Drug: Abilify Maintena

Aripiprazole is an atypical antipsychotic which is present in ABILIFY MAINTENA as its monohydrate polymorphic form. Aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)- 1-piperazinyl]butoxy]-3,4 dihydrocarbostyril monohydrate. The empirical formula is C23H27Cl2N3O2•H2O and its molecular weight is 466.40. The chemical structure is: ABILIFY MAINTENA (aripiprazole) is an extended-release injectable suspension available in 400-mg or 300-mg strength pre-filled dual chamber syringes and 400-mg or 300-mg strength vials. The labeled strengths are calculated based on the anhydrous form (aripiprazole). Inactive ingredients (per administered dose) for 400 mg and 300 mg strength products, respectively, include carboxymethyl cellulose sodium (16.64 mg and 12.48 mg), mannitol (83.2 mg and 62.4 mg), sodium phosphate monobasic monohydrate (1.48 mg and 1.11 mg) and sodium hydroxide (pH adjuster).

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The following adverse reactions are discussed in more detail in other sections of the labeling:
  • Increased Mortality in Elderly Patients with Dementia - Related Psychosis Use [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
  • Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
  • Neuroleptic Malignant Syndrome [see WARNINGS AND PRECAUTIONS]
  • Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS]
  • Metabolic Changes [see WARNINGS AND PRECAUTIONS]
  • Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS]
  • Leukopenia, Neutropenia, and Agranulocytosis [see WARNINGS AND PRECAUTIONS]
  • Seizures [see WARNINGS AND PRECAUTIONS]
  • Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS]
  • Body Temperature Regulation [see WARNINGS AND PRECAUTIONS]
  • Dysphagia [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety Database of ABILIFY MAINTENA and Oral Aripiprazole Aripiprazole has been evaluated for safety in 16,114 adult patients who participated in multiple-dose, clinical trials in schizophrenia and other indications, and who had approximately 8,578 patient-years of exposure to oral aripiprazole. A total of 3,901 patients were treated with oral aripiprazole for at least 180 days, 2,259 patients were treated with oral aripiprazole for at least 360 days, and 933 patients continuing aripiprazole treatment for at least 720 days. ABILIFY MAINTENA 300-400 mg every 4 weeks has been evaluated for safety in 1,287 adult patients in clinical trials in schizophrenia, with approximately 1,281 patient-years of exposure to ABILIFY MAINTENA. A total of 832 patients were treated with ABILIFY MAINTENA for at least 180 days (at least 7 consecutive injections) and 630 patients treated with ABILIFY MAINTENA had at least 1 year of exposure (at least 13 consecutive injections). The conditions and duration of treatment with ABILIFY MAINTENA included doubleblind and open-label studies. The safety profile of ABILIFY MAINTENA is expected to be similar to that of oral aripiprazole. Therefore, most of the safety data presented below are derived from trials with the oral formulation. In patients who tolerated and responded to treatment with oral aripiprazole and single-blind ABILIFY MAINTENA and were then randomized to receive ABILIFY MAINTENA or placebo injections under double-blind conditions, the incidence of adverse reactions was similar between the two treatment groups. Adverse Reactions of ABILIFY MAINTENA and Oral Aripiprazole Adverse Reactions Associated with Discontinuation of Oral Aripiprazole Based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral aripiprazole was administered to adults with schizophrenia in doses ranging from 2 mg/day to 30 mg/day, the incidence of discontinuation due to adverse reactions was 7% in oral aripiprazole-treated and 9% in placebo-treated patients. The types of adverse reactions that led to discontinuation were similar for the aripiprazole-treated and placebo-treated patients. Commonly Observed Adverse Reactions of Oral Aripiprazole Based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral aripiprazole was administered to adults with schizophrenia in doses ranging from 2 mg/day to 30 mg/day, the only commonly observed adverse reaction associated with the use of oral aripiprazole in patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%). Less Common Adverse Reactions in Adults Treated with Oral Aripiprazole Table 7 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania), including only those reactions that occurred in 2% or more of patients treated with oral aripiprazole (doses ≥ 2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset. Table 7: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral Aripiprazole
System Organ Class Preferred Term Percentage of Patients Reporting Reactiona Oral Aripiprazole
(n=1843) Placebo
(n=1166) Eye Disorders   Blurred Vision 3 1 Gastrointestinal Disorders   Nausea 15 11   Constipation 11 7   Vomiting 11 6   Dyspepsia 9 7   Dry Mouth 5 4   Toothache 4 3   Abdominal Discomfort 3 2   Stomach Discomfort 3 2 General Disorders and Administration Site Conditions   Fatigue 6 4   Pain 3 2 Musculoskeletal and Connective Tissue Disorders   Musculoskeletal Stiffness 4 3   Pain in Extremity 4 2   Myalgia 2 1   Muscle Spasms 2 1 Nervous System Disorders   Headache 27 23   Dizziness 10 7   Akathisia 10 4   Sedation 7 4   Extrapyramidal Disorder 5 3   Tremor 5 3   Somnolence 5 3 Psychiatric Disorders   Agitation 19 17   Insomnia 18 13   Anxiety 17 13   Restlessness 5 3 Respiratory, Thoracic, and Mediastinal Disorders   Pharyngolaryngeal Pain 3 2   Cough 3 2 a Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race. Dose-Related Adverse Reactions of Oral Aripiprazole Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed oral doses of aripiprazole (2 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, and 30 mg/day) to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%). Injection Site Reactions of ABILIFY MAINTENA In the open-label, stabilization phase of a study with ABILIFY MAINTENA in patients with schizophrenia, the percent of patients reporting any injection site-related adverse reaction was 6.3% for ABILIFY MAINTENA-treated patients. The mean intensity of injection pain reported by subjects using a visual analog scale (0=no pain to 100=unbearably painful) was minimal and improved in subjects receiving ABILIFY MAINTENA from the first to the last injection in the open-label, stabilization phase (6.1 to 4.9). Investigator evaluation of the injection site for pain, swelling, redness and induration following injections of ABILIFY MAINTENA in the open-label, stabilization phase were rated as absent for 74%-96% of subjects following the first injection and 77%-96% of subjects following the last injection. Extrapyramidal Symptoms of Oral Aripiprazole In short-term, placebo-controlled trials in schizophrenia, the incidence of reported EPS-related events, excluding events related to akathisia, for oral aripiprazole-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 8% vs. 4% for placebo. Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Abnormal Involuntary Movement Scale (for dyskinesias). In the schizophrenia trials, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, –0.05). Similarly, in a long-term (26-week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Abnormal Involuntary Movement Scale (for dyskinesias) did not show a difference between aripiprazole and placebo. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials of Oral Aripiprazole The adverse reactions reported in a 26-week, double-blind trial comparing oral aripiprazole and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for oral aripiprazole vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤ 49 days), and were of limited duration (7/12 ≤ 10 days). Tremor infrequently led to discontinuation ( < 1%) of oral aripiprazole. In addition, in a long-term, active-controlled study, the incidence of tremor was 5% (40/859) for oral aripiprazole. Other Adverse Reactions Observed During the Premarketing Evaluation of Oral Aripiprazole Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with oral aripiprazole at multiple doses ≥ 2 mg/day during any phase of a trial within the database of 13,543 adult patients. All events assessed as possible adverse drug reactions have been included with the exception of more commonly occurring events. In addition, medically/clinically meaningful adverse reactions, particularly those that are likely to be useful to the prescriber or that have pharmacologic plausibility, have been included. Events already listed in other parts of Adverse Reactions (6), or those considered in WARNINGS AND PRECAUTIONS (5) or Overdosage (10) have been excluded. Although the reactions reported occurred during treatment with aripiprazole, they were not necessarily caused by it. Events are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients; and those occurring in fewer than 1/1000 patients. Blood and Lymphatic System Disorders: ≥ 1/1000 patients and < 1/100 patients - thrombocytopenia Cardiac Disorders: ≥ 1/1000 patients and < 1/100 patients - palpitations, cardiopulmonary failure, myocardial infarction, cardio-respiratory arrest, atrioventricular block, extrasystoles, angina pectoris, myocardial ischemia; < 1/1000 patients – atrial flutter, supraventricular tachycardia, ventricular tachycardia Eye Disorders: ≥ 1/1000 patients and < 1/100 patients - photophobia, diplopia, eyelid edema, photopsia Gastrointestinal Disorders: ≥ 1/1000 patients and < 1/100 patients - gastroesophageal reflux disease, swollen tongue, esophagitis; < 1/1000 patients - pancreatitis General Disorders and Administration Site Conditions: ≥ 1/100 patients - asthenia, peripheral edema, chest pain; ≥ 1/1000 patients and < 1/100 patients - face edema, angioedema; < 1/1000 patients – hypothermia Hepatobiliary Disorders: < 1/1000 patients - hepatitis, jaundice Immune System Disorders: ≥ 1/1000 patients and < 1/100 patients - hypersensitivity Injury, Poisoning, and Procedural Complications: ≥ 1/100 patients - fall; < 1/1000 patients - heat stroke Investigations: ≥ 1/1000 patients and < 1/100 patients - blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased; < 1/1000 patients - blood lactate dehydrogenase increased, glycosylated hemoglobin increased Metabolism and Nutrition Disorders: ≥ 1/1000 patients and < 1/100 patients - anorexia, hyponatremia, hypoglycemia, polydipsia; < 1/1000 patients - diabetic ketoacidosis Musculoskeletal and Connective Tissue Disorders: ≥ 1/1000 patients and < 1/100 patients - muscle rigidity, muscular weakness, muscle tightness, mobility decreased; < 1/1000 patients - rhabdomyolysis Nervous System Disorders: ≥ 1/100 patients - coordination abnormal; ≥ 1/1000 patients and < 1/100 patients - speech disorder, hypokinesia, hypotonia, myoclonus, akinesia, bradykinesia; < 1/1000 patients - choreoathetosis Psychiatric Disorders: ≥ 1/100 patients - suicidal ideation; ≥ 1/1000 patients and < 1/100 patients – loss of libido, suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self injury, completed suicide, tic, homicidal ideation; < 1/1000 patients - catatonia, sleep walking Renal and Urinary Disorders: ≥ 1/1000 patients and < 1/100 patients - urinary retention, polyuria, nocturia Reproductive System and Breast Disorders: ≥ 1/1000 patients and < 1/100 patients - menstruation irregular, erectile dysfunction, amenorrhea, breast pain; < 1/1000 patients - gynecomastia, priapism Respiratory, Thoracic, and Mediastinal Disorders: ≥ 1/100 patients - nasal congestion, dyspnea Skin and Subcutaneous Tissue Disorders: ≥ 1/100 patients - rash (including erythematous, exfoliative, generalized, macular, maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic dermatitis, neurodermatitis, and drug eruption), hyperhydrosis; ≥ 1/1000 patients and < 1/100 patients - pruritus, photosensitivity reaction, alopecia, urticaria Postmarketing Experience The following adverse reactions have been identified during post-approval use of oral aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: rare occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm). Read the Abilify Maintena (aripiprazole extended-release injectable suspension) Side Effects Center for a complete guide to possible side effectsLearn More »

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Dosage Overview For The Treatment Of Schizophrenia ABILIFY MAINTENA is only to be administered by intramuscular injection by a healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ABILIFY MAINTENA. The recommended starting and maintenance dose of ABILIFY MAINTENA is 400 mg monthly (no sooner than 26 days after the previous injection). After the first ABILIFY MAINTENA injection, continue treatment with oral aripiprazole (10 mg to 20 mg) or other oral antipsychotic for 14 consecutive days to maintain therapeutic antipsychotic concentrations during initiation of therapy. If there are adverse reactions with the 400 mg dosage, consider reducing the dosage to 300 mg once monthly. Dosage Adjustments For Missed Doses If the second or third doses are missed:
  • If more than 4 weeks and less than 5 weeks have elapsed since the last injection, administer the injection as soon as possible.
