Olandus 5/Olandus 10/Olandus ODT 15

Olandus 5/Olandus 10/Olandus ODT 15

olanzapine

Manufacturer:

Cadila Healthcare

Distributor:

Metro Drug

Marketer:

Zydus Healthcare Phils
Full Prescribing Info
Contents
Olanzapine.
Description
It is an antipsychotic agent belonging to thienobenzodiazepine class.
Olandus 5: Each film-coated tablet contains: Olanzapine (Olandus 5) 5 mg.
Olandus 10: Each film-coated tablet contains: Olanzapine (Olandus 10) 10 mg.
Olandus ODT 15: Each orally disintegrating tablet contains: Olanzapine 15 mg.
Action
Pharmacology: Pharmacodynamics: Olandus 5/Olandus 10: Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors: serotonin 5HT2A/2C, dopamine D1-4, muscarinic M1-5, histamine H1 and adrenergic 1 receptors. Olanzapine binds weakly to GABAA, benzodiazepine (BZD), and adrenergic receptors. The mechanism of action of Olanzapine, as with other antipsychotic drugs, is unknown. However, it has been proposed that this drug's antipsychotic activity is mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonisms. Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of Olanzapine. Olanzapine's antagonism of muscarinic M1-5 receptor may explain its anticholinergic effects. Olanzapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Olanzapine's antagonism of adrenergic 1 receptors may explain the orthostatic hypotension observed with this drug.
Olandus ODT 15: Olanzapine is an atypical antipsychotic, antimanic and mood stabilising agent that demonstrates a broad pharmacological profile across a number of receptor systems.
In preclinical studies, Olanzapine exhibited a range of receptor affinities (Ki; < 100 nmol) for serotonin 5HT2A/2C, 5HT3, 5HT6; 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 5HT2 than dopamine D2 receptors and in in-vivo models, greater 5HT2 than D2 activity. 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 increased responding in an 'anxiolytic' test.
In a single 10 mg oral dose Positron Emission Tomography (PET) study in healthy volunteers, Olanzapine produced higher receptor occupancy at the 5HT2A receptor than at the dopamine D2 receptor. A Single Photon Emission Computed Tomography (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 clinical trials with over 2,900 schizophrenic patients, with both positive and negative symptoms, Olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms of schizophrenia.
Pharmacokinetics: Olandus 5/Olandus 10: The pharmacokinetics of Olanzapine have been studied in about 200 healthy individuals (including those from special populations) in traditional pharmacokinetic studies. In addition, pharmacokinetic data (usually from population pharmacokinetic modelling in efficacy trials) have been obtained from more than 1800 patients with schizophrenia or related psychoses treated with Olanzapine ranged from 0.5 to 15 mg in healthy individuals and from 1 to 30 mg in patients with schizophrenia.
Absorption and distribution: The plasma concentrations of Olanzapine after single doses are linear and dose - proportional with in the approved dosage range (5 to 20 mg) in healthy volunteers and in patients with schizophrenia volunteers and in patients with schizophrenia. After administration of a single oral 12.5 mg dose of Olanzapine to 6 healthy volunteers, the mean maximum plasma concentration (Cmax) was 11 μg/L and was achieved = 5 hours (Tmax) after the dose. About 40 % of the administered dose of Olanzapine undergoes first-pass metabolism and the bioavailability of the drug is no different in the fed and fasting states. Olanzapine is highly bound (93%) to plasma proteins (Primarily to albumin and also to 1-acid glycoprotein). The drug appears to be widely distributed in tissues, as evidenced by a large volume of distribution (Vd) [10 to 22 L/kg]. In vitro, approximately 5 to 14% of Olanzapine (83% as unchanged drug) is transferred across the human placenta over 4 hours of perfusion.
Plasma concentrations of Olanzapine after multiple doses are also linearly related to dose and can be predicted from single dose Cmax and area under the plasma concentration - time curve (AUC) parameters. When administered once daily, Olanzapine achieves steady state Cmax concentrations in about a week; these are approximately twice those observed following single doses.
