Abilify Asimtufii Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................. 2

Table of Contents ................................................................................................................. 2

Part 1: Healthcare Professional Information.......................................................................... 5

1. 1.

   Indications..................................................................................................................... 5

   1.1. Pediatrics .................................................................................................................... 5

   1.2. Geriatrics .................................................................................................................... 5

2. 2. Contraindications .......................................................................................................... 5
3. 3. Serious Warnings and Precautions Box ........................................................................... 5
4. 4.

   Dosage and Administration ............................................................................................ 6

   4.1. Dosing Considerations ................................................................................................ 6

   4.2. Recommended Dose and Dosage Adjustment ........................................................... 6

   4.4. Administration ............................................................................................................ 8

   4.5. Missed Dose ............................................................................................................. 13

5. 5. Overdose ..................................................................................................................... 14
6. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................ 15
7. 7.

   Warnings and Precautions ........................................................................................... 15

   General ................................................................................................................................. 15

   Carcinogenesis and Genotoxicity ......................................................................................... 15

   Cardiovascular ...................................................................................................................... 15

   Driving and Operating Machinery ........................................................................................ 16

   Endocrine and Metabolism .................................................................................................. 17

   Genitourinary ....................................................................................................................... 18

   Hematologic ......................................................................................................................... 18

   Monitoring and Laboratory Tests ......................................................................................... 18

   Neurologic ............................................................................................................................ 19

   Psychiatric ............................................................................................................................. 20

   Skin…… .................................................................................................................................. 21

   7.1. Special Populations .................................................................................................. 21

   7.1.1. Pregnancy ......................................................................................................... 21

   7.1.2. Breastfeeding ................................................................................................... 21

   7.1.3. Pediatrics .......................................................................................................... 22

   7.1.4. Geriatrics .......................................................................................................... 22

8. 8.

   Adverse Reactions ....................................................................................................... 23

   8.1. Adverse Reaction Overview ..................................................................................... 23

   8.2. Clinical Trial Adverse Reactions ................................................................................ 24

   8.3. Less Common Clinical Trial Adverse Reactions ........................................................ 36

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ..................................................................................................... 38

   8.5. Post-Market Adverse Reactions ............................................................................... 39

9. 9.

   Drug Interactions ......................................................................................................... 40

   9.2. Drug Interactions Overview ..................................................................................... 40

   9.3. Drug-Behaviour Interactions .................................................................................... 40

   9.4. Drug-Drug Interactions ............................................................................................. 41

   9.5. Drug-Food Interactions ............................................................................................ 42

   9.6. Drug-Herb Interactions ............................................................................................. 42

   9.7. Drug-Laboratory Test Interactions ........................................................................... 43

10. 10.

    Clinical Pharmacology .................................................................................................. 43

    10.1. Mechanism of Action ............................................................................................... 43

    10.2. Pharmacodynamics .................................................................................................. 43

    10.3. Pharmacokinetics ..................................................................................................... 43

11. 11. Storage, Stability, and Disposal .................................................................................... 48

Part 2: Scientific Information .............................................................................................. 49

1. 13. Pharmaceutical Information ........................................................................................ 49
2. 14.

   Clinical Trials ............................................................................................................... 49

   14.1. Clinical Trials by Indication ....................................................................................... 49

   Schizophrenia ....................................................................................................................... 49

   Bipolar I Disorder .................................................................................................................. 56

3. 16. Non-Clinical Toxicology ................................................................................................ 59

Patient Medication Information ......................................................................................... 64

Part 1: Healthcare Professional Information

1. Indications

ABILIFY ASIMTUFII (aripiprazole prolonged release injectable suspension) is a once every two-month injection indicated for:

• treatment of schizophrenia in adult patients.
• maintenance monotherapy treatment of bipolar I disorder in adult patients.

The efficacy and safety of ABILIFY ASIMTUFII administered once every two months, for treatment of schizophrenia or bipolar I disorder are based on clinical trials that demonstrated the efficacy and safety of ABILIFY MAINTENA administered once monthly (see 14.1 Clinical Trials by Indication; 8 Adverse Reactions). In an open-label, multiple-dose, randomized, parallel-arm multi-center study in adult patients with schizophrenia or bipolar I disorder ABILIFY ASIMTUFII 960 mg, administered once every two months, was shown to provide similar aripiprazole concentrations to ABILIFY MAINTENA 400 mg, administered monthly, over the dosing interval (see 10.3 Pharmacokinetics).

1.1. Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada for patients <18 years of age; therefore, Health Canada has not authorized an indication for pediatric use (see 7.1.3 Pediatrics).

1.2. Geriatrics

Geriatrics (> 65 years of age): ABILIFY ASIMTUFII is not indicated in elderly patients with dementia (see 3 Serious Warnings and Precautions Box and 7.1.4 Geriatrics). The safety and efficacy of ABILIFY ASIMTUFII in patients 65 years of age or older have not been established. Caution should be used when treating geriatric patients (see 7.1.4 Geriatrics and 10.3 Pharmacokinetics).

2. Contraindications

• ABILIFY ASIMTUFII is contraindicated in patients who are hypersensitive to aripiprazole or to any ingredient in the formulation, including any non-medicinal ingredient, or to a component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.
• ABILIFY ASIMTUFII is contraindicated in patients who are known CYP2D6 poor metabolizers (see 4.2 Recommended Dose and Dosage Adjustment; 10.3 Pharmacokinetics).

3. Serious Warnings and Precautions Box

Increased Mortality in Elderly Patients with Dementia

Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to those treated with placebo (see 7.1.4 Geriatrics). ABILIFY ASIMTUFII is not approved for use in elderly patients with dementia.

4. Dosage and Administration

4.1. Dosing Considerations

For patients who have never taken aripiprazole, including those who are switching from other oral antipsychotics, establish tolerability with oral aripiprazole prior to initiating treatment with ABILIFY ASIMTUFII (see 8.1 Adverse Reaction Overview).

ABILIFY ASIMTUFII is only to be administered by intramuscular injection in the gluteal muscle by a healthcare professional.

4.2. Recommended Dose and Dosage Adjustment

Tolerability with oral aripiprazole must be established prior to initiating treatment with ABILIFY ASIMTUFII (see 4.1 Dosing Considerations). Titration of the dose of ABILIFY ASIMTUFII is not required.

Initiating ABILIFY ASIMTUFII

Based on clinical and modelling/simulation study data, the starting dose can be administered by following one of three regimens:

• One injection start from oral aripiprazole or another oral antipsychotic: On the day of treatment initiation, administer one injection of ABILIFY ASIMTUFII 960 mg and continue concurrent treatment with oral aripiprazole (10 mg to 20 mg) or current oral antipsychotic for 14 days. ABILIFY ASIMTUFII 960 mg should then be dosed once every two months (no sooner than every 56 days).
• Two injection start from oral aripiprazole or another oral antipsychotic: Patients must discontinue their current oral antipsychotic upon initiation of ABILIFY ASIMTUFII. On the day of treatment initiation, administer one injection of ABILIFY ASIMTUFII 960 mg and one injection of ABILIFY MAINTENA 400 mg at separate injection sites along with a single dose of oral aripiprazole 20 mg. ABILIFY ASIMTUFII 960 mg should then be dosed once every two months (no sooner than every 56 days).
• Transitioning from ABILIFY MAINTENA: Administer one injection of ABILIFY ASIMTUFII 960 mg, in place of the next scheduled injection (no sooner than 26 days after previous injection) of ABILIFY MAINTENA 400 mg. ABILIFY ASIMTUFII 960 mg should then be dosed once every two months (no sooner than every 56 days). The first ABILIFY ASIMTUFII injection may be administered in place of the second or any later injection of ABILIFY MAINTENA.

Training materials on dosage and administration of ABILIFY ASIMTUFII and ABILIFY MAINTENA are available to healthcare professionals by visiting the manufacturer’s website www.AbilifyAsimtufii.ca or by calling 1-877-341-9245.

Maintenance dose

The recommended maintenance dose of ABILIFY ASIMTUFII is 960 mg. ABILIFY ASIMTUFII should be administered as a single injection by a healthcare professional every two months (no sooner than 56 days after previous injection).

Patients may be given the ABILIFY ASIMTUFII injection up to 1 week before or 1 week after the two-month scheduled timepoint.

If there are adverse reactions with the ABILIFY ASIMTUFII 960 mg dosage, reduction of the dose to

720 mg once every two months or switching to ABILIFY MAINTENA 300 mg once monthly should be considered.

If ABILIFY ASIMTUFII is discontinued, its prolonged release characteristics must be considered.

Dosage Adjustments Based on Cytochrome P450 Activities

Refer to Table 1 for recommendations for patients who are known CYP2D6 poor metabolizers and for patients taking concomitant strong CYP3A4 inhibitors or strong CYP2D6 inhibitors (see 9.4 Drug-Drug Interactions).

