Zypadhera · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-094996 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile Adverse reactions seen with olanzapine pamoate Post-injection syndrome reactions have occurred with ZYPADHERA leading to symptoms consistent with olanzapine overdose (see sections 4.2 and 4.4). Clinical signs and symptoms included 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. Other adverse reactions observed in patients treated with ZYPADHERA were similar to those seen with oral olanzapine. In clinical trials with ZYPADHERA, the only adverse reaction reported at a statistically significantly higher rate in the ZYPADHERA group than in the placebo group was sedation (ZYPADHERA 8.2%, placebo 2.0%). Among all ZYPADHERA treated patients, sedation was reported by 4.7% of patients. In clinical trials with ZYPADHERA the incidence of injection site related adverse reactions was approximately 8%. The most commonly reported injection site related adverse reaction was pain (5%); some other injection site adverse reactions reported were (in decreasing frequency): nodule type reactions, erythema type reactions, non-specific injection site reactions, irritation, oedema type reactions, bruising, haemorrhage, and anaesthesia. These events occurred in about 0.1 to 1.1% of patients. 9 In a review of safety data from clinical trials and spontaneous postmarketing reports, injection site abscess was rarely (≥ 1/10,000 to < 1/1,000) reported. Adverse reactions seen with olanzapine The undesirable effects listed below have been observed following administration of olanzapine. Adults The most frequently (seen in ≥ 1% of patients ) reported adverse reactions associated with the use of olanzapine 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 phosphokin

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HOS-094992 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients with known risk of narrow-angle glaucoma.

HOS-094991 · has-indication-information · PDF-Seite 2

Maintenance treatment of adult patients with schizophrenia sufficiently stabilised during acute treatment with oral olanzapine.

HOS-094994 · has-interaction-information · PDF-Seite 8

Interaction studies have only been performed in adults. Caution should be exercised in patients who receive medicinal products that can induce hypotension or sedation. 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. Induction of CYP1A2 The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been observed. The clinical consequences are likely to be limited, but clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.2). Inhibition of CYP1A2 Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax 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. A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated. Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine. Potential for olanzapine to affect other medicinal products Olanzapine may antagonise the effects of direct and indirect dopamine agonists. Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). Thus no particular interaction is expected as verified through in vivo studies where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19). Olanzapine showed no interaction when co-administered with lithium or biperiden. Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine. General CNS activity Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression. The concomitant use of olanzapi

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HOS-094995 · has-pregnancy-information · PDF-Seite 8

8 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 olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. New-born infants exposed to antipsychotics (including olanzapine) 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 of oral olanzapine in breast-feeding, 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 an infant if they are taking olanzapine. Fertility Effects on fertility are unknown (see section 5.3 for preclinical information)

HOS-094993 · has-warning-information · PDF-Seite 4

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 in a healthcare facility by appropriately qualified personnel for at least 3 hours for signs and symptoms consistent with olanzapine overdose. 4 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

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