Aripiprazole Lauroxil Extended-release Injection

ARISTADA contains aripiprazole lauroxil, an atypical antipsychotic.

The chemical name of aripiprazole lauroxil is 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1yl]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. The chemical structure is:

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.

The following are discussed in more details in other sections of the labeling:

• Increased Mortality in Elderly Patients with Dementia-related Psychosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
• Cerebrovascular Adverse Reactions, Including Stroke [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
• Neuroleptic Malignant Syndrome [see WARNINGS AND PRECAUTIONS]
• Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS]
• Metabolic Changes [see WARNINGS AND PRECAUTIONS]
• Pathological Gambling and Other Compulsive Behaviors [see WARNINGS AND PRECAUTIONS]
• Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS]
• Falls [see WARNINGS AND PRECAUTIONS]
• Leukopenia, Neutropenia, and Agranulocytosis [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS]
• Body Temperature Regulation [see WARNINGS AND PRECAUTIONS]
• Dysphagia [see WARNINGS AND PRECAUTIONS]

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

ARISTADA

ARISTADA has been evaluated for safety in 1019 adult patients in clinical trials in schizophrenia.

The most common adverse reaction (incidence ≥ 5% and at least twice the rate of placebo in patients treated with ARISTADA) was akathisia.

Adverse reactions associated with the use of ARISTADA (incidence of 2% or greater, rounded to the nearest percent and ARISTADA incidence greater than placebo) that occurred are shown in Table 8.

Table 8: Adverse Reaction in 2% or More of ARISTADA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trial

In an open label pharmacokinetic study, the adverse reactions associated with the use of 441 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months were similar across the dose groups.

Injection site reactions were reported by 4% of patients treated with 441 mg ARISTADA and 5% of patients treated with 882 mg ARISTADA compared to 2% of patients treated with placebo. Most of these were injection site pain (3%, 4% and 2% in the 441 mg ARISTADA, 882 mg ARISTADA and placebo groups, respectively) and most were associated with the first injection, and decreased with each subsequent injection to less than or equal to 1% for both doses of ARISTADA and placebo. Other injection site reactions (induration, swelling and redness) occurred at less than 1%. In an open label pharmacokinetic study evaluating 441 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months, injection site reactions were similar across the dose groups.

In the 12-week schizophrenia efficacy study [see Clinical Studies], for ARISTADA-treated patients, the incidence of other EPS-related events, excluding akathisia and restlessness, was 5% and 7% for patients on 441 mg and 882 mg, respectively, versus 4% for placebo-treated patient (Table 9).

Table 9: Incidence of EPS Compared to Placebo

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.

Cardiac - angina pectoris, tachycardia, palpitations

Gastrointestinal disorders - constipation, dry mouth

General disorders - asthenia

Musculoskeletal - muscular weakness

Nervous system disorders - dizziness

Psychiatric disorders - anxiety, suicide

Adverse Reactions Reported In Clinical Trials With Oral Aripiprazole

The following is a list of additional adverse reactions that have been reported in clinical trials with oral aripiprazole and not reported above for ARISTADA.

Blood and Lymphatic System Disorders: thrombocytopenia

Cardiac Disorders: bradycardia, atrial flutter, cardiorespiratory arrest, atrioventricular block, atrial fibrillation, myocardial ischemia, myocardial infarction, cardiopulmonary failure

Eye Disorders: photophobia, diplopia

Gastrointestinal Disorders: gastroesophageal reflux disease

General Disorders and Administration Site Conditions: peripheral edema, chest pain, face edema

Hepatobiliary Disorders: hepatitis, jaundice

Immune System Disorders: hypersensitivity

Injury, Poisoning, and Procedural Complications: fall, heat stroke

Investigations: weight decreased, hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased, blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased

Metabolism and Nutrition Disorders: anorexia, hypokalemia, hyponatremia, hypoglycemia

Musculoskeletal and Connective Tissue Disorders: muscle tightness, rhabdomyolysis, mobility decreased

Nervous System Disorders: memory impairment, cogwheel rigidity, hypokinesia, myoclonus, bradykinesia, akinesia, myoclonus, coordination abnormal, speech disorder, choreoathetosis

Psychiatric Disorders: aggression, loss of libido, delirium, libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking

Renal and Urinary Disorders: urinary retention, nocturia

Reproductive System and Breast Disorders: erectile dysfunction, gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism

Respiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspnea

Skin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia, urticaria

Vascular Disorders: hypotension, hypertension

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of oral aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), pathological gambling, hiccups and blood glucose fluctuation.

Included as part of the PRECAUTIONS section.

Human Experience

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.

Management Of Overdosage

In case of overdosage, call the Poison control center immediately at 1-800-222-1222.