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Out of the Pipeline


Long-acting injectable aripiprazole for adult schizophrenia

Depot formulation and once-monthly dosing might improve adherence in patients with schizophrenia

Vol. 12, No. 05 / May 2013

In February 2013, the FDA approved a long-acting IM aripiprazole formulation for treating adult schizophrenia (Table 1).1 It is the fourth second-generation antipsychotic (SGA) depot formulation approved for treating schizophrenia, and the sixth depot antipsychotic if haloperidol and fluphenazine decanoate are considered.

Table 1

Depot aripiprazole: Fast facts

Brand name: Abilify Maintena

Class: Atypical antipsychotic

Indication: Adult schizophrenia

Approval date: February 28, 2013

Availability date: March 18, 2013

Manufacturer: Otsuka Pharmaceutical and Lundbeck

Dosing form: IM long-acting injection

Recommended dosage: 400 mg IM once a month; 200 to 300 mg IM if drug-drug interactions, poor cytochrome P450 2D6 metabolism, or adverse effects

Source: Reference 1

Clinical implications

Depot medications can improve treatment adherence2; however, long-term antipsychotic use can lead to irreversible adverse effects (dyskinesias), which in some cases were reduced by using newer antipsychotics.3

How it works

Similar to other SGAs, aripiprazole’s mechanism of action is unknown. Aripiprazole was developed based on the dopamine theory, in which dopamine hyperactivity in mesolimbic pathways of the brain leads to hallucinations, delusions, disorganization, and catatonia, and dopamine hypoactivity in mesocortical pathways and the prefrontal cortex causes alogia, anhedonia, autism, avolition, and problems with attention and abstract thinking.

Aripiprazole’s proposed mechanism of action on dopamine receptors is that of partial agonism,1 rather than antagonism, as is the case for other SGAs. In theory, aripiprazole antagonizes postsynaptic D2 receptors and activates presynaptic D2 autoreceptors, with subsequently decreased dopamine production and further stabilization of the dopamine system.4 Its antagonism of 5-HT2A is similar to other SGAs.5

Pharmacokinetics

After depot aripiprazole is injected into the gluteal muscle, the active moiety slowly is released into circulation. The effectiveness of depot aripiprazole is attributable to its active parent drug, aripiprazole monohydrate, and its active metabolite, dehydro-aripiprazole, which is the same as oral aripiprazole. Depot aripiprazole reaches maximum concentration in 5 to 7 days. The elimination half-life of depot aripiprazole is 29.9 days for a 300-mg dose and 46.5 days for a 400-mg dose if administered monthly.1

Aripiprazole does not undergo direct glucuronidation. It is metabolized predominantly through cytochrome P450 (CYP) 2D6 and 3A4 enzymes, which predisposes it to significant drug-drug interactions and may require dose adjustment (Table 2).1

Table 2

Dose adjustments of depot aripiprazole

Drug-drug interaction

Adjusted dose

CYP2D6 poor metabolizers

300 mg

CYP2D6 poor metabolizers taking CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, grapefruit juice)

200 mg

Lithium, valproate, desvenlafaxine, venlafaxine, escitalopram, dextromethorphan, omeprazole, warfarin

No significant interaction No dose adjustment

Sex, race, liver impairment, renal impairment, tobacco smokers

No dose adjustment

Patients taking 400 mg of depot aripiprazole with:

  • CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) or
    CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, grapefruit juice)

300 mg

  • CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) and
    CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, grapefruit juice)

200 mg

  • CYP3A4 inducers (carbamazepine)

Avoid use

Patients taking 300 mg of depot aripiprazole with:

  • CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) or
    CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, grapefruit juice)

200 mg

  • CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) and
    CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, grapefruit juice)

160 mg

  • CYP3A4 inducers (carbamazepine)

Avoid use

CYP: cytochrome P450
Source: Adapted from reference 1

Efficacy

The ability of depot aripiprazole to sustain long-term symptom control in adult patients with schizophrenia was demonstrated in a randomized-withdrawal, double-blind, placebo-controlled trial.1 Adults included had a DSM-IV-TR diagnosis of schizophrenia, had ≥3-year history of the illness, had undergone treatment with ≥1 antipsychotic, and had a history of relapse or symptom exacerbation when not receiving antipsychotics. Psychopathology was measured by the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity scale, the Clinical Global Impression-Improvement (CGI-I) scale, and the Clinical Global Impression-Severity of Suicide (CGI-SS) scale.1

The trial lasted 52 weeks, was divided into 4 phases, and concluded early because of demonstrated efficacy.

