes.
7Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported when olanzapine is stopped abruptly.
8 In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of normal range in approximately 30% of olanzapine-treated patients with normal baseline prolactin value. In the majority of these patients the elevations were generally mild, and remained below two times the upper limit of normal range. Generally, in olanzapine-treated patients potentially associated breast- and menstrual-related clinical manifestations (e.g., amenorrhoea, breast enlargement, galactorrhea in females, and gynaecomastia/breast enlargement in males) were uncommon. Potentially associated sexual function-related adverse reactions (e.g., erectile dysfunction in males and decreased libido in both genders) were commonly observed.
Long-term exposure (at least 48 weeks)
The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months.
Additional information on special populations
In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher incidence of death and cerebrovascular adverse reactions compared to placebo (see also section 4.4). Very common adverse reactions associated with the use of olanzapine in this patient group were abnormal gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations and urinary incontinence were observed commonly.
In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with Parkinson's disease, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo.
In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapine resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could be high plasma valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels (
4.9 Overdose
Signs and Symptoms
Very common symptoms in overdose (>10% incidence) include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and reduced level of consciousness, ranging from sedation to coma.
Other medically significant sequelae of overdose include delirium, convulsion, coma, possible neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (<2% of overdose cases), and cardiopulmonary arrest. Fatal outcomes have been reported for acute overdoses as low as 450mg, but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.
Management of Overdose
There is no specific antidote for olanzapine.
Symptomatic treatment and monitoring of vital organ function should be instituted according to clinical presentation, including treatment of hypotension and circulatory collapse, and support of respiratory function. Do not use epinephrine, dopamine, or other sympathomimetic agents with beta-agonist activity, since beta stimulation may worsen hypotension. Cardiovascular monitoring is necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Diazepines, oxazepines and thiazepines. ATC code: N05A H03.
Olanzapine is an antipsychotic, antimanic, and mood stabilising agent that demonstrates a broad pharmacologic profile across a number of receptor systems.
In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki <100nM) for serotonin 5-HT2A/2C, 5-HT3, 5-HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α1-adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5-HT2 than dopamine D2 receptors and greater 5-HT2 than D2 activity in in vivo models. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases responding in an 'anxiolytic' test.
In a single oral dose (10 mg) Positron Emission Tomography (PET) study in healthy volunteers, olanzapine produced a higher 5-HT2A than dopamine D2 receptor occupancy. In addition, a SPECT imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D2 occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.
In two of two placebo- and two of three comparator-controlled trials with oral olanzapine, in over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms.
In a multinational, double-blind, comparative study of schizophrenia, schizoaffective and related disorders, which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (P = 0.001) favouring oral olanzapine (-6.0) versus haloperidol (-3.1).
In patients with manic or mixed episode of bipolar disorder, oral olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Oral olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of oral olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.
In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.
In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; P = 0.055).
In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.
5.2 Pharmacokinetic Properties
In a pharmacokinetic study in healthy volunteers, a dose of 5 mg of ZYPREXA powder for solution for injection produced a maximum plasma concentration (Cmax) approximately 5-times higher than that seen with the same dose of olanzapine administered orally. The Cmax occurs earlier after intramuscular compared to oral use (15 to 45 minutes versus 5 to 8 hours). As with oral use, Cmax and area under the curve after intramuscular use are directly proportional to the dose administered. For the same dose of olanzapine administered intramuscularly and orally, the associated area under the curve, half-life, clearance, and volume of distribution are similar. The metabolic profiles following intramuscular and oral use are similar.
In non-smoking versus smoking subjects (males and females) administered olanzapine intramuscularly, the mean elimination half-life was prolonged (38.6 versus 30.4 hours) and the clearance was reduced (18.6 versus 27.7 l/hr).
Additional pharmacokinetic data following administration of oral olanzapine are described below.
Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide, which does not pass the blood brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites; both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent, olanzapine. After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.
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