Zyprexa 2.5 mg/5 mg/10 mg Tablets

Oral olanzapine: ZYPREXA and ZYPREXA VELOTAB tablets are indicated for the management of the manifestations of psychotic disorders. The antipsychotic efficacy of ZYPREXA was established in controlled trials of schizophrenic inpatients in the treatment of positive symptoms (such as delusions, hallucinations, disordered thinking, hostility and suspiciousness) and negative symptoms (such as blunted effect, emotional and social withdrawal, poverty of speech). It is recommended that responding patients be continued on ZYPREXA at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

ZYPREXA is also indicated for the treatment of an acute episode of moderate to severe mania and for preventing recurrence of manic or depressive episodes of bipolar disorder.

Intramuscular olanzapine: ZYPREXA IM injection is indicated for the control of agitation and disturbed behaviour in patients with schizophrenia and related psychoses and in patients with acute mania associated with Bipolar I disorder when oral therapy is not appropriate. Treatment with ZYPREXA IM should be discontinued and the use of ZYPREXA or ZYPREXA VELOTAB tablets should be initiated as soon as clinically appropriate.

Oral dosing: Psychotic Disorders: ZYPREXA and ZYPREXA VELOTAB tablets should be administered on a once-a-day schedule without regard to meals, generally beginning with an initial dose of 5 to 10 mg/day, with a target dose of 10 mg/day within several days. In order to evaluate efficacy and guard against side effects, dosage increases should not be considered before one week, since steady state for olanzapine would not be achieved for approximately one week. The dose range is from 5 mg to 20 mg per day. Increasing the dose over the routine daily dose of 10 mg is advised only after appropriate clinical assessment.

Acute mania in bipolar disorder: ZYPREXA should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 mg. Dosage adjustments within the dose range of 5 mg to 20 mg per day, if indicated, should generally occur at intervals of not less than 24 hours.

Preventing recurrence in bipolar disorder: The recommended starting dose is 10 mg per day. For patients who have been receiving ZYPREXA for treatment of manic episode, continue therapy for preventing recurrence at the same dose. An increase to a dose greater than the recommended starting dose, within the range of 5 mg to 20 mg per day, is advised only after appropriate clinical assessment and should generally occur at intervals of not less than 24 hours. The safety of doses above 20 mg/day has not been evaluated in clinical trials. Gradual tapering of the dose should be considered when discontinuing ZYPREXA.

Intramuscular dosing: ZYPREXA IM is for intramuscular use only. Do not administer intravenously or subcutaneously. The recommended dose for olanzapine injection is 10 mg administered as a single intramuscular injection. On the basis of individual clinical status, a second injection of up to 10 mg may be administered as early as 2 hours after the first injection, and a third injection of up to 10 mg may be administered as early as 4 hours after the second injection. The safety of total daily doses greater than 30 mg has not been evaluated in clinical trials. Treatment with olanzapine for injection should be discontinued and oral olanzapine in a range of 5 - 20 mg/day should be initiated as soon as clinically appropriate. Elderly patients: A lower starting dose of 2.5 - 5 mg per injection should be considered for elderly patients.

ZYPREXA is contra-indicated in patients who are hypersensitive to the product. It is also contra-indicated in patients with known risk of narrow-angle glaucoma.

Paediatric use: Safety and effectiveness in patients under 18 years of age have not been established.

Discontinuation reactions may occur, usually within a week of discontinuing ZYPREXA. These reactions may consist of a cholinergic syndrome (diaphoresis, diarrhoea, sialorrhoea, nausea and vomiting, anxiety, agitation, insomnia and tremor). ZYPREXA should therefore be gradually discontinued.

Intramuscular use: Serious/severe bradycardia and syncope may occur. In clinical studies there were cases with serious symptomatic hypotension, apnoea, and ventricular tachydysrhythmias including fatalities. In most of the serious cases there was a temporal relationship with the use of benzodiazepines. See u2018 Special Precautions u2019.

Hyperprolactinaemia: ZYPREXA elevates prolactin levels and a modest elevation persists during chronic administration. An increase in mammary gland neoplasms has been found in rodents after chronic administration of antipsychotic medicines and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumours in rodents is unknown.

Neuroleptic malignant syndrome (NMS): NMS has occurred infrequently in association with ZYPREXA. NMS is a potentially fatal symptom complex. 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. ZYPREXA should be discontinued should any of the clinical manifestations of NMS or high fever without additional clinical manifestations of NMS be observed.

