Aripiprazole lauroxil

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Aripiprazole lauroxil
Clinical data
Trade namesAristada, Aristada Initio
Other namesN-Lauroyloxymethylaripiprazole; 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
AHFS/Drugs.comMonograph
MedlinePlusa615048
Pregnancy
category
Routes of
administration		Intramuscular
ATC code
  • None
Legal status
Legal status
Identifiers
  • [7-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]-2-oxo-3,4-dihydroquinolin-1-yl]methyl dodecanoate
JSmol)
  • CCCCCCCCCCCC(=O)OCN1C(=O)CCC2=C1C=C(C=C2)OCCCCN3CCN(CC3)C4=C(C(=CC=C4)Cl)Cl
  • InChI=1S/C36H51Cl2N3O4/c1-2-3-4-5-6-7-8-9-10-16-35(43)45-28-41-33-27-30(19-17-29(33)18-20-34(41)42)44-26-12-11-21-39-22-24-40(25-23-39)32-15-13-14-31(37)36(32)38/h13-15,17,19,27H,2-12,16,18,20-26,28H2,1H3
  • Key:DDINXHAORAAYAD-UHFFFAOYSA-N

Aripiprazole lauroxil, sold under the brand name Aristada, is a

long-acting injectable atypical antipsychotic that was developed by Alkermes.[3][4][5] 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.[3][4][5] Aripiprazole lauroxil was approved by the U.S. Food and Drug Administration (FDA) on 5 October 2015.[6][7]

Medical uses

Aripiprazole lauroxil extended release injection gained FDA approval in 2015, as a treatment for adults with 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.[8]

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.[8][9]

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

Side effects

See also: List of adverse effects of aripiprazole

The most common side effects are akathisia. According to the drug's warning label and safety information, the side effects are large in variety.[11]

The complete list of side effects include: akathisia, contraindication cerebrovascular adverse reactions (including stroke),

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.[12]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[13] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[14] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[14] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[14] Symptoms generally resolve after a short period of time.[14]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[15] It may also result in reoccurrence of the condition that is being treated.[16] Rarely tardive dyskinesia can occur when the medication is stopped.[14]

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.[citation needed]

Common adverse reactions, reported in at least 5% of overdose cases, included

lethargy, loss of consciousness, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.[8]

Pharmacology

Mechanism of action

Arristada is injected intramuscularly as an atypical antipsychotic. In one 12-week clinical trial involving 622 participants, the efficacy of extended aripiprazole was demonstrated.[9][12] 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[when?] approved drug by the FDA, many validation of mechanisms of action are still being studied.[12][needs update]

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, α1-adrenergic, dopamine D4, histamine H1, and serotonin re-uptake site. No affinity for cholinergic muscarinic receptors have been found.[12]

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.[citation needed]

Bioactivation of aripiprazole lauroxil (N-lauroyloxymethylaripiprazole) into aripiprazole, with N-hydroxymethylaripiprazole as an intermediate.[3]

After five to six 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.[12]