  • If more than 5 weeks have elapsed since the last injection, restart concomitant oral aripiprazole for 14 days with the next administered injection.
If the fourth or subsequent doses are missed:
  • If more than 4 weeks and less than 6 weeks have elapsed since the last injection, administer the injection as soon as possible.
  • If more than 6 weeks have elapsed since the last injection, restart concomitant oral aripiprazole for 14 days with the next administered injection.
Dosage Adjustments For CYP450 Interactions Dosage adjustments are recommended in patients who are CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days (see Table 1). Dosage adjustments for 200 mg and 160 mg are obtained only by using the 300 mg or 400 mg strength vials for intramuscular gluteal injection. If the CYP3A4 inhibitor, or CYP2D6 inhibitor is withdrawn, the ABILIFY MAINTENA dosage may need to be increased [see Dosage Overview for the Treatment of Schizophrenia]. Avoid the concomitant use of CYP3A4 inducers with ABILIFY MAINTENA for greater than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels. Dosage adjustments are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days. Table 1: Dose Adjustments of ABILIFY MAINTENA in Patients who are CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/ or CYP3A4 Inducers for Greater than 14 days
  Adjusted Dose CYP2D6 Poor Metabolizers CYP2D6 Poor Metabolizers 300 mg CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors 200 mg* Patients Taking 400 mg of ABILIFY MAINTENA Strong CYP2D6 or CYP3A4 inhibitors 300 mg CYP2D6 and CYP3A4 inhibitors 200 mg* CYP3A4 inducers Avoid use Patients Taking 300 mg of ABILIFY MAINTENA Strong CYP2D6 or CYP3A4 inhibitors 200 mg* CYP2D6 and CYP3A4 inhibitors 160 mg* CYP3A4 inducers Avoid use *200 mg and 160 mg dosage adjustments are obtained only by using the 300 mg or 400 mg strength vials. ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe, and 2) Vials. Different Aripiprazole Formulations And Kits There are two aripiprazole formulations for intramuscular use with different dosages, dosing frequencies, and indications. ABILIFY MAINTENA is a long-acting aripiprazole formulation with 4 week dosing intervals indicated for the treatment of schizophrenia. In contrast, aripiprazole injection (9.75 mg per vial) is a short-acting formulation indicated for agitation in patients with schizophrenia or mania. Do not substitute these products. Refer to the prescribing information for aripiprazole injection for more information about aripiprazole injection. ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/ injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe available in 300 mg or 400 mg strength syringes [see Pre-filled Dual Chamber Syringe: Preparation And Administration Instructions], and 2) Single-use vials available in 300 mg or 400 mg strength vials [see Vial: Preparation and Administration Instructions Preparation Prior to Reconstitution]. The 200 mg and 160 mg dosage adjustments are obtained only by using the 300 mg or 400 mg strength vials. Pre-filled Dual Chamber Syringe: Preparation And Administration Instructions Preparation Prior to Reconstitution For deep intramuscular gluteal injection by healthcare professionals only. Do not administer by any other route. Inject full syringe contents immediately following reconstitution. Administer once monthly. Lay out and confirm that components listed below are provided in the kit:
  • One ABILIFY MAINTENA (aripiprazole) pre-filled dual chamber syringe (400 mg or 300 mg as appropriate) for extended release injectable suspension containing lyophilized powder and Sterile Water for Injection
  • One 21 gauge, 1.5 inch (38 mm) hypodermic safety needle with needle protection device for non-obese patients
  • One 21 gauge, 2 inch (50 mm) hypodermic safety needle with needle protection device for obese patients
Reconstitution of Lyophilized Powder in Pre-filled Dual Chamber Syringe Reconstitute at room temperature. (a) Push plunger rod slightly to engage threads. And then, rotate plunger rod until the rod stops rotating to release diluent. After plunger rod is at complete stop, middle stopper will be at the indicator line (See Figure 1). Figure 1
(b) Vertically shake the syringe vigorously for 20 seconds until drug is uniformly milky-white (See Figure 2). Figure 2
(c) Visually inspect the syringe for particulate matter and discoloration prior to administration. The reconstituted ABILIFY MAINTENA suspension should appear to be a uniform, homogeneous suspension that is opaque and milkywhite in color. Injection Procedure Use appropriate aseptic techniques throughout injection procedure. Do not administer intravenously or subcutaneously. (a) Twist and pull off Over-cap and Tip-cap (See Figure 3). Figure 3
(b) Select appropriate needle (See Figure 4). Figure 4
  • One 21 gauge, 1.5 inch (38 mm) hypodermic safety needle with needle protection device for non-obese patients
  • One 21 gauge, 2 inch (50 mm) hypodermic safety needle with needle protection device for obese patients
(c) While holding the needle cap, ensure the needle is firmly seated on the safety device with a push. Twist clockwise until SNUGLY fitted (See Figure 5). Figure 5
(d) Then PULL needle-cap straight up (see Figure 6). Figure 6
(e) Hold syringe UPRIGHT and ADVANCE PLUNGER ROD SLOWLY TO EXPEL THE AIR. Expel air until suspension fills needle base. If it's not possible to advance plunger rod to expel the air, check that plunger rod is rotated to a complete stop (See Figure 7). Figure 7
(f) Inject slowly into the gluteal muscle. Do not massage the injection site. Do not administer intravenously or subcutaneously. Disposal Procedure (a) Engage the needle safety device as described in Reconstitution of Lyophilized Powder in Vial and safely discard all kit components (See Figure 8). ABILIFY MAINTENA pre-filled dual chamber syringe is for single-use only. Figure 8
