Version May 2024
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole lauroxil is not approved for the treatment of patients with dementia-related psychosis.
Dosage guidance:
Dosing: Aripiprazole lauroxil is a prodrug of aripiprazole. All doses, for all routes of administration, are expressed as the equivalent amounts of aripiprazole base.
Dosage form information: Aripiprazole lauroxil is formulated as an ER suspension for IM injection. Another ER suspension for IM injection is available as aripiprazole monohydrate (see Aripiprazole monograph). When initiating aripiprazole lauroxil or restarting after missed doses, a 675 mg nanocrystal dispersion preparation of aripiprazole lauroxil (Aristada Initio) is an option for one-time use. The 675 mg nanocrystal dispersion (Aristada Initio) is not to be used for repeated dosing due to pharmacokinetic differences with other aripiprazole lauroxil strengths.
Schizophrenia: IM: Note: Establish tolerability with oral aripiprazole prior to initiating treatment. Avoid use of 675 mg nanocrystal dispersion (Aristada Initio) in known CYP2D6 poor metabolizers.
Initial dose options:
1-day oral overlap using Aristada Initio: Administer a single oral aripiprazole 30 mg dose, a single 675 mg dose of nanocrystal dispersion (Aristada Initio), plus the first dose of aripiprazole lauroxil based on current oral aripiprazole dose (see conversion below) with or within 10 days after administering the 675 mg dose.
or
21-day oral overlap: Administer oral aripiprazole for 21 days in conjunction with first dose of aripiprazole lauroxil based on the current oral aripiprazole dose (see conversion below).
Conversion of oral aripiprazole to IM aripiprazole lauroxil (Aristada):
Oral aripiprazole 10 mg/day: Initial IM aripiprazole lauroxil (Aristada) dose: 441 mg per month.
Oral aripiprazole 15 mg/day: Initial IM aripiprazole lauroxil (Aristada) dose: 662 mg per month or 882 mg every 6 weeks or 1,064 mg every 2 months.
Oral aripiprazole ≥20 mg/day: Initial IM aripiprazole lauroxil (Aristada) dose: 882 mg every month.
Dosage adjustment: Adjust aripiprazole lauroxil dose as needed; if a dose is required earlier than the recommended interval(s), do not administer <14 days after the previous injection.
Missed dose: Administer missed dose as soon as possible. Supplemental dose(s) may be appropriate; see table below. In patients who require oral supplemental dose(s), administer the same dose of oral aripiprazole that the patient was receiving prior to initiation of aripiprazole lauroxil, unless otherwise indicated.
|
Supplemental Dose Recommendations Following Missed Doses | |||
|---|---|---|---|
|
Dose of Last Aripiprazole Lauroxil (Aristada) Injection |
Length of Time Since Last Injection | ||
|
441 mg |
≤6 weeks |
>6 and ≤7 weeks |
>7 weeks |
|
662 mg |
≤8 weeks |
>8 and ≤12 weeks |
>12 weeks |
|
882 mg |
≤8 weeks |
>8 and ≤12 weeks |
>12 weeks |
|
1,064 mg |
≤10 weeks |
>10 and ≤12 weeks |
>12 weeks |
|
Dosage and Administration for Re-initiation of Aripiprazole Lauroxil (Aristada) Injection |
No supplementation required |
Supplement with: 1) Oral aripiprazole for 7 days or 2) Single dose of aripiprazole lauroxil nanocrystal dispersion (Aristada Initio) 675 mg |
Supplement with: 1) Oral aripiprazole for 21 days or 2) Single dose of aripiprazole lauroxil nanocrystal dispersion (Aristada Initio) 675 mg and a single dose of oral aripiprazole 30 mg |
Discontinuation of therapy: Switching to other treatments is generally advised if side effects are intolerable or treatment is not effective. However, if a patient insists on stopping treatment, gradual dose reduction to avoid withdrawal reactions is generally not needed with long-acting injectable antipsychotics. The risk of withdrawal symptoms from discontinuation of long-acting injectables is low because the rate of drug elimination is slow. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (Ref).