Phase I: Conversion phase switched patients from a different antipsychotic to oral aripiprazole. This phase lasted 4 to 6 weeks and included 633 patients. An additional 210 patients already receiving aripiprazole were entered directly into Phase II.

Phase II: Open-label, oral stabilization phase included 710 patients (60% males) age 18 to 60 who had a mean PANSS score 66. Patients received 10 to 20 mg/d of oral aripiprazole until they achieved stabilization, defined as PANSS score <80, CGI-I score ≤4, and CGI-SS score <2 for 4 consecutive weeks.

Phase III: IM depot stabilization (uncontrolled single blind) included 576 patients. Patients were started on depot aripiprazole, 400 mg monthly, and continued to take 10 to 20 mg/d of oral aripiprazole for 14 consecutive days. Depot aripiprazole was decreased to 300 mg monthly if a patient developed adverse effects. Patients continued to the double-blind phase when stabilization was achieved, as evidenced by PANSS score <80, CGI-I score ≤4, and CGI-SS score <2 for 12 consecutive weeks.

Phase IV: Maintenance (double-blind, randomized, placebo-controlled) included 403 patients. Two-thirds of patients continued to take the same dose of depot aripiprazole they took in Phase III. One-third of patients were switched to placebo. The primary efficacy endpoint was time to impending relapse, defined as the first occurrence of ≥1 criteria: hospitalization due to psychosis; violence toward self, others, or property; CGI-SS score ≥4 on part I or ≥7 on part II; or CGI-I score ≥5 and any individual PANSS score >4 for disorganization, hallucinations, suspiciousness, or abnormal thought content.1

Patients randomized to continue depot aripiprazole took longer to relapse or worsening of symptoms compared with the placebo group. Of 403 patients, 10% taking an active drug and 39.6% taking placebo relapsed within 360 days of randomization. This difference was statistically significant (P < .0001).1

Tolerability

One possible problem with any long-acting medication is increased duration of adverse effects (AEs), if they develop. Therefore, assessment of safety and tolerability is more important in depot formulations than in oral drugs. During the clinical trial, depot aripiprazole was well tolerated.6

During clinical trials, the most common AEs—insomnia (>5%), anxiety, and tremors—were mild to moderate and occurred within the first 4 weeks. Discontinuation of the medication because of AEs was low, and pain at the injection site was minimal.6 There were 2 deaths during the trial, which were unrelated to depot aripiprazole.6

Aripiprazole’s activity on the D2 receptor can cause extrapyramidal AEs. In head-to-head trials, patients taking aripiprazole had fewer extrapyramidal AEs than those taking risperidone or ziprasidone, but more than patients receiving olanzapine.7 Its moderate antagonism on α-adrenergic and histamine 1 (H1) receptors translates to low orthostatic hypotension, H1-mediated weight gain, and sedation. In clinical trials, weight gain and metabolic changes were comparable with placebo. In head-to-head trials, aripiprazole caused less weight gain and a higher incidence of increased cholesterol than olanzapine and risperidone, and less increase in blood glucose than olanzapine, but more than risperidone.8 Muscarinic 1-mediated cognitive impairment, dry mouth, constipation, urinary retention, and increased intraocular pressure were low.8 See Table 3 for aripiprazole's receptor binding profile.

Table 3

Aripiprazole’s receptor binding profile

 

Affinity

Ki (nM)a

Effects associated with activity on the receptor

D2

High

0.34

Partial agonist

D3

High

0.8

Partial agonist

5-HT1A

High

1.7

Partial agonist

5-HT2A

High

3.4

Antagonist

5-HT2C

Moderate

15

Partial agonist

5-HT7

Moderate

39

Antagonist

D4

Moderate

44

Partial agonist

α1-adrenergic

Moderate

57

Antagonist

H1

Moderate

61

Antagonist

M1

No appreciable activity

>1,000

No appreciable activity

aKi dissociation constant: lower numbers indicate higher affinity of the compound for the receptor
H1: histamine 1; M1: muscarinic 1
Source: References 1,6

Unique clinical issues

Clinical features for depot aripiprazole can be partially deduced based on data on oral aripiprazole. Advantages over other depot SGAs might include aripiprazole’s more favorable weight and metabolic profile.

