Aripiprazole

Aripiprazole is an Antipsychotic/Antimanic agent in Dopamine D₂ and serotonin 5-HT_1A receptors agonist / Serotonin 5-HT_2A receptors antagonist class.

Aripiprazole is an atypical antipsychotic used in the treatment of a wide variety of mood and psychotic disorders, such as schizophrenia, bipolar I, major depressive disorder, irritability associated with autism, and Tourette's syndrome.

Aripiprazole is well absorbed from the gastrointestinal tract, slow and prolonged absorption after IM injection. It has Bioavailability of approximately 87% (oral tab); 100% (IM). Time to peak plasma concentration: Within 3-5 hours (oral). Aripiprazole is having Volume of distribution of about 4.9 L/kg. Its Plasma protein binding is ≥99%, mainly to albumin. Aripiprazole is Extensively metabolized in the liver via dehydrogenation and hydroxylation by CYP3A4 and CYP2D6 isoenzymes, and N-dealkylation by CYP3A4 isoenzyme into dehydro-aripiprazole (major active metabolite). It is primarily excreted Via faeces (55%; approximately 18% as unchanged drug) and urine (approximately 25%; <1% as unchanged drug).

Aripiprazole shows side effects like Muscle stiffness, Restlessness, Blurred vision, Dizziness, Headache, Acid or sour stomach, Anxiety, Dry mouth, Running Nose, Weight gain, Tremors, Tingling of hands and feet, etc.

Aripiprazole is available in the form of oral tablet, oral solution, intramuscular solution, intramuscular powder for injection, oral tablet with sensor, intramuscular suspension.

Aripiprazole is available in India, US, Canada, Japan, Italy, Spain, France, Singapore, Switzerland, and Malaysia.

Aripiprazole belongs to the Selective Serotonin Reuptake Inhibitor/5-HT_1A Receptor Partial Agonist class and acts as an Antipsychotic/Antimanic agent.

Aripiprazole is a quinolinone antipsychotic which exhibits high affinity for D₂, D₃, 5-HT_1A, and 5-HT_2A receptors; moderate affinity for D₄, 5-HT_2C, 5-HT₇, alpha₁ adrenergic, and H₁ receptors. It also possesses moderate affinity for the serotonin reuptake transporter; has no affinity for muscarinic (cholinergic) receptors. Aripiprazole functions as a partial agonist at the D₂ and 5-HT_1A receptors, and as an antagonist at the 5-HT_2A receptor.

The Onset of action of Aripiprazole is not clinically established.

The Time to peak plasma concentration of Aripiprazole is approximately 3-5 hours (oral); 1-3 hours (anhydrous aripiprazole IM inj).

Aripiprazole is available in the form of oral tablet, oral solution, intramuscular solution, intramuscular powder for injection, oral tablet with sensor, intramuscular suspension.

Aripiprazole is an antipsychotic. It is used for the treatment of mental disorders like Schizophrenia (a mental disorder in which a person develops unreal thoughts and behaviours) and other mood disorders. This medicine can only control the symptoms but cannot cure the disease.

Aripiprazole is an Antipsychotic/Antimanic agent in Dopamine D₂ and serotonin 5-HT_1A receptors agonist / Serotonin 5-HT_2A receptors antagonist class.

Aripiprazole is an atypical quinolone antipsychotic. It acts as a partial agonist at dopamine D₂ and serotonin 5-HT_1A receptors, and as an antagonist at serotonin 5-HT_2A receptors.

Aripiprazole is approved for use in the following clinical indications

• Agitation/Aggression associated with psychiatric disorders, substance intoxication, or other organic causes
• Agitation/Aggression and psychosis associated with dementia, severe or refractory
• Bipolar disorder
• Delusional disorder
• Delusional infestation
• Huntington disease–associated chorea
• Major depressive disorder, treatment resistant
• Obsessive-compulsive disorder, treatment resistant
• Schizophrenia
• Tourette syndrome

• Agitation/Aggression associated with psychiatric disorders, substance intoxication, or other organic causes

Oral: Initial: 10 to 15 mg; may repeat based on response and tolerability every 2 hours up to 30 mg/day.

• Agitation/Aggression and psychosis associated with dementia, severe or refractory

Oral: Initial: 2 to 5 mg once daily; may increase dose based on response and tolerability in 5 mg increments at intervals ≥1 week up to 15 mg once daily. In patients without a clinically significant response after an adequate trial (eg, up to 4 weeks), taper and withdraw therapy. Only continue in patients with a demonstrated benefit and attempt to taper and withdraw at regular intervals; first taper attempt should occur ≤4 months of initiation.

