Abilify Maintena

ABILIFY MAINTENA (Powder and Solution for Prolonged-Release Suspension for Injection, 400 mg)

Abilify Maintena is intended for the maintenance treatment of schizophrenia in adult patients who have been stabilized with oral aripiprazole.

Contraindications

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

Dosage

For patients who have never taken aripiprazole before, tolerance to oral aripiprazole must be established before initiating treatment with Abilify Maintena.

No dose titration is required for Abilify Maintena.

Initial dosing options

• Single injection start:

On the first day, administer one injection of Abilify Maintena 400 mg. Continue treatment with 10 to 20 mg oral aripiprazole daily for 14 consecutive days to maintain therapeutic aripiprazole concentrations during treatment initiation.

• Two injection start:

On the first day, administer two separate injections of Abilify Maintena 400 mg at two different injection sites along with a 20 mg dose of oral aripiprazole.

Maintenance dose

The recommended maintenance dose after the initial injection is 400 mg. Abilify Maintena 400 mg should be administered once per month as a single-dose injection (no sooner than 26 days after the previous injection). If the 400 mg dose causes side effects, consider reducing the dose to 300 mg once per month.

What if I miss a dose?

Content summary

Here is a table summarizing the active ingredients and composition:

Additional ingredients (Excipients)

Powder:

• Carmellose sodium
• Mannitol (E421)
• Sodium dihydrogen phosphate monohydrate (E339)
• Sodium hydroxide (E524)

Liquid:

• Water for injection

Shelf life

• 3 years from the date of manufacture.

Storage after preparation

(300 mg/400 mg) – Vial Form

• Should be injected immediately after preparation.
• Can be stored in the vial for up to 4 hours at below 25°C.

(300 mg/400 mg) – Pre-filled Syringe

• Should be injected immediately after preparation.
• Can be stored in the syringe for up to 2 hours at below 25°C.

Special storage instructions

• Do not freeze.
• Pre-filled syringes must be stored in their original packaging to protect from light.

Instructions for use and disposal

Preparation and mixing

For Vial (Powder & Liquid Form):

• Shake the vial vigorously for at least 30 seconds until the suspension looks uniform.
• If not injected immediately, shake the vial again for at least 60 seconds before use.

For Pre-filled Syringe:

• Shake the syringe vertically for 20 seconds until the suspension appears milky white.
• If not injected immediately, store for a maximum of 2 hours at below 25°C.
• Shake for at least 20 seconds before use if left unused for more than 15 minutes.

Administration method

• Intramuscular use only:

Solution 400 mg and 300 mg are intended for intramuscular use only and should not be administered intravenously or subcutaneously.

• Administered by healthcare professionals only:

• The injection must be given by a healthcare provider.
• The suspension must be injected slowly as a single-dose injection (doses should not be split) into the gluteal muscle or deltoid muscle.
• Care must be taken to avoid accidental injection into a blood vessel.
• If initiating treatment with two injections, the medication should be administered at two different sites in two separate muscles. DO NOT inject both doses into the same deltoid or gluteal muscle simultaneously.
• For patients known to be slow CYP2D6 metabolizers, inject either into two separate deltoid muscles or into one deltoid muscle and one gluteal muscle. DO NOT inject into two gluteal muscles.

Injection guidelines

Gluteal muscle injection

• Standard needle: 38 mm, 22-gauge.
• For overweight patients (BMI > 28 kg/m²): 51 mm, 21-gauge.
• Alternate injection sites between the left and right gluteal muscles.

Deltoid muscle injection

• Standard needle: 25 mm, 23-gauge.
• For overweight patients: 38 mm, 22-gauge.
• Alternate injection sites between the left and right deltoid muscles.

Warnings and precautions

• Monitoring During Treatment: Antipsychotic treatment may take several days to weeks before the patient’s clinical condition improves. Patients should be closely monitored throughout this period.
• Use in Agitated or Severely Psychotic Patients: Abilify Maintena 400 mg/300 mg should not be used for treating acutely agitated or severely psychotic patients when immediate symptom control is required.

Risks

Suicidal behavior is part of the clinical picture of psychotic disorders and has, in some cases, been reported shortly after initiating or switching antipsychotic treatment, including treatment with aripiprazole. High-risk patients must be closely monitored during antipsychotic treatment.

Cardiovascular conditions

Aripiprazole should be used with caution in patients with known cardiovascular disease (history of heart attack, ischemic heart disease, heart failure, or conduction disorders), cerebrovascular disease, conditions that may predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive drugs), or hypertension, including accelerated or malignant hypertension.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medications. Since patients treated with antipsychotics often have acquired risk factors for VTE, all possible risk factors should be identified before and during treatment with aripiprazole, and preventive measures should be taken.