Seizures: ZYPREXA should be used cautiously in patients who have a history of seizures or are subject to factors which may lower seizure threshold. Seizures have been reported to occur infrequently in patients treated with olanzapine. In most of these cases, a history of seizures or risk factor for seizures was reported.

Tardive dyskinesia: ZYPREXA was associated with a low incidence of treatment emergent dyskinesia. If signs or symptoms of tardive dyskinesia appear in a patient on ZYPREXA, a dose reduction or discontinuation of treatment should be considered. However, some patients may benefit from continued treatment with ZYPREXA despite the presence of the syndrome. The risk of tardive dyskinesia increases with long-term exposure and symptoms can temporarily deteriorate or even arise after discontinuation of treatment.

Hepatic impairment: Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve and in patients who are being treated with potentially hepatotoxic medicines. Periodic assessment of transaminases is recommended in patients with significant hepatic disease. A 5 mg starting dose should be considered for patients with moderate hepatic impairment.

Safety experience in elderly patients with dementia-related psychosis: In elderly patients with dementia-related psychosis, the efficacy of ZYPREXA has not been established. In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5 % vs 1.5 %, respectively). Abnormal gait and falls were very common (> 10 %), urinary incontinence and respiratory infection were common, and there was an increased incidence in cerebrovascular incidents, including stroke. Risk factors that may predispose this patient population to increased mortality when treated with ZYPREXA include age u2265 80 years, sedation, concomitant use of benzodiazepines, or presence of pulmonary conditions (e.g. pneumonia, with or without aspiration).

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 ZYPREXA. Patients with an established diagnosis of diabetes mellitus who are started on ZYPREXA 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 ZYPREXA should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with ZYPREXA should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when ZYPREXA was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Given the primary CNS effects of olanzapine, caution should be exercised when ZYPREXA is taken in combination with other centrally acting agents (especially those that can cause CNS depression) and alcohol. As it exhibits in vitro dopamine antagonism, ZYPREXA may antagonise the effects of levodopa and dopamine agonists. Because of the potential for inducing hypotension, ZYPREXA may enhance the effects of certain antihypertensive agents.

In clinical trials with ZYPREXA IM, olanzapine was not associated with a persistent increase in absolute QT or in QTc intervals. In clinical trials with oral administration, olanzapine was not associated with a persistent increase in absolute QT intervals. Only 8 of 1 685 subjects had increased QTc intervals on multiple occasions. However, as with other antipsychotics, caution should be exercised when olanzapine is prescribed with medicines known to increase QTc intervals, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesemia.

Hypotension and/or bradycardia have been observed during intramuscular administration of olanzapine for injection. Olanzapine has u03b1-1 adrenergic antagonist activity. Caution should be exercised in patients who receive treatment with medicinal products that can lower blood pressure by mechanisms other than u03b1-1 adrenergic antagonism.

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.

Potential for other medicines to affect ZYPREXA: Single doses of antacid (aluminium, magnesium) or cimetidine did not affect the oral bioavailability of olanzapine. However, the concomitant administration of activated charcoal reduced the bioavailability of oral olanzapine by 50 to 60% and should be taken at least 2 hours before or after olanzapine. Fluoxetine (60 mg single dose or 60 mg daily for 8 days) in combination with olanzapine (5 mg single dose), causes a mean 16 % increase in the maximum concentration of olanzapine and a mean 16 % decrease in olanzapine clearance. The effect of repeat dosage of ZYPREXA and higher dosages has not been evaluated. Combination therapy is not advised. Administration of intramuscular lorazepam (2 mg) one hour after intramuscular olanzapine (5 mg) did not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam or total lorazepam. However, this coadministration of intramuscular lorazepam and intramuscular olanzapine added to the somnolence observed with either medicine alone.

Induction of CYP1A2: The metabolism of olanzapine may be induced by concomitant smoking or carbamazepine therapy causing subsequent slightly to moderately lower olanzapine plasma levels. The clinical consequences are likely to be limited, but clinical monitoring is recommended and an increase of olanzapine may be considered if necessary.

Inhibition of CYP1A2: Known potent inhibitors of CYP1A2 activity may decrease olanzapine clearance. Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine C max following fluvoxamine was 54 % in female non-smokers and 77 % in male smokers. The mean increase in olanzapine AUC was 52% and 108 % respectively. A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin or ketoconazole. A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.

