Aripiprazole lauroxil

Aripiprazole lauroxil (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 eight weeks for the treatment of schizophrenia.[1][2][3] Aripiprazole lauroxil was approved by the U.S. FDA on 5 October 2015.[4][5]

Aripiprazole lauroxil
Clinical data
Trade namesAristada
Other namesALKS-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
Routes of
administration		Intramuscular
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.261.570
Chemical and physical data
FormulaC36H51Cl2N3O4
Molar mass660.72 g·mol−1
3D model (JSmol)

Medical uses

Aripiprazole lauroxil extended release injection 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.[6]

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.[6][7]

Schizophrenia

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.[8] In the sister drug aripiprazole, side effects for patients were less frequently extrapyramidal than most antipsychotic drugs.

Side effects

The most common side effects are akathisia. According to the drug’s warning label and safety information, the side effects are large in variety.[9]

The complete list of side effects 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.[10]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[11] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[12] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[12] Less commonly there may be a felling of the world spinning, numbness, or muscle pains.[12] Symptoms generally resolve after a short period of time.[12]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[13] It may also result in reoccurrence of the condition that is being treated.[14] Rarely tardive dyskinesia can occur when the medication is stopped.[12]

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, 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.[6]

Pharmacology

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.[7][10] Its 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. Efficacy could be mediated through a combination of partial agonist activity D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Since it is a newly approved drug by the FDA, many validation of mechanisms of action are still being studied.[10]

Pharmacodynamics

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.[10]

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 doses 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.[10]

Pharmacokinetics of long-acting injectable antipsychotics
MedicationBrand nameClassVehicleDosageTmaxt1/2 singlet1/2 multiplelogPcRef
Aripiprazole lauroxilAristadaAtypicalWatera441–1064 mg/4–8 weeks24–35 days?54–57 days7.9–10.0
Aripiprazole monohydrateAbilify MaintenaAtypicalWatera300–400 mg/4 weeks7 days?30–47 days4.9–5.2
Bromperidol decanoateImpromen DecanoasTypicalSesame oil40–300 mg/4 weeks3–9 days?21–25 days7.9[15]
Clopentixol decanoateSordinol DepotTypicalViscoleob50–600 mg/1–4 weeks4–7 days?19 days9.0[16]
Flupentixol decanoateDepixolTypicalViscoleob10–200 mg/2–4 weeks4–10 days8 days17 days7.2–9.2[16][17]
Fluphenazine decanoateProlixin DecanoateTypicalSesame oil12.5–100 mg/2–5 weeks1–2 days1–10 days14–100 days7.2–9.0[18][19][20]
Fluphenazine enanthateProlixin EnanthateTypicalSesame oil12.5–100 mg/1–4 weeks2–3 days4 days?6.4–7.4[19]
FluspirileneImap, RedeptinTypicalWatera2–12 mg/1 week1–8 days7 days?5.2–5.8[21]
Haloperidol decanoateHaldol DecanoateTypicalSesame oil20–400 mg/2–4 weeks3–9 days18–21 days7.2–7.9[22][23]
Olanzapine pamoateZyprexa RelprevvAtypicalWatera150–405 mg/2–4 weeks7 days?30 days–
Oxyprothepin decanoateMeclopinTypical?????8.5–8.7
Paliperidone palmitateInvega SustennaAtypicalWatera39–819 mg/4–12 weeks13–33 days25–139 days?8.1–10.1
Perphenazine decanoateTrilafon DekanoatTypicalSesame oil50–200 mg/2–4 weeks??27 days8.9
Perphenazine enanthateTrilafon EnanthateTypicalSesame oil25–200 mg/2 weeks2–3 days?4–7 days6.4–7.2[24]
Pipotiazine palmitatePiportil LongumTypicalViscoleob25–400 mg/4 weeks9–10 days?14–21 days8.5–11.6[17]
Pipotiazine undecylenatePiportil MediumTypicalSesame oil100–200 mg/2 weeks???8.4
RisperidoneRisperdal ConstaAtypicalMicrospheres12.5–75 mg/2 weeks21 days?3–6 days–
Zuclopentixol acetateClopixol AcuphaseTypicalViscoleob50–200 mg/1–3 days1–2 days1–2 days4.7–4.9
Zuclopentixol decanoateClopixol DepotTypicalViscoleob50–800 mg/2–4 weeks4–9 days?11–21 days7.5–9.0
Note: All by intramuscular injection. Footnotes: a = Microcrystalline or nanocrystalline aqueous suspension. b = Low-viscosity vegetable oil (specifically fractionated coconut oil with medium-chain triglycerides). c = Predicted, from PubChem and DrugBank. Sources: Main: See template.

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.[9]

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.[7]

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.[8]

Dose Dosing Frequency Site of Injection
441 mg Monthly Deltoid or Gluteal
662 mg Monthly Gluteal
882 mg Every Six Weeks Gluteal
1064 mg Every Eight Weeks Gluteal

Missed doses

When a dose is missed, administer the next injection of aripiprazole lauroxil 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 aripiprazole lauroxil injection as listed:[8]

Dose of Patient's Last aripiprazole lauroxil 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

Once stabilized on aripiprazole, people taking CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers should refer to the dosing recommendations below, there are no dosage changes recommended for aripiprazole lauroxil if CYP450 modulators are added for less than two weeks.[8]

Concomitant Medicine Dose Changes for aripiprazole lauroxil
Strong CYP3A4 Inhibitor Reduce the dosage of aripiprazole lauroxil 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 aripiprazole lauroxil 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.
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References
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  2. Turncliff R, Hard M, Du Y, Risinger R, Ehrich EW (2014). "Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia". Schizophr. Res. 159 (2–3): 404–10. doi:10.1016/j.schres.2014.09.021. PMID 25266547.
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