Aristada

Name: Aristada

How should this medicine be used?

Aripiprazole injection comes as a solution (liquid) to be injected into a muscle by a healthcare provider. Aripiprazole extended-release injection come as a powder to be mixed with water (Abilify Maintena) and as a suspension (liquid) (Aristada) to be injected into a muscle by a healthcare provider. Aripiprazole injection is usually given as needed for agitation. If you are still agitated after you receive your first dose, you may be given one or more additional doses. Aripiprazole extended-release injection is usually given either once every 4 weeks (Abilify Maintena) or once every 4 or 6 weeks (Aristada).

Aripiprazole extended-release injection may help control your symptoms but will not cure your condition. Continue to keep appointments to receive aripiprazole extended-release injection even if you feel well. Talk to your doctor if you do not feel like you are getting better during your treatment with aripiprazole extended-release injection.

Clinical pharmacology

Mechanism Of Action

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. The mechanism of action of aripiprazole in schizophrenia is unknown. However, efficacy could be mediated through a combination of partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors.

Pharmacodynamics

Aripiprazole exhibits high affinity for dopamine D2 and D3 (Kis 0.34 and 0.8 nM respectively), serotonin 5-HT1A and 5-HT2A receptors (Kis 1.7 and 3.4 nM respectively), moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors (Kis 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). Actions at receptors other than D2, 5-HT1A, and 5-HT2A could explain some of the adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).

Pharmacokinetics

ARISTADA is a prodrug of aripiprazole and its activity is primarily due to aripiprazole, and to a lesser extent dehydro-aripiprazole (major metabolite of aripiprazole), which has been shown to have affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma.

Absorption

After single intramuscular injection the appearance of aripiprazole in the systemic circulation starts from 5 to 6 days and continues to be released for an additional 36 days. Aripiprazole concentrations increase with consecutive doses of ARISTADA and reach steady-state four months following treatment initiation. The concentration-time course of dehydro-aripiprazole followed that of aripiprazole.

With the addition of oral aripiprazole supplementation for 21 days at the time of the first ARISTADA dose, aripiprazole concentrations reach therapeutic levels within 4 days.

Aripiprazole exposure was similar for deltoid and gluteal intramuscular injections of 441 mg ARISTADA, thus are interchangeable.

Administration of 882 mg every 6 weeks or 1064 mg every 2 months results in plasma aripiprazole concentrations that were similar to exposure with 662 mg monthly and are within the range provided by doses of 441 mg monthly and 882 mg monthly. The doses of 441 mg monthly and 882 monthly showed a similar clinical response to each other.

Distribution

Based on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of ARISTADA was 268 L, indicating extensive extravascular distribution following absorption. At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. In healthy human volunteers administered 0.5 mg/day to 30 mg/day oral aripiprazole for 14 days, there was dose-dependent D2 receptor occupancy indicating brain penetration of aripiprazole in humans.

Elimination

Metabolism

The biotransformation of ARISTADA likely involves enzyme-mediated hydrolysis to form N-hydroxymethyl-aripiprazole, which subsequently undergoes hydrolysis to aripiprazole. Elimination of aripiprazole is mainly through hepatic metabolism involving CYP3A4 and CYP2D6. [see DOSAGE AND ADMINISTRATION].

Excretion

The mean aripiprazole terminal elimination half-life ranged from 53.9 days to 57.2 days after monthly, every 6-week and every 2 month injections of ARISTADA. The significantly longer aripiprazole apparent half-life compared to oral aripiprazole (mean 75 hours) is attributed to the dissolution and formation rate-limited elimination of aripiprazole following ARISTADA administration.

Drug Interaction Studies

No specific drug interaction studies have been performed with ARISTADA. The drug interaction data provided below is obtained from studies with oral aripiprazole.

Effects of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 1 and Figure 2, respectively. Based on simulation, a 4.5-fold increase in mean Cmax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. After oral administration, a 3-fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors.

