Aripiprazole

Aripiprazole
Structural formula of aripiprazole
Ball-and-stick model of the aripiprazole molecule
Names
Pronunciation/ˌeɪrɪˈpɪprəzoʊl/
AIR-i-PIP-rə-zohl
Abilify /əˈbɪlɪfaɪ/
ə-BIL-i-fy
Trade namesAbilify, others
IUPAC name
  • 7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
Clinical data
Drug classAtypical antipsychotic[1]
Main usesSchizophrenia, bipolar disorder[1]
Side effectsVomiting, constipation, sleepiness, dizziness, weight gain, movement disorders[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: C[2]
  • US: N (Not classified yet)[2]
    Routes of
    use    		By mouth (tablets, dissolving tablets, solution); IM (including a depot)
    Defined daily dose13.3 to 15 mg[3]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa603012
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability87%[4][5][6]
    Protein binding>99%[4][5][6]
    MetabolismLiver (mostly via CYP3A4 and 2D6[4][5][6])
    Elimination half-life75 hours (active metabolite is 94 hours)[4][5][6]
    ExcretionKidney (27%; <1% unchanged), Faecal (60%; 18% unchanged)[4][5][6]
    Chemical and physical data
    FormulaC23H27Cl2N3O2
    Molar mass448.39 g·mol−1
    3D model (JSmol)
    SMILES
    • Clc4cccc(N3CCN(CCCCOc2ccc1c(NC(=O)CC1)c2)CC3)c4Cl
    InChI
    • InChI=1S/C23H27Cl2N3O2/c24-19-4-3-5-21(23(19)25)28-13-11-27(12-14-28)10-1-2-15-30-18-8-6-17-7-9-22(29)26-20(17)16-18/h3-6,8,16H,1-2,7,9-15H2,(H,26,29) checkY
    • Key:CEUORZQYGODEFX-UHFFFAOYSA-N checkY

    Aripiprazole, sold under the brand name Abilify among others, is an atypical antipsychotic.[1] It is primarily used in the treatment of schizophrenia and bipolar disorder.[1] Other uses include as an add-on treatment in major depressive disorder, tic disorders and irritability associated with autism.[1] It is taken by mouth or injection into a muscle.[1] A Cochrane review found only low quality evidence of effectiveness in treating schizophrenia.[7] Additionally, since many people dropped out of the studies before they were completed, the strength of the conclusions was low.[7]

    Common side effects include vomiting, constipation, sleepiness, dizziness, weight gain and movement disorders.[1] Serious side effects may include neuroleptic malignant syndrome, tardive dyskinesia and anaphylaxis.[1] It is not recommended for older people with dementia-related psychosis due to an increased risk of death.[1] In pregnancy, there is evidence of possible harm to the baby.[1][8] It is not recommended in women who are breastfeeding.[1] It has not been very well studied in people less than 18 years old.[1] The exact mode of action is not entirely clear but may involve effects on dopamine and serotonin.[1]

    Aripiprazole was approved for medical use in the United States in 2002.[1] It is on the World Health Organization's List of Essential Medicines as an alternative to risperidone and quetiapine.[9] It is available as a generic medication.[10] In the United Kingdom, a month's supply costs the NHS about £2.75 as of 2019.[10] In the United States, the wholesale cost of this amount is US$10.[11] In 2017, it was the 112th most commonly prescribed medication in the United States, with more than six million prescriptions.[12][13] Aripiprazole was discovered in 1988 by scientists at Japanese firm Otsuka Pharmaceutical.[14][15]

    Medical uses

    Aripiprazole is primarily used for the treatment of schizophrenia or bipolar disorder.[1][16][6]

    Schizophrenia

    The 2016 NICE guidance for treating psychosis and schizophrenia in children and young people recommended aripiprazole as a second line treatment after risperidone for people between 15 and 17 who are having an acute exacerbation or recurrence of psychosis or schizophrenia.[17] A 2014 NICE review of the depot formulation of the drug found that it might have a role in treatment as an alternative to other depot formulations of second generation antipsychotics for people who have trouble taking medication as directed or who prefer it.[18]