Table 1: Dose Adjustments of ABILIFY ASIMTUFII in patients who are known CYP2D6 poor metabolizers and patients taking concomitant CYP2D6 inhibitors, CYP3A4 inhibitors, and/or CYP3A4 inducers*

*Dose recommendations for patients taking concomitant strong CYP3A4 inhibitors or strong CYP2D6 inhibitors are based on steady state aripiprazole concentrations predicted over the full 8-week dosing interval from simulations that introduced the concomitant inhibitors at the start of an ABILIFY ASIMTUFII dosing interval. The same recommendations may not be applicable to all durations and scenarios of concomitant use.

Special Populations

Elderly population

The safety and efficacy of ABILIFY ASIMTUFII in patients 65 years of age or older have not been established. No dosage adjustment of ABILIFY ASIMTUFII is recommended for elderly patients; however, owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant.

ABILIFY ASIMTUFII is not indicated in elderly patients with dementia (see 3 Serious Warnings and Precautions Box; 7.1.4 Geriatrics).

Renal impairment

No dosage adjustment of ABILIFY ASIMTUFII is required for patients with renal impairment.

Hepatic impairment

No dosage adjustment of ABILIFY ASIMTUFII is required for patients with mild or moderate hepatic impairment. There are insufficient data to establish dosing recommendations for patients with severe hepatic impairment. In these patients dosing should be managed cautiously; use of oral aripiprazole should be considered.

Other special populations

No dosage adjustment of ABILIFY ASIMTUFII is recommended based on gender, race, or smoking status.

4.4. Administration

ABILIFY ASIMTUFII comes in a kit. See instructions for injection/disposal procedures for single-use pre-filled syringes available in 720 mg or 960 mg strengths.

ABILIFY ASIMTUFII is for deep intramuscular gluteal injection only: do not administer intravenously or subcutaneously, or by any other route.

ABILIFY ASIMTUFII should be administered by a healthcare professional once every two months as a single injection.

ABILIFY ASIMTUFII pre-filled syringe is for single use only. Re-use may lead to infection or other illness/injury.

Prior to administration, visually inspect ABILIFY ASIMTUFII pre-filled syringe for particulate matter and discolouration. The suspension should appear to be a uniform, homogeneous suspension that is opaque and milky-white in colour. Do not use ABILIFY ASIMTUFII pre-filled syringe if the suspension is discoloured, or particulate matter is present.

Instructions for Preparation and Administration

Each kit contains one sterile pre-filled syringe containing ABILIFY ASIMTUFII (aripiprazole) 720 mg or 960 mg prolonged release injectable suspension and two safety needles:

• One sterile 1 1/2-inch, 22 gauge needle with black needle hub
• One sterile 2-inch, 21 gauge needle with green needle hub

Step 1: Preparation Prior to Administration

1. a) Remove the ABILIFY ASIMTUFII pre-filled syringe from the package.
2. b) Tap the syringe on your hand at least 10 (ten) times (Figure 1).
3. c) After tapping, shake the syringe vigorously for at least 10 (ten) seconds, until the medication is uniform (Figure 2).

Figure 1

Figure 2

Step 2: Select the appropriate needle

Needle selection is determined by patient body type.

For gluteal intramuscular administration only.

• For a person living without obesity – 22 gauge, 1 ½-inch (38 mm) safety needle with needle protection device
• For a person living with obesity – 21 gauge, 2-inch (51 mm) safety needle protection device

Determine the needle size required by body type.

Step 3: Attach the needle

1. a) Twist and pull off the pre-filled syringe tip-cap (Figure 3).
2. b) While holding the base of the needle, ensure the needle is firmly seated on the safety device with a push. Gently twist clockwise until SECURELY fitted (Figure 3).

Figure 3

Step 4: Expel Air

1. a) When you are ready to administer the injection of ABILIFY ASIMTUFII, hold the pre-filled syringe upright and remove the needle-cap straight up (Figure 4). Do not twist the needle-cap, as this may loosen the needle from the syringe.

Body Type	Needle Size	Needle Hub Colour
Person living without obesity	1 ½-inch (38 mm), 22 gauge
Person living with obesity	2-inch (51 mm), 21 gauge	green

Figure 4

1. b) Slowly advance the plunger rod upward to expel the air and until the suspension fills needle base (Figure 5). After expelling air from syringe, immediately inject slowly into the gluteal muscle.

Figure 5

Step 5: Inject the dose

1. a) Slowly inject the entire contents of the pre-filled syringe as a single intramuscular injection into the gluteal muscle of the patient (Figure 6). Do not massage the injection site.

Do not administer intravenously or subcutaneously or by any other route.

Ventrogluteal site

Dorsogluteal site

Figure 6

Step 6: Disposal Procedure

1. a) After the injection, press the safety shield on a hard surface to cover and lock shield over the needle (Figure 7 and Figure 8).

Figure 7 Figure 8

1. b) Immediately discard used syringe and the unused needle in an approved sharps container (Figure 9).
2. c) The unused needle should not be saved for future use.

Figure 9

4.5. Missed Dose

Steady state concentrations of aripiprazole are expected to be reached by the fourth consecutive injection of ABILIFY ASIMTUFII when administered at the recommended two-month intervals. The following recommendations for management of missed doses are based on modelling/simulation data.

Table 2: Management of Missed Doses of ABILIFY ASIMTUFII

5. Overdose

No cases of overdose were reported in clinical studies with aripiprazole injection. Because ABILIFY ASIMTUFII is to be administered by healthcare professionals, the potential for overdosage by patients is low.

While overdose is less likely with parenteral than oral medicinal products, reference information for oral aripiprazole overdose is presented below.

Symptoms

In post-marketing experience with oral aripiprazole, there is a single case of death that was possibly associated with accidental or intentional acute overdosage of aripiprazole alone. The patient ingested 900 mg of aripiprazole, was hospitalized in the intensive care unit for 10 to 14 days and died. The patient’s medical history included excessive alcohol use, although it is unclear whether alcohol was present at the time of overdosage. In the patient taking the largest confirmed amount of aripiprazole, 1680 mg, the only symptoms reported were vomiting, fatigue, and dizziness. Other potentially medically important signs and symptoms that have been observed during overdose included blood pressure increased, lethargy, somnolence, tachycardia, nausea, vomiting and diarrhea. In the patients who were evaluated in hospital settings, there were no reported observations indicating clinically important adverse change in vital signs, laboratory assessments, or electrocardiogram.

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

Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinal product involvement should be considered. Therefore, cardiovascular monitoring should be started immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Following any confirmed or suspected overdose with aripiprazole, close medical supervision and monitoring should continue until the patient recovers. There is no specific antidote to aripiprazole.

Consider the prolonged release characteristics of ABILIFY ASIMTUFII and the half-life of aripiprazole when assessing treatment needs and recovery.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-

7669).

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 3: Dosage Forms, Strengths, and Composition

Description

ABILIFY ASIMTUFII is available in two dosage strengths, 720 mg and 960 mg provided as an aqueous white prolonged release injectable suspension in pre-filled syringes. One carton contains one pre-filled syringe and 2 sterile safety needles (a 1 ½-inch (38 mm) 22 gauge needle and a 2-inch (51 mm) 21 gauge needle).

ABILIFY ASIMTUFII is presented in a pre-filled syringe (cyclic-olefin-copolymer) with bromobutyl plunger stopper and tip-cap and polypropylene plunger rod and finger grip.

7. Warnings and Precautions

Please see 3 Serious Warnings and Precautions Box at the beginning of Part 1: Healthcare Professional Information.

General

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 ASIMTUFII 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).

Carcinogenesis and Genotoxicity

For animal data, see 16 Non-Clinical Toxicology.

Cardiovascular

Orthostatic Hypotension

Aripiprazole may be associated with orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. Aripiprazole may induce orthostatic hypotension, tachycardia, dizziness, and sometimes syncope, especially at the initiation of treatment.

In the placebo-controlled trial in acute schizophrenia, presyncope occurred in 1/167 (0.6%) of patients treated with ABILIFY MAINTENA, while syncope and orthostatic hypotension each occurred in 1/172, (0.6%) of patients treated with placebo. There were no significant orthostatic changes in blood pressure for the ABILIFY MAINTENA-treated patients or placebo-treated patients (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 when comparing standing to supine values).

In the double-blind controlled phase of the schizophrenia maintenance clinical trials using ABILIFY MAINTENA, orthostatic related events were reported in 2/534 (0.4%) patients. 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 was 0.2% (1/575).

During the stabilization phase of the maintenance trial in adult patients with bipolar I disorder, syncope was the only orthostatic related adverse event reported in 0.2% of patients treated with ABILIFY MAINTENA. Incidence of potential clinically relevant orthostatic hypotension reported during the ABILIFY MAINTENA stabilization phase in bipolar I disorder was 0.2% (1/421) and during the double-blind, placebo-controlled phase, there were no differences reported in either treatment group.