Switching antipsychotics: An optimal, universal strategy for switching antipsychotic drugs has not been established. Strategies include: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Ref). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary.
No dosage adjustment necessary.
Note: Avoid for behavioral problems associated with dementia or delirium unless alternative nonpharmacologic therapies have failed and patient may harm self or others. If used, consider deprescribing attempts to assess continued need and/or lowest effective dose. Of note, use in certain indications may be appropriate (eg, schizophrenia) (Ref).
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Nervous system: Akathisia (11%)
1% to 10%:
Endocrine & metabolic: Weight gain (2%; ≥7% increase: 9% to 10%)
Local: Injection site reaction (4% to 5%), pain at injection site (3% to 4%)
Nervous system: Dystonia (2%), extrapyramidal reaction (5% to 7%), headache (5%), insomnia (3% to 4%), parkinsonism (4%), restlessness (3%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (1% to 2%)
<1%:
Cardiovascular: Orthostatic hypotension
Local: Erythema at injection site, induration at injection site, swelling at injection site
Frequency not defined:
Cardiovascular: Angina pectoris, palpitations, tachycardia
Gastrointestinal: Constipation, xerostomia
Nervous system: Anxiety, dizziness, myasthenia
Neuromuscular & skeletal: Asthenia
Postmarketing: Nervous system: Impulse control disorder (including compulsive shopping, intense gambling urges, binge eating, and hypersexuality)
Hypersensitivity (eg, anaphylaxis, pruritus, urticaria) to aripiprazole or any component of the formulation.
Concerns related to adverse effects:
• Altered cardiac conduction: May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics.
• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC/ANC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm3.
• Cerebrovascular effects: An increased incidence of cerebrovascular effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of antipsychotics for the unapproved use in elderly patients with dementia-related psychosis.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Dyslipidemia: Lipid changes, including increases in total cholesterol, LDL cholesterol, and triglycerides and decreases in HDL cholesterol, have been reported; risk profile may differ between antipsychotic agents. Compared to other antipsychotics, the risk of dyslipidemia with aripiprazole lauroxil is minimal-to-low (Solmi 2017).
• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (eg, Alzheimer disease), particularly in patients >75 years (Herzig 2017; Maddalena 2004).
• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Keepers 2020]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.
• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability.
• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. All patients should be monitored for symptoms of hyperglycemia (eg, polydipsia, polyuria, polyphagia, weakness). Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. Patients with risk factors for diabetes (eg, obesity or family history) should have a baseline fasting blood sugar and periodic assessment of glucose regulation. Hyperglycemia may resolve with discontinuation of therapy; however, some patients may require treatment of diabetes after discontinuation of therapy. Compared to other antipsychotics, the risk of hyperglycemia with aripiprazole lauroxil is minimal-to-low (Solmi 2017).
• Impulse control disorders: Has been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, uncontrolled sexual urges, uncontrolled spending, binge or compulsive eating, and/or other intense urges. Patients with prior history of impulse control issues may be at increased risk. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in most, but not all, cases (Gaboriau 2014; Moore 2014; Smith 2011).
• Neuroleptic malignant syndrome: Use may be associated with neuroleptic malignant syndrome; monitor for mental status changes, fever, muscle rigidity and/or autonomic instability.
• Orthostatic hypotension: May cause orthostatic hypotension; increased risk at initiation of therapy or during dose escalation. 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). Consider using lower starting dosages and slower titrations in these patients.
• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.
• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Monitoring of weight is recommended. Compared to other antipsychotics, the risk of weight gain with aripiprazole lauroxil is minimal (Solmi 2017).
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with cardiac disease, cerebrovascular disease, prior myocardial infarction, ischemic heart disease, or conditions which predispose to hypotension.
• Dementia: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death (APA [Reus 2016]). Aripiprazole lauroxil is not approved for the treatment of dementia-related psychosis.
• 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.