Metabolism and Elimination: After oral administration, Olanzapine is extensively metabolised. One study found that more than 85 % of the radioactivity in plasma was attributable to compounds other than the radio labelled parent drug. At least 10 metabolites have been identified. The major metabolite in the urine and faeces of healthy volunteers is 10-N-Glucuronide, an inactive product of uridine disphosphate glucuronyl transferase metabolism. Other apparently inactive metabolites include 4-N desmethyl Olanzapine [metabolised by cytochrome P-450 (CYP) 1A2], 4-N-Oxide metabolites (metabolised by the flavin-containing monooxygenase-3 system), and minor metabolite 2-hydroxymethyl Olanzapine (metabolised by CYP2D6). Formation of 4-desmethyl Olanzapine is significantly correlated with Olanzapine clearance (p <0.0002).
After administration of 12.5 mg of radio labelled Olanzapine 57% of the radioactivity was excreted in urine and 30 % in faeces within 15 to 21 days. In healthy volunteers, the mean elimination half life (t½) of Olanzapine was about 30 hours (5th to 95th percentile; 21 to 54 hours), and total body clearance (CL) was 25 L/h (5th to 95th percentile 12 to 47 L/h) [39.54). Olanzapine shows an approximate 4-fold interindividual variation in CL values. The pharmacokinetics of Olanzapine at steady-state are consistent with those generated in single dose studies. In healthy males, the CL and t½ of Olanzapine were similar in multiple and single dose studies.
Effects of patient characteristics: Various studies primarily involving single dose administration of Olanzapine at clinically relevant doses, have evaluated the effects of age, gender ethnicity, renal, dysfunction and hepatic disease on the pharmacokinetics of Olanzapine in general t½ was increased by approximately 50 % and CL reduced by about 30% in elderly (65 to 79 years of age) versus younger individuals. Likewise, women tended to have longer t½ and lower CL value than men (reported differences of 25 to 30%) and patients with hepatic dysfunction had CL values within the lower end of the range of CL values for healthy volunteers.
Differences in the pharmacokinetics Olanzapine were not noted between healthy individuals from various ethnic groups (African, Asian, Caucasian, Hispanic and Japanese) or between healthy volunteers and patients with significant renal impairment in view of the wide interindividual differences observed in pharmacokinetic studies with Olanzapine, there are no specific recommendations for dosage adjustments on the basis of individual patient characteristics.
The concentration to dose ratio of Olanzapine was found to vary by 26-fold in 56 patients with schizophrenia given Olanzapine 5 to 20 mg/day as monotherapy and as comedication. A minimum effective therapeutic plasma concentration of 9 μg/L was established from a study of 79 in patients treated with Olanzapine 1 or 10 mg/day in the HGAP trail in another study, 80% of 280 patients who received Olanzapine 5 to 20 mg/day had serum concentrations in the range 7 to 45 μg/L. Therapeutic drug monitoring of Olanzapine may have clinical utility as it can disclose noncompliance. Alert to extremes in concentration to dose ratios, and identify more responders or possible drug interactions.
Olandus ODT 15: Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. Absorption is not affected by food. Plasma concentrations of Olanzapine after oral administration were linear and dose proportional in trials studying doses from 1 to 20 mg.
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-hydroxy-methyl 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 to healthy subjects, the mean terminal elimination half-life was 33 hours (21 to 54 hours for 5th to 95th percentile) and the mean Olanzapine plasma clearance was 26 L/hr (12 to 47 L/hr for the 5th to 95th percentile). Olanzapine pharmacokinetics varied on the basis of smoking status, gender and age.
In healthy elderly (>65 years) subjects versus non-elderly healthy subjects, the mean elimination half-life of Olanzapine was prolonged (51.8 hr vs 33.8 hr) and the clearance was reduced (17.5 L/hr vs 18.2 L/hr). The pharmacokinetic variability observed in elderly subjects is within the variability seen in non-elderly subjects. In 44 patients with schizophrenia >65 years of age, dosing from 5 to 20 mg/day was not associated with any distinguishing profile of adverse events.
In female versus male subjects, the mean elimination half-life was somewhat prolonged (36.7 hr vs 32.3 hr) and the clearance was reduced (18.9 L/hr vs 27.3 L/hr). However, Olanzapine (5-20 mg) demonstrated a comparable safety profile in female (n=467) as in male patients (n=869).
