Presentation and Status in Health Basket
1, 3 X 300 mg
1, 3 X 400 mg
For patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior to initiating treatment. The recommended starting and maintenance dose is 400 mg. Titration of the dose of this medicinal product is not required. It should be administered once monthly as a single injection (no sooner than 26 days after the previous injection). After the first injection, treatment with 10 mg to 20 mg oral aripiprazole should be continued for 14 consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy. If there are adverse reactions with the 400 mg dosage, reduction of the dose to 300 mg once monthly should be considered.
See prescribing information for full details.
Elderly patients: The safety and efficacy in the treatment of schizophrenia in patients 65 years of age or older has not been established.
Renal impairment: No dosage adjustment is required for patients with renal impairment.
Hepatic impairment: No dosage adjustment is required for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients requiring cautious dosing, oral formulation should be preferred.
Known CYP2D6 poor metabolizers: In patients who are known to be CYP2D6 poor metabolizers, the starting and maintenance dose should be 300 mg. When used concomitantly with strong CYP3A4 inhibitors the dose should be reduced to 200 mg.
Dose adjustments due to interactions: Dosage adjustments should be done in patients taking concomitant strong CYP3A4 inhibitors or strong CYP2D6 inhibitors for more than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the dosage may need to be increased to the previous dose. In case of adverse reactions despite dose adjustments of aripiprazole, the necessity of concomitant use of CYP2D6 or CYP3A4 inhibitor should be reassessed. Concomitant use of CYP3A4 inducers with aripiprazole should be avoided for more than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels.
Dose adjustments of aripiprazole in patients who are taking concomitant strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4 inducers for more than 14 days: See prescribing information for full details.
Paediatric population: The safety and efficacy of aripiprazole in children and adolescents aged 0-17 years have not been established. No data are available.
Method of administration: This product is only intended for intramuscular use and should not be administered intravenously or subcutaneously. It should only be administered by a healthcare professional. Powder and solvent for prolonged-release suspension for injection .The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 4 hours in the vial. Powder and solvent for prolonged-release suspension for injection in pre-filled syringe: The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 2 hours in the syringe. The suspension should be injected slowly as a single injection (doses must not be divided) into the gluteal or deltoid muscle. Care should be taken to avoid inadvertent injection into a blood vessel.
Gluteal muscle administration: The recommended needle for gluteal administration is a 38 mm (1.5 inch), 22 gauge hypodermic safety needle. For obese patients (Body mass index > 28 kg/m2), a 50 mm (2 inch), 21 gauge hypodermic safety needle should be used. Gluteal injections should be alternated between the two gluteal muscles.
Deltoid muscle administration: The recommended needle for deltoid administration is a 25 mm (1 inch), 23 gauge hypodermic safety needle. For obese patients, a 38 mm (1.5 inch), 22 gauge hypodermic safety needle should be used. Deltoid injections should be alternated between the two deltoid muscles. The powder and solvent vials and the pre-filled syringe are for single-use only. Full instructions for use and handling of this product are provided in the package leaflet (information intended for healthcare professionals).
For maintenance treatment of schizophrenia in adult patients stabilised with oral aripiprazole.
Hypersensitivity to the active substance or to any of the excipients.
During antipsychotic treatment, improvement in the patient’s clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period. Use in patients who are in an acutely agitated or severely psychotic state. This product should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.
Suicidality: The occurrence of suicidal behaviour is inherent in psychotic illnesses, and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole. Close supervision of high risk patients should accompany antipsychotic treatment.
Cardiovascular disorders: Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with this product and preventive measures undertaken.
QT prolongation: In clinical trials of treatment with oral aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation.
Tardive dyskinesia: In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on this product, dose reduction or discontinuation of should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.
Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex associated with antipsychotic medicinal products. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. 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. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicinal products, including aripiprazole, must be discontinued.
Seizure: In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.
Elderly patients with dementia-related psychosis
Increased mortality: In three placebo-controlled trials of oral aripiprazole in elderly patients with psychosis associated with Alzheimer’s disease (n = 938; mean age: 82.4 years; range: 56-99 years), patients treated with aripiprazole are at an increased risk of death compared to placebo. The rate of death in oral aripiprazole-treated patients was 3.5 % compared to 1.7 % in the placebo group. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature.