Special populations:
• CYP2D6 poor metabolizers: Known CYP2D6 poor metabolizers may be at risk for elevated aripiprazole concentrations. Avoid use of the 675 mg strength aripiprazole lauroxil nanocrystal dispersion (Aristada Initio) in this population; dose adjustment is required with other strengths of aripiprazole lauroxil (Aristada).
Other warnings/precautions:
• Appropriate use: Medication errors, including substitution and dispensing errors, could occur between the 675 mg strength aripiprazole lauroxil nanocrystal dispersion (Aristada Initio) and other aripiprazole lauroxil strengths (Aristada). The 675 mg strength nanocrystal dispersion (Aristada Initio) is not intended for repeat dosing, and is only used as a single dose in combination with oral aripiprazole for initiation of long-term treatment with intramuscular aripiprazole lauroxil (Aristada) or as a single dose to reinitiate treatment after a missed dose of intramuscular aripiprazole lauroxil (Aristada). The 675 mg strength aripiprazole lauroxil nanocrystal dispersion (Aristada Initio) is not interchangeable with other aripiprazole lauroxil strengths (Aristada).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Prefilled Syringe, Intramuscular:
Aristada: 1064 mg/3.9 mL (3.9 mL); 441 mg/1.6 mL (1.6 mL); 662 mg/2.4 mL (2.4 mL); 882 mg/3.2 mL (3.2 mL)
Prefilled Syringe, Intramuscular [preservative free]:
Aristada Initio: 675 mg/2.4 mL (2.4 mL)
No
Prefilled Syringe (Aristada Initio Intramuscular)
675MG/2.4ML (per mL): $1,182.14
Prefilled Syringe (Aristada Intramuscular)
441 mg/1.6 mL (per mL): $1,158.49
662MG/2.4ML (per mL): $1,159.38
882MG/3.2ML (per mL): $1,158.49
1064MG/3.9ML (per mL): $1,146.71
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
IM: For IM administration only. Administer the 441 mg dose (Aristada) and the 675 mg nanocrystal dispersion dose (Aristada Initio) in the deltoid or gluteal muscle, and other dose strengths (Aristada) in the gluteal muscle. Inject in a rapid and continuous manner. Avoid administering aripiprazole lauroxil nanocrystal dispersion (Aristada Initio) and aripiprazole lauroxil (Aristada) concurrently in the same muscle. Prior to administration, tap the syringe at least 10 times and then shake the syringe vigorously ≥30 seconds to ensure a uniform suspension. If the syringe is not used within 15 minutes, shake again for 30 seconds. Use the appropriate sized needle for the injection site; a 21-gauge, 1 inch or 20-gauge, 1.5-inch needle for deltoid injection and a 20-gauge, 1.5- or 2-inch needle for gluteal injection. Use the longer needles for patients with a larger amount of subcutaneous tissue overlaying the injection site muscle.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Aristada: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207533s017,209830s005lbl.pdf#page=36
Aristada Initio: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207533s017,209830s005lbl.pdf#page=72
Schizophrenia: Treatment of schizophrenia in adults.
Limitations of use: The 675 mg strength aripiprazole lauroxil nanocrystal dispersion (Aristada Initio) is only to be used as a single dose in combination with oral aripiprazole for initiation of long-term treatment with aripiprazole lauroxil (Aristada) or as a single dose to reinitiate treatment after a missed dose of aripiprazole lauroxil (Aristada). It is not intended for repeat dosing.
ARIPiprazole may be confused with proton pump inhibitors (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, RABEprazole)
Aristada may be confused with Arista AH (hemostatic device), Arixtra
Beers Criteria: Antipsychotics are identified in the Beers Criteria as potentially inappropriate medications to be avoided in patients 65 years and older due to an increased risk of stroke and a greater rate of cognitive decline and mortality in patients with dementia. Evidence also suggests there may be an increased risk of mortality with use independent of dementia. Avoid antipsychotics for behavioral problems associated with dementia or delirium unless alternative nonpharmacologic therapies have failed and patient may harm self or others. In addition, antipsychotics should be used with caution in older adults due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults. Use may be appropriate for labeled indications including schizophrenia, bipolar disorder, Parkinson disease psychosis, major depressive disorder, or for short-term use as an antiemetic (Beers Criteria [AGS 2023]).