Figure 1: The Effects of Other Drugs on Aripiprazole Pharmacokinetics

Figure 2: The Effects of Other Drugs on Dehydro-aripiprazole Pharmacokinetics

The effects of aripiprazole on the exposures of other drugs are summarized in Figure 3.

Figure 3: The Effects of Oral Aripiprazole on Pharmacokinetics of Other Drugs

Specific Population Studies

A population pharmacokinetic analysis showed no effect of sex, race or smoking on ARISTADA pharmacokinetics [see Use in Specific Populations].

Exposures of aripiprazole and dehydro-aripiprazole using oral aripiprazole in specific populations are summarized in Figure 4 and Figure 5, respectively.

Figure 4: Effects of Intrinsic Factors on Aripiprazole Pharmacokinetics

Figure 5: Effects of Intrinsic Factors on Dehydro-aripiprazole Pharmacokinetics

Animal Toxicology And/Or Pharmacology

Intramuscular administration of aripiprazole lauroxil to rats and dogs was associated with injection site tissue reactions at all doses in rats treated up to 6 months at doses of 15, 29, and 103 mg/animal (which are approximately 0.3 to 2 times and 0.5 to 3 times the maximum recommended human dose [MRHD] of 1064 mg on mg/m² basis in males and females, respectively) and in dogs treated up to 9 months at doses of 147, 662, and 2058 mg/animal (which are approximately 0.5 to 6 times and 0.6 to 8 times the MRHD in males and females, respectively on mg/m² basis). These injection site tissue reactions consisted of localized granulomatous inflammation and granuloma formation. Transiently impaired limb function and swelling occurred in dogs. The granulomas did not completely resolve 2 months following the last injection in the 6 month rat study and 4 months following the last injection in the 9 month dog study (the low dose groups were not examined for reversibility in these studies).

Orally administered aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg, which is 19 times the oral MRHD of 30 mg/day on mg/m² basis, and in a 2-year carcinogenicity study at doses of 40 mg/kg and 60 mg/kg, which are 13 and 19 times the oral MRHD on mg/m² basis and 7 to 14 times human exposure at the oral MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.

Clinical Studies

Efficacy Of ARISTADA (441 mg monthly and 882 mg monthly)

The efficacy of ARISTADA in the treatment of patients with schizophrenia was established, in part, on the basis of efficacy data from trials with the oral formulation of aripiprazole. In addition, the efficacy of ARISTADA was established in a 12-week, randomized, double-blind, placebo-controlled, fixed-dose study in adult patients with schizophrenia meeting DSM-IV TR criteria [Study 1, n = 622; 207 (ARISTADA 441 mg monthly), 208 (ARISTADA 882 mg monthly), and 207 (placebo)]. After establishing tolerability to oral aripiprazole, patients received oral aripiprazole or placebo daily for the first 3 weeks. The intramuscular (IM) injections were administered on Days 1, 29 and 57.

Efficacy was assessed using Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Improvement Scale (CGI-I):

  • The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme). Total PANSS scores range from 30 to 210.
  • The CGI-I rates improvement in mental illness on a scale of 1 (very much improved) to 7 (very much worse) based on the change from baseline in clinical condition.

Eligible patients were 18 to 70 years of age with PANSS total score of 70 to 120 and a score of ≥ 4 for at least 2 of the selected Positive Scale items. Patients were also required to have a CGI-S score of ≥ 4.

The primary efficacy variable was the change from baseline to endpoint (Day 85) in PANSS total score. Statistically significant separation from placebo on PANSS total score change was observed in each ARISTADA dose group (Table 11).

Table 11: Primary Efficacy Results

Study Number Treatment Group Primary Efficacy Measure: PANSS Total Score
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI)
Study 1 ARISTADA 441 mg monthlyb 92.6
(10.2)
-20.9
(1.4)
-10.9
(-14.5, -7.3)
ARISTADA 882 mg monthlyb 92.0
(10.8)
-21.8
(1.4)
-11.9
(-15.4, -8.3)
Placebo 93.9
(11.3)
-9.8
(1.4)
--
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiple comparisons.
a Difference (drug minus placebo) in least-squares mean change from baseline.
b Doses that are demonstrated to be effective.

