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Aripiprazole lauroxil (USAN) (brand name Aristada) is a long-acting injectable atypical antipsychotic that was developed by Alkermes.[1][2][3] 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.[1][2][3] Aripiprazole lauroxil was approved by the U.S. FDA on 5 October 2015.[4][5]”.

Contents

1. Medical Uses 2. Side Effects 1.1. Overdose 1.2. Other Drug Interactions 3. Pharamacology 1.1. Mechanism of Action 1.2. Pharamacodynamics 1.3. Pharamaocokinetics

1. Medical Uses

Aripiprazole lauroxil extended release injection (Aristada) gained FDA approval in 2015 as a treatment for adults suffering from schizophrenia. Aristada is injected into the arm or buttocks of a patient by a health care professional once every four to six weeks. Aristada is a longer-lasting and injectable version of the schizophrenia pill Abilify, which means that the treatment is available in two doses.

Aristada has a warning on the box, stating an increased risk of death when using the drug for the treatment of behavioral problems in older people with dementia-related psychosis. Aristada, along with other drugs in its family, are not approved for treatment of patients with dementia-related psychosis.

2. Side Effects and Dosing

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.

2.1. Dosing:

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.

The dosages are determined based on the daily needs of the specific patient, but the timing and injection sites are not based on the needs of the patient and correspond to the amount in each dose.

Early Dosing:

-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.

Missed Doses:

-When a dose is missed, administer the next injection of Aristada as soon as possible.

* Chart available, Table 3 on link*

http://www.drugs.com/pro/aristada.html#t3

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:

-No dosage changes recommended for Aristada if CYP450 modulators are added for less than two weeks.

-Make dose changes to Aristada if CYP450 modulators are added for any period of time extending beyond 2 weeks.

-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 and CYP2D6 Inhibitors- 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.

Overdosing:

-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, in overdosage 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.

In case of overdose, call the Poison Control Center at 1-800-222-1222.

2.2.Other Drug Interactions:

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 and Agranulocytosis -Seizures -Potential for Cognitive and Motor Impairment -Body Temperature Regulation -Dysphagia -Injection-Site Reactions (Rash, swelling, redness, irritation at the point of injection) -Dystonia -Pregnancy/Nursing/Birth Complications

3. Pharmacology

3.1 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 unknown in the body. It is said that the drug is likely converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripirazole. The hydroxymethyl aripirazole is thus 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.

3.2 Pharamacodynamics:

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, doamine D4, histamine H1, and serotoinin reuptake site. No affinity for cholinergic muscarinic receptors have been found.

3.4 Pharmacokinetics

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.