Manufacture: INTAS Pharmaceuticals Ltd.

Zyprexa is used to treat certain mental/mood conditions (such as schizophrenia, bipolar disorder). It may also be used in combination with other medication to treat depression. This medication can help to decrease hallucinations and help you to think more clearly and positively about yourself, feel less agitated, and take a more active part in everyday life.

Zyprexa is indicated for the treatment of schizophrenia.

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

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

Special warnings and precautions for use

During antipsychotic treatment, improvement in a 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

Zyprexa is not recommended for use in patients with dementia-related psychosis and/or behavioural disturbances 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 Zyprexa-treated patients compared to patients treated with placebo (3.5% vs. 1.5%, respectively). The higher incidence of death was not associated with Zyprexa 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 Zyprexa-treated than in placebo-treated patients independent of these risk factors.

In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischaemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with Zyprexa compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All Zyprexa- 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 Zyprexa treatment. The efficacy of Zyprexa was not established in these trials.

Parkinson's disease

The use of Zyprexa in the treatment of dopamine agonist associated psychosis in patients with Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo (see section 4.8), and Zyprexa 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. Zyprexa was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with Zyprexa. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including Zyprexa must be discontinued.

Hyperglycaemia and diabetes

Hyperglycaemia and/or development or exacerbation of diabetes, occasionally associated with ketoacidosis or coma, has been reported uncommonly, including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported, which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g., measuring of blood glucose at baseline, 12 weeks after starting Zyprexa treatment and annually thereafter. Patients treated with any antipsychotic medicines, including Zyprexa, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g., at baseline, 4, 8 and 12 weeks after starting Zyprexa treatment and quarterly thereafter.

Lipid alterations

Undesirable alterations in lipids have been observed in Zyprexa-treated patients in placebo-controlled clinical trials (see section 4.8). Lipid alterations should be managed as clinically appropriate, particularly in dyslipidemic patients and in patients with risk factors for the development of lipids disorders. Patients treated with any antipsychotic medicines should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g., at baseline, 12 weeks after starting Zyprexa treatment and every 5 years thereafter.

Anticholinergic activity

While Zyprexa demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with Zyprexa 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, Zyprexa 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 Zyprexa and Valproate are used concomitantly.

Discontinuation of treatment

Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported rarely (≥ 0.01% and < 0.1%) when Zyprexa 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 Zyprexa, with no significant differences in associated cardiac events compared to placebo. However, caution should be exercised when Zyprexa is prescribed with medicines known to increase QTc interval, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia.

Thromboembolism

Temporal association of Zyprexa treatment and venous thromboembolism has been reported uncommonly (≥ 0.1% and < 1%). A causal relationship between the occurrence of venous thromboembolism and treatment with Zyprexa 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 Zyprexa, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, Zyprexa may antagonise the effects of direct and indirect dopamine agonists.

Seizures

Zyprexa 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 uncommonly in patients when treated with Zyprexa. 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, Zyprexa 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 Zyprexa, 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 Zyprexa clinical trials. It is recommended that blood pressure is measured periodically in patients over 65 years.

Sudden cardiac death

In postmarketing reports with Zyprexa, the event of sudden cardiac death has been reported in patients with Zyprexa. 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 Zyprexa was comparable to the risk of atypical antipsychotics included in a pooled analysis.

Pediatric population

Zyprexa 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.

Lactose

Zyprexa tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose galactose malabsorption should not take this medicine.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with Zyprexa. Nevertheless, because human experience is limited, Zyprexa should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.

New born infants exposed to antipsychotics (including Zyprexa) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

Breast-feeding

In a study in breast-feeding, healthy women, Zyprexa was excreted in breast milk. Mean infant exposure (mg/kg) at steady-state was estimated to be 1.8% of the maternal Zyprexa dose (mg/kg). Patients should be advised not to breast-feed an infant if they are taking Zyprexa.

Fertility

Effects on fertility are unknown (see section 5.3 for preclinical information).

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 Zyprexa may cause somnolence and dizziness, patients should be cautioned about operating machinery, including motor vehicles.

Undesirable effects

Adults

The most frequently (seen in ≥ 1% of patients) reported adverse reactions associated with the use of Zyprexa in clinical trials were somnolence, weight gain, eosinophilia, elevated prolactin, cholesterol, glucose and triglyceride levels (see section 4.4), glucosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases (see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema.