- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Legal category
PosologyPatients should be treated initially with oral olanzapine before administering ZYPADHERA, to establish tolerability and response.In order to identify the first ZYPADHERA dose for all patients, the scheme in Table 1 should be considered. Table 1 Recommended dose scheme between oral olanzapine and ZYPADHERA
|Target oral olanzapine dose||Recommended starting dose of ZYPADHERA||Maintenance dose after 2 months of ZYPADHERA treatment|
|10 mg/day||210 mg/2 weeks or 405 mg/4 weeks||150 mg/2 weeks or 300 mg/4 weeks|
|15 mg/day||300 mg/2 weeks||210 mg/2 weeks or 405 mg/4 weeks|
|20 mg/day||300 mg/2 weeks||300 mg/2 weeks|
Dose adjustmentPatients should be monitored carefully for signs of relapse during the first one to two months of treatment. 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. During treatment, dose may subsequently be adjusted on the basis of individual clinical status. After clinical reassessment, dose may be adjusted within the range 150 mg to 300 mg every 2 weeks or 300 to 405 mg every 4 weeks. (Table 1)
SupplementationSupplementation with oral olanzapine was not authorised in double-blind clinical studies. If oral olanzapine supplementation is clinically indicated, then the combined total dose of olanzapine from both formulations should not exceed the corresponding maximum oral olanzapine dose of 20 mg/day.
Switching to other antipsychotic medicinal productsThere are no systematically collected data to specifically address switching patients from ZYPADHERA to other antipsychotic medicinal products. Due to the slow dissolution of the olanzapine pamoate salt which provides a slow continuous release of olanzapine that is complete approximately six to eight months after the last injection, supervision by a clinician, especially during the first 2 months after discontinuation of ZYPADHERA, is needed when switching to another antipsychotic product, and is considered medically appropriate.
Elderly patientsZYPADHERA has not been systematically studied in elderly patients (> 65 years). ZYPADHERA is not recommended for treatment in the elderly population unless a well-tolerated and effective dose regimen using oral olanzapine has been established. A lower starting dose (150 mg/4 weeks) is not routinely indicated, but should be considered for those 65 and over when clinical factors warrant. ZYPADHERA is not recommended to be started in patients >75 years (see section 4.4).
Patients with renal and/or hepatic impairmentUnless a well-tolerated and effective dose regimen using oral olanzapine has been established in such patients, ZYPADHERA should not be used. A lower starting dose (150 mg every 4 weeks) should be considered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh class A or B), the starting dose should be 150 mg every 4 weeks and only increased with caution.
SmokersThe starting dose and dose range need not be routinely altered for non-smokers relative to smokers. The metabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.5).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 dose. When indicated, dose escalation should be performed with caution in these patients.
Paediatric populationThe safety and efficacy of ZYPADHERA in children and adolescents below 18 years has not been established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made.
Method of administrationFOR INTRAMUSCULAR USE ONLY. DO NOT ADMINISTER INTRAVENOUSLY OR SUBCUTANEOUSLY (See section 4.4) ZYPADHERA should only be administered by deep intramuscular gluteal injection by a healthcare professional trained in the appropriate injection technique and in locations where post-injection observation and access to appropriate medical care in the case of overdose can be assured. 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. Immediately prior to leaving the healthcare 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 (see section 4.4). The 3-hour observation period should be extended as clinically appropriate for patients who exhibit any signs or symptoms consistent with olanzapine overdose.For instructions for use, see section 6.6.
Use in patients who are in an acutely agitated or severely psychotic stateZYPADHERA 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 syndromeDuring 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. Immediately prior to leaving the healthcare 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 eventsThe most commonly reported injection site-related adverse reaction was pain. The majority of these reactions were 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 disturbancesOlanzapine 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 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 ischaemic 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 diseaseThe 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 diabetesHyperglycaemia 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 alterationsUndesirable 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 activityWhile 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 functionTransient, 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.
NeutropeniaCaution 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 treatmentAcute 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 intervalIn 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.
