5 mg, 10 mg
For the use of a Registered Medical Practitioner or a Hospital or a Institution only.
OLANZAPINE TABLETS USP (Olanzapine) is Antipsychotic. Chemically, Olanzapine is 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine. The molecular formula is C17H20N4S and molecular weight is 312.43.
STRUCTURAL FORMULA :
Its structural formula is :
OLANZAPINE TABLETS USP is white coloured, round film coated tablet having break line on one side and other side plain.
Each film coated tablet contains :
Olanzapine USP 5 mg
Colour : Titanium Dioxide B.P.
Each film coated tablet contains :
Olanzapine USP 10 mg
Colour : Titanium Dioxide B.P.
The exact mechanism by which olanzapine exerts its antipsychotic effect is unknown. However, this effect may be mediated through a combination of dopamine and serotonin 5-HT2 antagonism. Olanzapine is a selective monoaminergic antagonist with a strong affinity for serotonin 5-HT2A and 5-HT2C receptors, and dopamine D1, D2, D3, and D4 receptors. Olanzapine binds weakly to gamma-aminobutyric acid type A (GABAA), benzodiazepine (BZD), and beta-adrenergic receptors. Olanzapine’s high affinity binding to, and antagonism of, muscarinic M1, M2, M3, M4, and M5 receptors may explain its anticholinergic effects. Olanzapine also binds with high affinity to histamine H1 and alpha1 -adrenergic receptors. Antagonism of histamine H1 and alpha1 -adrenergic receptors may be responsible for the occurrence of somnolence and orthostatic hypotension, respectively, seen with olanzapine use.
Olanzapine is well absorbed from the gastrointestinal tract after oral doses but undergoes considerable first pass metabolism. Peak plasma concentrations are achieved about 5 to 8 hours after oral doses and about 15 to 45 minutes after an intramuscular dose. Olanzapine is about 93 % bound to plasma proteins. It is extensively metabolised in the liver, primarily by direct glucuronidation and by oxidation mediated through the cytochrome P450 isoenzymes CYP1A2, and, to a lesser extent, CYP2D6. The 2 major metabolites 10-N-glucuronide and 4’-N-desmethyl olanzapine appear to be inactive. About 57 % of a dose is excreted in the urine, mainly as metabolites, and about 30 % appears in the faeces. The mean plasma elimination half-life has been variously reported to be about 30 to 38 hours; half-lives tend to be longer in female than in male patients. Olanzapine is distributed into breast milk.
OLANZAPINE TABLETS USP is indicated for the treatment of schizophrenia. OLANZAPINE TABLETS USP is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response. OLANZAPINE TABLETS USP is indicated for the treatment of moderate to severe manic episode. In patients whose manic episode has responded to olanzapine treatment, OLANZAPINE TABLETS USP is indicated for the prevention of recurrence in patients with bipolar disorder.
OLANZAPINE TABLETS USP is for oral administration. OLANZAPINE TABLETS USP can be given without regard for meals, as absorption is not affected by food.
Schizophrenia : The recommended starting dose for olanzapine is 10 mg/day.
Manic episode : The starting dose is 15 mg as a single daily dose in monotherapy or 10 mg daily in combination therapy.
Preventing recurrence in bipolar disorder : The recommended starting dose is 10 mg/day. For patients who have been receiving olanzapine for treatment of manic episode, continue therapy for preventing recurrence 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 5-20 mg/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. Gradual tapering of the dose should be considered when discontinuing OLANZAPINE TABLETS USP.
OLANZAPINE TABLETS USP 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.
A lower starting dose (5 mg/day) is not routinely indicated but should be considered for those 65 and over when clinical factors warrant. Patients with 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.
The starting dose and dose range need not be routinely altered for female patients relative to male patients.
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.
Hypersensitivity to the active substance or to any of the excipients in OLANZAPINE TABLETS USP. Patients with known risk for narrow-angle glaucoma. OLANZAPINE TABLETS USP contains lactose which is contraindicated in patients with galactosaemia, the glucose-galactose malabsorption syndrome, or lactase deficiency.
WARNINGS AND 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 TABLETS USP 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 % versus 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 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 % versus 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.
The use of OLANZAPINE TABLETS USP 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.
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 TABLETS USP. 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 e.g. measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually thereafter. Patients treated with any antipsychotic
medicinal products, including olanzapine, 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.
