Abilify Maintena Injection

Abilify Maintena is indicated for maintenance treatment of schizophrenia in adult patients stabilised with oral aripiprazole.

Posology
For patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior to initiating treatment with Abilify Maintena. If Abilify Maintena is to be discontinued, its prolonged release characteristics should be kept in mind. The recommended starting and maintenance dose of Abilify Maintena is 400 mg. Titration of the dose of Abilify Maintena 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 per day 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.

Missed doses
If 2nd or 3rd dose is missed and time since last injection is:
Action
> 4 weeks and < 5 weeks
The injection should be administered as soon as possible and then the monthly injection schedule should be resumed.
> 5 weeks
Concomitant oral aripiprazole should be restarted for 14 days with next administered injection.
If 4th or subsequent doses are missed (i.e., after attainment of steady state) and time since last injection is:
Action
> 4 weeks and < 6 weeks
The injection should be administered as soon as possible and then the monthly injection schedule should be resumed.
> 6 weeks
Concomitant oral aripiprazole should be restarted for 14 days with next administered injection and then resume monthly injection schedule.

Special populations
Elderly
The safety and efficacy of Abilify Maintena in the treatment of schizophrenia in patients 65 years of age or older has not been established (see section 4.4).
Renal impairment
No dosage adjustment is required for patients with renal impairment (see section 5.2).
Hepatic impairment
No dosage adjustment is required for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment (Child Pugh C), the data available are insufficient to establish recommendations. Oral formulation should be preferred (see section 5.2).
Known CYP2D6 poor metabolisers
In patients who are known to be CYP2D6 poor metabolisers, the starting and maintenance dose should be 300 mg. When used concomitantly with strong CYP3A4 inhibitors the dose should be reduced to 200 mg (see section 4.5).
Dose adjustments due to interactions with CYP2D6 and/or CYP3A4 inhibitors and/or CYP3A4 inducers
Dosage adjustments should be made 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 (see section 4.5). In case of adverse reactions despite dose adjustments of Abilify Maintena, the necessity of concomitant use of CYP2D6 or CYP3A4 inhibitor should be reassessed. Concomitant use of CYP3A4 inducers with Abilify Maintena should be avoided for more than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels (see section 4.5).

Paediatric population
The safety and efficacy of Abilify Maintena in children and adolescents aged < 18 years have not been established. No data are available.
Method of administration
Abilify Maintena is only intended for intramuscular use and should not be administered intravenously or subcutaneously. It should only be administered by a healthcare professional. 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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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
Abilify Maintena 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 (see section 4.8). Close supervision of high risk patients should accompany antipsychotic treatment.
Cardiovascular disorders
Abilify Maintena 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 medicines) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicines. 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 Abilify Maintena and preventive measures undertaken (see section 4.8).
QT prolongation
Abilify Maintena should be used with caution in patients with a family history of QT prolongation (see section 4.8).
Tardive dyskinesia
Tardive dyskinesia has been reported with treatment with Abilify Maintena. If signs and symptoms of tardive dyskinesia appear in a patient on Abilify Maintena, dose reduction or discontinuation should be considered (see section 4.8). These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.
Body Temperature Regulation Disorder
Disruption of the body`s ability to regulate core temperature has been reported with antipsychotics such as aripiprazole, which may increase the risk of hyperthermia and/or hypothermia.
Neuroleptic Malignant Syndrome (NMS)
NMS is a potentially fatal symptom complex associated with the use of antipsychotics. 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 antipsychotics, including Abilify Maintena, must be discontinued (see section 4.8).
Seizures
Seizures were reported during treatment with aripiprazole. Abilify Maintena should be used with caution in patients who have a history of seizure disorders or have conditions associated with seizures (see section 4.8).
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 were 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 placebo. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature (see section 4.8).
Cerebrovascular adverse events
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 a fixed-dose trial, there was a significant dose-response relationship for cerebrovascular adverse reactions in patients treated with aripiprazole (see section 4.8).
Abilify Maintena 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 aripiprazole. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. Patients treated with Abilify Maintena 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 (see section 4.8).
Hypersensitivity
Hypersensitivity reactions, characterised by allergic symptoms, may occur with Abilify Maintena (see section 4.8).
Weight gain
Weight gain is commonly seen in schizophrenic patients due to use of antipsychotics, including aripiprazole. Weight gain co-morbidities and poorly managed life-style might lead to severe complications. Weight gain has been reported in clinical trials with Abilify Maintena and 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 (see section 4.8).
Dysphagia
Oesophageal dysmotility and aspiration have been associated with the use of aripiprazole. Abilify Maintena should be used cautiously in patients at risk for aspiration pneumonia.
Pathological gambling and other impulse control disorders
Patients can experience increased urges, particularly for gambling, and the inability to control these urges while receiving Abilify Maintena. Other urges reported include: increased sexual urges, compulsive shopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with Abilify Maintena. It should be noted that impulse-control symptoms can be associated with the underlying disorder; however, in some cases, urges were reported to have stopped when the dose was reduced or aripiprazole was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. A dose reduction or stopping of Abilify Maintena should be considered if a patient develops such urges (see section 4.8).
Falls
Abilify Maintena may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls. Caution should be taken when treating patients at higher risk, and a lower starting dose should be considered (e.g., elderly or debilitated patients; see section 4.2).
Sodium
Abilify Maintena contains less than 1 mmol of sodium (23 mg) per dose.