    A 2014 Cochrane review comparing aripiprazole and other atypical antipsychotics found that it is difficult to determine differences as data quality is poor.[19] A 2011 Cochrane review comparing aripiprazole with placebo concluded that high dropout rates in clinical trials, and a lack of outcome data regarding general functioning, behavior, mortality, economic outcomes, or cognitive functioning make it difficult to definitively conclude that aripiprazole is useful for the prevention of relapse.[7] A Cochrane review found only low quality evidence of effectiveness in treating schizophrenia.[7] Accordingly, part of its methodology on quality of evidence is based on quantity of qualified studies.[20]

    A 2013 review found that it is in the middle range of 15 antipsychotics for effectiveness, approximately as effective as haloperidol and quetiapine and slightly more effective than ziprasidone, chlorpromazine, and asenapine, with better tolerability compared to the other antipsychotic drugs (4th best for weight gain, 5th best for extrapyramidal symptoms, best for prolactin elevation, 2nd best for QTc prolongation, and 5th best for sedation). The authors concluded that for acute psychotic episodes aripiprazole results in benefits in some aspects of the condition.[21]

    In 2013 the World Federation of Societies for Biological Psychiatry recommended aripiprazole for the treatment of acute exacerbations of schizophrenia as a Grade 1 recommendation and evidence level A.[22]

    The British Association for Psychopharmacology similarly recommends that all persons presenting with psychosis receive treatment with an antipsychotic, and that such treatment should continue for at least 1–2 years, as "There is no doubt that antipsychotic discontinuation is strongly associated with relapse during this period". The guideline further notes that "Established schizophrenia requires continued maintenance with doses of antipsychotic medication within the recommended range (Evidence level A)".[23]

    The British Association for Psychopharmacology[23] and the World Federation of Societies for Biological Psychiatry suggest that there is little difference in effectiveness between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on each person's preference and side effect profile. The latter group recommends switching to aripiprazole when excessive weight gain is encountered during treatment with other antipsychotics.[22]

    Bipolar disorder

    Aripiprazole is effective for the treatment of acute manic episodes of bipolar disorder in adults, children, and adolescents.[24][25] Used as maintenance therapy, it is useful for the prevention of manic episodes, but is not useful for bipolar depression.[26][27] Thus, it is often used in combination with an additional mood stabilizer; however, co-administration with a mood stabilizer increases the risk of extrapyramidal side effects.[28]

    Major depression

    Aripiprazole is an effective add-on treatment for major depressive disorder; however, there is a greater rate of side effects such as weight gain and movement disorders.[29][30][31][32] The overall benefit is small to moderate and its use appears to neither improve quality of life nor functioning.[30] Aripiprazole may interact with some antidepressants, especially selective serotonin reuptake inhibitors (SSRIs). There are interactions with fluoxetine and paroxetine and lesser interactions with sertraline, escitalopram, citalopram and fluvoxamine, which inhibit CYP2D6, for which aripiprazole is a substrate. CYP2D6 inhibitors increase aripiprazole concentrations to 2-3 times their normal level.[33]

    Autism

    Short-term data (8 weeks) shows reduced irritability, hyperactivity, inappropriate speech, and stereotypy, but no change in lethargic behaviours.[34] Adverse effects include weight gain, sleepiness, drooling and tremors.[34] It is suggested that children and adolescents need to be monitored regularly while taking this medication, to evaluate if this treatment option is still effective after long-term use and note if side effects are worsening. Further studies are needed to understand if this drug is helpful for children after long term use.[34]

    Obsessive–compulsive disorder

    A 2014 systematic review concluded that add-on therapy with low dose aripiprazole is an effective treatment for obsessive-compulsive disorder that does not improve with SSRIs alone. The conclusion was based on the results of two relatively small, short-term trials, each of which demonstrated improvements in symptoms.[35] Risperidone (another second-generation antipsychotic) appears to be superior to aripiprazole for this indication, and is recommended by the 2007 American Psychiatric Association guidelines, though aripiprazole is cautiously recommended by a 2017 review by Pignon and colleagues.[36]

    Dosage

    The defined daily dose is 15 mg by mouth or by short acting injection and 13.3 mg by long acting injection.[3]

