Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
Special care must be taken to apply appropriate injection technique to avoid inadvertent intravascular or subcutaneous injection (see section 6.6).

Use in patients who are in an acutely agitated or severely psychotic state ZYPADHERA should not be used to treat patients with schizophrenia who are in an acutely agitated or severely psychotic state such that immediate symptom control is warranted.


Post-injection syndrome
During pre-marketing clinical studies, reactions that presented with signs and symptoms consistent with olanzapine overdose were reported in patients following an injection of ZYPADHERA. These reactions occurred in <0.1% of injections and approximately 2% of patients. Most of these patients have developed symptoms of sedation (ranging from mild in severity up to coma) and/or delirium (including confusion, disorientation, agitation, anxiety and other cognitive impairment). Other symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension and convulsion. In most cases, initial signs and symptoms related to this reaction have appeared within 1 hour following injection, and in all cases full recovery was reported to have occurred within 24 – 72 hours after injection. Reactions occurred rarely (<1 in 1,000 injections) between 1 and 3 hours, and very rarely (<1 in 10,000 injections) after 3 hours. Patients should be advised about this potential risk and the need to be observed for 3 hours in a healthcare facility each time ZYPADHERA is administered. Post-marketing reports of post-injection syndrome since the marketing authorization of ZYPADHERA are generally consistent with the experience seen in clinical studies.

After each injection, patients should be observed and monitored in a healthcare facility by appropriately qualified personnel for at least 3 hours for signs and symptoms consistent with olanzapine overdose. The medical staff at each facility will maintain records of time of injection, patient response and time of the patient leaving the center.

Immediately prior to leaving the health care facility, it should be confirmed that the patient is alert, oriented, and absent of any signs and symptoms of overdose. If an overdose is suspected, close medical supervision and monitoring should continue until examination indicates that signs and symptoms have resolved. The 3-hour observation period should be extended as clinically appropriate for patients who exhibit any signs or symptoms consistent with olanzapine overdose.

For the remainder of the day after injection, patients should be advised to be vigilant for signs and symptoms of overdose secondary to post injection adverse reactions, be able to obtain assistance if needed and should not drive or operate machinery (see section 4.7).

If parenteral benzodiazepines are essential for management of post injection adverse reactions, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended (see section 4.5).

Injection site related adverse events
The most commonly reported injection site related adverse reaction was pain. The majority of these reactions was reported to be of “mild” to “moderate” severity. In the event of an injection site related adverse reaction occuring, appropriate measures to manage these events should be taken (see section 4.8).

Dementia-related psychosis and/or behavioural disturbances
Olanzapine is not approved 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 oral olanzapine-treated patients compared to patients treated with placebo (3.5% vs. 1.5%, respectively). The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 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 oral olanzapine-treated than in placebo-treated patients independent of these risk factors.

In the same clinical trials, cerebrovascular adverse reactions (CVAEvents e.g., stroke, transient ischemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients  treated with oral olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively).
All oral olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre- existing risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials.

Parkinson's disease
The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo (see section 4.8), and oral olanzapine was not more effective than placebo in the treatment of psychotic symptoms.
In these trials, patients were initially required to be stable on the lowest effective dose of anti- Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian medicinal products and dosages throughout the study. Oral olanzapine 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 oral 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 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 olanzapine 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 olanzapine treatment and annually thereafter. Patients treated with any antipsychotic medicines, including ZYPADHERA, 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.

Lipid alterations
Undesirable alterations in lipids have been observed in olanzapine-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, including ZYPADHERA, 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.

Anticholinergic activity
While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.

Hepatic function
Transient, asymptomatic elevations of hepatic aminotransferases, ALT, AST have been seen commonly, especially in early treatment. Caution should be exercised and follow-up organised in patients with elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in  patients who are being treated with potentially hepatotoxic medicines. In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment should be discontinued.

Neutropenia
Caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, in patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with myeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly (see section 4.8).

Discontinuation of treatment
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported rarely (≥0.01% and <0.1%) when oral olanzapine is stopped abruptly.

QT interval
In clinical trials with oral olanzapine, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF] ≥ 500 milliseconds [msec] at any time post baseline in patients with baseline QTcF<500 msec) were uncommon (0.1% to 1%) in patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. In clinical trials with olanzapine powder for solution for injection or ZYPADHERA, olanzapine was not associated with a persistent increase in absolute QT or in QTc intervals. However, caution should be exercised when olanzapine 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 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, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of direct and indirect dopamine agonists.

Seizures
Olanzapine should be used cautiously in patients who have a history of seizures or are subject to factors which may lower the seizure threshold. Seizures have been reported to occur uncommonly in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.

Tardive dyskinesia
In comparator studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However, the risk of tardive dyskinesia increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Postural hypotension
Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. It is recommended that blood pressure is measured periodically in patients over 65 years.


Sudden cardiac death
In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis.

Paediatric population
Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels (see sections 4.8 and 5.1).

Use in elderly (>75 years)
No information on the use of ZYPADHERA in patients >75 years is available. Due to biochemical and physiological modification and reduction of muscular mass, this formulation is not recommended to be started in this sub-group of patients.

Effects on Driving

4.7   Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. As olanzapine may cause somnolence and dizziness, patients should be cautioned about operating machinery, including motor vehicles.

Patients should be advised not to drive or operate machinery for the remainder of the day after each injection due to the possibility of a post-injection syndrome event leading to symptoms consistent with olanzapine overdose (see section 4.4).