Smoking induces the CYP1A2 metabolism of Olanzapine. Therefore, in smokers the clearance of Olanzapine is higher, on average, than the clearance in nonsmokers.
The plasma clearance of Olanzapine is lower in elderly versus non-elderly subjects and in females versus males. The magnitude of the impact of age, gender or smoking on Olanzapine clearance and half-life is small in comparison to the overall variability between individuals. The plasma protein binding of Olanzapine is about 93% over the concentration range of about 7 to about 1000 ng/mL. Olanzapine is bound to albumin and α1 acid glycoprotein.
Approximately 57% of radiolabelled Olanzapine is excreted in urine, principally as metabolites, approximately 7% is excreted unchanged in the urine after a single oral dose and approximately 30% is excreted in the faeces.
Renal Impairment: Only incomplete information is available on excretion in renal-impaired patients (creatinine clearance <10 mL/min) versus healthy subjects, suggesting there was no significant difference in mean elimination half-life (37.7 hr vs 32.4 hr) or drug clearance (21.2 L/hr vs 25.0 L/hr). The available data indicate a trend for decreased clearance and increased half-life with renal-impairment. Consequently, caution should be exercised in prescribing Olanzapine for patients with renal impairment and particularly in those with severe renal disease and in the elderly. Olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied.
Hepatic Impairment: Although the presence of hepatic impairment may be expected to reduce the clearance of Olanzapine, a study of the effect of impaired liver function in male subjects (n=6) with clinically significant (Childs Pugh Classification A and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine in the dose range 2.5-7.5 mg daily. Consequently, dosage adjustment may not be necessary if hepatic impairment is the sole consideration.
Indications/Uses
Olandus 5/Olandus 10: Used in the management of schizophrenia and for the treatment of moderate to severe mania associated with bipolar disorder.
Olandus ODT 15: It is indicated for the short-term treatment of acute manic episodes associated with Bipolar Disorder. It is also indicated for the treatment of schizophrenia. In patients whose manic episodes has responded to olanzapine treatment, olanzapine is indicated for the prevention of recurrence in patients with bipolar disorder.
Dosage/Direction for Use
Olandus 5/Olandus 10: Schizophrenia, combination therapy for mania, preventing recurrence in bipolar disorder: ADULT over 18 years: 10 mg daily adjusted to usual range of 5-20 mg daily; doses greater than 10 mg daily adjusted to usual range of 5-20 mg daily; doses greater than 10 mg daily only after reassessment; max. 30 mg daily. Monotherapy for mania: ADULT over 18 years: 15mg daily adjusted to usual range of 5-20 mg daily doses greater than 15 mg only after reassessment max. 20 mg daily.
Olandus ODT 15: Olanzapine orally disintegrating tablets should be placed in the mouth and allowed to completely dissolve before swallowing the saliva. A glass of water may be taken following administration to assist with swallowing the saliva. Alternatively, the Olanzapine ODT may be dispersed in a full glass of water immediately before administration.
Schizophrenia and Related Disorders: The recommended starting dose for Olanzapine orally disintegrating tablets is 5-10 mg/day, administered as a single daily dose without regard to meals. Daily dosage may subsequently be adjusted on the basis of individual clinical status within the range of 5-20 mg daily. An increase to a dose greater than the routine therapeutic dose of 10 mg/day is recommended only after appropriate clinical reassessment.
Acute Mania Associated with Bipolar Disorder: The recommended starting dose for Olanzapine orally disintegrating tablets is 10 or 15 mg administered once a day as monotherapy or 10 mg administered once daily in combination therapy with lithium or valproate. It may be given without regard to meals. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours. When dosage adjustments are necessary, dose increments/decrements of 5 mg daily are recommended. 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.
Preventing Recurrence in Bipolar Disorder: Patients who have been receiving Olanzapine for the treatment of acute mania should initially continue therapy for preventing recurrence in bipolar disorder at the same dose. For patients already in remission, the suggested starting dose for Olanzapine orally disintegrating tablets is 10 mg once a day. Subsequent daily dosage should be adjusted on the basis of clinical status within a range of 5 mg to 20 mg per day. Olanzapine ODT may be given without regard to meals, as its absorption is not affected by food.