    Side effects

    See also: List of adverse effects of aripiprazole

    In adults, side effects with greater than 10% incidence include weight gain, headache, akathisia, insomnia, and gastro-intestinal effects like nausea and constipation, and lightheadedness.[33][4][5][6][37] Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose.[33] A strong desire to gamble, binge eat, shop, and have sex may also occur.[38][39]

    Uncontrolled movement such as restlessness, tremors, and muscle stiffness may occur.[33]

    Discontinuation

    The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[40] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[41] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[41] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[41] Symptoms generally resolve after a short period of time.[41]

    There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[42] It may also result in reoccurrence of the condition that is being treated.[43] Rarely tardive dyskinesia can occur when the medication is stopped.[41]

    Overdose

    Children or adults who ingested acute overdoses have usually manifested central nervous system depression ranging from mild sedation to coma; serum concentrations of aripiprazole and dehydroaripiprazole in these people were elevated by up to 3-4 fold over normal therapeutic levels; as of 2008 no deaths had been recorded.[44][45]

    Interactions

    Aripiprazole is a substrate of CYP2D6 and CYP3A4. Coadministration with medications that inhibit (e.g. paroxetine, fluoxetine) or induce (e.g. carbamazepine) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole.[46] As such, anyone taking aripiprazole should be aware that their dosage of aripiprazole may need to be adjusted.

    Precautions should be taken in people with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics along with other medications that affect blood sugar levels and should be monitored regularly for worsening of glucose control. The liquid form (oral solution) of this medication may contain up to 15 grams of sugar per dose.[1]

    Antipsychotics like aripiprazole and stimulant medications, such as amphetamine, are traditionally thought to have opposing effects to their effects on dopamine receptors: stimulants are thought to increase dopamine in the synaptic cleft, whereas antipsychotics are thought to decrease dopamine. However, it is an oversimplification to state the interaction as such, due to the differing actions of antipsychotics and stimulants in different parts of the brain, as well as the effects of antipsychotics on non-dopaminergic receptors. This interaction frequently occurs in the setting of comorbid ADHD (for which stimulants are commonly prescribed) and off-label treatment of aggression with antipsychotics. Aripiprazole has shown some benefit in improving cognitive functioning in people with ADHD without other psychiatric comorbidities, though the results have been disputed. The combination of antipsychotics like aripiprazole with stimulants should not be considered an absolute contraindication.[47]

    Pharmacology

    Pharmacodynamics

    See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
    Aripiprazole[48][49]
    SiteKi (nM)ActionRef
    5-HT1A1.7–5.6Partial agonist[49][50][51]
    5-HT1B830ND[49]
    5-HT1D68ND[49]
    5-HT1E8,000ND[49]
    5-HT2A3.4–35Antagonist[51][49][50]
    5-HT2B0.11-0.36Inverse agonist[49]
    5-HT2C15–180Partial agonist[51][49][50]
    5-HT3628ND[49]
    5-HT5A1,240ND[49]
    5-HT6214–786Antagonist[51][49][50]
    5-HT79.6–39Antagonist[49][50][51]
    D1265–1,170ND[49]
    D20.34Partial agonist[52][50][49]
    D2L0.74–0.9Partial agonist[49]
    D30.8–9.7Partial agonist[51][49]
    D444–514Partial agonist[51][49]
    D595–2,590ND[51][49]
    α1A25.9ND[49][50]
    α1B34.4ND[49]
    α2A74.3ND[49][50]
    α2B102ND[49][50]
    α2C37.9ND[49][50]
    β1141ND[49]
    β2163ND[49]
    H127.9–61ND[49][50][51]
    H2>10,000ND[49]
    H3224ND[49]
    H4>10,000ND[49]
    M16,780ND[49]
    M23,510ND[49]
    M34,680ND[49][50]
    M41,520ND[49]
    M52,330ND[49]
    SERT98–1,080Blocker[51][49]
    NET2,090Blocker[49]
    DAT3,220Blocker[49]
    NMDA
    (PCP)    		4,001Antagonist[49]
    Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except 5-HT3 (rat), D4 (human/rat), H3 (guinea pig), and NMDA/PCP (rat).[49]