No interaction studies have been performed with Abilify Maintena. The information below is obtained from studies with oral aripiprazole. Due to its u03b11-adrenergic receptor antagonism, Abilify Maintena has the potential to enhance the effect of certain antihypertensive medicines.
Given the primary central nervous system (CNS) effects of aripiprazole, caution should be used when Abilify Maintena is administered in combination with alcohol or other CNS medicines with overlapping adverse reactions such as sedation (see section 4.8). If Abilify Maintena is administered concomitantly with medicines known to cause QT prolongation or electrolyte imbalance, caution should be used.
Potential for other medicines to affect Abilify Maintena
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 C max was unchanged. The AUC and C max 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 (see section 4.2).
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 C max by 63 % and 37 %, respectively. The AUC and C max 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 (see section 4.2). 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 (see section 4.2). Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage of Abilify Maintena 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 Abilify Maintena, 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 C max 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 C max and AUC after carbamazepine co-administration were 69 % and 71 % lower, respectively, than those following treatment with oral aripiprazole alone. Concomitant administration of Abilify Maintena 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 Abilify Maintena should be avoided because the blood levels of aripiprazole are decreased and may be below the effective levels.
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 (see section 4.8).

Pregnancy
Safety of Abilify Maintena has not been established in pregnancy. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). Patients must be advised to notify their medical practitioner if they become pregnant or intend to become pregnant during treatment with Abilify Maintena. Prescribers need to be aware of the long-acting properties of Abilify Maintena. 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 (see section 4.8).
Breastfeeding
Aripiprazole is excreted in human milk. Women using Abilify Maintena must not breastfeed their infants.
Fertility
Aripiprazole did not impair fertility based on data from reproductive toxicity studies in animals.

Abilify Maintena may affect the ability to drive and use machines. Patients should not drive and use machines until they know how treatment with Abilify Maintena affects them. Abilify Maintena has potential nervous system and visual effects, such as dizziness, sedation, somnolence, syncope, vision blurred, diplopia and seizures (see section 4.8).

Summary of the safety profile
The most frequently observed adverse drug reactions (ADRs) reported in u2265 5 % of patients in two double-blind, long-term trials of Abilify Maintena were weight increased (9.0 %), akathisia (7.9 %), insomnia (5.8 %), and injection site pain (5.1 %).
Tabulated list of adverse reactions
The incidences of the ADRs associated with aripiprazole therapy are tabulated below. The table is based on adverse reactions reported during clinical trials and/or post-marketing use. All ADRs are listed by system organ class and frequency; very common (u2265 1/10), common (u2265 1/100 to < 1/10), uncommon (u2265 1/1 000 to < 1/100), rare (u2265 1/10 000 to < 1/1 000), very rare (< 1/10 000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

In overdose, adverse events can be precipitated and/or be of increased severity. See section 4.8. Care must be taken to avoid inadvertent injection of Abilify Maintena 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. Treatment is symptomatic and supportive. The medical supervision and monitoring should continue until the patient recovers.
Signs and symptoms after overdose with aripiprazole tablets as no information on overdose with Abilify Maintena is available: Medically important signs and symptoms observed with overdose included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea. Signs and symptoms reported in children included somnolence, transient loss of consciousness and extrapyramidal symptoms.
Management of overdose
Management of overdose should concentrate on symptomatic and supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. The possibility of multiple medicine involvement should be considered. Therefore, cardiovascular monitoring should be started immediately and should include continuous electrocardiographic monitoring to detect possible dysrhythmias. Following any confirmed or suspected overdose with Abilify Maintena, close medical supervision and monitoring should continue until the patient recovers.
Haemodialysis
Haemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.