The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral aripiprazole (n=2643) included (aripiprazole incidence, placebo incidence): orthostatic hypotension (1.0%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.3%).

Aripiprazole should be used with caution in patients with known cardiovascular disease (e.g. history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Patients with a history of clinically significant cardiovascular disorders were excluded from clinical trials. Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

QT Interval

In clinical trials with ABILIFY MAINTENA, the incidence of QT prolongation was comparable to placebo. In post-marketing experience, QT prolongation has been reported very rarely with aripiprazole treatment. As with other antipsychotics, aripiprazole should be used with caution in patients with conditions such as congenital long QT syndrome and acquired long QT syndrome (e.g., due to concomitant use of a drug that prolongs the QT); a family history of QT prolongation; or other clinical conditions that predispose to arrhythmias (e.g., hypokalemia or hypomagnesemia or hypocalcemia) (see 8.2 Clinical Trial Adverse Reactions).

Driving and Operating Machinery

Antipsychotics, including aripiprazole, have the potential to impair judgment, thinking, or motor skills. While taking ABILIFY ASIMTUFII, patients should be cautioned to not drive, operate dangerous machinery or engage in activities that require alertness or physical coordination if they are experiencing any of these effects.

Endocrine and Metabolism

Hyperglycemia and Diabetes Mellitus

Diabetic ketoacidosis has occurred in patients treated with antipsychotics with no reported history of hyperglycemia. As with some other antipsychotics, exacerbation of pre-existing diabetes and hyperglycemia have been reported rarely and diabetic ketoacidosis and diabetic coma including some fatal cases, have been reported very rarely during the use of oral aripiprazole. In schizophrenia clinical trials with ABILIFY MAINTENA there have been few reports of hyperglycemia and diabetes, the incidence was 0.6% and 1.1% respectively in the maintenance trials and 0% and 0.6% in the acute trial. In the bipolar I disorder clinical trial, the incidence of hyperglycemia and diabetes were 0.8% and 0% respectively.

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 which did not include oral aripiprazole suggest an increased risk of treatment-emergent hyperglycemia-related adverse events 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 hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients should have baseline and periodic monitoring of blood glucose and body weight. Any patient treated with atypical antipsychotics should also 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 suspect drug. 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. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.

No specific studies have been conducted with ABILIFY ASIMTUFII in patients with hyperglycemia or diabetes mellitus, however overall findings in clinical trials have been similar to ABILIFY MAINTENA and oral aripiprazole.

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics (see 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data).

No specific studies have been conducted with ABILIFY ASIMTUFII in patients for dyslipidemia, however overall findings in clinical trials have been similar to ABILIFY MAINTENA and oral aripiprazole.

Weight Gain

Antipsychotic drugs have been associated with metabolic changes, including weight gain. Clinical monitoring of weight is recommended, (see 8.2 Clinical Trial Adverse Reactions - Weight).

Genitourinary

Priapism

Although no cases of priapism were reported in clinical trials with ABILIFY ASIMTUFII, rare cases of priapism have been reported with antipsychotic use including oral aripiprazole. As with other psychotropic drugs, this adverse reaction did not appear to be dose-dependent and did not correlate with the duration of treatment.

Hematologic

In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including 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. Patients with a history of a clinically significant low WBC or drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ABILIFY ASIMTUFII should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Discontinue ABILIFY ASIMTUFII in patients with severe neutropenia (absolute neutrophil count <1x10⁹/L) and follow their WBC counts until recovery, (see 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data).

Venous Thromboembolism

Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with antipsychotic drugs, including oral aripiprazole, in case reports and/or observational studies. When prescribing aripiprazole all potential risk factors for VTE should be identified and preventative measures undertaken.

Monitoring and Laboratory Tests

Monitoring for orthostatic vital signs is recommended in patients who may be vulnerable to hypotension (see 7 Cardiovascular).

Baseline measurements and periodic monitoring of blood glucose and body weight is recommended for all patients (see 7 Endocrine and Metabolism).

Frequent monitoring of CBC during the first few months of treatment is recommended in patients with a history of a clinically significant low WBC or drug-induced leukopenia/neutropenia. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur (see 7 Hematologic).

Neurologic

Neuroleptic Malignant Syndrome (NMS)

Neuroleptic malignant syndrome is a potentially fatal symptom complex that has been reported in association with antipsychotic drugs, including oral aripiprazole.

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 (CPK), myoglobinuria (rhabdomyolysis), and acute renal failure.

In arriving at a diagnosis, it is important to identify cases where 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 all antipsychotic drugs including ABILIFY ASIMTUFII and other drugs not essential to 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 for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of therapy should be very carefully considered. The patient should be carefully monitored, since recurrence of NMS has been reported.

Falls

Antipsychotics, including aripiprazole, may cause somnolence, postural hypotension, 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 patients on long-term antipsychotic therapy.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome is 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 increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increases. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of 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 that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, ABILIFY ASIMTUFII 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 such 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 on ABILIFY ASIMTUFII, drug discontinuation should be considered. However, some patients may require treatment with ABILIFY ASIMTUFII despite the presence of the syndrome.

Extrapyramidal Symptoms

See 8.2 Clinical Trial Adverse Reactions - Extrapyramidal Symptoms.

Seizure/Convulsion

As with other antipsychotic drugs, ABILIFY ASIMTUFII should be used 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.

Psychiatric

Suicide

The possibility of a suicide attempt is inherent in psychotic illnesses and close supervision and appropriate clinical management of high-risk patients should accompany drug therapy. As ABILIFY ASIMTUFII is to be administered by a healthcare professional, suicide due to an overdose is considered unlikely (see 5 Overdose).

Pathological Gambling and Other Impulse-Control Disorders

Post-marketing reports of pathological gambling have been reported in patients treated with aripiprazole. These reports suggest that patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. With regards to pathological gambling, patients with a prior history of gambling disorder may be at increased risk and should be monitored carefully. Other urges, reported very rarely, include: increased sexual urges, compulsive spending, binge or compulsive eating, and other impulsive and compulsive behaviours. Because patients may not recognize these behaviours as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive spending, 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; however, in some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Although impulse-control disorders have been reported very rarely, impulse-control disorders may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if patient develops such urges while taking aripiprazole.

Skin

Severe Cutaneous Adverse Reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) are potentially life-threatening adverse drug reactions that have been reported with atypical antipsychotic exposure (see 8.5 Post-Market Adverse Reactions). SCARs commonly present as a combination of the following symptoms: extensive cutaneous rash or exfoliative dermatitis, fever, lymphadenopathy and possible eosinophilia. Discontinue ABILIFY ASIMTUFII if severe cutaneous adverse reactions occur.

7.1. Special Populations

7.1.1. Pregnancy

Teratogenic effects

There are no adequate and well-controlled studies of aripiprazole in pregnant women. It is not known whether aripiprazole can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits (see 16 Non-Clinical Toxicology).

Non-teratogenic effects

Neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Prescribers need to be aware of the long-acting properties of ABILIFY ASIMTUFII. Aripiprazole plasma concentrations are sustained over a two-month period following gluteal injection(s) of ABILIFY ASIMTUFII (10.3 Pharmacokinetics, Figure 10). Aripiprazole has been detected in plasma in adult patients up to 34 weeks after a single-dose administration of ABILIFY ASIMTUFII.

The clinical significance of aripiprazole administered before pregnancy or anytime during pregnancy is not known. ABILIFY ASIMTUFII should not be used during pregnancy unless the expected benefits to the mother markedly outweigh the potential risks to the fetus.

Labour and Delivery

The effect of aripiprazole on labour and delivery in humans is unknown.

7.1.2. Breastfeeding

Aripiprazole is excreted in human breast milk. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from ABILIFY ASIMTUFII therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

7.1.3. Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada for patients < 18 years of age; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4. Geriatrics

The safety and efficacy of ABILIFY ASIMTUFII in patients 65 years of age or older have not been established. Caution should be used when treating geriatric patients.

In formal single-dose pharmacokinetic studies (with oral aripiprazole given in a single dose of 15 mg), aripiprazole clearance was 20% lower in elderly (>65 years) patients compared to younger adult patients (18 to 64 years). There was no detectable age effect, however, in the population pharmacokinetic analysis in schizophrenia patients. Also, the pharmacokinetics of aripiprazole after multiple doses in elderly patients appeared similar to that observed in young, healthy subjects.

Nevertheless, geriatric patients generally have decreased cardiac, hepatic and renal function, and more frequent use of concomitant medication. The presence of multiple factors that might increase the pharmacodynamic response to aripiprazole, or cause poorer tolerance or orthostasis, should lead to careful monitoring during the initial dosing period for elderly patients.