    Aripiprazole's mechanism of action is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone).[53][54][55][56] It shows differential engagement at the dopamine receptor (D2[49]). It appears to show predominantly antagonist activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors,[57] D3,[49][58][59] and partially D4[49][54]) and is a partial activator of serotonin (5-HT1A,[49][60][61] 5-HT2A,[49] 5-HT2B,[49] 5-HT6, and 5-HT7).[49][56] It also shows lower and likely insignificant effect on histamine (H1), epinephrine/norepinephrine (α), and otherwise dopamine (D4), as well as the serotonin transporter.[49][54] Aripiprazole acts by modulating neurotransmission overactivity of dopamine, which is thought to mitigate schizophrenia symptoms.[62]

    It appears to show predominantly antagonist activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors.[57] Aripiprazole is also a partial agonist of the D3 receptor.[49] In healthy human volunteers, D2 and D3 receptor occupancy levels are high, with average levels ranging between approximately 71% at 2 mg/day to approximately 96% at 40 mg/day.[58][59] Most atypical antipsychotics bind preferentially to extrastriatal receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.[63]

    Aripiprazole is also a partial agonist of the serotonin 5-HT1A receptor (intrinsic activity = 68%).[49][60][61] It is a very weak partial agonist of the 5-HT2A receptor (intrinsic activity = 12.7%),[49] and like other atypical antipsychotics, displays a functional antagonist profile at this receptor.[49] The drug differs from other atypical antipsychotics in having higher affinity for the D2 receptor than for the 5-HT2A receptor.[61] At the 5-HT2B receptor, aripiprazole acts as a potent inverse agonist.[49] Unlike other antipsychotics, aripiprazole is a high-efficacy partial agonist of the 5-HT2C receptor (intrinsic activity = 82%) and with relatively weak affinity;[49] this property may underlie the minimal weight gain seen in the course of therapy.[64] At the 5-HT7 receptor, aripiprazole is a very weak partial agonist with barely measurable intrinsic activity, and hence is a functional antagonist of this receptor.[49][56] Aripiprazole also shows lower but likely clinically insignificant affinity for a number of other sites, such as the histamine H1, α-adrenergic, and dopamine D4 receptors as well as the serotonin transporter, while it has negligible affinity for the muscarinic acetylcholine receptors.[49][54]

    Since the actions of aripiprazole differ markedly across receptor systems aripiprazole was sometimes an antagonist (e.g. at 5-HT6 and D2L), sometimes an inverse agonist (e.g. 5-HT2B), sometimes a partial agonist (e.g. D2L), and sometimes a full agonist (D3, D4). Aripiprazole was frequently found to be a partial agonist, with an intrinsic activity that could be low (D2L, 5-HT2A, 5-HT7), intermediate (5-HT1A), or high (D4, 5-HT2C). This mixture of agonist actions at D2-dopamine receptors is consistent with the hypothesis that aripiprazole has ‘functionally selective’ actions.[65] The ‘functional-selectivity’ hypothesis proposes that a mixture of agonist/partial agonist/antagonist actions are likely. According to this hypothesis, agonists may induce structural changes in receptor conformations that are differentially ‘sensed’ by the local complement of G proteins to induce a variety of functional actions depending upon the precise cellular milieu. The diverse actions of aripiprazole at D2-dopamine receptors are clearly cell-type specific (e.g. agonism, antagonism, partial agonism), and are most parsimoniously explained by the ‘functional selectivity’ hypothesis.[49]

    Since 5-HT2C receptors have been implicated in the control of depression, OCD, and appetite, agonism at the 5-HT2C receptor might be associated with therapeutic potential in obsessive compulsive disorder, obesity, and depression. 5-HT2C agonism has been demonstrated to induce anorexia via enhancement of serotonergic neurotransmission via activation of 5-HT2C receptors; it is conceivable that the 5-HT2C agonist actions of aripiprazole may, thus, be partly responsible for the minimal weight gain associated with this compound in clinical trials. In terms of potential action as an antiobsessional agent, it is worthwhile noting that a variety of 5-HT2A/5-HT2C agonists have shown promise as antiobsessional agents, yet many of these compounds are hallucinogenic, presumably due to 5-HT2A activation. Aripiprazole has a favorable pharmacological profile in being a 5-HT2A antagonist and a 5-HT2C partial agonist. Based on this profile, one can predict that aripiprazole may have antiobsessional and anorectic actions in humans.[49]