Cerebrovascular adverse reactions: In the same trials with oral aripiprazole, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78-88 years). Overall, 1.3 % of oral aripiprazole-treated patients reported cerebrovascular adverse reactions compared with 0.6 % of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse reactions in patients treated with aripiprazole. This product is not indicated for the treatment of patients with dementia-related psychosis.
Hyperglycaemia and diabetes mellitus: Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic medicines, including aripiprazole. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotic medicines are not available to allow direct comparisons. Patients treated with any antipsychotic medicinal products, including aripiprazole, 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.
Hypersensitivity: Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole.
Weight gain: Weight gain is commonly seen in schizophrenic patients due to use of antipsychotics known to cause weight gain, co-morbidities, poorly managed life-style and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed oral aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain.
Dysphagia: Oesophageal dysmotility and aspiration have been associated with antipsychotic medicinal product use, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.
Pathological gambling: Post-marketing reports of pathological gambling have been reported among patients prescribed oral aripiprazole, regardless of whether these patients had a prior history of gambling. Patients with a prior history of pathological gambling may be at increased risk and should be monitored carefully.
Serious impulse-control problems: Serious impulse-control problems, particularly pathological gambling, have been reported in patients treated with aripiprazole. These uncontrollable urges were reported to have stopped when the dose was reduced or the medicine was discontinued. Other uncontrollable urges reported less frequently (post marketing) than gambling include compulsive sexual behaviors, compulsive spending or shopping, binge or compulsive eating, and other urges with impulsive and compulsive features. Patients and caregivers should be informed of the possibility of these uncontrollable urges when prescribing aripiprazole, and patients should be asked about any new or increasing urges while they are being treated with aripiprazole. Patients should be advised to talk with their health care professional right away, if they experience new or increasing impulsive or compulsive behaviors, while on treatment. Lowering the dose or stopping aripiprazole should be considered, if a patient develops new or increased impulsive or compulsive behaviors.
The most frequently observed adverse drug reactions (ADRs) reported in ≥ 5 % of patients in two double-blind controlled clinical trials of this product were weight increased (9.0 %), akathisia (7.9 %), insomnia (5.8 %), and injection site pain (5.1 %).
See prescribing information for full details.
No specific interaction studies have been performed with this product. The information below is obtained from studies with oral aripiprazole. Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products. Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is administered in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation. If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used.
Potential for other medicinal products to affect this product: Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes, but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers.
Quinidine and other strong CYP2D6 inhibitors: In a clinical trial of oral aripiprazole in healthy subjects, a strong inhibitor of CYP2D6 (quinidine) increased aripiprazole AUC by 107 %, while Cmax was unchanged. The AUC and Cmax of dehydro-aripiprazole, the active metabolite, decreased by 32 % and 47 %, respectively. Other strong inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reduction should, therefore, be applied.
Ketoconazole and other strong CYP3A4 inhibitors: In a clinical trial of oral aripiprazole in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole) increased aripiprazole AUC and Cmax by 63 % and 37 %, respectively. The AUC and Cmax of dehydro-aripiprazole increased by 77 % and 43 %, respectively. In CYP2D6 poor metabolisers, concomitant use of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolisers. When considering concomitant administration of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. Other strong inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors may be expected to have similar effects and similar dose reductions should, therefore, be applied. Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage should be increased to the dose prior to the initiation of the concomitant therapy. When weak inhibitors of CYP3A4 (e.g., diltiazem) or CYP2D6 (e.g., escitalopram) are used concomitantly with this medicinal product, modest increases in plasma aripiprazole concentrations may be expected.
Carbamazepine and other CYP3A4 inducers: Following concomitant administration of carbamazepine, a strong inducer of CYP3A4, and oral aripiprazole to patients with schizophrenia or schizoaffective disorder, the geometric means of Cmax and AUC for aripiprazole were 68 % and 73 % lower, respectively, compared to when oral aripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of Cmax and AUC after carbamazepine co-administration were 69 % and 71 % lower, respectively, than those following treatment with oral aripiprazole alone. Concomitant administration of aripiprazole and other inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John’s Wort) may be expected to have similar effects. The concomitant use of CYP3A4 inducers with aripiprazole should be avoided because the blood levels of aripiprazole are decreased and may be below the effective levels.
