ARISTADA® (aripiprazole lauroxil) extended-release injectable suspension

ARISTADA® (aripiprazole lauroxil) extended-release injectable suspension

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ARISTADA® (aripiprazole lauroxil)

ARISTADA contains aripiprazole lauroxil, an atypical antipsychotic.

The chemical name of aripiprazole lauroxil is 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1- yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin-1-yl)methyl dodecanoate. The empirical formula is C36H51Cl2N3O4 and its molecular weight is 660.7 g/mol.

ARISTADA is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in the following strengths of aripiprazole lauroxil (and deliverable volumes from a single-use pre-filled syringe): 441 mg (1.6 mL), 662 mg (2.4 mL), 882 mg (3.2 mL) and 1064 mg (3.9 mL). The inactive ingredients include sorbitan monolaurate (3.8 mg/mL), polysorbate 20 (1.5 mg/mL), sodium chloride (6.1 mg/mL), sodium phosphate dibasic anhydrous, sodium phosphate monobasic and water for injection.

Indications and usage

ARISTADA is an atypical antipsychotic indicated for the treatment of schizophrenia

Mechanism of Action

Aripiprazole lauroxil is a prodrug of aripiprazole. Following intramuscular injection, aripiprazole lauroxil is likely converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole. The mechanism of action of aripiprazole in schizophrenia is unknown. However, efficacy could be mediated through a combination of partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors.

Dosage and administration

  • To be administered by intramuscular injection in the deltoid (441 mg dose only) or gluteal (441 mg, 662 mg, 882 mg or 1064 mg) muscle by a healthcare professional.
  • For patients naïve to aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA.
  • In conjunction with the first ARISTADA injection, administer treatment with oral aripiprazole for 21 consecutive days for 441 mg, 662 mg, 882 mg, and 1064 mg.
  • ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg dose every 6 weeks, or 1064 mg dose every 2 months.
  • Dosing regimen adjustments may be required for missed doses.
  • Dose adjustments are required for 1) known CYP2D6 poor metabolizers and 2) for patients taking CYP3A4 inhibitors, CYP2D6 inhibitors, or CYP3A4 inducers for more than 2 weeks.

Contraindications

ARISTADA is contraindicated in patients with a known hypersensitivity reaction to aripiprazole. Hypersensitivity reactions have ranged from pruritus/urticaria to anaphylaxis

Warnings and precautions

Increased Mortality in Elderly Patients with Dementia-related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Cerebrovascular Adverse Reactions, Including Stroke: In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated patients. ARISTADA is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome: A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur in association with antipsychotic drugs, including ARISTADA. 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.

Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

If signs and symptoms of tardive dyskinesia appear in a patient treated with ARISTADA drug discontinuation should be considered. However, some patients may require treatment with ARISTADA despite the presence of the syndrome.

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia/ Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with oral aripiprazole. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Orthostatic Hypotension: Aripiprazole may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions related to orthostatic hypotension can include dizziness, lightheadedness and tachycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose, and monitor orthostatic vital signs.

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Falls: Antipsychotics including ARISTADA may cause somnolence, postural hypotension, or motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for those patients on long-term antipsychotic therapy.

Potential for Cognitive and Motor Impairment: ARISTADA, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with ARISTADA does not affect them adversely.

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. ARISTADA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Adverse reactions

Most commonly observed adverse reaction with ARISTADA (incidence ≥5% and at least twice that for placebo) was akathisia

Drug interactions

Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine): The concomitant use of oral aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of oral aripiprazole alone. With concomitant use of ARISTADA with a strong CYP3A4 inhibitor or CYP2D6 inhibitor for more than 2 weeks reduce the ARISTADA dose

Strong CYP3A4 Inducer (e.g., aripiprazole and carbamazepine, rifampin): The concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of oral aripiprazole alone. With concomitant use of ARISTADA with a strong CYP3A4 inducer for more than 2 weeks consider increasing the ARISTADA dose.

Antihypertensive Drugs: Due its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly.

Benzodiazepines (e.g., lorazepam): The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone. Monitor sedation and blood pressure. Adjust dose accordingly.

Use in specific populations

Pregnancy: Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Limited published data on aripiprazole use in pregnant women are not sufficient to inform any drug-associated risks for birth defects or miscarriage.

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recover within hours or days without specific treatment; others required prolonged hospitalization.

Lactation: Aripiprazole is present in human breast milk; however, there are insufficient data to assess the amount in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ARISTADA and any potential adverse effects on the breastfed infant from ARISTADA or from the underlying maternal condition.

Pediatric Use: Safety and effectiveness of ARISTADA in patients <18 years of age have not been evaluated.

Geriatric Use: Safety and effectiveness of ARISTADA in patients >65 years of age have not been evaluated.

CYP2D6 Poor Metabolizers: Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM).

Hepatic and Renal Impairment: No dosage adjustment for ARISTADA is required based on a patient’s hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute).

Overdosage

The largest known case of acute ingestion with a known outcome involved 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) in a patient who fully recovered.

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

Storage

Store at room temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (between 59°F and 86°F).

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