ThromboembolismTemporal 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 activityGiven 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 antagonise the effects of direct and indirect dopamine agonists.
SeizuresOlanzapine 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 dyskinesiaIn 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 hypotensionPostural 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 deathIn 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 populationOlanzapine 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 patients (>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.
Potential interactions affecting olanzapineSince olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.
Induction of CYP1A2The 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 CYP1A2Fluvoxamine, 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 productsOlanzapine 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 activityCaution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson's disease and dementia is not recommended (see section 4.4).
QTc intervalCaution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval (see section 4.4).
PregnancyThere 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-feedingIn 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.
FertilityEffects on fertility are unknown (see section 5.3 for preclinical information).
Summary of the safety profile
Adverse reactions seen with olanzapine pamoatePost-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. 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 olanzapineThe undesirable effects listed below have been observed following administration of olanzapine.
AdultsThe 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 phosphokinase and oedema.
Tabulated list of adverse reactionsThe following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the data available).
|Very common||Common||Uncommon||Rare||Not known|
|Blood and the lymphatic system disorders|
|Eosinophilia Leukopenia10Neutropenia10||Thrombocytopenia 11|
|Immune system disorders|
|Metabolism and nutrition disorders|
|Weight gain1||Elevated cholesterol levels2,3Elevated glucose levels4Elevated triglyceride levels2,5Glucosuria Increased appetite||Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases (see section 4.4)11||Hypothermia12|
|Nervous system disorders|
|Somnolence||Dizziness Akathisia6Parkinsonism6 Dyskinesia6||Seizures where in most cases a history of seizures or risk factors for seizures were reported11Dystonia (including oculogyration)11Tardive dyskinesia11Amnesia 9Dysarthria||Neuroleptic malignant syndrome (see section 4.4) 12Discontinuation symptoms7, 12|
|Bradycardia QTc prolongation (see section 4.4)||Ventricular tachycardia/fibrillation, sudden death (see section 4.4) 11|
|Orthostatic hypotension10||Thromboembolism (including pulmonary embolism and deep vein thrombosis) (see section 4.4)|
|Respiratory, thoracic and mediastinal disorders|
|Mild, transient anticholinergic effects including constipation and dry mouth||Abdominal distension9||Pancreatitis11|
|Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment (see section 4.4)||Hepatitis (including hepatocellular, cholestatic or mixed liver injury) 11|
|Skin and subcutaneous tissue disorders|
|Rash||Photosensitivity reaction Alopecia|
|Musculoskeletal and connective tissue disorders|
|Renal and urinary disorders|
|Urinary incontinence, Urinary retention Urinary hesitation11|
|Pregnancy, puerperium and perinatal conditions|
|Drug withdrawal syndrome neonatal (see section 4.6)|
|Reproductive system and breast disorders|
|Erectile dysfunction in males Decreased libido in males and females||Amenorrhea Breast enlargement Galactorrhea in females Gynaecomastia/ breast enlargement in males||Priapism12|
|General disorders and administration site conditions|
|Asthenia Fatigue Oedema Pyrexia10Injection site pain||Injection site abscess|
|Elevated plasma prolactin levels8||Increased alkaline phosphatase10High creatine phosphokinase11High Gamma Glutamyltransferase 10High uric acid 10||Increased total bilirubin|
Long-term exposure (at least 48 weeks)The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months.
Additional information on special populationsIn clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher incidence of death and cerebrovascular adverse reactions compared to placebo (see also section 4.4). Very common adverse reactions associated with the use of olanzapine in this patient group were abnormal gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations and urinary incontinence were observed commonly. In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with Parkinson's disease, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo.In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapine resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could be high plasma valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels (≥ 10%) of tremor, dry mouth, increased appetite, and weight gain. Speech disorder was also reported commonly. During treatment with olanzapine in combination with lithium or divalproex, an increase of ≥ 7% from baseline body weight occurred in 17.4% of patients during acute treatment (up to 6 weeks). Long-term olanzapine treatment (up to 12 months) for recurrence prevention in patients with bipolar disorder was associated with an increase of ≥ 7% from baseline body weight in 39.9% of patients.
