Boxed Warnings
Warning. The potential for signs and symptoms of sedation and/or delirium consistent with olanzapine overdose exists after every injection of Zyprexa Relprevv. Zyprexa Relprevv should be administered by appropriately qualified health professionals in a healthcare facility with access to emergency services for management of olanzapine overdose. Healthcare professionals who prescribe or administer Zyprexa Relprevv should be aware of this potential risk and the consequent need to monitor patients for at least two hours after each injection. The two hour period should be extended as clinically appropriate for patients who exhibit any potential signs or symptoms of a post-injection syndrome event. See Section 4.4 Special Warnings and Precautions for Use, Post-injection syndrome.
1 Name of Medicine
Zyprexa Relprevv (olanzapine pamoate monohydrate - alternatively named olanzapine embonate monohydrate).
2 Qualitative and Quantitative Composition
Olanzapine pamoate monohydrate, equivalent to olanzapine 210 mg.
Olanzapine pamoate monohydrate, equivalent to olanzapine 300 mg.
Olanzapine pamoate monohydrate, equivalent to olanzapine 405 mg.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Zyprexa Relprevv 210 mg, 300 mg and 405 mg is available in a Type I cerium oxide vial. One carton provides a kit containing 1 vial of olanzapine pamoate monohydrate, one vial of sterile diluent, one 3 mL syringe with pre-attached 19-gauge 38 mm Hypodermic Needle-Pro safety needle, one 19-gauge 38 mm Hypodermic Needle-Pro safety needle and two 19-gauge 50 mm Hypodermic Needle-Pro safety needles.
4 Clinical Particulars
4.9 Overdose
If signs and symptoms of overdose consistent with inadvertent intravascular administration are observed appropriate supportive measures should be instituted (see Section 4.4 Special Warnings and Precautions for Use, Post-injection syndrome). Although overdose is less likely with this parenteral preparation that is administered by a healthcare professional, reference information for oral olanzapine overdose is presented below.
Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions and salivation. In dogs, olanzapine caused sedation, ataxia, tremors, tachycardia, laboured respiration, miosis and anorexia. In monkeys, prostration and semi-consciousness were observed.
Signs and symptoms. Very common symptoms (≥ 10% incidence) reported in Zyprexa overdose include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms and reduced level of consciousness ranging from sedation to coma.
Other medically significant sequelae of Zyprexa overdose include delirium, convulsion, 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 overdoses as low as 450 mg but survival has also been reported following acute overdose of 2 g.
Management of overdose. There is no specific antidote to Zyprexa. Induction of emesis is not recommended. Standard procedures for management of overdose may be indicated. The possibility of multiple drug involvement should be considered.
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. The use of activated charcoal for overdose should be considered because the concomitant administration of activated charcoal was shown to reduce the oral bioavailability of olanzapine by 50% to 60%. In patients who are not fully conscious or who have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. Olanzapine is not substantially removed by haemodialysis.
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. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents such as noradrenaline. Adrenaline, dopamine or other sympathomimetic agents should not be used since beta stimulation may worsen hypotension in the setting of alpha blockade induced by Zyprexa. Cardiovascular monitoring should be considered to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers.
Contact the Poisons Information Centre in Australia (telephone 13 11 26) or the National Poisons Centre in New Zealand (telephone 0800 POISON or 0800 764 766) for advice on management of overdose with Zyprexa or Zyprexa Relprevv.
5 Pharmacological Properties
5.3 Preclinical Safety Data
Genotoxicity. Olanzapine was not genotoxic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo tests. Pamoic acid was positive in an in vitro chromosome aberration assay but negative in a range of other in vitro and in vivo tests, with the weight of evidence indicating that it does not represent a genotoxic liability at the proposed clinical dose.
Carcinogenicity. Carcinogenicity studies with olanzapine showed the development of mammary adenocarcinomas at oral doses of 2 mg/kg/day or greater in mice and 2.5 mg/kg/day or greater in rats (similar to or less than the maximum recommended clinical oral dose, based on mg/m2. The respective no-effect doses were 0.5 and 1 mg/kg/day (less than the maximum recommended clinical oral dose). Monthly intramuscular administration of olanzapine pamoate monohydrate to rats at doses up to 20 mg/kg (males) or 50 mg/kg (females) for 2 years was not associated with tumour formation, although rat exposures (plasma AUC) to pamoic acid and olanzapine were similar to and less than the respective exposures to pamoic acid and olanzapine at the maximum recommended clinical dose of Zyprexa Relprevv.
The increased incidence of mammary tumours may be due to an endocrine mechanism, possibly involving elevation of circulating prolactin levels in response to the dopamine D2-receptor antagonistic activity of olanzapine. Mammary tumours are known to occur in rats and mice treated with other drugs that antagonise dopamine D2-receptors. Neither clinical studies nor epidemiological studies, conducted to date, have shown an association between these drugs and carcinogenesis, but the available evidence is considered too limited to be conclusive at this time. The use of Zyprexa Relprevv in patients with familial history or previously detected breast cancer should be avoided. Caution should also be exercised when considering Zyprexa Relprevv treatment in patients with pituitary tumours.
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Chemical structure. Chemically, olanzapine pamoate monohydrate is 10H-thieno[2,3-b][1,5]benzodiazepine, 2-methyl-4-(4-methyl-1-piperazinyl)- 4,4'-methylenebis [3-hydroxy-2-naphthalene-carboxylate] (1:1) monohydrate. The formula is C17H22N4SC23H14O6H2O. Olanzapine pamoate monohydrate is a yellow solid that is practically insoluble in water with a molecular weight of 718.8.
Olanzapine pamoate monohydrate has the following structural formula:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSOLAPAM.gif CAS number. The CAS number for olanzapine pamoate monohydrate is 221373-18-8.
7 Medicine Schedule (Poisons Standard)
S4 - Prescription only Medicine.
Summary Table of Changes
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/ZYPRELST.gif