(b) Rotate sites of injections between the two gluteal muscles. Vial: Preparation and Administration Instructions Preparation Prior to Reconstitution For deep intramuscular gluteal injection by healthcare professionals only. Do not administer by any other route. Inject immediately after reconstitution. Administer once monthly.
  1. Lay out and confirm that components listed below are provided in the kit:
    • Vial of ABILIFY MAINTENA (aripiprazole) for extended-release injectable suspension lyophilized powder
    • 5 mL vial of Sterile Water for Injection, USP
    • One 3 mL luer lock syringe with pre-attached 21 gauge, 1.5 inch (38 mm) hypodermic safety needle with needle protection device
    • One 3 mL luer lock disposable syringe with luer lock tip
    • One vial adapter
    • One 21 gauge, 1.5 inch (38 mm) hypodermic safety needle with needle protection device for non-obese patients
    • One 21 gauge, 2 inch (50 mm) hypodermic safety needle with needle protection device for obese patients
  2. ABILIFY MAINTENA should be suspended using the Sterile Water for Injection as supplied in the kit.
  3. The Sterile Water for Injection and ABILIFY MAINTENA vials are for single-use only.
  4. Use appropriate aseptic techniques throughout reconstitution and reconstitute at room temperature.
  5. Select the amount of Sterile Water for Injection needed for reconstitution (see Table 2).
Table 2: Amount of Sterile Water for Injection Needed for Reconstitution
400 mg Vial 300 mg Vial Dose Sterile Water for Injection Dose Sterile Water for Injection 400 mg 1.9 mL 300 mg 1.5 mL Important: There is more Sterile Water for Injection in the vial than is needed to reconstitute ABILIFY MAINTENA (aripiprazole) for extended-release injectable suspension. The vial will have excess Sterile Water for Injection; discard any unused portion. Reconstitution of Lyophilized Powder in Vial (a) Remove the cap of the vial of Sterile Water for Injection and remove the cap of the vial containing ABILIFY MAINTENA lyophilized powder and wipe the tops with a sterile alcohol swab. (b) Using the syringe with pre-attached hypodermic safety needle, withdraw the pre-determined Sterile Water for Injection volume from the vial of Sterile Water for Injection into the syringe (see Figure 9). Residual Sterile Water for Injection will remain in the vial following withdrawal; discard any unused portion. Figure 9
(c) Slowly inject the Sterile Water for Injection into the vial containing the ABILIFY MAINTENA lyophilized powder (see Figure 10). Figure 10
(d) Withdraw air to equalize the pressure in the vial by pulling back slightly on the plunger. Subsequently, remove the needle from the vial. Engage the needle safety device by using the one-handed technique (see Figure 11). Gently press the sheath against a flat surface until the needle is firmly engaged in the needle protection sheath. Visually confirm that the needle is fully engaged into the needle protection sheath, and discard. Figure 11
(e) Shake the vial vigorously for 30 seconds until the reconstituted suspension appears uniform (see Figure 12). Figure 12
(f) Visually inspect the reconstituted suspension for particulate matter and discoloration prior to administration. The reconstituted ABILIFY MAINTENA is a uniform, homogeneous suspension that is opaque and milky-white in color. (g) If the injection is not performed immediately after reconstitution keep the vial at room temperature and shake the vial vigorously for at least 60 seconds to re-suspend prior to injection. (h) Do not store the reconstituted suspension in a syringe. Preparation Prior to Injection (a) Use appropriate aseptic techniques throughout injection of the reconstituted ABILIFY MAINTENA suspension. (b) Remove the cover from the vial adapter package (see Figure 13). Do not remove the vial adapter from the package. Figure 13
(c) Using the vial adapter package to handle the vial adapter, attach the prepackaged luer lock syringe to the vial adapter (see Figure 14). Figure 14
(d) Use the luer lock syringe to remove the vial adapter from the package and discard the vial adapter package (see Figure 15). Do not touch the spike tip of the adapter at any time. Figure 15
(e) Determine the recommended volume for injection (Table 3). Table 3: ABILIFY MAINTENA Reconstituted Suspension Volume to Inject
400 mg Vial 300 mg Vial Dose Volume to Inject Dose Volume to Inject 400 mg 2 mL — — 300 mg 1.5 mL 300 mg 1.5 mL 200 mg 1 mL 200 mg 1 mL 160 mg 0.8 mL 160 mg 0.8 mL (f) Wipe the top of the vial of the reconstituted ABILIFY MAINTENA suspension with a sterile alcohol swab. (g) Place and hold the vial of the reconstituted ABILIFY MAINTENA suspension on a hard surface. Attach the adapter-syringe assembly to the vial by holding the outside of the adapter and pushing the adapter's spike firmly through the rubber stopper, until the adapter snaps in place (see Figure 16). Figure 16
(h) Slowly withdraw the recommended volume from the vial into the luer lock syringe to allow for injection (see Figure 17). A small amount of excess product will remain in the vial. Figure 17
Injection Procedure (a) Detach the luer lock syringe containing the recommended volume of reconstituted ABILIFY MAINTENA suspension from the vial. (b) Select one of the following hypodermic safety needles and attach the needle to the luer lock syringe containing the suspension for injection. While holding the needle, ensure the needle is firmly seated on the safety device with a push. Twist clockwise until snugly fitted and then pull the needle cap straight away from the needle (see Figure 18).
