Aripiprazole


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Schizophrenia Initial: 10 or 15 mg once daily. Maintenance: 15 mg once daily. Adjust dose at intervals of at least 2 weeks. Max: 30 mg/day. Acute manic or mixed episodes of bipolar disorder Monotherapy: Initial: 15 mg once daily. Adjunctive therapy to lithium or valproate: Initial: 10-15 mg once daily. Dose may be increased according to patient response. Max: 30 mg/day. Adjunctive therapy of major depressive disorder Initial: 2-5 mg once daily, may be adjusted gradually in increments of up to 5 mg at intervals of at least 1 week according to patient response and tolerability. Max: 15 mg/day. IM Acute manic episodes of bipolar disorder For rapid control of agitation and disturbed behaviours when oral therapy is inappropriate: As anhydrous aripiprazole solution for inj: Initial: 9.75 mg as single dose via deep inj, may be followed by a further dose after at least 2 hours if necessary. Recommended dose range: 5.25-15 mg as a single dose. Max: 3 inj/day; 30 mg/day (combined oral and IM dose). Schizophrenia For rapid control of agitation and disturbed behaviours when oral therapy is inappropriate: As anhydrous aripiprazole solution for inj: Initial: 9.75 mg as single dose via deep inj, may be followed by a further dose after at least 2 hours if necessary. Recommended dose range: 5.25-15 mg as a single dose. Max: 3 inj/day; 30 mg/day (combined oral and IM dose). Maintenance in patients stabilised with oral aripiprazole therapy: As aripiprazole monohydrate prolonged-release susp for inj: 400 mg once monthly via deep inj (minimum of 26 days between inj). After the 1st inj, therapy with 10-20 mg daily oral aripiprazole must be continued for 14 consecutive days. Dose may be reduced to 300 mg once monthly if necessary. As aripiprazole lauroxil extended-release susp for inj: Recommended initial dose: Single monthly inj equivalent to 300 mg, 450 mg or 600 mg of aripiprazole; alternatively, 600 mg once every 6 weeks. Dosage requirements and frequency may vary depending on the concomitant dose of oral aripiprazole therapy, available preparation, and inj site (refer to detailed product guideline).
Dosage Details
Intramuscular
Acute manic episodes of bipolar disorder
Adult: For rapid control of agitation and disturbed behaviours when oral therapy is inappropriate: As anhydrous aripiprazole solution for inj: Initially, 9.75 mg as single dose via deep inj, may be followed by a further dose after at least 2 hours if necessary. Recommended dose range: 5.25-15 mg as a single dose. Max: 3 inj daily; 30 mg daily (combined oral and IM dose). Switch to oral therapy as soon as possible if ongoing aripiprazole treatment is clinically indicated.
Elderly: Lower initial dose may be required.

Intramuscular
Schizophrenia
Adult: For rapid control of agitation and disturbed behaviours when oral therapy is inappropriate: As anhydrous aripiprazole solution for inj: Initially, 9.75 mg as single dose via deep inj, may be followed by a further dose after at least 2 hours if necessary. Recommended dose range: 5.25-15 mg as a single dose. Max: 3 inj daily; 30 mg daily (combined oral and IM dose). Switch to oral therapy as soon as possible if ongoing aripiprazole treatment is clinically indicated. Maintenance in patients stabilised with oral aripiprazole therapy: As aripiprazole monohydrate prolonged-release susp for inj: 400 mg once monthly via deep inj (minimum of 26 days between inj). After the 1st inj, therapy with 10-20 mg daily oral aripiprazole must be continued for 14 consecutive days. Dose may be reduced to 300 mg once monthly if necessary. As aripiprazole lauroxil extended-release susp for inj: Recommended initial dose: Single monthly inj equivalent to 300 mg, 450 mg or 600 mg of aripiprazole; alternatively, 600 mg once every 6 weeks. Dosage requirements and frequency may vary depending on the concomitant dose of oral aripiprazole therapy, available preparation, and inj site (refer to detailed product guideline).
Elderly: For rapid control of agitation and disturbed behaviours when oral therapy is inappropriate: As anhydrous aripiprazole solution for inj: Lower initial dose may be required.

Oral
Acute manic episodes of bipolar disorder, Acute mixed episodes of bipolar disorder
Adult: As monotherapy: Initially, 15 mg once daily. As adjunctive therapy to lithium or valproate: Initially, 10-15 mg once daily. Dose may be increased according to patient response. Max: 30 mg daily. For recurrence prevention of manic episodes: Continue therapy at the same dose on which patient was stabilised; dosage adjustments must be according to the clinical status of the patient.
Child: 10-17 years As monotherapy or adjunctive therapy to lithium or valproate: Initially, 2 mg daily for 2 days, titrated to 5 mg daily for 2 additional days, and then to the recommended target dose of 10 mg daily. Subsequent dose increases, if necessary, must be given in 5 mg increments. Max: 30 mg daily.
Elderly: Lower initial dose may be required.

Oral
Schizophrenia
Adult: Initially, 10 or 15 mg once daily. Maintenance: 15 mg once daily. Adjust dose at intervals of at least 2 weeks. Max: 30 mg daily.
Child: 13-17 years Initially, 2 mg daily for 2 days, titrated to 5 mg daily for 2 additional days, and then to the recommended target dose of 10 mg daily. Subsequent dose increases, if necessary, must be given in 5 mg increments. Max: 30 mg daily.
Elderly: Lower initial dose may be required.

Oral
Major depressive disorder
Adult: As adjunctive therapy to antidepressants: Initially, 2-5 mg once daily, may be adjusted gradually in increments of up to 5 mg at intervals of at least 1 week according to patient response and tolerability. Max: 15 mg daily.

Oral
Irritability associated with autistic disorder
Child: 6-17 years Initially, 2 mg daily, increased to 5 mg daily; subsequent dose increases may be in increments of up to 5 mg at intervals of at least 1 week according to patient response and tolerability. Max: 15 mg daily.

Oral
Tourette's syndrome
Child: 6-18 years <50 kg: Initially, 2 mg daily for 2 days, increased to the target dose of 5 mg daily. In patients not achieving optimal control of tics, dose may be further increased after an interval of at least 1 week up to Max 10 mg daily; ≥50 kg: Initially, 2 mg daily for 2 days, increased to 5 mg daily for 5 days, and then to the target dose of 10 mg daily on day 8 of treatment. In patients not achieving optimal control of tics, dose may be further increased in 5 mg increments at intervals of at least 1 week. Max: 20 mg daily.
Special Patient Group
Oral:
For Schizophrenia; Acute mixed or manic episodes of bipolar disorder:

Patient taking potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, clarithromycin) or CYPD26 (e.g. quinidine, fluoxetine, paroxetine): Reduce to half of the usual dose.

Patient taking potent CYP3A4 inducers (e.g. carbamazepine, rifampicin): Increase to double the usual dose.

Patient taking a combination of strong, moderate, and weak inhibitors of CYP2D6 and CYP3A4: Reduce to quarter of the usual dose.

IM:
Patient taking inhibitors of CYP3A4 and/or CYP2D6 for >14 days: Refer to individual product guideline for detailed dosage adjustments.

Patient taking CYP3A4 inducers for >14 days: As aripiprazole monohydrate: Avoid use.

Pharmacogenomics:

Aripiprazole is mainly metabolised in the liver by CYP2D6 and CYP3A4 isoenzymes into its major active metabolite, dehydro-aripiprazole. Genetic variations in CYP2D6 gene may affect the plasma concentrations, elimination half-lives, and drug interactions of aripiprazole.

Individuals who are considered as poor CYP2D6 metabolisers may experience increased plasma concentrations of aripiprazole and dehydro-aripiprazole with approx 1.5-1.7-fold and 1.3-1.5-fold higher levels than in normal metabolisers, respectively. The risk of side effects is increased in these individuals; therefore, dosage adjustments may be needed. The prevalence of CYP2D6 poor metabolisers is approx 8% in Caucasians, 3-8% in Blacks/African Americans and up to 2% in Asians. Genetic testing for CYP2D6 may be considered prior to initiation of treatment.

Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of November 2018:
Phenotype
Genotype Recommendations
CYP2D6 poor metabolisers Carriers of 2 loss-of-function alleles, or 1 loss-of-function and 1 reduced-function allele
Reduce the max aripiprazole dose to 67-75% of the standard max dose. Max: 10 mg/day or 300 mg/month.