Use in Elderly Patients with Dementia

Overall Mortality

Elderly patients with dementia treated with oral atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of 13 placebo-controlled trials of various atypical antipsychotic drugs (modal duration of 10 weeks) in these patients showed a mean 1.6-fold increase in the death rate in the drug-treated patients. In three placebo-controlled studies of aripiprazole in elderly patients with Alzheimer’s disease (n=938; mean age: 82.4 years; range: 56-99 years), the rate of death in aripiprazole-treated patients was 3.5%, compared to a rate of 1.7% in the placebo group during or within 30 days after termination from the double-blind phase of the studies. 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. ABILIFY ASIMTUFII is not indicated for the treatment of elderly patients with dementia (see 3 Serious Warnings and Precautions Box).

Cerebrovascular Adverse Events, Including Stroke in Elderly Patients with Dementia

In placebo-controlled clinical studies with oral aripiprazole (two flexible dose and one fixed dose study) of elderly patients with dementia, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients. In the fixed-dose study, there was a statistically significant dose-response relationship for cerebrovascular adverse events in patients treated with aripiprazole. Aripiprazole is not indicated for the treatment of patients with dementia (see 3 Serious Warnings and Precautions Box).

Frequent Treatment Emergent Adverse Events in Elderly Patients with Dementia

In the placebo-controlled studies of elderly patients with dementia (n=595 treated with oral aripiprazole, n=343 treated with placebo), the following treatment-emergent adverse events (TEAEs)

were reported at an incidence of ≥3% and aripiprazole incidence at least twice that for placebo: lethargy [placebo 2%, aripiprazole 5%], somnolence (including sedation) [placebo 3%, aripiprazole 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, aripiprazole 5%], excessive salivation (placebo 0%, aripiprazole 4%), and light-headedness (placebo 1%, aripiprazole 4%).

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including oral aripiprazole. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, particularly in those with advanced Alzheimer’s dementia. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. The emergence of difficulty swallowing or excessive somnolence could predispose patients to accidental injury or aspiration (see 7.1.4 Geriatrics - Use in Elderly Patients with Dementia).

8. Adverse Reactions

8.1. Adverse Reaction Overview

The safety of ABILIFY ASIMTUFII administered once every two months, for treatment of schizophrenia or maintenance monotherapy treatment of bipolar I disorder, is supported by the placebo-controlled clinical trials that evaluated the safety of ABILIFY MAINTENA administered once monthly, and a 32-week open-label study in which patients with schizophrenia or bipolar I disorder were treated with ABILIFY ASIMTUFII or ABILIFY MAINTENA (see 8.2 Clinical Trial Adverse Reactions).

ABILIFY MAINTENA

In the schizophrenia trials, the most frequently observed adverse events (AEs) reported in ≥ 5 % of patients in two double-blind pivotal maintenance clinical studies of ABILIFY MAINTENA were insomnia, weight increased, akathisia, headache, anxiety, weight decreased, nasopharyngitis and injection site pain. Overall, these adverse events were mild to moderate in severity and were similar to those in the placebo treated patients (Table 4).

Based on the placebo-controlled trial of ABILIFY MAINTENA in the acute phase of schizophrenia, the most commonly observed adverse events associated with the use of aripiprazole in patients (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were increased weight, akathisia, sedation, and injection site pain (Table 5).

In the bipolar I disorder trial of ABILIFY MAINTENA, none of the adverse events in the double-blind, placebo-controlled phase were reported at an incidence ≥ 5 % of patients and at least twice the incidence of placebo. Based on the placebo-controlled trial of ABILIFY MAINTENA in patients with bipolar I disorder, the most frequently observed adverse events reported in ≥ 5 % of ABILIFY MAINTENA patients and greater than placebo were weight increased, akathisia, anxiety, restlessness, and somnolence (Table 6).

ABILIFY ASIMTUFII

The most commonly observed adverse events (incidence of at least 5%) in patients with schizophrenia or bipolar I disorder treated with ABILIFY ASIMTUFII during the 32-week open-label study were weight increased, injection site pain, akathisia, anxiety, headache, insomnia, and constipation. Injection site pain and headache were reported twice as frequently with ABILIFY ASIMTUFII compared to ABILIFY MAINTENA (Table 7).

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Adverse Events Reported with ABILIFY MAINTENA

ABILIFY MAINTENA administered once monthly has been evaluated for safety in 2,649 adult patients in clinical trials in schizophrenia. Of the 2,649 adult schizophrenia patients exposed to ABILIFY MAINTENA, 2,567 patients have been treated with ABILIFY MAINTENA 400 mg/ 300 mg. Of the 2,649 patients exposed to ABILIFY MAINTENA, 1,316 patients have received at least 9 injections of ABILIFY MAINTENA 400 mg/300 mg, (i.e., have been treated for at least 9 months), 941 patients have received at least 13 injections (i.e., have been treated for at least 12 months), and 632 patients received at least 26 injections (i.e., have been treated for 24 months). Table 4 and Table 5 present the adverse events reported at a rate of 2% or greater in the schizophrenia maintenance and acute treatment clinical trials, respectively.

ABILIFY MAINTENA has been evaluated for safety in 804 adult patients in clinical trials in bipolar I disorder, with approximately 530 patient-years of exposure to ABILIFY MAINTENA. A total of 419 patients were treated with ABILIFY MAINTENA for at least 7 consecutive injections (i.e., have been treated for at least 6 months) and 287 patients treated with ABILIFY MAINTENA had at least 13 consecutive injections (i.e., have been treated for at least 12 months). Table 6 presents the adverse events reported at a rate of 2% or greater in the bipolar I disorder clinical trial.

Table 4: Adverse Events occurring in 2% or more of patients with schizophrenia in both placebo and active controlled maintenance clinical trials

Table 5: Adverse Events occurring in 2% or more of patients with schizophrenia in the Acute Phase Placebo controlled clinical trial and greater than placebo

Table 6: Adverse Events occurring in 2% or more of patients with bipolar I disorder in the placebo controlled clinical trial and greater than placebo

Adverse Events Leading to Discontinuation of Treatment

In the schizophrenia trials, overall adverse reactions that led to discontinuation were similar for the aripiprazole-treated and placebo-treated patients in both the acute and maintenance phase studies. During double-blind treatment phase of the maintenance trials (Controlled Trials), TEAEs resulting in discontinuation of trial medication were experienced by 40/534 (7.5%) ABILIFY MAINTENA 400 mg/300 mg patients, 19/266 (7.1%) oral aripiprazole tablets 10-30 mg patients, 24/131 (18.3%) aripiprazole IM depot 50 mg/25 mg patients, and 18/134 (13.4%) placebo patients. In the acute schizophrenia trial, there was overall little difference in the incidence of discontinuations due to adverse reactions between ABILIFY MAINTENA-treated (4%) and placebo-treated (8%) patients.

During the double-blind, placebo-controlled phase of the bipolar I disorder trial, fewer patients experienced a TEAE resulting in discontinuation in the ABILIFY MAINTENA group (23/132; 17.4%) compared to the placebo group (34/133; 25.6%). The following TEAEs led to discontinuation of study medication in more than 1 patient in either treatment group (ABILIFY MAINTENA vs placebo): mania (2.3% vs 8.3%), bipolar I disorder (1.5% vs 6.0%), bipolar disorder (3.8% vs 3.0%), depression (3.0% vs 2.3%), akathisia (1.5% vs 0.0%), affective disorder (0.0% vs 1.5%), and major depression (0.0% vs 1.5%).

Adverse Events Reported with ABILIFY ASIMTUFII

In a 32-week multiple-dose open-label study in adult patients with schizophrenia or bipolar I disorder, 266 patients were randomized to receive either ABILIFY ASIMTUFII 960 mg once every 2 months (132 patients) or ABILIFY MAINTENA 400 mg once monthly (134 patients). A total of the 132 patients treated with ABILIFY ASIMTUFII 960 mg received at least one injection. A total of 114 patients were treated with ABILIFY ASIMTUFII 960 mg for at least four months and received at least two consecutive injections. A total of 104 patients were treated with ABILIFY ASIMTUFII 960 mg for at least 8 months and received at least four consecutive injections. Of the total 266 patients receiving ABILIFY ASIMTUFII 960 mg or ABILIFY MAINTENA 400 mg, 185 had schizophrenia and 81 had bipolar I disorder. For patients who did not have a history of tolerating aripiprazole, including those switching from other oral antipsychotics, three single oral doses of aripiprazole 10 mg were administered on three consecutive days (30 mg total) in addition to their current oral antipsychotic, mood stabilizer, and if applicable, antidepressant at least 14 days prior to the first injection of study medication, to establish tolerability.

Table 7 lists the adverse events reported in the open-label study in patients with schizophrenia or bipolar I disorder. No new TEAEs were identified for ABILIFY ASIMTUFII.