Substrate of CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Agents With Seizure Threshold Lowering Potential: May enhance the adverse/toxic effect of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy
Amisulpride (Oral): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of neuroleptic malignant syndrome or increased QTc interval may be increased. Risk C: Monitor therapy
Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider avoiding atypical antipsychotic use in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modification
ARIPiprazole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Asenapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Benperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
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 coadministered with blonanserin. Risk D: Consider therapy modification
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brexpiprazole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Cabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combination
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Cariprazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
ChlorproMAZINE: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ChlorproMAZINE. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Clothiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
CloZAPine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP2D6 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Decrease aripiprazole lauroxil dose to next lower strength if used with strong CYP2D6 inhibitors for over 14 days. No dose adjustment needed if using the lowest dose (441 mg) or if a CYP2D6 PM. Max dose is 441 mg if also taking strong CYP3A4 inhibitors. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of ARIPiprazole Lauroxil. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Patients taking the 441 mg dose of aripiprazole lauroxil increase their dose to 662 mg if used with a strong CYP3A4 inducer for more than 14 days. No dose adjustment is necessary for patients using the higher doses of aripiprazole lauroxil. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of ARIPiprazole Lauroxil. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Decrease aripiprazole lauroxil dose to next lower strength if used with strong CYP3A4 inhibitors for over 14 days. No dose adjustment needed if using the lowest dose (441 mg). Max dose is 441 mg in CYP2D6 PMs or if also taking strong CYP2D6 inhibitors. Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Deutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor therapy
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Donepezil: May enhance the neurotoxic (central) effect of Antipsychotic Agents. Risk C: Monitor therapy
Doxylamine: CNS Depressants may enhance the CNS depressant effect of Doxylamine. Risk C: Monitor therapy
DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Flupentixol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
FluPHENAZine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Galantamine: May enhance the neurotoxic (central) effect of Antipsychotic Agents. Risk C: Monitor therapy
Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Risk C: Monitor therapy
Haloperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Haloperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Huperzine A: May enhance the neurotoxic (central) effect of Antipsychotic Agents. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Iloperidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iloperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Loxapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Loxapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Lumateperone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Lurasidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination
MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for extrapyramidal symptoms and excessive sedation may be increased. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Molindone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
OLANZapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of OLANZapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone 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. Risk D: Consider therapy modification
Paliperidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Periciazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Perphenazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Pimozide: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Pimozide. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Pipamperone [INT]: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Pipamperone [INT]. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Piribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Risk X: Avoid combination
Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Prochlorperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Promazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
QUEtiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of QUEtiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Risk C: Monitor therapy
RisperiDONE: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of RisperiDONE. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Rivastigmine: May enhance the neurotoxic (central) effect of Antipsychotic Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
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. Risk C: Monitor therapy
Sertindole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sertindole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor therapy
Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Risk X: Avoid combination
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for NMS and extrapyramidal symptoms may be increased. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Thioridazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Thioridazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Thiothixene: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Trifluoperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ziprasidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Ziprasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Zuclopenthixol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Aripiprazole crosses the placenta; aripiprazole and dehydro-aripiprazole can be detected in the cord blood at delivery (Nguyen 2011; Watanabe 2011).
Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization.
Data collection to monitor pregnancy and infant outcomes following exposure to aripiprazole lauroxil is ongoing. Health care providers are encouraged to enroll women exposed to aripiprazole lauroxil during pregnancy in the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry.