Valproate and lithium: When either valproate or lithium was administered concomitantly with aripiprazole, there was no clinically significant change in aripiprazole concentrations, and, therefore, no dose adjustment is necessary when either valproate or lithium is administered with this product.
Potential for this product to affect other medicinal products: In clinical studies, oral doses of 10-30 mg/day of aripiprazole had no significant effect on the metabolism of substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), 2C9 (warfarin), 2C19 (omeprazole), and 3A4 (dextromethorphan). Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. Thus, this product is unlikely to cause clinically important medicinal product interactions mediated by these enzymes. When aripiprazole was administered concomitantly with lamotrigine, dextromethorphan, warfarin, omeprazole, escitalopram, or venlafaxine there was no clinically important change in concentrations of these medicinal products. Thus, no dosage adjustment of these medicinal products is required when co-administered with this product.
Serotonin syndrome: Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as SSRI/SNRI, or with medicinal products that are known to increase aripiprazole concentrations.
Pregnancy and Lactation
Pregnancy: There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Patients must be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with this product. Due to insufficient safety information in humans and concerns raised by animal reproductive studies, this medicinal product should not be used in pregnancy unless the expected benefit clearly justifies the potential risk to the foetus. Prescribers need to be aware of the long-acting properties of this product. New-born infants exposed to antipsychotics (including aripiprazole) 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, new-born infants should be monitored carefully.
Lactation: Aripiprazole is excreted in human breast milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from aripiprazole therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
No cases of overdose associated with adverse reactions were reported in clinical studies with aripiprazole. Care must be taken to avoid inadvertent injection of this medicinal product into a blood vessel. Following any confirmed or suspected accidental overdose/inadvertent intravenous administration, close observation of the patient is needed and if any potentially medically serious sign or symptom develops, monitoring, which should include continuous electrocardiographic monitoring, is required. The medical supervision and monitoring should continue until the patient recovers. A simulation of dose dumping showed that the predicted median aripiprazole concentration reaches a peak of 4500 ng/ml or approximately 9 times the upper therapeutic range. In case of dose dumping, aripiprazole concentrations are predicted to descend rapidly to the upper limit of the therapeutic window after approximately 3 days. By the 7th day, the median aripiprazole concentrations further decline to concentrations following an IM depot dose with no dose dumping. While overdose is less likely with parenteral than oral medicinal products, reference information for oral aripiprazole overdose is presented below.
Signs and symptoms: In clinical trials and post-marketing experience, accidental or intentional acute overdose of aripiprazole alone was identified in adult patients with reported estimated doses up to 1,260 mg (41 times highest recommended daily aripiprazole dose) with no fatalities. The potentially medically important signs and symptoms observed included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental overdose with aripiprazole alone (up to 195 mg) in children have been received with no fatalities. The potentially medically serious signs and symptoms reported included somnolence, transient loss of consciousness and extrapyramidal symptoms.
Management of overdose: Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinal product involvement should be considered. Therefore, cardiovascular monitoring should be started immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Following any confirmed or suspected overdose with aripiprazole, close medical supervision and monitoring should continue until the patient recovers.
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 highly bound to plasma proteins.
Effects on ability to drive and use machines: Aripiprazole can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred, diplopia. Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to this medicinal product is known.
Fertility: Aripiprazole did not impair fertility based on data from reproductive toxicity studies.
Shelf life After reconstitution: Powder and solvent for prolonged-release suspension for injection: Chemical and physical in-use stability has been demonstrated for 4 hours at 25°C. From a microbiological point of view, unless the method of opening/reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of user. Shake the vial vigorously for at least 60 seconds to re-suspend prior to injection. Do not store the reconstituted suspension in the syringe. Powder and solvent for prolonged-release suspension for injection in pre-filled syringe. If the injection is not performed immediately after reconstitution, the syringe can be kept below 25 °C for up to 2 hours. Shake the syringe vigorously for at least 20 seconds to re-suspend prior to injection if the syringe has been left for more than 15 minutes
Special precautions for storage: Do not freeze. Keep the syringe in the outer carton in order to protect from light.