Paediatric populationOlanzapine is not indicated for the treatment of children and adolescent patients below 18 years. Although no clinical studies designed to compare adolescents to adults have been conducted, data from the adolescent trials were compared to those of the adult trials. The following table summarises the adverse reactions reported with a greater frequency in adolescent patients (aged 13-17 years) than in adult patients or adverse reactions only identified during short-term clinical trials in adolescent patients. Clinically significant weight gain (≥ 7%) appears to occur more frequently in the adolescent population compared to adults with comparable exposures. The magnitude of weight gain and the proportion of adolescent patients who had clinically significant weight gain were greater with long-term exposure (at least 24 weeks) than with short-term exposure. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10).
|Metabolism and nutrition disordersVery common: Weight gain13, elevated triglyceride levels14, increased appetite. Common: Elevated cholesterol levels15.|
|Nervous system disordersVery common: Sedation (including: hypersomnia, lethargy, somnolence).|
|Gastrointestinal disordersCommon: Dry mouth.|
|Hepatobiliary disordersVery common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4).|
|Investigations Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16.|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via UK: www.mhra.gov.uk/yellowcard or Ireland: IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, www.imb.ie, firstname.lastname@example.org.
Signs and symptomsVery 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 oral overdoses as low as 450 mg but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.
ManagementThere is no specific antidote for olanzapine. 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.
Pharmacodynamic effectsOlanzapine is an antipsychotic, antimanic and mood stabilising agent that demonstrates a broad pharmacologic profile across a number of receptor systems.In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki < 100 nM) for serotonin 5-HT2A/2C, 5-HT3, 5-HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α-1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5-HT2 than dopamine D2 receptors and greater 5-HT2 than D2 activity in in vivo models. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases responding in an anxiolytic test.In a Positron Emission Tomography (PET) study in patients treated with ZYPADHERA (300 mg/4 weeks), mean D2 receptor occupancy was 60% or higher at the end of a 6-month period, a level consistent with that found during treatment with oral olanzapine.
Clinical efficacyThe effectiveness of ZYPADHERA in the treatment and maintenance treatment of schizophrenia is consistent with the established effectiveness of the oral formulation of olanzapine.A total of 1469 patients with schizophrenia were included in 2 pivotal trials:The first, an 8-week, placebo-controlled trial conducted in adult patients (n=404) who were experiencing acute psychotic symptoms. Patients were randomised to receive injections of ZYPADHERA 405 mg every 4 weeks, 300 mg every 2 weeks, 210 mg every 2 weeks, or placebo every 2 weeks. No oral antipsychotic supplementation was allowed. Total Positive and Negative Symptom Scores (PANSS) showed significant improvement from baseline (baseline mean Total PANSS Score 101) to endpoint (mean changes -22.57, -26.32, -22.49 respectively) with each dose of ZYPADHERA (405 mg every 4 weeks, 300 mg every 2 weeks, and 210 mg every 2 weeks) as compared to placebo (mean change -8.51). Visitwise mean change from baseline to endpoint in PANSS Total Score indicated that by Day 3, patients in the 300 mg/2 weeks and 405 mg/4 weeks treatment groups had statistically significantly greater reductions in PANSS Total Score compared to placebo (-8.6, -8.2, and -5.2, respectively). All 3 ZYPADHERA treatment groups showed statistically significantly greater improvement than placebo beginning by end of Week 1. These results support efficacy for ZYPADHERA over 8 weeks of treatment and a drug effect that was observed as early as 1 week after starting treatment with ZYPADHERA.The second, a long-term study in clinically stable patients (n=1065) (baseline mean Total PANSS Score 54.33 to 57.75), who were initially treated with oral olanzapine for 4 to 8 weeks and then switched to continue on oral olanzapine or to ZYPADHERA for 24 weeks. No oral antipsychotic supplementation was allowed. ZYPADHERA treatment groups of 150 mg and 300 mg given every 2 weeks (doses pooled for analysis) and 405 mg given every 4 weeks were non-inferior to the combined doses of 10, 15 and 20 mg of oral olanzapine (doses pooled for analysis) as measured by rates of exacerbation of symptoms of schizophrenia (respective exacerbation rates, 10%, 10%, 7%). Exacerbation was measured by worsening of items on the PANSS derived BPRS Positive Scale and hospitalisation due to worsening of positive psychotic symptoms. The combined 150 mg and 300 mg/2 week treatment group was non-inferior to the 405 mg/4 week treatment group (exacerbation rates 10% for each group) at 24 weeks after randomisation.