Potential for ZYPREXA to affect other medicines: Olanzapine may antagonise the effects of direct and indirect dopamine agonists. In clinical trials with single doses of ZYPREXA, no inhibition of the metabolism of imipramine/desipramine (P450-CYP2D6 or P450-CYP3A/1A2), warfarin (P450-CYP2C9), theophylline (P450-CYP1A2) or diazepam (P450-CYP3A4 and P450-CYP2C19) was evident. ZYPREXA showed no interaction when coadministered with lithium or biperiden. Also, in in vitro studies with human liver microsomes, olanzapine showed little potential to inhibit cytochromes P450-CYP1A2, -CYP2C9, -CYP2C19, -CYP2D6, and -CYP3A4. Given the extensive clinical and in vitro studies, ZYPREXA would not be expected to interfere with the metabolism of most medicines. Studies in vitro using human liver microsomes, determined that ZYPREXA has little potential to inhibit the glucuronidation of valproate, the major metabolic pathway for valproate. Further, valproate was found to have little effect on the metabolism of ZYPREXA 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.

Safety of ZYPREXA during pregnancy and lactation has not been established.

ZYPREXA may cause somnolence. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that ZYPREXA therapy does not affect them adversely.

The following table summarizes the core side effects identified with ZYPREXA during oral and intramuscular clinical trials and/or during postmarketing experience:

Body System/Adverse Reaction Terms Frequency Events u2265 10 % < 10 % and u2265 1 % < 1 % and u2265 0,1 % < 0,1 % and u2265 0,01 % < 0,01 % Very Common Common Uncommon Rare Very Rare Body as a Whole Allergic reaction X Asthenia X Discontinuation reaction X Photosensitivity reaction X Weight gain X Cardiovascular Bradycardia X Orthostatic hypotension X Venous thromboembolism X Digestive System Constipation X Dry mouth X Hepatitis X Increased Appetite X Pancreatitis X Haematologic Leucopenia X Thrombocytopenia X Metabolic Diabetic coma X Diabetic ketoacidosis X Hypercholesterolaemia 1 X Hyperglycaemia X Hypertriglyceridaemia 1 X Peripheral oedema X Musculoskeletal Rhabdomyolysis X Nervous System Akathisia X Dizziness X Seizures X

Common (< 10 % and u2265 1 %) undesirable effects associated specifically with use of intramuscular olanzapine in clinical trials included hypotension, tachycardia, and bradycardia.

The following table summarizes additional core side effects identified only during the intramuscular clinical trials:

Body System/Adverse Reaction Terms Frequency Events u2265 10 % < 10 % and u2265 1 % < 1 % and u2265 0,1 % < 0,1 % and u2265 0,01 % < 0,01 % Very Common Common Uncommon Rare Very Rare Cardiovascular Hypotension X Tachycardia X Bradycardia X

The following table summarizes additional core side effects identified only during clinical trials in patients with dementia of the Alzheimeru2019s type:

Body System/Adverse Reaction Terms Frequency Events u2265 10 % < 10 % and u2265 1 % < 1 % and u2265 0,1 % < 0,1 % and u2265 0,01 % < 0,01 % Very Common Common Uncommon Rare Very Rare Nervous System Abnormal gait X Falls X Urogenital System Urinary incontinence X Respiratory System Pneumonia X

The following table summarizes additional core side effects identified only during clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with Parkinsonu2019s disease:

Body System/Adverse Reaction Terms Frequency Events u2265 10 % < 10 % and u2265 1 % < 1 % and u2265 0,1 % < 0,1 % and u2265 0,01 % < 0,01 % Very Common Common Uncommon Rare Very Rare Nervous System Hallucinations X Parkinsonian symptomatology X

The following table summarizes additional core side effects identified only during bipolar mania clinical trials in patients receiving olanzapine in combination with lithium or valproate:

Body System/Adverse Reaction Terms Frequency Events u2265 10 % < 10 % and u2265 1 % < 1 % and u2265 0,1 % < 0,1 % and u2265 0,01 % < 0,01 % Very Common Common Uncommon Rare Very Rare Body as a whole Weight gain X Digestive system Dry mouth X Increased appetite X Nervous System Speech disorder X Tremor X

Signs and symptoms: Very common symptoms reported in ZYPREXA overdose (u2265 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 ZYPREXA 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 1 500 mg.

Treatment: The possibility of multiple medicine involvement should be considered. 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 ZYPREXA; therefore appropriate symptomatic and supportive measures should be initiated. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents. Induction of emesis is not recommended. Do not use epinephrine, dopamine or other sympathomimetics with u03b2-agonist activity, since u03b2-stimulation may worsen hypotension in the setting of olanzapine-induced u03b1-blockade. Close medical supervision and monitoring should continue until the patient recovers.