Table 7: Adverse events occurring in 2% or more of patients treated with ABILIFY ASIMTUFII in a 32-week open-label, multiple-dose study

Adverse Events Leading to Discontinuation of Treatment

During the open-label study in adult patients with schizophrenia or bipolar I disorder, 3.0% of the patients treated with ABILIFY ASIMTUFII and 7.5% of the patients treated with ABILIFY MAINTENA discontinued treatment due to adverse events.

Demographic Differences

An examination of demographic subgroup categories for adverse reactions experienced in the open-label study did not show evidence of differences in safety on the basis of age, gender, or race for the adverse reactions reported by at least 5% of patients treated with ABILIFY ASIMTUFII and at least twice the rate of ABILIFY MAINTENA (i.e., injection site pain and headache). Some less commonly reported treatment emergent adverse events were reported more frequently in women compared to men during treatment with ABILIFY ASIMTUFII (see 10.3 Pharmacokinetics, Special Populations and Conditions).

Injection Site Adverse Events

The investigator rated pain, redness, swelling, and induration at the injection site at the same visits where patients assessed pain using a Visual Analog Scale (VAS; 0 mm = no pain to 100 mm = unbearably painful). Analyses of injection site assessments (investigator-rated and subject -reported VAS) were performed to evaluate the safety/tolerability of ABILIFY MAINTENA (Table 8) and ABILIFY ASIMTUFII (Table 9).

ABILIFY MAINTENA

Injection site assessments were completed after all injections during the ABILIFY MAINTENA schizophrenia and bipolar I disorder trials. The injection site adverse drug reaction profile was consistent across schizophrenia and bipolar studies. Across long-term trials, patient evaluations of injection site pain based on the VAS scale tended to lessen in frequency and intensity over time. In addition, overall, reactions were reported to be of mild to moderate severity.

During the double-blind phase of schizophrenia maintenance studies, 37/534 (6.9%) ABILIFY MAINTENA 400 mg/300 mg patients, 7/266 (2.6%) oral aripiprazole tablets 10-30 mg patients, 1/131 (0.8%) aripiprazole IM depot 50 mg/25 mg IM patients, and 5/134 (3.7%) placebo patients experienced TEAEs related to the injection site.

In the data from the acute phase double-blind placebo-controlled trial with ABILIFY MAINTENA in patients with schizophrenia, the percent of patients reporting any injection site-related adverse reaction was 5.4% for ABILIFY MAINTENA-treated patients. The mean intensity of injection pain reported by patients using a visual analog scale (0=no pain to 100=unbearably painful) was minimal in patients receiving ABILIFY MAINTENA (7.1 after first injection, and 7.7 after last injection).

In the data from the double-blind, placebo-controlled phase in patients with bipolar I disorder, the percentage of patients reporting injection site-related adverse reactions was similar between ABILIFY MAINTENA (0.8%) and placebo (1.5%).

Table 8: Investigator assessments of pain, swelling and induration at the injection site and Patient VAS scores for ABILIFY MAINTENA

*Range of percent is based on rating in the 4 domains (pain, redness, swelling, and induration)

** The open-label analyses were done to understand the injection site reaction parameters after initiation of ABILIFY MAINTENA as well as during its continued use in the double-blind, placebo-controlled phase.

In an open label study comparing bioavailability of ABILIFY MAINTENA administered in the deltoid or gluteal muscle, injection site related reactions were observed in both groups at approximately equal rates and the majority were mild and improved on subsequent injections.

ABILIFY ASIMTUFII

In the 32-week open-label study with 266 patients with schizophrenia or bipolar I disorder, the percentage of patients reporting any injection site-related adverse reactions (all reported as injection site pain) was 18.2% for patients treated with ABILIFY ASIMTUFII 960 mg and 9.0% for patients treated with ABILIFY MAINTENA 400 mg. In both treatment groups, the majority of the injection site pain events coincided with the first injection of ABILIFY ASIMTUFII 960 mg (21/24 patients) or ABILIFY MAINTENA 400 mg (7/12 patients) and was reported with decreasing frequency upon subsequent injections. The overall mean visual analog scale scores (0=no pain to 100=unbearably painful) for patient-reported rating of pain were similar in both treatment groups at the last injection: 0.8 pre-dose and 1.4 post-dose for the ABILIFY ASIMTUFII 960 mg group compared to 1.3 post-dose for the ABILIFY MAINTENA 400 mg group. None of the events of injection site pain were categorized as severe or serious, and none led to discontinuation.

Table 9: Investigator assessments of pain, redness, swelling and induration at the injection site and Patient VAS scores for ABILIFY ASIMTUFII

*Range of percent is based on rating in the 4 domains (pain, redness, swelling, and induration)

Extrapyramidal Symptoms (EPS)

ABILIFY MAINTENA

The table below presents the percentage of patients experiencing treatment emergent EPS and EPS related events during the double-blind phases of the 38-and 52-week trials in schizophrenia.

Table 10: Patients experiencing EPS and EPS related Events in the schizophrenia maintenance trials

There was minimal variation in EPS symptoms during the double-blind phases of the schizophrenia trials, as assessed by mean changes from baseline in the Simpson Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BARS) rating scales. Although there were statistically significant differences between the mean change from baseline in the BARS global score between ABILIFY MAINTENA 400 mg/300 mg and oral aripiprazole tablets 10-30 mg (Weeks 8 and 38) and between ABILIFY MAINTENA 400 mg/300 mg and aripiprazole IM depot 50 mg/25 mg (Week 8, Week 12 and Week 36), the mean changes were not considered to be clinically relevant.

Similar results were observed in the 12-week placebo-controlled study in the acute phase of schizophrenia, with akathisia occurring in 11.4% of the patients on ABILIFY MAINTENA compared to 3.5% of placebo patients and parkinsonism occurring in 5.4% of ABILIFY MAINTENA patients compared to 2.3% of placebo patients.

During the double-blind, placebo-controlled phase of the bipolar I disorder trial, 36/132 (27.3%) ABILIFY MAINTENA-treated patients and 22/133 (16.5%) placebo-treated patients had treatment-emergent EPS and EPS-related AEs. In the ABILIFY MAINTENA (vs. placebo) group, EPS and EPS-related events reported by ≥ 2% of patients were akathisia and psychomotor hyperactivity events (22.0% vs 12.8%), parkinsonism events (5.3% vs 3.8%), dyskinetic (2.3% vs 1.5%), and dystonic events (2.3% vs 0.0%).

The most frequently reported treatment-emergent EPS and EPS-related AE was akathisia with 28/132 (21.2%) ABILIFY MAINTENA-treated patients and 17/133 (12.8%) placebo-treated patients experiencing an event. One ABILIFY MAINTENA-treated and no placebo-treated patients experienced an SAE of akathisia and 2 ABILIFY MAINTENA-treated patients were discontinued due to akathisia. There were no other EPS-related SAEs and no other TEAEs leading to discontinuation reported.

ABILIFY ASIMTUFII

Data from the open-label study of patients treated with ABILIFY ASIMTUFII showed minimal change from baseline in EPS symptoms, as assessed by the Simpson-Angus Rating scale (SAS), the Abnormal Involuntary Movement Scale (AIMS) and the Barnes Akathisia Rating Scale (BARS). The incidence of treatment emergent EPS-related events, for patients treated with ABILIFY ASIMTUFII 960 mg was 18.2% compared to 13.4% for patients treated with ABILIFY MAINTENA 400 mg.

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.

Weight

ABILIFY MAINTENA

One placebo-controlled trial with ABILIFY MAINTENA was conducted in hospitalized patients in the acute phase of schizophrenia, the mean change in body weight was +2.8 kg (N=144) in the ABILIFY MAINTENA-treated patients and +0.8 kg (N=141) in the placebo-treated patients, as assessed in patients with a median exposure of 85 days and a post baseline weight result at the last visit. The incidence of weight gain of > 7% from baseline to last visit was 22% for the ABILIFY MAINTENA 400 mg/300 mg group, and 9% for the placebo group.

During double-blind treatment in the maintenance schizophrenia trials (Controlled Trials), TEAEs related to weight were reported for 87/534 (16.3%) ABILIFY MAINTENA 400 mg/300 mg patients, 52/266 (19.5%) oral aripiprazole tablets 10-30 mg patients, 19/131 (14.5%) aripiprazole IM depot 50 mg/25 mg patients, and 17/134 (12.7%) placebo patients. TEAEs related to weight that were reported included increased weight, decreased weight, overweight, and edema.

