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Drug Details

Olanzapine 2.5mg Film-coated Tablets

• Drug Class Description
  antipsychotic - ATC code: N05A H03
• Generic Name
  olanzapine
• Presentation
  Film-coated tablet. Round, biconvex, white film-coated tablet 6mm in diameter, marked with “O” on one side.
• Description
  Each film-coated tablet contains 2.5mg olanzapine. Excipients: 2.5mg film-coated tablet contains 58.3mg lactose anhydrous and 0.064mg lecithin soya (E322).
• Indications
  

  Olanzapine is indicated for the treatment of schizophrenia.

  Olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.

  Olanzapine is indicated for the treatment of moderate to severe manic episode.

  In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the prevention of recurrence in patients with bipolar disorder.

• Adult Dosage
  

  Schizophrenia: The recommended starting dose for olanzapine is 10mg/day.

  Manic episode: The starting dose is 15mg as a single daily dose in monotherapy or 10mg daily in combination therapy.

  Preventing recurrence in bipolar disorder: The recommended starting dose is 10mg/day. For patients who have been receiving olanzapine for treatment of manic episode, therapy for preventing recurrence should be continued at the same dose. If a new manic, mixed, or depressive episode occurs, olanzapine treatment should be continued (with dose optimisation as needed), with supplementary therapy to treat mood symptoms, as clinically indicated.

  During treatment for schizophrenia, manic episode and recurrence prevention in bipolar disorder, daily dosage may subsequently be adjusted on the basis of individual clinical status within the range 5-20mg/day. An increase to a dose greater than the recommended starting dose is advised only after appropriate clinical reassessment and should generally occur at intervals of not less than 24 hours.

  Olanzapine can be given without regards for meals as absorption is not affected by food. Gradual tapering of the dose should be considered when discontinuing olanzapine.

  Renal and/or hepatic impairment

  A lower starting dose (5mg) should be considered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh Class A or B), the starting dose should be 5mg and only increased with caution.

  Gender

  The starting dose and dose range need not be routinely altered for female patients relative to male patients.

  Smokers

  The starting 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 starting dose. Dose escalation, when indicated, should be conservative in such patients.

• Child Dosage
  

  Olanzapine is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. A greater magnitude of weight gain, lipid and prolactin alterations has been reported in short term studies of adolescent patients than in studies of adult patients.

• Elderly Dosage
  

  A lower starting dose (5mg/day) is not routinely indicated but should be considered for those 65 and over when clinical factors warrant.

• Contra Indications
  

  Hypersensitivity to the active substance or to any of the excipients.

  Patients with known risk for narrow-angle glaucoma.

• Special Precautions
  

  During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

  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 4.4mg) 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 ischemic 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, 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 2.5mg/day and titrated to a maximum of 15mg/day based on investigator judgement.

  Neuroleptic Malignant Syndrome (NMS)

  NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. 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 creatinine 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 medicinal products, 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. 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. Patients treated with any antipsychotic agents, including olanzapine film-coated tablets, 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.

  Lipid alterations

  Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebocontrolled clinical trials. 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 olanzapine film-coated tablets, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines.

  Anticholinergic activity

  While olanzapine demonstrated anticholinergic activity in vitro, experience during the 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 leukocyte 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.

  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, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF] 500 milliseconds [msec] at any time post baseline in patients with baseline QTcF<500 msec) were uncommon (0.1% to 1%) in patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. However, as with other antipsychotics, caution should be exercised when olanzapine is prescribed with medicinal products known to increase QTc interval, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia.

  Venous thromboembolism

  Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with olanzapine and preventive measures undertaken.

  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 antagonize 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 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 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.

  Paediatric population

  Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels. Long-term outcomes associated with these events have not been studied and remain unknown.

  Lactose

  Olanzapine Film-coated Tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

  Lecithin soya

  If a patient is hypersensitive to peanut or soya, this medicine should not be used.

• Interactions
  

  Interaction studies have only been performed in adults.

  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.

  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 nonsmokers and 77% 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.

  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.

  General CNS activity

  Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.

  The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson's disease and dementia is not recommended.

  QTc interval

  Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval.

• Adverse Drug Reactions
  

  Adults

  The most frequently (seen in 1% of patients) reported adverse reactions associated with the use of olanzapine in clinical trials were somnolence, weight gain, eosinophilia, elevated prolactin, cholesterol, glucose and triglyceride levels, glucosuria, increased appetite, dizziness, akathisia, parkinsonism, dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases, rash, asthenia, fatigue and oedema.

