1 Name of Medicine
Aripiprazole.
2 Qualitative and Quantitative Composition
Each Arizole tablet contains 2, 5, 10, 15, 20 and 30 mg aripiprazole.
List of excipients with known effects. Each tablet contains lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Arizole 2 mg tablets*. Green, coloured, modified rectangular shaped uncoated tablets debossed with '61' on one side and 'H' on other side.
Arizole 5 mg tablets. Blue coloured, modified rectangular shaped, uncoated tablets debossed with '62' on one side and 'H' on other side.
Arizole 10 mg tablets. White coloured, modified rectangular shaped, uncoated tablets debossed with '63' on one side and 'H' on other side.
Arizole 15 mg tablets. White coloured, round shaped, uncoated tablets debossed with '64' on one side and 'H' on other side.
Arizole 20 mg tablets. White coloured, round shaped, uncoated tablets debossed with '65' on one side and 'H' on other side.
Arizole 30 mg tablets. White coloured, round shaped, uncoated tablets debossed with '66' on one side and 'H' on other side.
* Not marketed in Australia.
4 Clinical Particulars
4.9 Overdose
Human experience. In clinical studies, and postmarketing experience accidental or intentional acute overdosage of aripiprazole alone was identified in adult patients with estimated doses up to 1260 mg with no fatalities. The potentially medically important signs and symptoms observed in adult patients who overdosed with aripiprazole alone at doses up to 1260 mg included lethargy, blood pressure increased, somnolence, tachycardia and vomiting. In addition, reports of accidental overdose with aripiprazole alone (up to 195 mg) in children have been received. The potentially medically serious signs and symptoms reported include somnolence, and transient loss of consciousness. In the patients who were evaluated in hospital settings, there were no reported observations indicating a clinically significant adverse change in vital signs, laboratory assessments, or ECG.
Management of overdose. No specific information is available on the treatment of overdose with aripiprazole. The possibility of multiple drug involvement should be considered. Therefore cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.
Charcoal. In the event of an overdose of aripiprazole, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. In a single-dose study in which 15 mg of aripiprazole was administered to fully compliant, fully conscious, healthy, male volunteers and followed by activated charcoal (50 g), administered one hour after aripiprazole, aripiprazole AUC and Cmax was decreased by 51 and 41%, respectively, compared to historic controls, suggesting that charcoal may be effective for overdose management.
Haemodialysis. Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management, since aripiprazole is not eliminated unchanged by the kidneys and is highly bound to plasma proteins.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.3 Preclinical Safety Data
Genotoxicity. Aripiprazole was tested in a standard range of assays for gene mutation, chromosomal damage, and DNA damage and repair. Aripiprazole was non-genotoxic in the in vitro bacterial reverse-mutation assay, the in vitro forward gene mutation assay in mouse lymphoma cells, in vitro bacterial DNA repair assay, and the unscheduled DNA synthesis assay in rat hepatocytes. However, aripiprazole and its minor metabolite 2,3-DCPP were clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells in both the presence and absence of metabolic activation. A positive response for aripiprazole in 1 of 6 in vivo mouse micronucleus tests was attributed to drug-induced hypothermia.
Carcinogenicity. Lifetime carcinogenicity studies were conducted in ICR mice and in Sprague-Dawley (SD) and Fischer (F344) rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2 to 5 and 0.3 to 3 times the maximum recommended human dose [MRHD] based on mg/m2, respectively). SD rats were dosed orally by gavage for 2 years at 10, 20, 40, and 60 mg/kg/day (3 to 18 times the MRHD based on mg/m2). There was no evidence of tumorigenesis in male mice or rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.1 to 0.9 times MRHD based on AUC and 0.5 to 5 times the MRHD based on mg/m2). In female rats the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (< 0.1 times MRHD based on AUC and 3 times the MRHD based on mg/m2); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral gavage dose of 60 mg/kg/day (10 times the MRHD based on AUC and 18 times MRHD based on mg/m2). In male rats, the incidence of benign and combined benign/malignant phaeochromocytomas were also increased at an oral gavage dose of 60 mg/kg/day (10 times the MRHD based on AUC and 18 times the MRHD based on mg/m2).
Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. Hyperprolactinaemia was observed in female mice in a 13-week dietary study at doses associated with mammary gland and pituitary tumours, but not in female rats in 4- and 13-week dietary studies at doses associated with mammary gland tumours. Hyperprolactinaemia was observed in female rats after 5 and 13 weeks of oral administration at doses up to that associated with adrenocortical tumours, but serum prolactin was decreased at this dose in male rats. The relationship between tumourigenic findings with aripiprazole and prolactin is unclear and the relevance for human risk of prolactin-mediated endocrine tumours is unknown. The adrenocortical response in female rats is considered a consequence of increased adrenocortical cell proliferation secondary to chronic drug-related adrenocortical cytotoxicity; the no-effect exposure (plasma AUC) was about fold 7 clinical exposure at the MRHD.
Animal toxicology. Choleliths (gallsand and/or gallstones) were observed in the bile of monkeys given aripiprazole orally for 4 - 52 weeks at doses of 25-125 mg/kg/day (1 - 3 times the MRHD based on plasma AUC and 15-76 times the MRHD based on mg/m2) and were attributed to precipitation of sulfate conjugates of hydroxy metabolites, which exceeded their solubility limits in bile. Human biliary concentrations of these sulfate conjugates after repeated daily administration of the MRHD are substantially lower (0.2 - 14% of their in vitro solubility limits).
Bilateral retinal degeneration was observed in albino rats given oral aripiprazole for 6 months or two years at exposures of 6-13 times the clinical exposure at the MRHD (based on plasma AUC). The exposure at the NOEL dose was 3 times that at the MRHD. A subsequent 18-month study reported this finding in albino but not pigmented rats, possibly due to lack of photoprotective ocular melanin in the albino rats, although it is unknown whether pigmentation prevented or merely delayed retinal degeneration in the pigmented rats. The clinical relevance of this finding is uncertain.
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Aripiprazole is a novel antipsychotic agent with unique pharmacologic properties and a chemical structure that differs from current antipsychotic agents. Since aripiprazole is insoluble in water with its equilibrium solubility being about 0.00001% w/v, its pKa was established in 20% aqueous ethanol pKa = 7.6 (20% ethanol, at 25°C). The partition coefficients (Po/w) of aripiprazole range from 3.4 at pH 2.0 to > 1000 at pH 6.0.
Chemical structure. The name of the medicine is aripiprazole.
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSARIPIP.gif Chemical name: 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one.
Molecular formula: C23H27Cl2N3O2. Molecular weight: 448.39.
CAS number. 129722-12-9.
7 Medicine Schedule (Poisons Standard)
S4 (Prescription Only Medicine).
Summary Table of Changes
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/ARIZOLST.gif