During the double-blind, active-controlled phase of the 38-week ABILIFY MAINTENA schizophrenia trial, the incidence of weight gain of ≥ 7% from baseline to last visit was 9.5% for the ABILIFY MAINTENA 400 mg/300 mg group, 11.7% for oral aripiprazole tablets 10-30 mg group and 4.6% for the aripiprazole IM depot 50 mg/25 mg group. The incidence of weight loss of ≥ 7% from baseline to last visit was 10.2% for ABILIFY MAINTENA 400 mg/300 mg, 4.5% for oral aripiprazole tablets 10-30 mg, and 9.9% for aripiprazole IM depot 50 mg/25 mg. During double-blind treatment, mean change in body weight from baseline to last visit was -0.2kg for ABILIFY MAINTENA, +0.7kg for oral aripiprazole tablets and -1.1 for aripiprazole IM depot 50 mg/25 mg. Overall in the maintenance clinical trials there was no difference in the incidence of weight gain between ABILIFY MAINTENA and placebo.

During the double-blind, placebo-controlled phase of the 52-week ABILIFY MAINTENA schizophrenia trial, the incidence of weight gain of ≥ 7% from baseline to last visit was similar between ABILIFY MAINTENA and placebo: 6.4% for the ABILIFY MAINTENA 400 mg/300 mg group and 5.2% for the placebo group. The incidence of weight loss of ≥ 7% from baseline to last visit was 6.4% for the ABILIFY MAINTENA 400 mg/300 mg group and 6.7% for the placebo group. During double-blind treatment, mean change in body weight from baseline to last visit was -0.2kg for ABILIFY MAINTENA and -0.4kg for placebo.

During the double-blind, placebo-controlled phase of the bipolar I disorder trial, the incidence of weight gain ≥ 7% at any time was reported for 18.0% for ABILIFY MAINTENA-treated patients and 12.9% for placebo- treated patients; the incidence of weight loss ≥ 7% at any time was reported for 9.4% ABILIFY MAINTENA-treated patients and 12.1% placebo-treated patients. At the last visit, the incidence of potentially clinically relevant weight gain was 13.3% ABILIFY MAINTENA-treated patients and 12.1% placebo-treated patients; the incidence of weight loss ≥ 7% at last visit was reported for 5.5% ABILIFY MAINTENA-treated patients and 10.6% placebo-treated patients. The mean change (SD) from baseline at Week 52 was 1.3 (5.9) kg for ABILIFY MAINTENA-treated and 1.5 (6.1) kg for placebo-treated patients; and at last visit was 0.9 (5.3) kg for ABILIFY MAINTENA-treated and 0.0 (5.9) kg for placebo-treated patients.

ABILIFY ASIMTUFII In the open-label, multiple-dose, randomized study in adult patients with schizophrenia or bipolar I disorder, in which ABILIFY ASIMTUFII (960 mg) was compared to ABILIFY MAINTENA (400 mg), the overall incidence of weight gain (≥ 7%) from baseline was 40.6% for the ABILIFY ASIMTUFII group and 42.9% for the ABILIFY MAINTENA group. The mean change in body weight from baseline to last visit was +3.6 kg in the ABILIFY ASIMTUFII group and +3.0 kg in the ABILIFY MAINTENA group.

Weight increase seen with ABILIFY ASIMTUFII was consistent with the known safety profile of ABILIFY MAINTENA and oral aripiprazole. None of the events of weight increased were categorized as severe or serious, and none led to discontinuation.

QT Interval

ABILIFY MAINTENA

During double-blind treatment in patients with schizophrenia, 1/534 (0.2%) ABILIFY MAINTENA 400 mg/300 mg patients had a TEAE related to QT interval change (prolonged ECG QT).

In the double-blind, placebo-controlled phase of the bipolar I disorder trial and the open-label trial, there were no QT interval-related TEAEs reported.

In the clinical trials of treatment with ABILIFY MAINTENA across indications, the incidence of QT prolongation was comparable to placebo. As with other antipsychotics, aripiprazole should be used with caution in patients with a family history of QT prolongation.

ABILIFY ASIMTUFII

During the open-label, multiple-dose, randomized study in adult patients with schizophrenia or bipolar I disorder, there were no notable differences in mean values and changes from baseline for ECG parameters observed between patients treated with ABILIFY ASIMTUFII and patients treated with ABILIFY MAINTENA.

No TEAEs related to QT interval change were reported for either ABILIFLY ASIMTUFII or ABILIFY MAINTENA.

Prolactin

ABILIFY MAINTENA

Changes in prolactin levels were comparable across trials, irrespective of indication (schizophrenia or bipolar I disorder), and there were no clinically relevant mean changes from baseline to the last visit with regard to prolactin levels during the double-blind treatment phase of either trial.

In the double-blind active-controlled phase of the 38-week schizophrenia trial, from baseline to last visit, there was a mean decrease in prolactin levels in the ABILIFY MAINTENA 400 mg/300 mg group (−0.33 ng/mL) compared with a mean increase in the oral aripiprazole tablets 10-30 mg group (0.79 ng/mL) and aripiprazole IM depot 50 mg/25 mg (1.11 ng/mL) groups. The incidence for ABILIFY MAINTENA 400 mg/300 mg patients with prolactin levels >1 time the upper limit of normal range (ULN) at any assessment was 5.4% compared with 3.5% of oral aripiprazole tablets 10-30 mg, and 4.7% of aripiprazole IM depot 50 mg/25 mg patients, with a higher incidence in male patients than female patients in each treatment group.

In the double-blind placebo-controlled phase of the 52-week schizophrenia trial, from baseline to last visit, there was a mean decrease in prolactin levels in the ABILIFY MAINTENA 400 mg/300 mg group (−0.38 ng/mL) compared with a mean increase in the placebo group (1.67 ng/mL). The incidences of ABILIFY MAINTENA 400 mg/300 mg patients with prolactin levels >1 time the upper limit of normal range (ULN) was 1.9% compared to 7.1% for placebo patients.

In the double-blind, placebo-controlled phase of the bipolar I disorder trial, the mean changes from baseline to last visit in prolactin were minimal in the ABILIFY MAINTENA 400 mg/300 mg group (0.15 ng/mL) compared to placebo (3.00 ng/mL) and none of the changes were considered to be clinically meaningful. There were no clinically meaningful differences in the incidence of prolactin levels above the ULN between treatment groups and no incidence of > 3 × ULN reported during the double-blind, phase of this trial. No clinically meaningful differences in shifts in prolactin between treatment groups or gender were reported. During the double-blind phase, no ABILIFY MAINTENA-treated and 0.8% of placebo-treated patients experienced the prolactin-related TEAE of hyperprolactinaemia.

ABILIFY ASIMTUFII

During the open-label, multiple-dose, randomized study in adult patients with schizophrenia or bipolar I disorder, there were decreases in prolactin levels at the last visit when compared to baseline in the ABILIFY ASIMTUFII and ABILIFY MAINTENA treatment groups. Overall mean decreases from baseline to last visit were -5.6 ng/mL in the ABILIFY ASIMTUFII group (schizophrenia -5.4 ng/mL; bipolar disorder -5.9 ng/mL) and -6.1 ng/mL in the ABILIFY MAINTENA group (schizophrenia -7.1 ng/mL; bipolar disorder -4.1 ng/mL). The incidence of blood prolactin levels > 1 times ULN at any assessment in patients with schizophrenia was 1.2% for patients treated with ABILIFY ASIMTUFII and 5.1% for patients treated with ABILIFY MAINTENA. The incidence of blood prolactin levels > 1 times ULN at any assessment in patients with bipolar I disorder was 2.6% for patients treated with ABILIFY ASIMTUFII and 1.3% for patients treated with ABILIFY MAINTENA.

8.3. Less Common Clinical Trial Adverse Reactions

Treatment emergent adverse events listed below were reported by less than 2% of patients and at least as frequently in the placebo group on ABILIFY MAINTENA during the randomization phase of the schizophrenia clinical trials or by less than 2% of patients on ABILIFY ASIMTUFII during an open-label, multiple-dose, randomized study in adult patients with schizophrenia or bipolar I disorder.

Blood and Lymphatic System Disorders: Bicytopenia, lymphadenopathy, neutropenia, thrombocytopenia.

Cardiac Disorders: Cardiac arrest, acute myocardial infarction, atrioventricular block first degree, cardiac failure congestive, ventricular extrasystoles.

Ear and Labyrinth disorders: Deafness, vertigo.

Eye Disorders: Conjunctivitis allergic, eye irritation, eye pain, eyelid ptosis, oculogyric crisis, photophobia.

Gastrointestinal Disorders: Abdominal pain, abdominal pain upper, anorectal discomfort, aphthous ulcer, colitis, dental caries, diverticulum, dyspepsia, dysphagia, frequent bowel movements, gastritis, gastroesophageal reflux disease, gingival edema, gingival pain, gingivitis, hemorrhoids, inguinal hernia, loose tooth, periodontitis, poor dental condition, tongue disorder, tooth impacted, tooth loss.