FDA-approved drug label annotation:
Phenotype
Recommendations
CYP2D6 poor metabolisers
Oral: Reduce to half of the usual dose.
CYP2D6 poor metabolisers who are also taking strong CYP3A4 inhibitors
Oral: Reduce to quarter of the usual dose.

FDA- and EMA-approved drug label annotations:
Phenotype
Recommendations
CYP2D6 poor metabolisers
IM: As aripiprazole monohydrate: Reduce dose to 300 mg once monthly.
CYP2D6 poor metabolisers who are also taking CYP3A4 inhibitors
IM: As aripiprazole monohydrate: Reduce dose to 200 mg.

As for aripiprazole lauroxil, the FDA-approved drug label annotation recommends dose reduction in CYP2D6 poor metabolisers who are concomitantly taking strong CYP3A4 inhibitors (refer to detailed product guideline for dosage adjustments). Additionally, the aripiprazole lauroxil nanocrystal dispersion should be avoided in CYP2D6 poor metabolisers.
Administration
May be taken with or without food.
Reconstitution
Lyophilised powder in vial (as aripiprazole monohydrate IM inj): Reconstitute a vial labelled as 300 mg with 1.5 mL sterile water for inj or a vial labelled as 400 mg with 1.9 mL sterile water for inj to a final concentration of 200 mg/mL.
Special Precautions
Patient with known CV disease (e.g. history of MI, ischaemic heart disease, conduction abnormalities, heart failure), cerebrovascular disease, conditions predisposing to hypotension (e.g. hypovolaemia, undergoing antihypertensive treatment), hypertension (including accelerated or malignant); family history of QT prolongation, diabetes mellitus or its risk factors (e.g. obesity, family history), prior history of impulse control issues, Lewy body dementia, Parkinson’s disease, history of seizures; at risk of seizures (e.g. head trauma, alcoholism, brain damage), at risk of aspiration pneumonia (e.g. Alzheimer dementia); pre-existing low WBC count/absolute neutrophil count, history of drug-induced leucopenia/neutropenia. Patient subjected to dehydration or strenuous exercise, exposed to extreme heat, receiving drugs with anticholinergic effects. CYP2D6 poor metabolisers; patient taking CYP3A4 and/or CYP2D6 inhibitors, or potent CYP3A4 inducers. IM: Avoid use in patient receiving CYP3A4 inducers for >14 days (aripiprazole monohydrate). Not approved for the treatment of dementia-related psychosis. Avoid abrupt withdrawal. Severe hepatic impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Suicidal thoughts and behaviour, venous thromboembolism, QT prolongation, extrapyramidal symptoms (e.g. tardive dyskinesia, akathisia, parkinsonism); dyslipidaemia, weight gain, oesophageal dysmotility and aspiration; impulse control disorders (e.g. pathological gambling, increased sexual urges, compulsive shopping, binge or compulsive eating); falls, orthostatic hypotension, worsening depression, seizure, impaired core body temperature regulation; hypersensitivity reactions.
Cardiac disorders: Tachycardia.
Endocrine disorders: Hyperprolactinaemia.
Eye disorders: Blurred vision, diplopia.
Gastrointestinal disorders: Constipation, nausea, dyspepsia, vomiting, salivary hypersecretion, dry mouth.
General disorders and administration site conditions: Fatigue, pyrexia, lethargy, inj site pain or induration (IM).
Investigations: Increased blood creatine phosphokinase.
Metabolism and nutrition disorders: Diabetes mellitus, increased or decreased appetite.
Musculoskeletal and connective tissue disorders: Musculoskeletal stiffness.
Nervous system disorders: Headache, sedation, tremor, dizziness, drooling, dystonia.
Psychiatric disorders: Insomnia, anxiety, restlessness, somnolence, agitation.
Reproductive system and breast disorders: Erectile dysfunction.
Respiratory, thoracic and mediastinal disorders: Nasopharyngitis, hiccups.
Potentially Fatal: Hyperglycaemia associated with ketoacidosis or hyperosmolar coma; arrhythmia, blood dyscrasias (e.g. leucopenia, neutropenia, agranulocytosis), cerebrovascular events (e.g. TIA, stroke). Rarely, neuroleptic malignant syndrome.
Patient Counseling Information
This drug may cause somnolence, sedation, and blurred vision; if affected, do not drive or operate machinery.
MonitoringParameters