  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 (1/10)

  Common (1/100 to <1/10)

  Uncommon (1/1,000 to <1/100)

  Rare (1/10,000 to <1/1,000)

  Very rare (<1/10,000)

  Not known (cannot be estimated from the available data)

  Very common	Common	Uncommon	Not known
  Blood and the lymphatic system disorders
  	Eosinophilia	Leukopenia Neutropenia	Thrombocytopenia
  Immune system disorders
  			Allergic reaction
  Metabolism and nutrition disorders
  Weight gain1	Elevated cholesterol levels2,3 Elevated glucose levels4 Elevated triglyceride levels2,5 Glucosuria Increased appetite		Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases Hypothermia
  Nervous system disorders
  Somnolence	Dizziness Akathisia6 Parkinsonism6 Dyskinesia6		Seizures where in most cases a history of seizures or risk factors for seizures were reported Neuroleptic malignant syndrome Dystonia (including oculogyration) Tardive dyskinesia Discontinuation symptoms7
  Cardiac disorders
  		Bradycardia QTc prolongation	Ventricular tachycardia/fibrillation, sudden death
  Vascular disorders
  	Orthostatic hypotension		Venous thromboembolism (including pulmonary embolism and deep vein thrombosis)
  Gastrointestinal disorders
  	Mild, transient anticholinergic effects including constipation and dry mouth		Pancreatitis
  Hepato-biliary disorders
  	Transient, asymptomatic elevations of hepatic aminotransferase (ALT, AST), especially in early treatment		Hepatitis (including hepatocellular, cholestatic or mixed liver injury)
  Skin and subcutaneous tissue disorders
  	Rash	Photosensitivity reaction Alopecia
  Musculoskeletal and connective tissue disorders
  			Rhabdomyolysis
  Renal and urinary disorders
  		Urinary incontinence	Urinary hesitation
  Reproductive system and breast disorders
  			Priapism
  General disorders and administration site conditions
  	Asthenia Fatigue Oedema
  Investigations
  Elevated plasma prolactin levels8		High creatine phosphokinase Increased total bilirubin	Increased alkaline phosphatase

  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 7% of baseline body weight was very common (22.2%), 15% was common (4.2%) and 25% was uncommon (0.8%). Patients gaining 7%, 15% and 25% of their baseline body weight with long-term exposure (at least 48 weeks) were very common (64.4%, 31.7% and 12.3% respectively).

  ² Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

  ³Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high ( 6.2 mmol/l). Changes in total fasting cholesterol levels from borderline at baseline ( 5.17-< 6.2 mmol/l) to high ( 6.2 mmol/l) were very common.

  ⁴ Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high ( 7 mmol/l). Changes in fasting glucose from borderline at baseline ( 5.56 - < 7 mmol/l) to high ( 7 mmol/l) were very common.

  ⁵ Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high ( 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline ( 1.69 mmol/l - < 2.26 mmol/l) to high ( 2.26 mmol/l) were very common.

  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.

  ⁷ Acute 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/HCL 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 4-6 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.

  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 ( 10%) of tremor, dry mouth, increased appetite, and weight gain. Speech disorder was also reported commonly. During treatment with olanzapine in combination with lithium or divalproex, an increase of 7% from baseline body weight occurred in 17.4% of patients during acute treatment (up to 6 weeks). Long-term olanzapine treatment (up to 12 months) for recurrence prevention in patients with bipolar disorder was associated with an increase of 7% from baseline body weight in 39.9% of patients.

  Padiatric population

  Olanzapine is not indicated for the treatment of children and adolescent patients below 18 years. Although no clinical studies designed to compare adolescents to adults have been conducted, data from the adolescent trials were compared to those of the adult trials.

  The following table summarises the adverse reactions reported with a greater frequency in adolescent patients (aged 13-17 years) than in adult patients or adverse reactions only identified during short-term clinical trials in adolescent patients. Clinically significant weight gain ( 7%) appears to occur more frequently in the adolescent population compared to adults with comparable exposures. The magnitude of weight gain and the proportion of adolescent patients who had clinically significant weight gain were greater with long-term exposure (at least 24 weeks) than with short-term exposure.

  Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

  The frequency terms listed are defined as follows:

  Very common ( 10%)

  Common ( 1% and < 10%).

  Metabolism and nutrition disorders Very common: Weight gain9, elevated triglyceride levels10, increased appetite. Common: Elevated cholesterol levels11

  Nervous system disorders Very common: Sedation (including: hypersomnia, lethargy, somnolence).

  Gastrointestinal disorders Common: Dry mouth

  Hepato-biliary disorders Very common: Elevations of hepatic aminotranferases.

  Investigations Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels12.

  ⁹ Following short term treatment (median duration 22 days), weight gain 7% of baseline body weight (kg) was very common (40.6%), 15% of baseline body weight was common (7.1%) and 25% was common (2.5%). With long-term exposure (at least 24 weeks), 89.4% gained 7%, 55.3% gained 15% and 29.1% gained 25% of their baseline body weight.

  ¹⁰ Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high ( 1.467 mmol/l) and changes in fasting triglycerides from borderline at baseline ( 1.016 mmol/l - < 1.467 mmol/l) to high ( 1.467 mmol/l).

  ¹¹ Changes in total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high ( 5.17 mmol/l) were observed commonly. Changes in total fasting cholesterol levels from borderline at baseline ( 4.39 - < 5.17 mmol/l) to high ( 5.17 mmol/l) were very common.

  ¹² Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.