General Disorders and Administration Site Conditions: Asthenia, chest discomfort, gait disturbance, influenza like illness, infusion site hematoma, infusion site swelling, injection site discomfort, injection site pruritus, injection site induration, injection site mass, injection site reaction, injection site swelling, edema peripheral, pain, sluggishness, suprapubic pain, thirst, vessel puncture site hematoma, vessel puncture site pain.

Hepatobiliary disorders: Cholecystitis chronic, cholelithiasis, hepatic cirrhosis, hepatic steatosis, hepatosplenomegaly.

Immune System Disorders: Drug hypersensitivity.

Infections and Infestations: Acarodermatitis, anal abscess, appendicitis perforated, bacterial vaginosis, body tinea, cellulitis, cystitis, ear infection, Escherichia urinary tract infection, folliculitis, fungal infection, fungal skin infection, furuncle, gastroenteritis, gastroenteritis viral, herpes virus infection, herpes zoster, hordeolum, impetigo, lice infestation, localized infection, mastitis, oral candidiasis, pharyngitis, pharyngitis streptococcal, pilonidal disease, pneumonia, respiratory tract infection, viral rhinitis, subcutaneous abscess, tinea pedis, tooth abscess, tooth infection, viral upper respiratory tract infection, vaginal infection, varicella, viral infection, vulvovaginal mycotic infection.

Injury, Poisoning and Procedural Complications: Accident, ankle fracture, carbon monoxide poisoning, contusion, face injury, fall, foot fracture, gun shot wound, injury, joint dislocation, ligament sprain, multiple injuries, muscle injury, hand fracture, muscle strain, radius fracture, skeletal injury, skin abrasion, skin laceration, thermal burn, tooth fracture, toxicity to various agents, wound.

Investigations: Alanine aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased, blood cholesterol decreased, blood glucose decreased, blood glucose increased, blood insulin increased, blood lactate dehydrogenase increased, blood pressure increased, blood prolactin decreased, blood prolactin increased, blood triglycerides decreased, blood triglycerides increased, body temperature increased, liver function test increased, weight decreased, electrocardiogram abnormal, electrocardiogram QT prolonged, electrocardiogram T wave amplitude decreased, electrocardiogram T wave inversion, gamma-glutamyltransferase increased, glucose urine present, glycosylated haemoglobin increased, heart rate decreased, hepatic enzyme increased, liver function test abnormal, neutrophil count decreased, protein urine, waist circumference increased, white blood cell count decreased, white blood cells urine.

Metabolism and Nutrition Disorders: Appetite disorder, diabetes mellitus, gout, hypercholesterolemia, hypercalcemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hyperuricemia, hypoglycemia, overweight, type 2 diabetes mellitus.

Musculoskeletal and Connective Tissue Disorders: Arthritis, faciitis, fibromyalgia, joint stiffness, joint swelling, muscle rigidity, muscle spasms, muscle tightness, muscle twitching, musculoskeletal stiffness, nuchal rigidity, neck pain, rotator cuff syndrome, trismus.

Neoplasms benign malignant and unspecified: Basal cell carcinoma, breast fibroma, pancreatic carcinoma.

Nervous System Disorders: Bradykinesia, cogwheel rigidity, disturbance in attention, drooling, dystonia, extrapyramidal disorder, hypersomnia, hypoesthesia, intention tremor, migraine, movement disorder, oromandibular dystonia, parkinsonism, sciatica, parosmia, poor quality sleep, psychomotor hyperactivity, restless legs syndrome, sinus headache, syncope, tension headache.

Psychiatric Disorders: Abnormal dreams, affect lability, agitation, apathy, bipolar disorder, bruxism, bulimia nervosa, delusion, depression, dysphoria, hallucination auditory, hypersexuality, hyposomnia, libido decreased, middle insomnia, mood altered, nightmare, panic attack, panic reaction, psychotic disorder, sleep disorder, suicidal ideation, suicide attempt, tension.

Renal and Urinary Disorders: Glycosuria, micturition urgency, nephrolithiasis, pollakiuria, polyuria

Reproductive System and Breast Disorders: Adnexa uteri pain, breast mass, breast tenderness, erectile dysfunction, galactorrhea, gynecomastia, ovarian cyst, vulvovaginal dryness.

Respiratory Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, asthma, dysphonia, dyspnea, epistaxis, hiccups, nasal septum deviation, oropharyngeal pain, paranasal sinus hypersecretion, respiratory tract congestion, rhinalgia, rhinitis allergic, sinus congestion, wheezing.

Skin and Subcutaneous Tissue Disorders: Dermatitis allergic, acne, blister, dry skin, eczema, erythema, hyperkeratosis, pruritus, psoriasis, rash, rash macular, rosacea, skin induration, skin lesion, skin striae, urticaria.

Vascular Disorders: Orthostatic hypotension.

Adverse Events reported with Oral Aripiprazole

Short-Term, Placebo-Controlled Trials of Adult Patients with Schizophrenia

Based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which aripiprazole was administered orally in doses ranging from 2 to 30 mg/day the only commonly observed adverse event 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 (placebo 4%; aripiprazole 8%).

Long-Term, Double-Blind, Placebo-Controlled Trials in Adult Patients with Schizophrenia

The adverse events reported in a 26-week, double-blind trial comparing oral aripiprazole and placebo in adult 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 (52-week), active-controlled study, the incidence of tremor for oral aripiprazole was 5% (40/859).

Short-Term, Placebo-Controlled Trials of Adult Patients with Bipolar Disorder

The following findings are based on a pool of 3-week, placebo-controlled, bipolar mania trials in which aripiprazole was administered orally at doses of 15 or 30 mg/day. Overall, in patients with bipolar mania, there was little difference in the incidence of discontinuation due to adverse events between aripiprazole-treated (11%) and placebo-treated (10%) patients. The types of adverse events that led to discontinuation were similar between the aripiprazole and placebo-treated patients. Akathisia, the most common adverse event leading to discontinuation in the aripiprazole group, led to withdrawal of 2% of aripiprazole-treated patients and 0.3% of patients on placebo. Commonly reported adverse events associated with the use of aripiprazole in patients with bipolar mania (incidence of 5% or greater and aripiprazole incidence at least twice that of placebo) was, for aripiprazole and placebo (respectively): akathisia: 13/917 and 4/753, sedation: 8/917 and 3/753, restlessness: 6/917 and 2/753, and extrapyramidal disorder: 5/917 and 2/753.

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Clinical Trial Findings

No clinically relevant mean changes from baseline in serum chemistry, hematology, urinalysis, or other laboratory test (insulin, fasting insulin) results were observed during any of the clinical trials with ABILIFY MAINTENA or ABILIFY ASIMTUFII.

In both schizophrenia maintenance trials differences in the mean (± SD) change from the double-blind treatment phase baseline at the last visit in WBC, fasting glucose, lipids, and CPK levels were negligible between the ABILIFY MAINTENA 400 mg/300 mg group, and oral aripiprazole tablets 10-30 mg group, aripiprazole IM depot 50 mg/25 mg group or placebo groups and were considered to be of no clinical relevance. Mean changes in total CPK have been associated with NMS, and higher percentages of elevated creatine phosphokinase have been observed in oral aripiprazole-treated adult patients compared to placebo-treated patients in short-term and long-term clinical trials; however mean decreases were noted for ABILIFY MAINTENA 400 mg/300 mg in the active controlled trial and the differences between the ABILIFY MAINTENA and placebo groups were negligible in the placebo-controlled maintenance trial. In the acute placebo-controlled trial no clinically relevant mean changes from baseline in serum chemistry, hematology, urinalysis or other laboratory tests were observed during the acute treatment phase.

In the bipolar I disorder placebo-controlled and open label trials, no subject met the criteria for Hy’s law relative to laboratory values of potential clinical relevance.

In clinical studies of oral aripiprazole, in a long-term (26-week) placebo-controlled trial in adult patients with schizophrenia there were no clinically important differences between the aripiprazole and placebo patients in the mean change from baseline in prolactin, fasting glucose, triglyceride, HDL, LDL, and total cholesterol measurements. Higher percentages of elevated creatine phosphokinase were observed in aripiprazole-treated adult patients compared to placebo-treated patients in short-term and long-term clinical trials. The most common AEs that were temporally associated with elevated CPK levels were musculoskeletal stiffness, myalgia, chest pain, fall, and muscle rigidity.

8.5. Post-Market Adverse Reactions

The following adverse reactions have been identified during post-approval use of 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.

The adverse events listed below were reported during the post-marketing use of aripiprazole.