  • 21 gauge, 1.5 inch (38 mm) hypodermic safety needle with needle protection device for non-obese patients.
  • 21 gauge, 2 inch (50 mm) hypodermic safety needle with needle protection device for obese patients.
Figure 18
(c) Slowly inject the recommended volume as a single intramuscular injection into the gluteal muscle. Do not massage the injection site. Do not administer intravenously or subcutaneously. Disposal Procedure (a) Engage the needle safety device as described in Section 2.6, Step (d) of Reconstitution of Lyophilized Powder in Vial. Dispose of the vials, adapter, needles, and syringe appropriately after injection. The Sterile Water for Injection and ABILIFY MAINTENA vials are for single-use only. (b) Rotate sites of injections between the two gluteal muscles.

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Carbamazepine Or Other CYP3A4 Inducers Concomitant use of ABILIFY MAINTENA with carbamazepine or other CYP3A4 inducers decreases the concentrations of aripiprazole. Avoid use of ABILIFY MAINTENA in combination with carbamazepine and other inducers of CYP3A4 for greater than 14 days [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Ketoconazole Or Other Strong CYP3A4 Inhibitors Concomitant use of ABILIFY MAINTENA with ketoconazole or other CYP3A4 inhibitors for more than 14 days increases the concentrations of aripiprazole and reduction of the ABILIFY MAINTENA dose is recommended [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Due to prolonged-release characteristics of ABILIFY MAINTENA, short-term co-administration of ketoconazole or other inhibitors of CYP3A4 with ABILIFY MAINTENA does not require a dose adjustment. Quinidine Or Other Strong CYP2D6 Inhibitors Concomitant use of ABILIFY MAINTENA with quinidine or other CYP2D6 inhibitors increases the concentrations of aripiprazole after longer-term use (i.e., over 14 days) and reduction of the ABILIFY MAINTENA is recommended [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Due to prolongedrelease characteristics of ABILIFY MAINTENA, short-term co-administration of quinidine or other CYP2D6 inhibitors with ABILIFY MAINTENA does not require a dose adjustment. CNS Depressants Given the CNS depressant effects of aripiprazole, use caution when ABILIFY MAINTENA is taken in combination with other centrally-acting drugs or alcohol. Anti-Hypertensive Agents Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Last reviewed on RxList: 12/12/2014
This monograph has been modified to include the generic and brand name in many instances.

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ABILIFY MAINTENA (aripiprazole) is indicated for the treatment of schizophrenia. Efficacy was demonstrated in a placebo-controlled, randomized-withdrawal maintenance trial in patients with schizophrenia and additional support for efficacy was derived from oral aripiprazole trials [see Clinical Studies].

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ABILIFY MAINTENA is contraindicated in patients with a known hypersensitivity to aripiprazole. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole [see ADVERSE REACTIONS]. Last reviewed on RxList: 12/12/2014
This monograph has been modified to include the generic and brand name in many instances.

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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.

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Dosage Forms And Strengths
  • Pre-filled dual chamber syringe with lyophilized powder for intramuscular gluteal injection for extended-release injectable suspension: 300 mg and 400 mg in a single-use pre-filled dual chamber syringe.
  • Vials with lyophilized powder for intramuscular gluteal injection for extended-release injectable suspension: 300 mg and 400 mg in a singleuse vial.