Figure 6: Change from Baseline in PANSS Total Score

Abbreviations: AL= ARISTADA; PBO=placebo; PANSS=Positive and Negative Syndrome Scale. Vertical dotted line indicates end of oral supplementation.

Subgroup analyses did not suggest any clear evidence of differential responsiveness in treatment outcome as a function of age, gender, race, or weight.

The secondary efficacy endpoint was defined as the CGI-I score at Day 85. Both ARISTADA treatment groups demonstrated statistically significantly better CGI-I scores versus placebo.

Efficacy Of ARISTADA 662 mg Monthly, 882 mg Every 6 Weeks And 1064 mg Every 2 Months

The efficacy of ARISTADA 662 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months in the treatment of adults with schizophrenia was established by pharmacokinetic bridging which demonstrated that these dosing regimens resulted in plasma aripiprazole concentrations that are within the range provided by doses of 441 mg monthly and 882 mg monthly. As depicted in Figure 6, the doses of 441 mg monthly and 882 mg monthly showed clinical responses similar to each other in the ARISTADA placebo-controlled trial.

Aristada Overdose

If Aristada is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Warnings

Black Box Warnings

Not approved for dementia-related psychosis; patients with dementia-related psychosis who are treated with antipsychotic drugs are at increased risk of death, as shown in short-term controlled trials; deaths reported in trials appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature

Antidepressants increased risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 years) taking antidepressants for major depressive disorders and other psychiatric illnesses, as shown in short-term studies; monitor for worsening and emergence of suicidal thoughts and behaviors

Contraindications

Documented hypersensitivity for aripiprazole

Cautions

Risk of extrapyramidal symptoms (EPS) (eg, pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia; monitor

Tardive dyskinesia may occur; may consider discontinuation of therapy if clinically indicated

Use may be associated with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity and/or autonomic instability

May cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries; perform complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy

Use caution in patients with known cardiovascular disease, cerebrovascular disease, or predisposition to hypotension; may increase incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities)

Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope

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

May increase risk of suicidal tendencies in children and adolescents

FDA warning regarding off-label use for dementia in elderly

Patients may act on dangerous impulses

Monitor for orthostatic hypotension

May cause seizures or convulsions; use cautiously in patients with history of seizures or with conditions that lower the seizure threshold

May cause CNS depression, which may impair physical or mental abilities; use caution when operating heavy machinery

Use caution in patients at risk of pneumonia; antipsychotic therapy has been associated with esophageal dysmotility and aspiration

Impairment of core body temperature regulation possible; use caution in dehydration, heat exposure, strenuous exercise, and concomitant medication possessing anticholinergic effects

Leukopenia, neutropenia, and agranulocytosis

  • Leukopenia/neutropenia and agranulocytosis reported; possible risk factors for leukopenia/neutropenia include preexisting low white blood cell (WBC) count and history of drug-induced leukopenia/neutropenia
  • If patient has history of clinically significant low WBC count or drug-induced leukopenia/neutropenia, monitor complete blood count (CBC) frequently during first few months of therapy; discontinue drug at first sign of clinically significant WBC decline <1000/mcL in absence of other causative factors, and continue monitoring WBC count until recovery

Metabolic changes

  • Atypical antipsychotics have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk, including dyslipidemia and body weight gain
  • Increased risk of hyperglycemia and diabetes; in some cases, hyperglycemia concomitant with use of atypical antipsychotics has been associated with ketoacidosis, hyperosmolar coma, or death; monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness; monitor glucose regularly in patients with and at risk for diabetes
  • Significant weight gain reported with therapy; monitor waist circumference and BMI

Uses of Aristada

  • It is used to treat schizophrenia.

What are some other side effects of Aristada?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Headache.
  • Weight gain.
  • Restlessness.
  • Irritation where the shot is given.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

How do I store and/or throw out Aristada?