Children: The safety and efficacy of Olanzapine have not been established in patients under 18 years of age.
Elderly patients: A low starting dose of 5 mg/day should be considered for those patients 65 and over when clinical factors warrant.
Patients with hepatic and/or renal impairment: Small single-dose clinical pharmacology studies did not reveal any major alterations in Olanzapine pharmacokinetics in subjects with renal or hepatic impairment. However, as clinical experience is limited in these patients, a lower starting dose (5 mg/day) should be considered. Further dose adjustments, when indicated, should be conservative in these patients.
Female compared with male patients: The starting dose and dose range need not be routinely altered for female patients relative to male patients.
Non-smoking patients compared with smoking patients: The starting dose and dose range need not be routinely altered for non-smoking patients relative to smoking patients.
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.
Overdosage
Olandus 5/Olandus 10: In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. 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.
Olandus ODT 15: Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions and salivation. In dogs, olanzapine caused sedation, ataxia, tremors, tachycardia, laboured respiration, miosis and anorexia. In monkeys, prostration and semi-consciousness were observed.
Signs and Symptoms: Very common symptoms (>10% incidence) reported in Olanzapine overdose include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms and reduced level of consciousness ranging from sedation to coma.
Other medically significant sequelae of Olanzapine overdose include delirium, convulsion, 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 450 mg but survival has also been reported following acute overdose of 2 g.
Management of Overdose: There is no specific antidote to Olanzapine. Induction of emesis is not recommended. Standard procedures for management of overdose may be indicated. 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. The use of activated charcoal for overdose should be considered because the concomitant administration of activated charcoal was shown to reduce the oral bioavailability of Olanzapine by 50 to 60%. In patients who are not fully conscious or who have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. Olanzapine is not substantially removed by haemodialysis.
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. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents such as noradrenaline. Adrenaline, dopamine or other sympathomimetic agents should not be used since beta stimulation may worsen hypotension in the setting of alpha blockade induced by olanzapine. Cardiovascular monitoring should be considered to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers.
Contraindications
Olanzapine is contraindicated in those patients with a known hypersensitivity to any ingredient of the product.
Special Precautions
Olandus 5/Olandus 10: A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs. 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.
A syndrome of potentially irreversible, involuntary, dyskinetic movements known as tardive dyskinesia may develop in patients treated with antipsychotic drugs. Olanzapine tablets should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. 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.
Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its 1-adrenergic antagonistic properties. This risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg once daily. A more gradual titration to the target dose should be considered if hypotension occurs. Olanzapine tablets 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).
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.
Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with preexisting 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.
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.
Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Olanzapine tablets 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. Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Olanzapine tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for Olanzapine tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Olanzapine tablets should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma, or a history of paralytic ileus.
Use in Pregnancy & Lactation: There are no adequate and well-controlled trials with Olanzapine in pregnant females. 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. It is not known if Olanzapine is excreted in human milk. It is recommended that women receiving Olanzapine tablets should not breast feed. Safety and effectiveness of the drug in pediatric patients have not been established.
Olandus ODT 15: 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.
Concomitant illnesses: While Olanzapine demonstrated anticholinergic activity in vitro, experience during clinical trials revealed a low incidence of related events. As clinical experience with Olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, narrow-angle glaucoma or paralytic ileus and related conditions.
Hyperglycaemia and Diabetes Mellitus: Hyperglycaemia, 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 increased background 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 hyperglycaemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycaemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycaemia related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics 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 hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
Lipid Alterations: Undesirable alterations in lipids have been observed in Olanzapine-treated patients in placebo-controlled trials. Olanzapine-treated patients had a greater mean increase in fasting total cholesterol, LDL cholesterol, and triglycerides compared to 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. Appropriate clinical monitoring is recommended.
Weight Gain: Potential consequences of weight gain should be considered prior to starting Olanzapine. As with all antipsychotics, patients receiving Olanzapine should receive regular monitoring of weight. In clinical trials significant weight gain was observed across all baseline Body Mass Index (BMI) categories in olanzapine-treated patients.
Hepatic: Transient, asymptomatic elevations of hepatic transaminases, alanine transferase (ALT), aspartate transferase (AST) have been seen occasionally, especially in early treatment. Rare postmarketing reports of hepatitis have been noted. Very rare cases of jaundice, cholestatic or mixed liver injury have also been reported in the postmarketing period. Caution should be exercised 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 drugs.
Blood: As with other neuroleptic drugs, caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, 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. Thirty-two patients with clozapine-related neutropenia or agranulocytosis histories received olanzapine without decreases in baseline neutrophil counts.
Neuroleptic Malignant Syndromes (NMS): NMS, a potentially fatal syndrome complex, is associated with antipsychotic drugs, including Olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. In such an event or with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic drugs, including olanzapine should be discontinued.
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 such patients when treated with Olanzapine.
Cardiac: Postural hypotension was infrequently observed in elderly subjects in clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.
Sudden cardiac death: In a retrospective observational study, patients treated with atypical antipsychotics (including Olanzapine) or typical antipsychotics had a similar dose-related increase of presumed sudden cardiac death compared to non-users of antipsychotics, with almost twice the risk than that for non-users. In post-marketing reports with Olanzapine, the event of sudden cardiac death has been reported very rarely.
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: Oesophageal dysmotility and aspiration have been associated with antipsychotic drug use. Olanzapine orally disintegrating tablets and other antipsychotic agents 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 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.
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 increased risk in mortality and the risk of cerebrovascular accident.
Parkinson's diseases: The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson's disease is not recommended.
Use in Pregnancy: Category C. 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. Neonates exposed to antipsychotic drugs (including Olanzapine) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been post-market reports of agitation, hypertonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required additional medical treatment or monitoring. Olanzapine ODT should be used during pregnancy only if the anticipated benefit outweighs the risk, and the administered dose and duration of treatment should be as low and as short as possible.
Use in Lactation: In a study in lactating, 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 if they are taking Olanzapine.
Use in the Elderly: Caution should be used when Olanzapine is administered to the elderly, especially if there are other factors that may influence drug metabolism and/or pharmacodynamic parameters.
Use In Pregnancy & Lactation
Olandus 5/Olandus 10: There are no adequate and well-controlled trials with Olanzapine in pregnant females. 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. It is not known if Olanzapine is excreted in human milk. It is recommended that women receiving Olanzapine tablets should not breast feed. Safety and effectiveness of the drug in pediatric patients have not been established.
Olandus ODT 15: Use in Pregnancy: Category C. 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. Neonates exposed to antipsychotic drugs (including Olanzapine) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been post-market reports of agitation, hypertonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required additional medical treatment or monitoring. Olanzapine ODT should be used during pregnancy only if the anticipated benefit outweighs the risk, and the administered dose and duration of treatment should be as low and as short as possible.
Use in Lactation: In a study in lactating, 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 if they are taking Olanzapine.
Adverse Reactions
Olandus 5/Olandus 10: The most frequently reported adverse effects with Olanzapine are somnolence and weight gain. Olanzapine has been associated with a low incidence of extrapyramidal symptoms including tardive dyskinesia. Hyperprolactinaemia may occur but is usually asymptomatic. Other adverse effects include increased appetite, peripheral oedema, and rarely elevated creatine kinase concentrations.
Olandus ODT 15: Adverse events identified from clinical trials of olanzapine: Body as a whole: Very common (≥10%): weight gain: weight gain ≥7% baseline body weight. Common (≥1% and <10%): asthenia, fatigue, weight gain ≥15% baseline body weight. Uncommon (≥0.1% and <1%): photosensitivity reaction.
Cardiovascular system: Common (≥1% and <10%): orthostatic hypotension. Uncommon (≥0.1% and <1%): bradycardia.
Digestive system: Common (≥1% and <10%): constipation; dry mouth; increased appetite.
Metabolic: Common (≥1% and <10%): peripheral oedema. Rare (<0.l% and ≥0.01%): elevated creatinine phosphokinase levels.