QT prolongation

In clinical studies of oral aripiprazole treatment, 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 studies up to one year, uncommon cases of dyskinesia were reported during treatment with aripiprazole. If signs or symptoms of tardive dyskinesia appear in a patient treated with aripiprazole, dose reduction or discontinuation of the drug should be considered. These symptoms may temporarily worsen or even appear after discontinuation of treatment.

Neuroleptic malignant syndrome (NMS)

NMS is a potentially life-threatening syndrome associated with antipsychotic use. Rare cases of NMS have been reported during treatment with aripiprazole in clinical studies.

Clinical manifestations of NMS include hyperthermia, muscle rigidity, altered mental status, and signs of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias).

Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Elevated creatine phosphokinase and rhabdomyolysis, not necessarily associated with NMS, have also been reported.

If a patient develops signs or symptoms indicative of NMS, or experiences unexplained high fever without other clinical manifestations of NMS, all antipsychotics, including aripiprazole, should be discontinued.

Seizures

Uncommon cases of seizures were reported during clinical studies of aripiprazole treatment. Therefore, aripiprazole must be used with caution in patients with a history of seizures or conditions associated with seizures.

Elderly patients with dementia-related psychosis

Increased mortality

Elderly patients with psychosis associated with Alzheimer’s disease who were treated with aripiprazole were found to have an increased risk of death compared to placebo. Results from three placebo-controlled studies (n = 938; average age: 82.4 years; range: 56 to 99 years) showed that the incidence of death in patients treated with oral aripiprazole was 3.5%, compared to 1.7% in the placebo group. Although the causes of death varied, most deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia).

Cerebrovascular adverse events

In the aforementioned studies with oral aripiprazole, cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (average age: 84 years; range: 78 to 88 years). In these studies, a total of 1.3% of patients reported cerebrovascular adverse events while on oral aripiprazole, compared to 0.6% of placebo-treated patients. This difference was not statistically significant. However, in one of these studies, a fixed-dose study, a significant dose-response relationship for cerebrovascular adverse events was observed in patients treated with aripiprazole.

Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with aripiprazole. Risk factors that may predispose patients to severe complications include obesity and a family history of diabetes. Patients treated with aripiprazole should be observant for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes mellitus, or risk factors for diabetes, should be regularly monitored for deteriorating glucose control.

Hypersensitivity

Hypersensitivity reactions, characterized by allergic symptoms, may occur with aripiprazole.

Weight gain

Weight gain is often observed in patients with schizophrenia, which may be due to the use of antipsychotics known to cause weight gain, comorbid conditions, or poor lifestyle habits, potentially leading to severe complications. Weight gain has been reported post-marketing in patients prescribed oral aripiprazole.

When weight gain occurs, it is typically in patients with pronounced risk factors, such as a history of diabetes, thyroid disorders, or pituitary adenomas. In clinical studies, aripiprazole has not been shown to induce clinically relevant weight gain.

Dysphagia

Esophageal dysmotility and aspiration have been linked to the use of aripiprazole. Medicine should be used with caution in patients at risk for aspiration pneumonia.

Other impulse control disorders

Patients may experience increased urges, particularly related to gambling, and an inability to control these impulses while taking aripiprazole. Other reported urges include increased sexual drive, compulsive shopping, binge eating, or compulsive eating, as well as other impulsive or compulsive behaviors.

It is important that prescribers specifically ask patients or their caregivers about the development of new or increased urges for gambling, sexual drive, compulsive shopping, binge eating, or compulsive eating, or other urges during aripiprazole treatment.

Note that impulse control symptoms may be related to the underlying disorder, although in some cases, these urges have been reported to subside after dose reduction or discontinuation of the drug. If undetected, impulse control disorders may cause harm to the patient or others. Dose reduction or discontinuation of the medication should be considered if the patient develops such urges.

Falls

Aripiprazole may cause drowsiness, orthostatic hypotension, and motor and sensory instability, which may lead to falls. Caution should be exercised when treating high-risk patients, where a lower starting dose should be considered (e.g., for elderly or debilitated patients.

Interactions with other drugs

No interaction studies have been conducted with Abilify Maintena. The information below is based on studies of oral aripiprazole.

Potential of other drugs to affect aripiprazole

When discontinuing CYP2D6 or CYP3A4 inhibitors, the dose of aripiprazole should be increased to the pre-combination dose. Moderate increases in aripiprazole plasma concentrations are expected when combined with weak CYP3A4 (e.g., diltiazem) or weak CYP2D6 inhibitors (e.g., escitalopram).

Serotonin syndrome

Cases of serotonin syndrome have been reported in patients taking aripiprazole. Possible signs and symptoms of this condition may occur, especially when used concomitantly with other serotonergic medications, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), or medications known to increase aripiprazole concentrations.