Screen patients for bipolar disorder before initiation of therapy for depression. Monitor mental status, vital signs (as clinically indicated), blood pressure (at baseline; repeat after 3 months then annually); weight, height, BMI, waist circumference; CBC, electrolytes and LFT (as clinically indicated), fasting plasma glucose level/HbA1c and lipid panel (at baseline; repeat after 3 months then yearly), ECG (as needed). Closely monitor for clinical worsening, suicidality, or unusual changes in behaviour, particularly during initiation of therapy or dosage adjustments. Assess for involuntary movements or parkinsonian signs, and tardive dyskinesia. Perform ocular examination yearly in patients >40 years or every 2 years in younger patients.
Overdosage
Symptoms: Somnolence, lethargy, nausea, vomiting, diarrhoea, tachycardia, tremor, transient loss of consciousness, extrapyramidal symptoms, acidosis, aggression, increased AST and blood creatine phosphokinase; atrial fibrillation, bradycardia, confusional state, hyper- or hypotension, hypokalaemia, prolonged QT interval, aspiration pneumonia, respiratory arrest, status epilepticus, and coma. Management: Supportive and symptomatic treatment. Maintain adequate airway, oxygenation and ventilation. Initiate CV with continuous ECG monitoring immediately to detect possible arrhythmias. Administer activated charcoal (50 g) within 1 hour after ingestion to decrease absorption.
Drug Interactions
May enhance the effects of certain antihypertensive agents. Enhanced sedation with lorazepam. May increase plasma concentration with potent inhibitors of CYP2D6 (e.g. quinidine, fluoxetine, paroxetine) or CYP3A4 (e.g. ketoconazole, itraconazole, clarithromycin). May decrease plasma concentrations with potent CYP3A4 inducers (e.g. carbamazepine, rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine). Increased risk of serotonin syndrome with other serotonergic drugs (e.g. serotonin-norepinephrine reuptake inhibitors, SSRIs).
Food Interaction
May enhance the CNS depressant effects of alcohol. May decrease plasma levels with St. John’s wort.
Action
Description: Aripiprazole is an atypical quinolone antipsychotic. It acts as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptors.
Onset: Aripiprazole: 1-3 weeks (initial); Aripiprazole lauroxil: Within 4 days (concomitant use with oral aripiprazole therapy).
Pharmacokinetics:
Absorption: Well absorbed from the gastrointestinal tract; slow and prolonged absorption after IM inj. Bioavailability: 87% (oral tab); 100% (IM). Time to peak plasma concentration: Within 3-5 hours (oral); 1-3 hours (anhydrous aripiprazole IM inj).
Distribution: Widely distributed throughout the body. Crosses the placenta and enters breast milk. Volume of distribution: 4.9 L/kg (aripiprazole); 268 L (aripiprazole lauroxil). Plasma protein binding: ≥99%, mainly to albumin.
Metabolism: Extensively metabolised in the liver via dehydrogenation and hydroxylation by CYP3A4 and CYP2D6 isoenzymes, and N-dealkylation by CYP3A4 isoenzyme into dehydro-aripiprazole (major active metabolite). Aripiprazole lauroxil: Undergoes enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole and further hydrolysed to aripiprazole.
Excretion: Via faeces (55%; approx 18% as unchanged drug); urine (approx 25%; <1% as unchanged drug). Elimination half-life: Approx 75 hours (aripiprazole); 94 hours (dehydro-aripiprazole); IM: dose-dependent. CYP2D6 poor metabolisers: Approx 146 hours (aripiprazole).
Chemical Structure

Chemical Structure Image
Aripiprazole

Source: National Center for Biotechnology Information. PubChem Database. Aripiprazole, CID=60795, https://pubchem.ncbi.nlm.nih.gov/compound/Aripiprazole (accessed on Jan. 21, 2020)

Storage
Tab/oral solution: Store between 15-30°C. Lyophilised powder in vial/pre-filled syringe: Store between 15-30°C. Do not freeze. Protect from light.
MIMS Class
ATC Classification
N05AX12 - aripiprazole ; Belongs to the class of other antipsychotics.
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Disclaimer: This information is independently developed by MIMS based on Aripiprazole from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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