Nervous system: Very common (≥10%): somnolence. Common (≥1% and <10%): dizziness; akathisia.
Clinical chemistry: Very common (≥10%): prolactin-increased, cholesterol-total (fasting borderline to high), triglycerides (fasting borderline to high), glucose (fasting borderline to high). Common (≥1% and <10%): alanine transferase (ALT)-increased; aspartate transferase (AST)-increased, cholesterol-total (fasting normal to high), triglycerides (fasting normal to high), glucose (fasting normal to high), glycosuria.
Hepatic Transaminases: Transient, asymptomatic elevations of hepatic transaminases, ALT and AST, have been seen occasionally.
Haematology: Common (≥1% and <10%): eosinophilia.
Eosinophilia: Asymptomatic eosinophilia was occasionally seen.
Undesirable Effects for Special Populations: Elderly Patients: Undesirable effects associated with the use of Olanzapine in clinical trials with elderly patients with dementia-related psychosis: Body as a whole: Very common (≥10%): falls.
Nervous system: Very common (≥10%): abnormal gait.
Urogenital system: Common (≥1% and <10%): urinary incontinence.
Respiratory system: Common (≥1% and <10%): pneumonia.
Adolescents (Ages 13-17 years): Body as a whole: Very common (≥10%): weight gain ≥7% of baseline body weight 40.6%.
Common (≥1% and <10%): weight gain ≥15% of baseline body weight 7.1%.
Digestive system: Very common (≥10%): increased appetite 24.0%.
Common (≥1% and <10%): dry mouth 6.1%.
Nervous system: Very common (≥10%): sedation (including hypersomnia, lethargy, sedation, somnolence) 44.1%.
Clinical chemistry: Very common (≥10%): ALT >3 x ULN (all randomised patients with ALT baseline ≤3 x ULN) 12.1%, AST-increased 27.6%, total bilirubin-decreased 22.1%, GGT-increased 10.1%, prolactin-increased 47.4%, cholesterol-total (fasting borderline to high) 38.9%, triglycerides (fasting normal to high) 26.9%, triglycerides (fasting borderline to high) 59.5%, glucose (fasting borderline to high) 14.3%.
Common (≥1% and <10%): cholesterol-total (fasting normal to high) 6.9%.
Very rare (<0.01%): glucose (fasting normal to high).
Adverse events based on post marketing spontaneous reports with oral olanzapine: Body as a whole: Very rare (<0.01%): allergic reaction (e.g. anaphylactoid reaction, angioedema, pruritis or urticaria); discontinuation reaction (acute symptoms such as sweating, insomnia, tremor, anxiety, nausea or vomiting have been reported very rarely when olanzapine is stopped suddenly).
Digestive system: Very rare (<0.01%): pancreatitis.
Hepatobiliary disorders: Rare (<0.1% and ≥0.01%): hepatitis.
Very rare (<0.01%): jaundice.
Metabolic: Rare (<0.1% and ≥0.01%): hyperglycaemia.
Very rare (<0.01%): diabetic coma; diabetic ketoacidosis; exacerbation of pre-existing diabetes; hypertriglyceridemia (random triglyceride levels of ≥11.29 mmol/L); hypercholesterolaemia (random cholesterol levels of ≥6.21 mmol/L).
Nervous system: Rare (<0.1% and ≥0.01%): seizures.
Very rare (<0.01%): neuroleptic malignant syndrome.
Skin and appendages: Rare (<0.1% and ≥0.01%): rash.
Very rare (<0.01%): alopecia.
Urogenital system: Very rare (<0.01%): priapism; urinary hesitation, urinary incontinence.
Haematology: Rare (<0.1% and ≥0.01%): leucopenia, including neutropenia.
Very rare (<0.01%): thrombocytopenia.
Cardiovascular: Very rare (<0.01%): venous thromboembolism, including pulmonary embolism and deep vein thrombosis. Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac arrest and torsades de pointes have been reported very rarely with the use of neuroleptics and may be considered a class effect.
Musculoskeletal System: Very rare (<0.01%): rhabdomyolysis.
Clinical chemistry: Very rare (<0.01%): alkaline phosphatase increased; total bilirubin increased, creatine phosphokinase increased.