The reconstituted extended-release injectable suspension is a uniform, homogeneous suspension that is opaque and milky-white in color. Storage And Handling Pre-filled Dual Chamber Syringe ABILIFY MAINTENA (aripiprazole) pre-filled dual chamber syringe for extendedrelease injectable suspension in single-use syringes is available in 300 mg or 400 mg strength syringes. The pre-filled dual chamber syringe consists of a front chamber that contains the lyophilized powder of aripiprazole monohydrate and a rear chamber that contains sterile water for injection. The 300 mg kit includes (NDC 59148-045-80)
  • 300 mg single-use pre-filled dual chamber syringe containing ABILIFY MAINTENA (aripiprazole) and Sterile Water for Injection for extendedrelease injectable suspension lyophilized powder
  • One 21 gauge, 1.5 inch (38 mm) hypodermic safety needle with needle protection device for non-obese patients
  • One 21 gauge, 2 inch (50 mm) hypodermic safety needle with needle protection device for obese patients
The 400 mg kit includes (NDC 59148-072-80):
  • 400 mg single-use pre-filled dual chamber syringe containing ABILIFY MAINTENA (aripiprazole) and Sterile Water for Injection for extendedrelease injectable suspension lyophilized powder
  • One 21 gauge, 1.5 inch (38 mm) hypodermic safety needle with needle protection device for non-obese patients
  • One 21 gauge, 2 inch (50 mm) hypodermic safety needle with needle protection device for obese patients
Single-Use Vial ABILIFY MAINTENA (aripiprazole) extended-release injectable suspension in singleuse vials is available in 300 mg or 400 mg strength vials. The 300 mg kit includes (NDC 59148-018-71)
  • 300 mg single-use vial of ABILIFY MAINTENA (aripiprazole) extendedrelease injectable suspension lyophilized powder
  • 5 mL single-use vial of Sterile Water for Injection, USP
  • One 3 mL luer lock syringe with pre-attached 21 gauge, 1.5 inch hypodermic safety needle with needle protection device
  • One 3 mL luer lock disposable syringe with luer lock tip
  • One vial adapter
  • One 21 gauge, 1.5 inch (38 mm) hypodermic safety needle with needle protection device for non-obese patients
  • One 21 gauge, 2 inch (50 mm) hypodermic safety needle with needle protection device for obese patients
The 400 mg kit includes (NDC 59148-019-71)
  • 400 mg single-use vial of ABILIFY MAINTENA (aripiprazole) extended release injectable suspension lyophilized powder
  • 5 mL single use vial of Sterile Water for Injection, USP
  • One 3 mL luer lock syringe with pre-attached 21 gauge, 1.5 inch hypodermic safety needle with needle protection device
  • One 3 mL luer lock disposable syringe with luer lock tip
  • One vial adapter
  • One 21 gauge, 1.5 inch (38 mm) hypodermic safety needle with needle protection device for non-obese patients
  • One 21 gauge, 2 inch (50 mm) hypodermic safety needle with needle protection device for obese patients
Storage Pre-filled Dual Chamber Syringe Store below 30°C [86°F]. Do not freeze. Protect the syringe from light by storing in the original package until time of use. Vial Store at 25 °C (77 °F), excursions permitted between 15 °C and 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature]. Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Revised: 09/2014 Last reviewed on RxList: 12/12/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis. Cerebrovascular Adverse Reactions, Including Stroke In Elderly Patients With Dementia-Related Psychosis In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, in oral aripiprazole-treated patients (mean age: 84 years; range: 78-88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse reactions in patients treated with oral aripiprazole. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including ABILIFY MAINTENA. Rare cases of NMS occurred during aripiprazole treatment in the worldwide clinical database. 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 exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) 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 requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully 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 rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to 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 are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown. Given these considerations, ABILIFY MAINTENA 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 1) is known to respond to antipsychotic drugs and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. 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 ABILIFY MAINTENA drug discontinuation should be considered. However, some patients may require treatment with ABILIFY MAINTENA 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. Although the following metabolic data were collected in patients treated with oral formulations of aripiprazole, the findings pertain to patients receiving ABILIFY MAINTENA as well. Hyperglycemia/Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with diabetic ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole [see ADVERSE REACTIONS]. 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 reactions is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Because aripiprazole was not marketed at the time these studies were performed, it is not known if aripiprazole is associated with this increased risk. Precise risk estimates for hyperglycemiarelated adverse reactions in patients treated with atypical antipsychotics are not available. 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 required continuation of anti-diabetic treatment despite discontinuation of the atypical antipsychotic drug. In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or bipolar disorder, the mean change in fasting glucose in aripiprazole-treated patients (+4.4 mg/dL; median exposure 25 days; N=1057) was not significantly different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799). Table 4 shows the proportion of aripiprazole-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days). Table 4: Changes in Fasting Glucose From Placebo-Controlled Monotherapy Trials in Adult Patients
  Category Change (at least once) from Baseline Treatment Arm n/N % Fasting Glucose Normal to High ( < 100 mg/dL to ≥ 126 mg/dL) Aripiprazole 31/822 3.8 Placebo 22/605 3.6 Borderline to High ( ≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL) Aripiprazole 31/176 17.6 Placebo 13/142 9.2 At 24 weeks, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively]. Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. There were no significant differences between aripiprazole- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/ nonfasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients. Table 5 shows the proportion of adult patients, primarily from pooled schizophrenia and bipolar disorder monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from 17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 days, except for placebo-treated patients with baseline normal fasting LDL measurements, who had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median exposure 40 to 42 days). Table 5: Changes in Blood Lipid Parameters From Placebo-Controlled Monotherapy Trials in Adults
  Treatment Arm n/N % Total Cholesterol Aripiprazole 34/1357 2.5 Normal to High ( < 200 mg/dL to ≥ 240 mg/dL) Placebo 27/973 2.8 Fasting Triglycerides Aripiprazole 40/539 7.4 Normal to High ( < 150 mg/dL to ≥ 200 mg/dL) Placebo 30/431 7.0 Fasting LDL Cholesterol Aripiprazole 2/332 0.6 Normal to High ( < 100 mg/dL to ≥ 160 mg/dL) Placebo 2/268 0.7 HDL Cholesterol Aripiprazole 121/1066 11.4 Normal to Low ( ≥ 40 mg/dL to < 40 mg/dL) Placebo 99/794 12.5 In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively. Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. In an analysis of 13 placebo-controlled monotherapy trials, primarily from pooled schizophrenia and bipolar disorder, with a median exposure of 21 to 25 days, the mean change in body weight in aripiprazole-treated patients was +0.3 kg (N=1673) compared to –0.1 kg (N=1100) in placebo-controlled patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was –1.5 kg (n=73) compared to –0.2 kg (n=46) in placebo-treated patients. Table 6 shows the percentage of adult patients with weight gain ≥ 7% of body weight in the 13 pooled placebo-controlled monotherapy trials. Table 6: Percentage of Patients From Placebo-Controlled Trials in Adult Patients with Weight Gain ≥ 7% of Body Weight
  Indication Treatment Arm N Patients n (%) Weight gain ≥ 7% of body weight Schizophreniaa Aripiprazole 852 69 (8.1) Placebo 379 12 (3.2) Bipolar Maniab Aripiprazole 719 16 (2.2) Placebo 598 16 (2.7) a 4-6 weeks duration.