  • If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

Aristada Dosage and Administration

2.1 Recommended Dosage

Aristada is only to be administered as an intramuscular injection by a healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with Aristada. Due to the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability. Refer to the prescribing information of oral aripiprazole for the recommended dosage and administration of the oral formulation.

Depending on individual patient's needs, treatment with Aristada can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg administered every 6 weeks or 1064 mg administered every 2 months. The 441 mg, 662 mg, 882 mg and 1064 mg doses correspond to 300 mg, 450 mg, 600 mg and 724 mg of aripiprazole, respectively [see Clinical Pharmacology (12.3)]. In conjunction with the first Aristada injection, administer treatment with oral aripiprazole for 21 consecutive days.

Table 1: Aristada Dosing Frequency and Site of Injection
Dose Dosing Frequency Site of Intramuscular Injection
441 mg Monthly Deltoid or Gluteal
662 mg Monthly Gluteal
882 mg Monthly or every 6 weeks Gluteal
1064 mg Every 2 months Gluteal

Use the following Aristada doses for patients who are stabilized on oral aripiprazole, as shown in Table 2.

Table 2: Aristada Doses Based on Oral Aripiprazole Total Daily Dose
Oral Aripiprazole Dose Intramuscular Aristada Dose Concomitant Oral Aripiprazole (duration)
10 mg per day 441 mg every month First 21 days
15 mg per day 662 mg every month
882 mg every 6 weeks
1064 mg every 2 months
First 21 days
20 mg or higher per day 882 mg every month First 21 days

In conjunction with the first Aristada injection, continue treatment with oral aripiprazole for 21 consecutive days.

Dose may be adjusted as needed. When making dose and dosing interval adjustments, the pharmacokinetics and prolonged-release characteristics of Aristada should be considered [see Clinical Pharmacology (12.3)].

2.2 Missed Doses

When a dose is missed, administer the next injection of Aristada as soon as possible. If the time elapsed since the last Aristada injection exceeds the length of time noted in Table 3, use oral aripiprazole supplementation with the next Aristada injection as recommended below.

Table 3: Recommendation for Concomitant Oral Aripiprazole Supplementation Following Missed Dosesa

a The patient should supplement with the same dose of oral aripiprazole as when the patient began Aristada (see Table 2).

Dose of Patient's Last Aristada Injection Length of Time Since Last Injection
No Oral Supplementation Required Supplement with 7 Days Oral Aripiprazole Supplement with 21 Days Oral Aripiprazole
Monthly 441 mg ≤ 6 weeks > 6 and ≤ 7 weeks > 7 weeks
Monthly 662 mg ≤ 8 weeks > 8 and ≤ 12 weeks > 12 weeks
Monthly 882 mg ≤ 8 weeks > 8 and ≤ 12 weeks > 12 weeks
882 mg every 6 weeks ≤ 8 weeks > 8 and ≤ 12 weeks > 12 weeks
1064 mg every 2 months ≤ 10 weeks > 10 and ≤ 12 weeks > 12 weeks

Early Dosing

The recommended Aristada dosing interval is monthly for the 441 mg, 662 mg and 882 mg doses, every 6 weeks for the 882 mg dose, or every 2 months for the 1064 mg dose and should be maintained. In the event of early dosing, an Aristada injection should not be given earlier than 14 days after the previous injection.

Dose Adjustments for CYP450 Considerations

Refer to the prescribing information for oral aripiprazole for recommendations regarding dosage adjustments due to drug interactions, for the first 21 days when the patient is taking oral aripiprazole concomitantly with the first dose of Aristada.

Once stabilized on Aristada, refer to the dosing recommendations below for patients taking CYP2D6 inhibitors, CYP3A4 inhibitors, or CYP3A4 inducers:

  • No dosage changes recommended for Aristada, if CYP450 modulators are added for less than 2 weeks.
  • Make dose changes to Aristada if CYP450 modulators are added for greater than 2 weeks (see Table 4).
Table 4: Aristada Dose Adjustments with Concomitant CYP450 Modulator Use

a For the 882 mg dose administered every 6 weeks and the 1064 mg administered every 2 months, the next lower strength should be 441 mg administered monthly.