• Bipolar disorder

Oral: Acute mania or episodes with mixed features (labeled use), acute hypomania (off-label use), and maintenance treatment (labeled use, formulation specific) as monotherapy or adjunctive therapy: Initial: 10 to 15 mg once daily; may increase dose based on response and tolerability in 5 to 10 mg/day increments at intervals of ≥1 week up to a maximum of 30 mg/day.

Single injection start: IM: 400 mg once monthly (doses should be separated by ≥26 days). Continue (overlap) oral aripiprazole or other oral antipsychotic for 14 days during initiation of the ER injection.

Double injection start: IM: Initial: Administer a single oral aripiprazole 20 mg dose, plus two 400 mg injections in separate injection sites (eg, right deltoid and left gluteal muscle). Maintenance: 400 mg once monthly (doses should be separated by ≥ 26 days).

• Delusional disorder

Oral: Initial: 2 to 5 mg once daily; gradually increase to 10 mg/day; if needed, may further increase dose at intervals of ≥1 week based upon response and tolerability up to 30 mg/day.

• Delusional infestation

Oral: Initial: 2 mg once daily; may increase dose gradually based on response and tolerability in 2 mg increments at intervals ≥2 weeks up to 12 mg/day (Ref). Some patients may require doses up to 30 mg/day for optimal response. After achieving adequate response, maintain for ≥1 to 3 months before attempting to taper and discontinue.

• Huntington disease–associated chorea

Oral: Initial: 2 mg once daily; may increase dose gradually based on response and tolerability up to a usual range of 7.5 to 15 mg/day.

• Major depressive disorder, treatment resistant

Oral: Initial: 2 to 5 mg/day; may increase dose based on response and tolerability in 5 mg increments at intervals ≥1 week up to a manufacturer's maximum of 15 mg/day. A further increase up to 20 mg/day may be necessary in some patients for optimal response. Although the manufacturer's labeling recommends waiting ≥2 weeks before increasing dose due to long half-life of aripiprazole, it may be appropriate to increase dose at 1 week for some patients.

• Obsessive-compulsive disorder, treatment resistant

Oral: Initial: 5 mg once daily; may increase dose gradually based on response and tolerability in 5 mg increments at intervals ≥1 week up to 15 mg/day.

• Schizophrenia

Oral: Initial: 5 to 15 mg once daily; may increase dose based on response and tolerability in 5 mg increments at an interval of ≥4 days with initial low dose (eg, 5 mg) and at intervals ≥1 week thereafter up to a maximum of 30 mg/day. Although the manufacturer's labeling recommends waiting ≥2 weeks before increasing dose due to long half-life of aripiprazole, it may be appropriate to increase dose at 1 week for some patients.

Single injection start: IM: 400 mg once monthly (doses should be separated by ≥26 days). Continue (overlap) oral aripiprazole or other oral antipsychotic for 14 days during initiation of the ER injection.

Double injection start: IM: Initial: Administer a single oral aripiprazole 20 mg dose, plus two 400 mg injections in separate injection sites (eg, right deltoid and left gluteal muscle). Maintenance: 400 mg once monthly (doses should be separated by ≥26 days).

• Tourette syndrome

Oral: Initial: 2.5 mg once daily; may increase dose based on response and tolerability in 2.5 mg increments at intervals ≥3 days up to 30 mg/day.

Aripiprazole is available in various strengths as 5 mg; 10 mg; 15 mg; 20 mg; 30 mg; 2 mg; 1 mg/mL; 9.75 mg/1.3 mL; 300 mg; 400 mg; 720 mg/2.4 mL; 960 mg/3.2 mL; 441 mg/1.6 mL; 662 mg/2.4 mL; 882 mg/3.2 mL; 1064 mg/3.9 mL; 675 mg/2.4 mL.

Aripiprazole is available in the form of oral tablet, oral solution, intramuscular solution, intramuscular powder for injection, oral tablet with sensor, intramuscular suspension.

Avoid high-fat meals, it delays time to peak plasma level.

Aripiprazole is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis.

• Suicidal thoughts

Aripiprazole should be used with caution due to the increased risk of suicidal thoughts. Closely observe for any change in behavior or mood while taking this medicine. 

• Diabetes and Dyslipidaemia

Aripiprazole may increase the blood sugar levels and cholesterol levels in the body. Your doctor may recommend regular monitoring of your blood sugar, cholesterol, and fat levels, as well as your body weight.

• Tardive dyskinesia

Aripiprazole should be used with extreme caution if you have a history of Tardive Dyskinesia (involuntary movements of the tongue, lips, face, trunk, and extremities) due to the increased risk of recurrent symptoms.