Undesirable alterations in lipids have been observed in OLANZAPINE TABLETS USP treated patients in placebo controlled clinical trials. Lipid alterations should be managed as clinically appropriate, particularly in dyslipidemic patients and in patients with risk factors
for the development of lipid disorders. Patients treated with any antipsychotic medicinal products, including olanzapine, 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.
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 TABLETS USP in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.
Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), aspartate transferase (AST), have been seen commonly, especially in early treatment. Caution should be exercised and follow-up organized 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 medicinal products. In cases where
hepatitis (including hepatocellular, cholestatic, or mixed liver injury) has been diagnosed, OLANZAPINE TABLETS USP treatment should be discontinued.
Caution should be exercised in patients with low leucocyte and/or neutrophil counts for any reason, in patients receiving medicinal products 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 TABLETS USP 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.
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 TABLETS USP, with no significant differences in associated cardiac events compared to placebo. However, as with other antipsychotics, caution should be exercised when OLANZAPINE TABLETS USP 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.
Temporal association of olanzapine treatment and venous thromboembolism has been reported uncommonly (≥0.1 % and <1 %). A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients with schizophrenia often present with acquired risk factors for venous thromboembolism, all possible risk factors of VTE, e.g., immobilisation of patients, should be identified and preventive measures undertaken.
General CNS activity
Given the primary CNS effects of OLANZAPINE TABLETS USP, caution should be used when it is taken in combination with other centrally acting medicinal products and alcohol. As it exhibits in vitro dopamine antagonism, OLANZAPINE TABLETS USP may
antagonise the effects of direct and indirect dopamine agonists.
OLANZAPINE TABLETS USP 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 TABLETS USP. In most of these cases, a history of seizures or risk factors for seizures were reported.
In comparator studies of one year or less duration, OLANZAPINE TABLETS USP 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 TABLETS USP, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.
Postural hypotension was infrequently observed in the elderly in OLANZAPINE TABLETS USP 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 TABLETS USP, 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 TABLETS USP was comparableto the risk of atypical antipsychotics included in a pooled analysis.
OLANZAPINE TABLETS USP 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. OLANZAPINE TABLETS USP should be used cautiously in diabetic patients.
Pregnancy : Category C
Teratogenic Effects :
In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the maximum recommended human daily oral dose on a mg/m2 basis, respectively) no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable foetuses were observed at a dose of 18 mg/kg/day (9 times the maximum recommended human daily oral dose on a mg/m2 basis). Gestation was prolonged at 10 mg/kg/day (5 times the maximum recommended human daily oral dose on a mg/m2 basis). In an oral rabbit teratology study, foetal toxicity (manifested as increased resorptions and daily oral dose on a mg/m2 basis). Because animal reproduction studies are not always predictive of human response, this drugshould be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Placental transfer of olanzapine occurs in rat pups. There are no adequate and well-controlled trials with olanzapine in pregnant females. Seven pregnancies were observed during clinical trials with olanzapine, including 2 resulting in normal births, 1 resulting in neonatal death due to a cardiovascular defect, 3 therapeutic abortions, and 1 spontaneous abortion.
Non-Teratogenic Effects :
Neonates exposed to olanzapine, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, 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 intensive care unit support and prolonged hospitalization. Olanzapine should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Nursing mothers :
In a study in lactating, healthy women, olanzapine was excreted in breast milk. Mean infant dose at steady state was estimated to be 1.8 % of the maternal olanzapine dose. It is recommended that women receiving olanzapine should not breast-feed.
Paediatric Use :
Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic transaminase levels. When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and hyperlipidaemia. Safety and effectiveness of olanzapine in children <13 years of age have not been established. Safety and effectiveness of olanzapine and fluoxetine in combination in children and adolescents <18 years of age have not been established.
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.
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 450 mg, but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.
TREATMENT OF OVERDOSAGE :
There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standard procedures for management of overdose may be indicated (i.e. gastric lavage, administration of activated charcoal). The concomitant administration of activated charcoal was shown to reduce the oral bioavailability of olanzapine by 50 to 60 %. 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.
Store below 30ºC (86ºF), protected from moisture and light.
Do not refrigerate.
SHELF LIFE :
24 months from the date of manufacture.
OLANZAPINE TABLETS USP contain Olanzapine USP 5 mg/10 mg.
2 Strips of 10 Tablets per Box.
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.