Women of childbearing potential

Plasma exposure to aripiprazole after a single dose of Abilify Maintena is expected to persist for up to 34 weeks. This should be considered when initiating treatment in women of childbearing potential regarding potential future pregnancy or breastfeeding. Abilify Maintena should only be used in women planning pregnancy if absolutely necessary.

Gestation

There are no adequate and well-controlled studies of aripiprazole in pregnant women. Congenital malformations have been reported. However, a causal relationship with aripiprazole has not been established. Animal studies cannot rule out potential toxic effects on fetal development. Patients should be advised to inform their doctor if they become pregnant or plan to become pregnant while taking aripiprazole.

Newborns exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse effects, including extrapyramidal symptoms and/or withdrawal symptoms after birth, which may vary in severity and duration. Reported symptoms include agitation, hypertension, hypotension, tremor, somnolence, respiratory distress, or feeding problems. Therefore, newborns should be closely monitored.

Maternal exposure to Abilify Maintena before and during pregnancy may result in adverse effects in the newborn. Abilify Maintena should not be used during pregnancy unless absolutely necessary.

Breastfeeding

Aripiprazole/metabolites are excreted into breast milk in amounts likely to affect the newborn/infant if Abilify Maintena is administered to breastfeeding women. Since a single dose of Abilify Maintena is expected to persist in plasma for up to 34 weeks, breastfed infants may be at risk even if medicine was administered long before breastfeeding began. Patients already undergoing treatment or who have received treatment within the past 34 weeks should not breastfeed.

Fertility

Aripiprazole did not impair fertility based on reproductive toxicology studies.

Driving and machine operation

Aripiprazole has minor to moderate effects on the ability to drive and operate machines due to potential effects on the nervous system and vision, such as sedation, somnolence, syncope, blurred vision, and diplopia.

Neutropenia

Neutropenia has been reported in the clinical program for Abilify Maintena 400 mg/300 mg. It typically appeared on day 16 after the first injection and had a median duration of 18 days.

Extrapyramidal symptoms (EPS)

In studies on stable patients with schizophrenia, Abilify Maintena 400 mg/300 mg was associated with a higher frequency of EPS (18.4%) compared to oral aripiprazole (11.7%).

Akathisia was the most common symptom (8.2%). It typically appeared around day 10 after the first injection and had a median duration of 56 days. Patients with akathisia were usually treated with anticholinergic medications, primarily benzatropine mesylate and trihexyphenidyl. To a lesser extent, akathisia was treated with substances such as propranolol and benzodiazepines (clonazepam and diazepam).

Parkinsonism-type side effects were the second most common (6.9% for Abilify Maintena 400 mg/300 mg, 4.15% for oral aripiprazole [10 mg to 30 mg tablets], and 3.0% for placebo).

Dystonia

Symptoms of dystonia, i.e., prolonged abnormal muscle contractions, may occur in susceptible individuals during the first days of treatment. Symptoms of dystonia include spasms in the neck muscles, which in some cases develop into a feeling of tightness in the throat, difficulty swallowing and breathing, and/or tongue protrusion. While these symptoms can occur at low doses, they are more frequent and severe with high-potency drugs and higher doses of first-generation antipsychotics. An increased risk of acute dystonia has been observed in male patients and younger age groups.

Weight changes

Prolactin

In clinical studies for approved indications and post-marketing, both increases and decreases in serum prolactin relative to baseline were observed with aripiprazole.

Overdose

Pharmacokinetics

Absorption

• Aripiprazole absorption into the bloodstream is slow and prolonged after administration of Abilify Maintena 400 mg/300 mg, due to low solubility of aripiprazole particles.
• The mean absorption half-life of Abilify Maintena 400 mg/300 mg is 28 days.
• The relative bioavailability extended-release injection was 100% compared to the immediate-release intramuscular formulation.
• After a single-dose injection, peak plasma concentrations (Cmax) were higher when administered in the deltoid muscle compared to the gluteal muscle.

Distribution

• Aripiprazole is widely distributed throughout the body, with an apparent volume of distribution of 4.9 L/kg, indicating extensive extravascular distribution.
• More than 99% of aripiprazole and its active metabolite (dehydroaripiprazole) are bound to serum proteins, mainly albumin.

Metabolism

• Aripiprazole is primarily metabolized in the liver through three pathways:
  1. Dehydrogenation
  2. Hydroxylation (mediated by CYP3A4 and CYP2D6 enzymes)
  3. N-dealkylation (mediated by CYP3A4)
• Dehydroaripiprazole, the active metabolite, accounts for 29.1–32.5% of the total aripiprazole exposure (AUC).