Paediatric populationZYPADHERA has not been studied in the paediatric population. Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term oral olanzapine studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Oral olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. During treatment with oral olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.
AbsorptionOlanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites; both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent, olanzapine.After a single IM injection with ZYPADHERA, the slow dissolution of the olanzapine pamoate salt in muscle tissue begins immediately and provides a slow continuous release of olanzapine for more than four weeks. The release becomes diminishingly smaller within eight to twelve weeks. Antipsychotic supplementation is not required at the initiation of ZYPADHERA treatment (see section 4.2).The combination of the release profile and the dosage regimen (IM injection every two or four weeks) result in sustained olanzapine plasma concentrations. Plasma concentrations remain measurable for several months after each ZYPADHERA injection. The half-life of olanzapine after ZYPADHERA is 30 days compared to 30 hours following oral administration. The absorption and elimination are complete approximately six to eight months after the last injection.
DistributionOral olanzapine is rapidly distributed. The plasma protein binding of olanzapine is about 93% over the concentration range of 7 to about 1000 ng/mL. In plasma, olanzapine is bound to albumin and α1-acid glycoprotein.After repeated IM injections with 150 to 300 mg ZYPADHERA every two weeks, the 10th to 90th percentile of steady-state plasma concentrations of olanzapine were between 4.2 and 73.2 ng/ml. The plasma concentrations of olanzapine observed across the dose range of 150mg every 4 weeks to 300mg every 2 weeks illustrate increased systemic olanzapine exposure with increased ZYPADHERA doses. During the initial three months of treatment with ZYPADHERA, accumulation of olanzapine was observed but there was no additional accumulation during long-term use (12 months) in patients who were injected with up to 300 mg every two weeks.
EliminationOlanzapine plasma clearance after oral olanzapine is lower in females (18.9 l/hr) versus males (27.3 l/hr), and in non-smokers (18.6 l/hr) versus smokers (27.7 l/hr). Similar pharmacokinetic differences between males and females and smokers and non-smokers were observed in ZYPADHERA clinical trials. However, the magnitude of the impact of gender, or smoking on olanzapine clearance is small in comparison to the overall variability between individuals.
ElderlyNo specific investigations have been conducted in the elderly with ZYPADHERA. ZYPADHERA is not recommended for treatment in the elderly population (65 years and over) unless a well-tolerated and effective dosage regimen using oral olanzapine has been established. In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 hours) and the clearance was reduced (17.5 versus 18.2 l/hr). The pharmacokinetic variability observed in the elderly is within the range for the non-elderly. In 44 patients with schizophrenia >65 years of age, dosing from 5 to 20 mg/day was not associated with any distinguishing profile of adverse events.
Renal impairmentIn renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hours) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57% of radiolabelled olanzapine appeared in urine, principally as metabolites. Although patients with renal impairment were not studied with ZYPADHERA, it is recommended that a well-tolerated and effective dosage regimen using oral olanzapine is established in patients with renal impairment before treatment with ZYPADHERA is initiated (see section 4.2).
SmokersIn smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hours) of orally administered olanzapine was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8 hours and 14.1 l/hr, respectively). Although patients with hepatic impairment were not studied with ZYPADHERA, it is recommended that a well-tolerated and effective dosage regimen using oral olanzapine is established in patients with hepatic impairment before treatment with ZYPADHERA is initiated (see section 4.2).In a study of oral olanzapine given to Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.