b 3 weeks duration. Orthostatic Hypotension Aripiprazole may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. Orthostasis occurred in 4/576 (0.7%) patients treated with ABILIFY MAINTENA during the stabilization phase, including abnormal orthostatic blood pressure (1/576, 0.2%), postural dizziness (1/576, 0.2%), presyncope (1/576, 0.2%) and orthostatic hypotension (1/576, 0.2%). In the stabilization phase, the incidence of significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥ 20 mmHg accompanied by an increase in heart rate ≥ 25 when comparing standing to supine values) was 0.2% (1/575). Leukopenia, Neutropenia, And Agranulocytosis Class Effect In clinical trials and post-marketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including oral aripiprazole. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC 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 ABILIFY MAINTENA at the first sign of a clinically 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 ABILIFY MAINTENA in patients with severe neutropenia (absolute neutrophil count < 1000/mm³) and follow their WBC counts until recovery. Seizures As with other antipsychotic drugs, use ABILIFY MAINTENA 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 ABILIFY MAINTENA, like other antipsychotics, may impair judgment, thinking, or motor skills. Instruct patients to avoid operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with ABILIFY MAINTENA 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 ABILIFY MAINTENA 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, including ABILIFY MAINTENA. ABILIFY MAINTENA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Increased Mortality in Elderly Patients with Dementia-Related Psychosis]. Patient Counseling Information See FDA-approved patient labeling (Medication Guide) Discuss the following issues with patients for whom they prescribe ABILIFY MAINTENA. Increased Mortality in Elderly Patients with Dementia-Related Psychosis Advise patients and caregivers that elderly patients with dementia-related psychoses treated with antipsychotic drugs are at increased risk of death. Aripiprazole is not approved for elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS]. Neuroleptic Malignant Syndrome Counsel patients and caregivers that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see WARNINGS AND PRECAUTIONS]. Tardive Dyskinesia Advise patients that abnormal involuntary movements have been associated with the administration of antipsychotic drugs. Counsel patients to notify their physician if they notice any movements which they cannot control in their face, tongue, or other body part [see WARNINGS AND PRECAUTIONS]. Hyperglycemia and Diabetes mellitus Advise patients of the symptoms of hyperglycemia and diabetes mellitus. Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those that develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment [see WARNINGS AND PRECAUTIONS]. Orthostatic Hypotension Advise patients of the risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see WARNINGS AND PRECAUTIONS]. Leukopenia/Neutropenia Advise patients with a pre-existing low WBC count or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while receiving ABILIFY MAINTENA [see WARNINGS AND PRECAUTIONS]. Interference with Cognitive and Motor Performance Because ABILIFY MAINTENA may have the potential to impair judgment, thinking, or motor skills, instruct patients to be cautious about operating hazardous machinery, including automobiles, until they are reasonably certain that ABILIFY MAINTENA therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS]. Heat Exposure and Dehydration Advise patients regarding appropriate care in avoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS]. Concomitant Medication Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see DRUG INTERACTIONS]. Pregnancy Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy with ABILIFY MAINTENA [see Use In Specific Populations]. Nursing Aripiprazole is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue ABILIFY MAINTENA, taking into account the importance of the drug to the mother [see Use in Specific Populations]. Alcohol Advise patients to avoid alcohol while taking ABILIFY MAINTENA [see CLINICAL PHARMACOLOGY]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis Lifetime carcinogenicity studies were conducted in ICR mice and in Sprague-Dawley (SD) and F344 rats. Aripiprazole was administered for 2 years in the diet at dosesof 1 mg/kg/day, 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day to ICR mice and 1 mg/kg/day, 3 mg/kg/day, and 10 mg/kg/day to F344 rats (0.2 times to 5 times and 0.3 times to 3 times the oral maximum recommended human dose [MRHD] of 30 mg/day based on mg/m² body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10 mg/kg/day, 20 mg/kg/day, 40 mg/kg/day, and 60 mg/kg/day (3 times to 19 times the oral MRHD of 30 mg/day based on mg/m² body surface area). Aripiprazole did not induce tumors in male mice or rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 mg/kg/day to 30 mg/kg/day (0.1 times to approximately 1 times human exposure at the oral MRHD of 30 mg/day based on AUC and 0.5 times to 5 times the oral MRHD of 30 mg/day based on mg/m² body surface area). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (0.1 times human exposure at the oral MRHD of 30 mg/day based on AUC and 3 times the oral MRHD of 30 mg/day based on mg/m² body surface area); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (14 times human exposure at the oral MRHD of 30 mg/day based on AUC and 19 times the oral MRHD of 30 mg/day based on mg/m² body surface area). Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13-week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4-week and 13-week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown. Mutagenesis Aripiprazole was not mutagenic when tested in the in vitro bacterial mutation assay, the in vitro bacterial DNA repair assay, and the in vitro mouse lymphoma gene mutation assay. The clastogenic potential of aripiprazole was tested in the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and its metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells both in the presence and absence of metabolic activation. The metabolite, 2,3-DCPP, produced increases in numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the oral in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans. Impairment of Fertility Female rats were treated with oral doses of 2 mg/kg/day, 6 mg/kg/day, and 20 mg/kg/day (0.6 times, 2 times, and 6 times the oral maximum recommended human dose [MRHD] of 30 mg/day on a mg/m² body surface area) of aripiprazole from 2 weeks prior to mating through day 7 of gestation. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 6 mg/kg and 20 mg/kg and decreased fetal weight was seen at 20 mg/kg. Male rats were treated with oral doses of 20 mg/kg/day, 40 mg/kg/day, and 60 mg/kg/day (6 times, 13 times, and 19 times the oral MRHD of 30 mg/day on a mg/m² body surface area) of aripiprazole from 9 weeks prior to mating through mating. Disturbances in spermatogenesis were seen at 60 mg/kg and prostate atrophy was seen at 40 mg/kg and 60 mg/kg, but no impairment of fertility was seen. Use In Specific Populations Pregnancy Pregnancy Category C Risk Summary Adequate and well controlled studies with aripiprazole have not been conducted in pregnant women. Neonates exposed to antipsychotic drugs (including ABILIFY MAINTENA) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits at doses 1 - 10 times the oral maximum recommended human dose [MRHD] of 30 mg/day based on a mg/m² body surface area. ABILIFY MAINTENA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover within hours or days without specific treatment; others may require prolonged hospitalization. Animal Data Pregnant rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (1 times, 3 times, and 10 times the oral maximum recommended human dose [MRHD] of 30 mg/day on a mg/m² body surface area) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg. Treatment caused a slight delay in fetal development, as evidenced by decreased fetal weight (30 mg/kg), undescended testes (30 mg/kg), and delayed skeletal ossification (10 mg/kg and 30 mg/kg). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 mg/kg and 30 mg/kg), and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to 30 mg/kg. Postnatally, delayed vaginal opening was seen at 10 mg/kg and 30 mg/kg and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg. Some maternal toxicity was seen at 30 mg/kg; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. In pregnant rats receiving aripiprazole injection intravenously (3 mg/kg/day, 9 mg/kg/day, and 27 mg/kg/day) during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose, which also caused some maternal toxicity. Pregnant rabbits were treated with oral doses of 10 mg/kg/day, 30 mg/kg/day, and 100 mg/kg/day (2 times, 3 times, and 11 times human exposure at the oral MRHD of 30 mg/day based on AUC and 6 times, 19 times, and 65 times the oral MRHD of 30 mg/day based on mg/m² body surface area) of aripiprazole during the period of organogenesis. Decreased maternal food consumption and increased abortions were seen at 100 mg/kg. Treatment caused increased fetal mortality (100 mg/kg), decreased fetal weight (30 mg/kg and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30 mg/kg and 100 mg/kg), and minor skeletal variations (100 mg/kg). In pregnant rabbits receiving aripiprazole injection intravenously (3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day) during the period of organogenesis, the highest dose, which caused pronounced maternal toxicity, resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 10 mg/kg, which produced 5 times the human exposure at the oral MRHD based on AUC and is 6 times the oral MRHD of 30 mg/day based on mg/m² body surface area. In a study in which rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (1 times, 3 times, and 10 times the oral MRHD of 30 mg/day on a mg/m² body surface area) of aripiprazole perinatally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at 30 mg/kg. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were seen at this dose. In rats receiving aripiprazole injection intravenously (3 mg/kg/day, 8 mg/kg/day, and 20 mg/kg/day) from day 6 of gestation through day 20 postpartum, an increase in stillbirths was seen at 8 mg/kg and 20 mg/kg, and decreases in early postnatal pup weights and survival were seen at 20 mg/kg. These doses produced some maternal toxicity. There were no effects on postnatal behavioral and reproductive development. Nursing Mothers Aripiprazole is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of ABILIFY MAINTENA in patients < 18 years of age have not been evaluated. Geriatric Use Safety and effectiveness of ABILIFY MAINTENA in patients > 60 years of age have not been evaluated. In oral single-dose pharmacokinetic studies (with aripiprazole given in a single oral dose of 15 mg), aripiprazole clearance was 20% lower in elderly ( ≥ 65 years) subjects compared to younger adult subjects (18 to 64 years). There was no detectable age effect, however, in the population pharmacokinetic analysis of oral aripiprazole in schizophrenia patients. Also, the pharmacokinetics of oral aripiprazole after multiple doses in elderly patients appeared similar to that observed in young, healthy subjects. No dosage adjustment of ABILIFY MAINTENA is recommended for elderly patients [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. CYP2D6 Poor Metabolizers Approximately 8% of Caucasians and 3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM). Dosage adjustment is recommended in CYP2D6 poor metabolizers due to high aripiprazole concentrations [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Last reviewed on RxList: 12/12/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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