    Wood and Reavill's (2007) review of published and unpublished data proposed that, at therapeutically relevant doses, aripiprazole may act essentially as a selective partial agonist of the D2 receptor without significantly affecting the majority of serotonin receptors.[57] A positron emission tomography imaging study found that 10 to 30 mg/day aripiprazole resulted in 85 to 95% occupancy of the D2 receptor in various brain areas (putamen, caudate, ventral striatum) versus 54 to 60% occupancy of the 5-HT2A receptor and only 16% occupancy of the 5-HT1A receptor.[66][61] It has been suggested that the low occupancy of the 5-HT1A receptor by aripiprazole may have been an erroneous measurement however.[67]

    Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic mesolimbic pathway, which is thought to be a cause of positive schizophrenia symptoms.[62] Due to its agonist activity on D2 receptors, aripiprazole may also increase dopaminergic activity to optimal levels in the mesocortical pathways where it is reduced.[62]

    Pharmacokinetics

    Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. Cmax (maximum plasma concentration) is achieved 3–5 hours after oral dosing. Bioavailability of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation), principally by the enzymes CYP2D6 and CYP3A4. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via feces and urine.[54] When dosed daily, brain concentrations of aripiprazole will increase for a period of 10–14 days, before reaching stable constant levels.

    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[68]
    Clopentixol decanoateSordinol DepotTypicalViscoleob50–600 mg/1–4 weeks4–7 days ?19 days9.0[69]
    Flupentixol decanoateDepixolTypicalViscoleob10–200 mg/2–4 weeks4–10 days8 days17 days7.2–9.2[69][70]
    Fluphenazine decanoateProlixin DecanoateTypicalSesame oil12.5–100 mg/2–5 weeks1–2 days1–10 days14–100 days7.2–9.0[71][72][73]
    Fluphenazine enanthateProlixin EnanthateTypicalSesame oil12.5–100 mg/1–4 weeks2–3 days4 days ?6.4–7.4[72]
    FluspirileneImap, RedeptinTypicalWatera2–12 mg/1 week1–8 days7 days ?5.2–5.8[74]
    Haloperidol decanoateHaldol DecanoateTypicalSesame oil20–400 mg/2–4 weeks3–9 days18–21 days7.2–7.9[75][76]
    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[77]
    Pipotiazine palmitatePiportil LongumTypicalViscoleob25–400 mg/4 weeks9–10 days ?14–21 days8.5–11.6[70]
    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.

    Chemistry

    Aripiprazole is a phenylpiperazine and is chemically related to nefazodone, etoperidone, and trazodone.[78][79]

    • Aripiprazole 2 and 5 mg tablets
      Aripiprazole 2 and 5 mg tablets
    • Aripiprazole 10 mg tablets
      Aripiprazole 10 mg tablets
    • Aripiprazole 15 mg tablets
      Aripiprazole 15 mg tablets
    • Aripiprazole 400mg injection
      Aripiprazole 400mg injection

    History

    Aripiprazole was discovered by scientists at Otsuka Pharmaceutical and was called OPC-14597.[14][80] It was first published in 1995.[80][81] Otsuka initially developed the drug, and partnered with Bristol-Myers Squibb (BMS) in 1999 to complete development, obtain approvals, and market aripiprazole.[82]

    It was approved by the FDA for schizophrenia on November 15, 2002 and the European Medicines Agency on 4 June 2004; for acute manic and mixed episodes associated with bipolar disorder on October 1, 2004; as an adjunct for major depressive disorder on November 20, 2007;[83] and to treat irritability in children with autism on 20 November 2009.[84] Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.[33]

    Aripiprazole has been approved by the FDA for the treatment of both acute manic and mixed episodes, in people older than 10 years.[85]