Pharmacokinetics of long-acting injectable antipsychotics
Medication Brand name Class Vehicle Dosage Tmax t1/2 single t1/2 multiple logPc Ref
Aripiprazole lauroxil Aristada Atypical Watera 441–1064 mg/4–8 weeks 24–35 days ? 54–57 days 7.9–10.0
Aripiprazole monohydrate
 Abilify Maintena Atypical Watera 300–400 mg/4 weeks 7 days ? 30–47 days 4.9–5.2
Bromperidol decanoate Impromen Decanoas Typical Sesame oil 40–300 mg/4 weeks 3–9 days ? 21–25 days 7.9 [17]
Clopentixol decanoate
 Sordinol Depot Typical Viscoleob 50–600 mg/1–4 weeks 4–7 days ? 19 days 9.0 [18]
Flupentixol decanoate
 Depixol Typical Viscoleob 10–200 mg/2–4 weeks 4–10 days 8 days 17 days 7.2–9.2 [18][19]
Fluphenazine decanoate
 Prolixin Decanoate Typical Sesame oil 12.5–100 mg/2–5 weeks 1–2 days 1–10 days 14–100 days 7.2–9.0 [20][21][22]
Fluphenazine enanthate
 Prolixin Enanthate Typical Sesame oil 12.5–100 mg/1–4 weeks 2–3 days 4 days ? 6.4–7.4 [21]
Fluspirilene Imap, Redeptin Typical Watera 2–12 mg/1 week 1–8 days 7 days ? 5.2–5.8 [23]
Haloperidol decanoate Haldol Decanoate Typical Sesame oil 20–400 mg/2–4 weeks 3–9 days 18–21 days 7.2–7.9 [24][25]
Olanzapine pamoate
 Zyprexa Relprevv Atypical Watera 150–405 mg/2–4 weeks 7 days ? 30 days –
Oxyprothepin decanoate Meclopin Typical ? ? ? ? ? 8.5–8.7
Paliperidone palmitate
 Invega Sustenna Atypical Watera 39–819 mg/4–12 weeks 13–33 days 25–139 days ? 8.1–10.1
Perphenazine decanoate
 Trilafon Dekanoat Typical Sesame oil 50–200 mg/2–4 weeks ? ? 27 days 8.9
Perphenazine enanthate Trilafon Enanthate Typical Sesame oil 25–200 mg/2 weeks 2–3 days ? 4–7 days 6.4–7.2 [26]
Pipotiazine palmitate
 Piportil Longum Typical Viscoleob 25–400 mg/4 weeks 9–10 days ? 14–21 days 8.5–11.6 [19]
Pipotiazine undecylenate
 Piportil Medium Typical Sesame oil 100–200 mg/2 weeks ? ? ? 8.4
Risperidone Risperdal Consta Atypical
Microspheres
 12.5–75 mg/2 weeks 21 days ? 3–6 days –
Zuclopentixol acetate
 Clopixol Acuphase Typical Viscoleob 50–200 mg/1–3 days 1–2 days 1–2 days 4.7–4.9
Zuclopentixol decanoate
 Clopixol Depot Typical Viscoleob 50–800 mg/2–4 weeks 4–9 days ? 11–21 days 7.5–9.0
Note: All by
fractionated coconut oil with medium-chain triglycerides). c = Predicted, from PubChem and DrugBank
. Sources: Main: See template.

Chemistry

In contrast to many other

laurate ester of N-hydroxymethylaripiprazole.[3] Following cleavage of the laurate ester, N-hydroxymethylaripiprazole is further metabolized to aripiprazole, making aripiprazole lauroxil a prodrug of aripiprazole with N-hydroxymethylaripiprazole as an intermediate.[28][27]

References

  1. ^ a b "Aripiprazole Use During Pregnancy". Drugs.com. 5 February 2020. Retrieved 29 August 2020.
  2. FDA
    . Retrieved 22 Oct 2023.
  3. ^
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  4. ^
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  5. ^
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  6. S2CID 207208248
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  7. ^ "Aristada (Aripiprazole lauroxil) FDA Approval History".
  8. ^ a b c "Aristada intramuscular : Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD". WebMD. Retrieved 2016-04-18.
  9. ^
    PMID 26609204
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  10. ^ "Aristada". Drugs.com.
  11. ^ "ARISTADA (aripiprazole lauroxil) | Treatment Prescribing Information". aristada.com. Archived from the original on 2016-04-03. Retrieved 2016-04-18.
  12. ^ a b c d e "DailyMed - ARISTADA- aripiprazole lauroxil injection, suspension, extended release". dailymed.nlm.nih.gov. Retrieved 2016-04-18.
  13. ISBN 978-0-85369-845-6
    . Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
  14. ^
    ISBN 9780198527480
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  15. S2CID 6267180
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  16. ISBN 9788847026797
    .
  17. ^ Parent M, Toussaint C, Gilson H (1983). "Long-term treatment of chronic psychotics with bromperidol decanoate: clinical and pharmacokinetic evaluation". Current Therapeutic Research. 34 (1): 1–6.
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    PMID 6931472
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  19. ^ a b Reynolds JE (1993). "Anxiolytic sedatives, hypnotics and neuroleptics.". Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. pp. 364–623.
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  21. ^
    PMID 444352
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  22. ^ Young D, Ereshefsky L, Saklad SR, Jann MW, Garcia N (1984). Explaining the pharmacokinetics of fluphenazine through computer simulations. (Abstract.). 19th Annual Midyear Clinical Meeting of the American Society of Hospital Pharmacists. Dallas, Texas.
  23. PMID 4992598
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  24. PMID 3545764
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  26. ^ Larsson M, Axelsson R, Forsman A (1984). "On the pharmacokinetics of perphenazine: a clinical study of perphenazine enanthate and decanoate". Current Therapeutic Research. 36 (6): 1071–88.
  27. ^
    PMID 33507525
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  28. ^
    S2CID 73504046
    .

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