Acute (single-dose) toxicitySigns of oral toxicity in rodents were characteristic of potent antipsychotic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, laboured respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in prostration and, at higher doses, semi-consciousness.
Repeated-dose toxicityIn studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland.Haematologic toxicity: Effects on haematology parameters were found in each species, including dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12 mg dose). In cytopenic dogs, there were no undesirable effects on progenitor and proliferating cells in the bone marrow.
Reproductive toxicityOlanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Oestrous cycles were affected at doses of 1.1 mg/kg (3-times the maximum human dose) and reproduction parameters were influenced in rats given 3 mg/kg (9-times the maximum human dose). In the offspring of rats given olanzapine, delays in foetal development and transient decreases in offspring activity levels were seen.
MutagenicityOlanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and oral in vivo mammalian tests.
CarcinogenicityBased on the results of oral studies in mice and rats, it was concluded that olanzapine is not carcinogenic.
SolventCarmellose sodiumMannitolPolysorbate 80Water for injectionsHydrochloric acid (for pH adjustment)Sodium hydroxide (for pH adjustment)
FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY. DO NOT ADMINISTER INTRAVENOUSLY OR SUBCUTANEOUSLY.Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
STEP 1: Preparing materialsIt is recommended that gloves are used as ZYPADHERA may irritate the skin.Reconstitute ZYPADHERA powder for prolonged release suspension for injection only with the solvent provided in the pack using standard aseptic techniques for reconstitution of parenteral products.
STEP 2: Determining solvent volume for reconstitutionThis table provides the amount of solvent required to reconstitute ZYPADHERA powder for prolonged release suspension for injection.
|ZYPADHERA vial strength (mg)||Volume of solvent to add (ml)|
STEP 3: Reconstituting ZYPADHERA1. Loosen the powder by lightly tapping the vial. 2. Open the pre-packaged Hypodermic syringe and needle with needle protection device. Peel blister pouch and remove device. Attach a syringe (if not already attached) to the Luer connection of the device with an easy twisting motion. Seat the needle firmly on the device with a push and a clockwise twist, then pull the needle cap straight away from the needle. Failure to follow these instructions may result in a needlestick injury.3. Withdraw the pre-determined solvent volume (Step 2) into the syringe.4. Inject the solvent volume into the powder vial.5. Withdraw air to equalize the pressure in the vial. 6. Remove the needle, holding the vial upright to prevent any loss of solvent. 7. Engage the needle safety device. Press the needle into the sheath using a one-handed technique. Perform a one-handed technique by GENTLY pressing the sheath against a flat surface. AS THE SHEATH IS PRESSED (Fig. 1), THE NEEDLE IS FIRMLY ENGAGED INTO THE SHEATH (Fig. 2).8. Visually confirm that the needle is fully engaged into the needle protection sheath. Only remove the device with the engaged needle from the syringe when required by a specific medical procedure. Remove by grasping the Luer hub of the needle protection device with thumb and forefinger, keeping the free fingers clear of the end of the device containing the needle point (Fig. 3).9. Tap the vial firmly and repeatedly on a hard surface until no powder is visible. Protect the surface to cushion impact (see Figure A).10. Visually check the vial for clumps. Unsuspended powder appears as yellow, dry clumps clinging to the vial. Additional tapping may be required if clumps remain (see Figure B).11. Shake the vial vigorously until the suspension appears smooth and is consistent in colour and texture. The suspended product will be yellow and opaque (see Figure C).If foam forms, let vial stand to allow foam to dissipate. If the product is not used immediately, it should be shaken vigorously to re-suspend. Reconstituted ZYPADHERA remains stable for up to 24 hours in the vial.AdministrationSTEP 1: Injecting ZYPADHERAThis table confirms the final ZYPADHERA suspension volume to inject. Suspension concentration is 150 mg/ml olanzapine.
|Dose (mg)||Final volume to inject (ml)|
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