    In 2006, the FDA required the companies to add a black box warning to the label, warning that older people who were given the drug for dementia-related psychosis were at greater risk of death.[86]

    In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.[87] That same year, BMS settled a case with the U.S. government in which it paid $515 million; the case covered several drugs but the focus was on BMS's off-label marketing of aripiprazole for children and older people with dementia.[88]

    In 2011 Otsuka and Lundbeck signed a collaboration to develop a depot formulation of apripiprazole.[89]

    As of 2013, Abilify had annual sales of US$7 billion.[90] In 2013 BMS returned marketing rights to Otsuka, but kept manufacturing the drug.[91] Also in 2013, Otsuka and Lundbeck received U.S. and European marketing approval for an injectable depot formulation of aripiprazole.[92][93]

    Otsuka's U.S. patent on aripiprazole expired on October 20, 2014 but due to a pediatric extension, a generic did not become available until April 20, 2015.[85] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.[94] On November 15, 2010, this challenge was rejected by the U.S. District Court in New Jersey.[95]

    Otsuka's European patent EP0367141 which would have expired on 26 October 2009, was extended by a Supplementary Protection Certificate (SPC) to 26 October 2014.,[96] The UK Intellectual Property Office decided[97] on 4 March 2015 that the SPC could not be further extended by six months under Regulation (EC) No 1901/2006. Even if the decision is successfully appealed, protection in Europe will not extend beyond 26 April 2015.

    From April 2013 to March 2014, sales of Abilify amounted to almost $6.9 billion.[98]

    In April 2015, the FDA announced the first generic versions.[99][100] In October 2015, aripiprazole lauroxil, a prodrug of aripiprazole that is administered via intramuscular injection once every four to six weeks for the treatment of schizophrenia, was approved by the FDA.[101][102]

    In 2016, BMS settled cases with 42 U.S. states that had charged BMS with off-label marketing to older people with dementia; BMS agreed to pay $19.5 million.[86][103]

    In November 2017, the FDA approved Abilify MyCite, a digital pill containing a sensor intended to record when its consumer takes their medication.[104][105]

    Society and culture

    Cost

    In the United States, the wholesale cost of this amount is US$10.[11] In 2017, it was the 112th most commonly prescribed medication in the United States, with more than six million prescriptions.[12][13]

    • Aripiprazole costs (USA)
      Aripiprazole costs (USA)
    • Aripiprazole prescriptions (USA)
      Aripiprazole prescriptions (USA)

    Regulatory status

    Regulatory administration (country)[106][107][108]SchizophreniaAcute maniaBipolar maintenanceMajor depressive disorder (as an adjunct)Irritability in autism
    Food and Drug Administration (US)YesYesYes (as an adjunct to lithium/valproate)YesYes (children and adolescents)
    Therapeutic Goods Administration (AU)YesYes (as an adjunct to lithium/valproate)YesNoNo
    Medicines and Healthcare products Regulatory Agency (UK)YesYesYes (to prevent mania)NoNo

    Research

    Urine drug screens are used to test for recreational drug use. There are case reports of 2 children accidentally ingesting large quantities of aripiprazole and subsequently testing positive for amphetamines on urine drug screens; both children then had gas chromatography-mass spectrometry analysis sent on their blood and urine that were negative for amphetamines.[109]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 "Aripiprazole, ARIPiprazole Lauroxil Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Archived from the original on 1 October 2020. Retrieved 26 February 2019.
    2. 1 2 "Aripiprazole Use During Pregnancy". Drugs.com. 22 August 2019. Archived from the original on 12 November 2020. Retrieved 7 February 2020.
    3. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 6 August 2020. Retrieved 9 September 2020.
    4. 1 2 3 4 5 6 "Abilify (aripiprazole) tablet Abilify (aripiprazole) solution Abilify Discmelt (aripiprazole) tablet, orally disintegrating Abilify (aripiprazole) injection, solution [Otsuka America Pharmaceutical, Inc.]". DailyMed. Otsuka America Pharmaceutical, Inc. April 2013. Archived from the original on 17 October 2011. Retrieved 22 October 2013.
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