Aripiprazole is present in breast milk. The manufacturer recommends the development and health benefits of breastfeeding be considered along with the mother's clinical need for therapy and any potential adverse effects on the breastfed infant from aripiprazole or from the underlying maternal condition. Available data is related to the use of the oral preparation; refer to the Aripiprazole monograph for additional information.
|
Frequency of Antipsychotic Monitoringa,b | ||
|---|---|---|
|
Monitoring parameter |
Frequency of monitoring |
Comments |
|
Adherence |
Every visit |
|
|
Blood chemistries (electrolytes, renal function, liver function, TSH) |
Annually |
|
|
CBC |
As clinically indicated |
Check frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia |
|
Extrapyramidal symptoms |
Every visit; 4 weeks after initiation and dose change; annually. Use a formalized rating scale at least annually or every 6 months if high riskc |
|
|
Fall risk |
Every visit |
|
|
Fasting plasma glucose/HbA1c |
12 weeks after initiation and dose change; annually |
Check more frequently than annually if abnormal. Follow diabetes guidelines. |
|
Lipid panel |
12 weeks after initiation and dose change; annually |
Check more frequently than annually if abnormal. Follow lipid guidelines. |
|
Mental status and alertness |
Every visit |
|
|
Metabolic syndrome history |
Annually |
Evaluate for personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease |
|
Prolactin |
Ask about symptoms at every visit until dose is stable. Check prolactin level if symptoms are reported. |
Hyperprolactinemia symptoms: Changes in menstruation, libido, gynecomastia, development of galactorrhea, and erectile and ejaculatory function |
|
Tardive dyskinesia |
Every visit; annually. Use a formalized rating scale at least annually or every 6 months if high riskd |
|
|
Vital signs (BP, orthostatics, temperature, pulse, signs of infection) |
Every visit (at least weekly during first 3 to 4 weeks of treatment); 4 weeks after dose change. |
|
|
Weight/Height/BMI |
8 and 12 weeks after initiation and dose change; quarterly |
Consider monitoring waist circumference at baseline and annually, especially in patients with or at risk for metabolic syndrome. Consider changing antipsychotic if BMI increases by ≥1 unit. Some experts recommend checking weight and height at every visit. |
|
a For all monitoring parameters, it is appropriate for check at baseline and when clinically relevant (based on symptoms or suspected ADRs) in addition to the timeline. b ADA 2004; APA [Keepers 2020]; de Hert 2011; Gugger 2011; manufacturer’s labeling. c Risk factors for extrapyramidal symptoms (EPS) include prior history of EPS, high doses of antipsychotics, young age (children and adolescents at higher risk than adults), and dopaminergic affinity of individual antipsychotic. d Risk factors for tardive dyskinesia include age >55 years; females; White or African ethnicity; presence of a mood disorder, intellectual disability, or CNS injury; and past or current EPS. | ||
Aripiprazole lauroxil is a prodrug of aripiprazole. Following intramuscular injection, aripiprazole lauroxil is likely converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole. Aripiprazole is a quinolinone antipsychotic that exhibits high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors; moderate affinity for D4, 5-HT2C, 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-HT1A receptors, and as an antagonist at the 5-HT2A receptor (de Bartolomeis 2015).
Onset of action:
Aristada: 5 to 6 days following injection; within 4 days following injection when administered concomitantly with oral aripiprazole.
Aristada Initio (675 mg strength nanocrystal dispersion): Reaches systemic circulation on day of injection; reaches clinically relevant serum concentrations 4 days following injection when administered concomitantly with oral aripiprazole 30 mg.
Duration of action: Aristada: 36 days following appearance in the systemic circulation.
Distribution: Vd: 268 L.
Protein binding: >99%, primarily to albumin.
Metabolism: Prodrug; undergoes enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole followed by enzyme-mediated hydrolysis to aripiprazole. Aripiprazole undergoes hepatic metabolism via CYP2D6, CYP3A4 (dehydro-aripiprazole metabolite has affinity for D2 receptors similar to the parent drug and represents 40% of the parent drug exposure in plasma) (Sheehan 2010).
Half-life elimination:
Aristada: 53.9 to 57.2 days.
Aristada Initio (675 mg strength nanocrystal dispersion): 15 to 18 days.
Time to peak, serum: Aristada Initio (675 mg strength nanocrystal dispersion): 16 to 35 days (median 27 days).
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