Zypadhera

/ Eli Lilly

FOR INTRAMUSCULAR USE ONLY. DO NOT ADMINISTER INTRAVENOUSLY OR SUBCUTANEOUSLY.
This product should only be administered by deep intramuscular gluteal injection by a healthcare professional trained in the appropriate injection technique and in an authorized healthcare facility where post-injection observation and immediate access to emergency and resuscitation services in the case of overdose can be assured. 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. 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. Patients should be treated initially with oral olanzapine before administering this product, to establish tolerability and response. For Instructions for Use see  prescribing information. Do not confuse  210 mg, 300 mg, 405 mg powder and solvent for prolonged release suspension for injection with olanzapine 10 mg powder for solution for injection. In order to identify the first dose for all patients see prescribing information.

For the treatment of schizophrenia. Efficacy was established in two clinical trials in patients with schizophrenia.The product is available only through a restricted distribution program and must not be dispensed directly to a patient.The use is limited to patients who have been diagnosed as non-compliant regarding taking prescribed medicdbines and as a consequence are prone to outbursts of psychotic episodes. Should not be used in patients whose condition is adequately controlled with oral Zyprexa. For a patient to receive treatment, the prescriber, healthcare facility, patient, and pharmacy must all be enrolled in the ZypAdhera Patient Care Program, conducted by Lilly.

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

Special care must be taken to apply appropriate injection technique to avoid inadvertent intravascular or subcutaneous injection.
Use in patients who are in an acutely agitated or severely psychotic state: this product 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 Delirium/Sedation 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 this product. 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 this product is administered. Prior to giving the injection, the healthcare professional should determine that the patient will not travel alone to their destination. 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. 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. 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. 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.
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.
Dementia-related psychosis and/or behavioural disturbances: Olanzapine is not approved for the treatment of dementia-related psychosis and/or behavioural disturbances and is not recommended for use in this particular group of patients 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 preexisting 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, 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 antiParkinsonian 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 rarely, including some fatal cases. 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 agents, including this product, 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.
For full details see prescribing information.

Post-injection Delirium/Sedation syndrome reactions have occurred with this product leading to symptoms consistent with olanzapine overdose. 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 this product were similar to those seen with oral olanzapine. In clinical trials with this product, 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 treated patients, sedation was reported by 4.7% of patients. In clinical trials with this product 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.
The undesirable effects listed below have been observed following administration of oral olanzapine but may occur following administration of this product.
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, glucosuria, increased appetite, dizziness, akathisia, parkinsonism, dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases, rash, asthenia, fatigue and oedema.
For full details see prescribing information.

Paediatric population: 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.
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 nonsmokers 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 olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson’s disease and dementia is not recommended.
QTc interval: Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval.
For full details see prescribing information.

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. Neonates 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.

If signs and symptoms of overdose consistent with post injection Delirium/Sedation syndrome are observed, appropriate supportive measures should be taken. While overdose is less likely with parenteral than oral medicinal products, reference information for oral olanzapine overdose is presented below:
Signs & symptoms: Very 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.
Management: There 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.