Contraindications

Depot aripiprazole is contraindicated in patients with known sensitivity to aripiprazole or other components of the formulation. Because of pharmacokinetic drug-drug interactions, using depot aripiprazole should be avoided in patients taking strong CYP3A4 inducers (eg, rifampin and carbamazepine). Dose adjustment is recommended in patients who are taking moderate CYP2D6 and 3A4 inhibitors, such as paroxetine, fluoxetine, ketoconazole, or erythromycin.1 A “black-box” warning of increased mortality in older patients with dementia-related psychosis applies for depot aripiprazole as well as for other atypical antipsychotics.1

Depot aripiprazole is pregnancy category C and should be used in pregnant or breastfeeding mothers only when benefits outweigh the risks. Use of depot aripiprazole in geriatric and pediatric populations has not been studied; however, patients age ≥65 who received oral aripiprazole, 15 mg/d, showed decreased clearance by 20%.1

Dosing

Depot aripiprazole is available as a lyophilized powder that needs to be reconstituted in sterile water. The drug can be stored at room temperature. The kit includes two 21-gauge needles, a 1.5-inch needle for non-obese patients and a 2-inch needle for obese patients. Depot aripiprazole should be given to patients who demonstrate tolerability to oral aripiprazole. The starting and maintenance dose of depot aripiprazole is 400 mg injected into the gluteal muscle, once a month. If a patient develops an AE, decrease the monthly dose to 300 mg. Rotate the injection site between gluteal muscles to reduce AEs from injection.

Because of the potential for significant pharmacokinetic drug-drug interactions, dose adjustment is recommended for patients who are CYP2D6 poor metabolizers and those taking certain other medications (Table 4).1 See Table 4 for the recommended dosage adjustment in the case of missed doses.

Table 4

Adjusting depot aripiprazole after missed doses

 

Doses missed since last injection

Second or third dose

Fourth or subsequent dose

>4 weeks and <5 weeks

>5 weeks

>4 weeks and <6 weeks

>6 weeks

Oral aripiprazole

 

Administer for 14 days

 

Administer for 14 days

Depot aripiprazole

Administer as soon as possible

Administer next injection

Administer as soon as possible

Administer next injection

Source: Reference 1

After depot aripiprazole is injected into the gluteal muscle, the patient receives 10 to 20 mg/d of oral aripiprazole for 14 consecutive days to avoid a drop in plasma concentrations into subtherapeutic levels.

Related Resource

  • Abilify Maintena [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Company; 2013.

Drug Brand Names

  • Aripiprazole • Abilify
  • Aripiprazole depot • Maintena
  • Carbamazepine • Tegretol
  • Desvenlafaxine • Pristiq
  • Dextromethorphan • Delsym
  • Erythromycin • E-Mycin
  • Escitalopram • Lexapro
  • Fluoxetine • Prozac
  • Fluphenazine • Prolixin
  • Haloperidol • Haldol
  • Itraconazole • Sporanox
  • Ketoconazole • Nizoral
  • Lithium • Eskalith, Lithobid
  • Olanzapine • Zyprexa
  • Omeprazole • Prilosec
  • Paliperidone • Invega
  • Paroxetine • Paxil
  • Quinidine • Quinidex
  • Rifampin • Rifadin
  • Risperidone • Risperdal
  • Valproate • Depakote
  • Venlafaxine • Effexor
  • Warfarin • Coumadin
  • Ziprasidone • Geodon

Disclosure

Dr. Lincoln receives grant or research support from the Wichita Center for Graduate Medical Education.

References

1. Abilify Maintena [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Company; 2013.

2. Leucht C, Heres S, Kane JM, et al. Oral versus depot antipsychotic drugs for schizophrenia—a critical systematic review and meta-analysis of randomized long-term trials. Schizophr Res. 2011;127(1-3):83-92.

3. de Araújo AN, de Sena EP, de Oliveira IR, et al. Antipsychotic agents: efficacy and safety in schizophrenia. Drug Healthc Patient Saf. 2012;4:173-180.

4. Mailman RB, Murty V. Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? Curr Pharm Des. 2010;16(5):488-501.

5. Roth BL, Meltzer HY. The role of serotonin in schizophrenia. http://www.acnp.org/g4/GN401000117/CH115.html. Published 2000. Accessed March 27 2013.

6. Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012;73(5):617-624.

7. Rummel-Kluge C, Komossa K, Schwarz S, et al. Second-generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr Bull. 2012;38(1):167-177.

8. Rummel-Kluge C, Komossa K, Schwarz S, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2010;123(2-3):225-233.

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