• Withdrawal syndrome

Abrupt discontinuation of Aripiprazole may increase the risk of side effects, especially if you have been using a high dose for a long duration. Your doctor may recommend a gradual dose reduction to minimise these reactions.

• Orthostatic hypotension

May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).

• Cardiovascular disease

Use with caution in patients with cardiac disease, cerebrovascular disease, prior myocardial infarction, ischemic heart disease, or conditions that predispose to hypotension.

• Parkinson disease

Use with caution in patients with Parkinson disease; antipsychotics may aggravate motor disturbances.

• Seizures

Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.

Consumption of alcohol is not recommended during treatment with Aripiprazole due to the increased risk of severe side effects such as dizziness, difficulty in concentration, impaired judgment, confusion, nausea, vomiting, etc.

Aripiprazole is present in human breast milk. Because of the potential for serious adverse reactions in nursing infants from Aripiprazole, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the mother.

Neonates exposed to antipsychotic drugs (including Aripiprazole) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. Adequate and well controlled studies with Aripiprazole have not been conducted in pregnant women. Animal reproduction studies were conducted with aripiprazole in rats and rabbits during organogenesis, and in rats during the pre-and post-natal period. Oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses higher than the maximum recommended human dose (MRHD) produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses higher than the maximum recommended human dose (MRHD) produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. Administer Aripiprazole during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Avoid high-fat meals, it delays time to peak plasma level.

Common

Headache, nervousness, restlessness, dizziness, feeling unsteady, or having trouble keeping your balance, heartburn, constipation, diarrhea, stomach pain, weight gain, changes in appetite, increased salivation, pain, especially in the arms, legs, or joints, tiredness.

Rare

• Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be co-administered with blonanserin.
• 1,2-Benzodiazepine: The risk or severity of CNS depression can be increased when Aripiprazole is combined with 1,2-Benzodiazepine.
• Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants.
• Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used.
• Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended.
• Iohexol: Agents with Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs.
• Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary.
• Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression.
• Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
• Serotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome.
• Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol.
• Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects.

The common side effects of Aripiprazole include the following

Common side effects

Muscle stiffness, Restlessness, Blurred vision, Dizziness, Headache, Acid or sour stomach, Anxiety, Dry mouth, Running Nose, Weight gain, Tremors, Tingling of hands and feet, etc.

• Pregnancy

Pregnancy Category C

Neonates exposed to antipsychotic drugs (including Aripiprazole) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. Adequate and well controlled studies with Aripiprazole have not been conducted in pregnant women. Animal reproduction studies were conducted with aripiprazole in rats and rabbits during organogenesis, and in rats during the pre-and post-natal period. Oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses higher than the maximum recommended human dose (MRHD) produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses higher than the maximum recommended human dose (MRHD) produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. Administer Aripiprazole during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

Aripiprazole is present in human breast milk. Because of the potential for serious adverse reactions in nursing infants from Aripiprazole, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the mother.

• Pediatric Use

Safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established.

• Geriatric Use

No dosage adjustment is recommended for elderly patients.

Symptoms: Somnolence, lethargy, nausea, vomiting, diarrhea, tachycardia, tremor, transient loss of consciousness, extrapyramidal symptoms, acidosis, aggression, increased AST and blood creatine phosphokinase; atrial fibrillation, bradycardia, confusional state, hyper- or hypotension, hypokalemia, 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.

• Pharmacodynamic

Aripiprazole exhibits high affinity for dopamine D₂ and D₃, serotonin 5-HT_1a and 5-HT_2a receptors, moderate affinity for dopamine D₄, serotonin 5-HT_2c and 5-HT₇, alpha₁-adrenergic and histamine H₁ receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC₅₀>1000 nM).

• Pharmacokinetics

Absorption

Aripiprazole is Well absorbed from the gastrointestinal tract; slow and prolonged absorption after IM injection. It is having Bioavailability of approximately 87% (oral tab); 100% (IM). Time to peak plasma concentration: Within 3-5 hours (oral);

Distribution

Aripiprazole is having Volume of distribution of about 4.9 L/kg. Its Plasma protein binding is ≥99%, mainly to albumin.

Metabolism and Excretion

Aripiprazole is Extensively metabolized in the liver via dehydrogenation and hydroxylation by CYP3A4 and CYP2D6 isoenzymes, and N-dealkylation by CYP3A4 isoenzyme into dehydro-aripiprazole (major active metabolite). It is primarily excreted Via faeces (55%; approximately 18% as unchanged drug) and urine (approximately 25%; <1% as unchanged drug).

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