|Synonyms||ALKS-9070; ALKS-9072; RDC-3317; Dodecanoic acid-[7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2-oxo-1(2H)-quinolinyl]methyl ester|
|Chemical and physical data|
|Molar mass||660.71384 g/mol|
|3D model (JSmol)|
Aripiprazole lauroxil (USAN) (brand name Aristada) is a long-acting injectable atypical antipsychotic that was developed by Alkermes. It is an N-acyloxymethyl prodrug of aripiprazole that is administered via intramuscular injection once every four to six weeks for the treatment of schizophrenia. Aripiprazole lauroxil was approved by the U.S. FDA on 5 October 2015.
Aripiprazole lauroxil extended release injection (Aristada) gained FDA approval in 2015 as a treatment for adults suffering from schizophrenia. Like any long-term acting injectable, aripiprazole lauroxil provides assurance to families and health care professionals that patients receive therapeutic medication throughout the day.
Aripiprazole lauroxil is injected into the arm or buttocks of a patient by a health care professional once every four to six weeks. Aripiprazole lauroxil is a longer-lasting and injectable version of the schizophrenia pill aripiprazole, which means that the treatment is available in two doses. Aripiprazole lauroxil, along with other drugs in its family, are not approved for treatment of elderly patients with dementia-related psychosis.
The approval of aripiprazole lauroxil from the Food and Drug Administration in 2015 was solely for the treatment of schizophrenia in adults. The ability to supplement aripiprazole lauroxil with oral supplements of aripiprazole allows for dosing flexibility, which is important for the treatment of schizophrenia, as symptoms and intensity of the disease vary greatly from patient to patient. Additionally, as in concurrence with its sister drug aripiprazole, aripiprazole lauroxil is similar in effect of typical antipsychotic drugs. In the sister drug aripiprazole, side effects for patients were less frequently extrapyramidal than most antipsychotic drugs.
Aristada can be administered in three dosages of 441 mg, 662 mg and 882 mg. The smallest dosage can be injected in the Deltoid or Gluteus of the patient, while the higher doses must be injected into the Gluteus. Dosages of 441 mg or 662 mg must be repeated once every four weeks, while the dosage of 882 mg must be repeated once every six weeks.
Aristada dosing is recommended to occur once every four weeks for doses of 441 mg or 662 mg. The recommended dosing for 882 mg is once every six weeks. These durations between doses should be maintained as much as possible. An Aristada injection should not be given any earlier than at least 14 days after the most recent injection.
|Dose||Dosing Frequency||Site of Injection|
|441 mg||Monthly||Deltoid or Gluteal|
|882 mg||Every Six Weeks||Gluteal|
When a dose is missed, administer the next injection of Aristada as soon as possible. It is important to keep the timing of the administration of the drug somewhat regular, as irregular dosing can produce sometimes unpredictable effects on the patient. If the length of time since an injection exceeds the length of time as listed in the following table, use oral Aripiprazole supplementation with the next Aristada injection as listed:
|Dose of Patient's Last Aristada Injection||No Oral Supplementation Required||Supplement for 7 Days||Supplement for 21 Days|
|Monthly 441 mg||6 weeks or less||6–7 weeks||7 weeks or more|
|Monthly 662 mg||8 weeks or less||8–12 weeks||12 weeks or more|
|Monthly 882 mg||8 weeks or less||8–12 weeks||12 weeks or more|
|882 mg every six weeks||8 weeks or less||8–12 weeks||12 weeks or more|
Dose adjustments for CYP450 consideration
Once stabilized on Aristada, patients taking CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers should refer to the dosing recommendations below, there are no dosage changes recommended for Aristada if CYP450 modulators are added for less than two weeks.
|Concomitant Medicine||Dose Changes for Aristada|
|Strong CYP3A4 Inhibitor||Reduce the dosage of Aristada to the next lowest dose, do not lower dose if the patient is already taking the lowest dosage of 441 mg, if tolerated.|
|Strong CYP2D6 Inhibitor||Reduce the dosage of Aristada to the next lowest dose, do not change for those taking 441 mg dose, if tolerated.|
|Both Strong CYP3A4 Inhibitor
and Strong CYP2D6 Inhibitor
|No dosage adjustment necessary for patients taking 441 mg, if tolerated. Avoid use for patients taking the 662 mg or 882 mg dose.|
|CYP3A4 Inducers||No dose adjustment is necessary for patients taking the 662 mg or 882 mg dose. Increase the dosage for patients taking 441 mg to 662 mg.|
The largest known case of ingestion with a known outcome involved a 1260 mg of oral aripiprazole, 42 times the recommended dose. The patient survived and fully recovered.
Common adverse reactions, reported in at least 5% of overdose cases, included vomiting, somnolence, and tremor. Other clinically important signs and symptoms of overdoses include acidosis, aggression, atrial fibrillation, bradycardia, coma, confusion, convulsion, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.
The most common side effect reported by participants in Aristada’s clinical trials was akathisia. According to the drug’s warning label and safety information, the side effects of Aristada usage are large in variety.
The complete list of side effects of Aristada use, according to the official drug label, include: Akathisia, Contraindication Cerebrovascular Adverse Reactions (Including Stroke), Neuroleptic Malignant Syndrome, Tardive Dyskinesia, metabolic changes, Hyperglycemia/Diabetes Mellitus, Dyslipidemia, weight gain, Orthostatic Hypotension, Leukopenia, Neutropenia, Agranulocytosis, seizures, potential for Cognitive and Motor Impairment, difficulties with body temperature regulation, Dysphagia, Injection-Site Reactions (rash, swelling, redness, irritation at the point of injection), Dystonia and pregnancy and nursing complications.
Mechanism of action
Arristada is injected into the intramuscles as an atypical antipsychotic. In one 12-week clinical trial involving 622 participants, the efficacy of extended aripiprazole was demonstrated. It’s mechanism of action is not completely known, but is thought to be converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripirazole. The hydroxymethyl aripirazole is then hydrolysed to aripiprazole. Aristada efficacy could be mediated through a combination of partial agonist activity D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Since Aristada is a newly approved drug by the FDA many validation of mechanisms of action are still being studied.
Aripiprazole exhibits high affinity for serotonin 5-HT1A, 5-HT2A receptors, dopamine D2, and dopamine D3. Moderate affinity is exhibited for serotonin 5-HT7, alpha1-adrenergic, dopamine D4, histamine H1, and serotonin re-uptake site. No affinity for cholinergic muscarinic receptors have been found.
Aristada’s activity in the body is due to aripiprazole and also dehydro-aripiprazole. Dehydro-aripirazole has been shown to have affinities for D2 receptors. These D2 receptors have similarities to aripiprazole whereas they represent 30-40% of exposure of aripiprazole in plasma.
After 5 to 6 days of the single intramuscular injection appearance of aripiprazole in circulation, it additionally will be released for 36 days. In the fourth monthly injection, consecutive does of Aristada will reach steady-state. With additional supplements of the oral aripiprazole at a dosage of 21 days during the first dose of Aristada, aripiprazole concentrations within 4 days can reach therapeutic levels.
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