Concomitant Medicine Dose Change for Aristadaa
Strong CYP3A4 Inhibitor Reduce the dose of Aristada to the next lower strength. No dosage adjustment is necessary in patients taking 441 mg Aristada, if tolerated.
For patients known to be poor metabolizers of CYP2D6: Reduce dose to 441 mg from 662 mg, 882 mg, or 1064 mg. No dosage adjustment is necessary in patients taking 441 mg Aristada, if tolerated.
Strong CYP2D6 Inhibitor Reduce the dose of Aristada to the next lower strength. No dosage adjustment is necessary in patients taking 441 mg Aristada, if tolerated.
For patients known to be poor metabolizers of CYP2D6: No dose adjustment required.
Both Strong CYP3A4 Inhibitor and Strong CYP2D6 Inhibitor Avoid use for patients at 662 mg, 882 mg, or 1064 mg dose. No dosage adjustment is necessary in patients taking 441 mg Aristada, if tolerated.
CYP3A4 Inducers No dose adjustment for 662 mg, 882 mg, or 1064 mg dose; increase the 441 mg dose to 662 mg.

Important Administration Instructions

The kit contains a syringe containing Aristada sterile aqueous suspension and 2 or 3 safety needles depending on dose (a 2-inch 20 gauge needle with yellow needle hub, a 1 ½-inch 20 gauge needle with yellow needle hub, and a 1-inch 21 gauge needle with green needle hub (441 mg kit only)) for intramuscular injection. All materials should be stored at room temperature.

A | 5 ML SYRINGE containing Aristada sterile aqueous suspension

B | 20 GAUGE NEEDLE, 2-INCH with yellow needle hub

C | 20 GAUGE NEEDLE, 1½-INCH with yellow needle hub

D | 21 GAUGE NEEDLE, 1-INCH with green needle hub

1. TAP and SHAKE the syringe.

1a. Tap the syringe at least 10 times to dislodge any material which may have settled.

1b. Shake the syringe vigorously for a minimum of 30 seconds to ensure a uniform suspension. If the syringe is not used within 15 minutes, shake again for 30 seconds.

2. SELECT the injection needle.

2a. Select injection site.

2b. Select needle length based on injection site. For patients with a larger amount of subcutaneous tissue overlaying the injection site muscle, use the longer of the needles provided.

Table 5: Injection Site and Associated Needle Length
INJECTION SITE NEEDLE LENGTH
441 mg dose
Deltoid 21 GAUGE, 1-INCH or 20 GAUGE, 1½-INCH
Gluteal 20 GAUGE, 1½-INCH or 20 GAUGE, 2-INCH
662 mg dose
Gluteal 20 GAUGE, 1½-INCH or 20 GAUGE, 2-INCH
882 mg dose
Gluteal 20 GAUGE, 1½-INCH or 20 GAUGE, 2-INCH
1064 mg dose
Gluteal 20 GAUGE, 1½-INCH or 20 GAUGE, 2-INCH

3. ATTACH the injection needle.

Attach the appropriate needle securely with a clockwise twisting motion. Do NOT overtighten. Overtightening could lead to needle hub cracking.

4. PRIME the syringe to remove air.

4a. Bring the syringe into upright position and tap the syringe to bring air to the top.

4b. Remove air by depressing the plunger rod. A few drops of suspension will be released.

5. ADMINISTER the entire content intramuscularly. Do not inject by any other route. Inject in a rapid and continuous manner (less than 10 seconds).

6. DISPOSE of the needle. Cover the needle by pressing the safety device. Dispose of used and unused items in a proper waste container.

Warnings and Precautions

Increased Mortality in Elderly Patients with Dementia-related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Aristada is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.2)].

Cerebrovascular Adverse Reactions, Including Stroke

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated patients. Aristada is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1)].