Drug Interactions
Olandus 5/Olandus 10: Given the primary CNS effects of Olanzapine, caution should be used when Olanzapine tablets are taken in combination with other centrally acting drugs and alcohol. Because of its potential for inducing hypotension, Olanzapine tablets may enhance the effects of certain antihypertensive agents. Olanzapine may antagonize the effects of levodopa and dopamine agonists. The metabolism of Olanzapine is mediated to some extent by the cytochrome P450 isozyme CYP1A2. Concomitant administration of drugs which inhibit or act as a substrate to this isozyme may affect plasma concentrations of Olanzapine. The clearance of Olanzapine is increased by tobacco smoking.
Olandus ODT 15: Given the primary central nervous system effects of Olanzapine, caution should be used when it is taken in combination with other centrally acting drugs and alcohol. As it exhibits in vitro dopamine antagonism, Olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Caution should be exercised when Olanzapine is used concomitantly with medicines known to cause electrolyte imbalance or to increase QT interval.
Potential for other medicines to affect Olanzapine: Single-doses of antacids (containing aluminium and magnesium) or cimetidine do not affect the oral bioavailability of Olanzapine. The concomitant administration of activated charcoal reduces the oral bioavailability of Olanzapine by 50 to 60%.
Fluoxetine (60 mg single dose or 60 mg daily for 8 days) caused a 16% increase in the maximum plasma concentration of Olanzapine and a 16% decrease in Olanzapine clearance. The magnitude of this is small in comparison to the overall variability between individuals and therefore dose modification is not routinely recommended.
The metabolism of Olanzapine may be induced by concomitant smoking (the clearance of olanzapine is 33% lower and the terminal elimination half-life is 21% longer in non-smokers compared to smokers) or carbamazepine therapy (clearance is increased 44% and the terminal elimination half-life is reduced by 20% when administered with carbamazepine). Smoking and carbamazepine therapy induce P450-1A2 activity. The pharmacokinetics of theophylline, which is metabolised by P450-1A2, is not altered by olanzapine.
Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of Olanzapine. This results in a mean increase in Olanzapine Cmax following fluvoxamine of 54% in female non-smokers 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 or any other P450-1A2 inhibitor, such as ciprofloxacin.
Potential for Olanzapine to affect other medicines: In clinical trials with single doses of olanzapine, no inhibition of the metabolism of imipramine/ desipramine (P450-2D6, P450- 3A or P450-1A2), warfarin (P450-2C19), theophylline (P450-1A2) or diazepam (P450-3A4 and P450-2C19) was evident. Olanzapine showed no interaction when coadministered with lithium or biperiden. The in vitro ability of Olanzapine to inhibit metabolism by five principle cytochromes has been examined. These studies found inhibitory constants for 3A4 (491 mcM), 2C9 (751 mcM), 1A2 (36 mcM), 2C19 (920 mcM), 2D6 (89 mcM) that compared to Olanzapine plasma concentrations of approximately 0.2 mcM, would mean maximum inhibition of these P450 systems by Olanzapine would be less than 0.7%. The clinical relevance of these findings is unknown.
Steady state concentrations of Olanzapine had no effect on the pharmacokinetics of ethanol (45 mg/70 kg). However, additive pharmacological effects such as increased sedation may occur when ethanol is ingested together with Olanzapine.
Studies in vitro using human liver microsomes showed that Olanzapine has little potential to inhibit the major metabolic pathway of valproate, which is glucuronidation. Further, valproate was found to have little effect on the oxidative metabolism of Olanzapine in vitro. Daily concomitant in vivo administration of 10 mg Olanzapine for 2 weeks did not affect steady state plasma concentrations of valproate. Therefore, concomitant Olanzapine administration does not require dosage adjustment of valproate.
Storage
Store at temperatures not exceeding 30°C.
Olandus 5/Olandus 10: Protect from light.
MIMS Class
ATC Classification
N05AH03 - olanzapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics
Presentation/Packing
Olandus 5: FC tab 5 mg x 100's.
Olandus 10: FC tab 10 mg x 100's.
Olandus ODT 15: OD tab 15 mg x 100's.
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