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur in association with antipsychotic drugs, including Aristada. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been reported.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.

Given these considerations, Aristada should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient treated with Aristada drug discontinuation should be considered. However, some patients may require treatment with Aristada despite the presence of the syndrome.

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia/ Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with oral aripiprazole. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients require continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

In the long-term, open-label schizophrenia study with Aristada, 14% of patients with normal hemoglobin A1c (<5.7%) at baseline developed elevated levels (≥5.7%) post-baseline.

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

In the long-term, open-label schizophrenia study with Aristada, shifts in baseline fasting total cholesterol from normal (<200 mg/dL) to high (≥240 mg/dL) were reported in 1% of patients; shifts in baseline fasting LDL cholesterol from normal (<100 mg/dL) to high (≥160 mg/dL) were reported in 1% of patients; and shifts in baseline fasting triglycerides from normal (<150 mg/dL) to high (≥200 mg/dL) were reported in 8% of patients. In the same study, shifts in baseline fasting total cholesterol from borderline (≥ 200 mg/dL and <240 mg/dL) to high (≥240 mg/dL) were reported in 15% of patients; shifts in baseline fasting LDL cholesterol from borderline (≥100 mg/dL and <160 mg/dL) to high (≥160 mg/dL) were reported in 8% of patients; and shifts in baseline fasting triglycerides from borderline (≥150 mg/dL and <200 mg/dL) to high (≥200 mg/dL) were reported in 35% of patients. In addition, the proportion of patients with shifts in fasting HDL cholesterol from normal (≥40 mg/dL) to low (<40 mg/dL) was reported in 15% of patients.

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

The proportion of adult patients with weight gain ≥7% of body weight is presented in Table 7.

Table 7: Proportion of Adult Patients with Shifts in Weight in the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trial
Placebo
N = 207
(%)
Aristada
441 mg
N = 207
(%)
882 mg
N = 208
(%)
Weight Gain
≥7% increase from baseline 6 10 9

5.6 Pathological Gambling and Other Compulsive Behaviors

Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviors may result in harm for the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.

Orthostatic Hypotension

Aripiprazole may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions related to orthostatic hypotension can include dizziness, lightheadedness and tachycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose, and monitor orthostatic vital signs.

Orthostatic hypotension was reported for one patient in the Aristada 882 mg group (0.5%) and no patients in the Aristada 441 mg and placebo groups in the 12-week schizophrenia efficacy study [see Clinical Studies (14)]. In the long-term open-label schizophrenia study, orthostatic hypotension was reported for 1 (0.2%) patient treated with Aristada. Orthostatic hypotension was defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when comparing standing to supine values.

Falls

Antipsychotics including Aristada may cause somnolence, postural hypotension, or motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for those patients on long-term antipsychotic therapy.

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of Aristada at the first sign of a clinical significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue Aristada in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.

Seizures

As with other antipsychotic drugs, use Aristada cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Potential for Cognitive and Motor Impairment

Aristada, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with Aristada does not affect them adversely.

Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Aristada for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aristada and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Overdosage

Human Experience

The largest known case of acute ingestion with a known outcome involved 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) in a patient who fully recovered.

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

Management of Overdosage

In case of overdosage, call the Poison control center immediately at 1-800-222-1222.

How is Aristada given?

Aristada is injected into a muscle once every month. A healthcare provider will give you this injection.

If you have never used Aristada before, your doctor may want to you also take this medicine by mouth (in a tablet or liquid form) for 2 weeks after your first injection.

Keep using all of your other anti-psychotic medications for at least 2 weeks after your first injection of Aristada.

Drink plenty of liquids. You can easily become dehydrated while using Aristada.

Your doctor will need to check your progress while you are using this medicine.

What should I avoid while receiving Aristada?

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Dizziness or severe drowsiness can cause falls, fractures, or other injuries.

Avoid drinking alcohol. Dangerous side effects could occur.

Avoid becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise. It is easier to become dangerously overheated and dehydrated while you are using Aristada.

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