Eye Disorders: Diplopia

Gastrointestinal Disorders: Pancreatitis

Hepatobiliary Disorders: Hepatic failure, hepatitis, jaundice

Investigations: Aspartate aminotransferase (AST or SGOT) increased, blood glucose fluctuation, blood glucose increased, gamma-glutamyltransferase (GGT) increased

Metabolism and Nutrition Disorders: Anorexia, hyponatremia

Nervous System Disorders: Generalized tonic-clonic seizure, restless legs syndrome, speech disorder

Psychiatric Disorders: Hypersexuality, impulse-control disorders, pathological gambling

Renal and Urinary Disorders: Urinary retention

Skin and Subcutaneous Tissue Disorders: Allergic reaction (e.g., anaphylactic reaction, angioedema, laryngospasm, oropharyngeal spasm), alopecia, drug reaction with eosinophilia and systemic symptoms (DRESS), hyperhidrosis

Although a causal relationship has not been established, cases of suicide attempt, suicidal ideation, and completed suicide have been reported post marketing.

As with other antipsychotics, sudden death, torsades de pointes, ventricular tachycardia, arrhythmia, cardiopulmonary arrest and QT prolongation have been reported during treatment with oral aripiprazole. These events during aripiprazole treatment have been very rare or isolated. Many of the patients had pre-existing cardiovascular disease, were on concomitant medications known to prolong the QT interval, had risk factors for QT prolongation, took an overdose of oral aripiprazole, and/or were morbidly obese. Very rarely, QT prolongation has been reported in the absence of confounding factors.

Isolated cases of Serotonin Syndrome have been reported with the concomitant use of aripiprazole and serotonergic drugs such as Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) and Selective Serotonin Reuptake Inhibitor (SSRI).

Complex sleep-related behaviours such as somnambulism and sleep-related eating disorder have been associated with the use of atypical antipsychotic drugs, including aripiprazole.

In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has also been reported. Therefore, it is recommended that patients have their complete blood count (CBC) tested prior to starting ABILIFY ASIMTUFII and then periodically throughout treatment (see 7 Hematologic; 7 Monitoring and Laboratory Tests).

Atypical antipsychotic drugs, including aripiprazole, have been associated with cases of sleep apnea, with or without concomitant weight gain. In patients who have a history of or are at risk for sleep apnea, aripiprazole should be prescribed with caution.

9. Drug Interactions

9.2. Drug Interactions Overview

No specific drug interaction studies have been performed with ABILIFY ASIMTUFII. The information below was obtained from studies with oral aripiprazole.

If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used.

9.3. Drug-Behaviour Interactions

Alcohol/CNS Drugs

Given the primary CNS effects of aripiprazole, as with most psychoactive medications, combination use of aripiprazole with alcohol or other CNS drugs with overlapping undesirable effects such as sedation, should be avoided.

Smoking

Aripiprazole is not metabolized by CYP1A enzymes. Therefore, no dosage adjustment is required for smokers (see 10.3 Pharmacokinetics, Smoking).

9.4. Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies with orally administered aripiprazole, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 11: Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Potential for other drugs to affect aripiprazole

Aripiprazole is metabolized by multiple pathways involving the CYP2D6 and CYP3A4 enzymes and dosage adjustments are recommended (see 4.2 Recommended Dose and Dosage Adjustment - Table 1).

Strong CYP2D6 inhibitors

Based on population PK analyses for ABILIFY ASIMTUFII, concomitant strong CYP2D6 inhibitors decrease aripiprazole clearance by approximately 51%. Simulation results suggest that aripiprazole exposure (median AUC_tau,ss) following administration of ABILIFY ASIMTUFII 720 mg with concomitant CYP2D6 strong inhibitors is about 51% higher than exposure following administration of ABILIFY ASIMTUFII 960 mg without concomitant CYP2D6 strong inhibitors.

Strong CYP3A4 inhibitors

Based on population PK analyses for ABILIFY ASIMTUFII, concomitant use of strong CYP3A4 inhibitors reduce clearance of aripiprazole by approximately 24%. Simulation results suggest that aripiprazole exposure (median AUC_tau,ss) following administration of ABILIFY ASIMTUFII 720 mg with concomitant CYP3A4 strong inhibitors is comparable (2% lower in median AUC_tau,ss) to exposure following administration of ABILIFY ASIMTUFII 960 mg without concomitant use of CYP3A4 strong inhibitor.

Potential for aripiprazole to Affect Other Drugs

In clinical studies, oral doses of 10-30 mg/day had no significant effect on the metabolism of substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), 2C9 (warfarin), 2C19 (omeprazole), and 3A4 (dextromethorphan). Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. Thus, ABILIFY ASIMTUFII is unlikely to cause clinically important medicinal product interactions mediated by these enzymes. No dosage adjustment of dextromethorphan, warfarin, omeprazole, escitalopram, or venlafaxine is required when co-administered with ABILIFY ASIMTUFII.

9.5. Drug-Food Interactions

Interactions with food have not been established.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

The mechanism of action of aripiprazole, as with other drugs having efficacy in schizophrenia or bipolar I disorder is unknown. It has been proposed that the efficacy of aripiprazole may be mediated through a combination of partial agonist activity at D₂ and 5-HT_1A receptors and antagonist activity at 5-HT_2A receptors; however, the clinical relevance of these interactions has not been established. Actions at receptors other than D₂, 5-HT_1A, and 5-HT_2A may explain some of the other adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors). The clinical relevance of these receptor interactions with aripiprazole is unknown.

10.2. Pharmacodynamics

Aripiprazole exhibits high affinity for dopamine D₂ and D₃ and serotonin 5-HT_1A and 5-HT_2A receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively) and has moderate affinity for dopamine D₄, serotonin 5-HT_2C and 5-HT₇, α₁-adrenergic, histamine H₁ receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM and 61 nM, respectively), and the serotonin reuptake site (Ki=98 nM). Aripiprazole also displays 5-HT_1A partial agonist and 5-HT_2A antagonist activity in nonclinical studies.

10.3. Pharmacokinetics

Overview:

The activity of ABILIFY ASIMTUFII is presumably primarily due to the parent drug, aripiprazole, and to a lesser extent, to its major metabolite, dehydro-aripiprazole, which has been shown to have affinities for D₂ receptors similar to the parent drug and represents approximately 29% of the parent drug exposure in plasma at steady state.

The pharmacokinetics of aripiprazole after administration of ABILIFY ASIMTUFII are based on gluteal administration.

ABILIFY ASIMTUFII delivers aripiprazole over a two-month period.

The aripiprazole pharmacokinetic parameters in adult patients with a diagnosis of schizophrenia or bipolar I disorder were compared following the administration of ABILIFY ASIMTUFII 960 mg and ABILIFY MAINTENA 400 mg in a randomized, open-label, parallel-arm, multiple-dose, multi-centre comparative pharmacokinetic study. Plasma aripiprazole concentrations were measured following the fourth injection of ABILIFY ASIMTUFII 960 mg and after the seventh and eighth injections of ABILIFY MAINTENA 400 mg.

In the clinical study, ABILIFY ASIMTUFII 960 mg, administered in the gluteal muscle once every two months, resulted in aripiprazole total plasma exposures that were comparable to those observed following administration of ABILIFY MAINTENA 400 mg, dosed once monthly (Table 12). Mean observed maximum plasma concentrations (C_max) and trough plasma concentrations of aripiprazole at the end of the dosing interval were similar for ABILIFY ASIMTUFII 960 mg as compared to ABILIFY MAINTENA 400 mg. The mean aripiprazole plasma concentration-time profiles following the fourth administration of ABILIFY ASIMTUFII 960 mg (n=102) or the seventh and eighth administrations of ABILIFY MAINTENA 400 mg (n=93) in the gluteal muscle of patients with schizophrenia or bipolar I disorder are shown in Figure 10.

Table 12: Geometric Mean (CV%) Comparative Pharmacokinetic Parameters, Geometric Mean Ratio and 90% Confidence Interval Following the Fourth Administration of ABILIFY ASIMTUFII 960 mg or the Seventh and Eighth Administration of ABILIFY MAINTENA 400 mg in the Open-Label Study

¹Area under the concentration – time curve over the 56 day dosing interval (AUC_0-56) following the fourth administration of ABILIFY ASIMTUFII 960 mg (n = 34) or the sum of the AUC over the two 28 day dosing intervals (AUC_0-28) following the seventh and eighth administration of ABILIFY MAINTENA 400 mg (n = 32)

²Trough aripiprazole plasma concentrations on Day 56 following the fourth administration of ABILIFY ASIMTUFII 960 mg (C₅₆) (n = 96) or on Day 28 following the eighth administration of ABILIFY MAINTENA 400 mg (C₂₈) (n = 82)

³ Peak plasma aripiprazole concentrations for ABILIFY ASIMTUFII (n = 34) and ABILIFY MAINTENA (n=32)

Figure 10: Mean plasma concentration vs time profile following the fourth administration of ABILIFY ASIMTUFII 960 mg or the seventh and eighth administration of ABILIFY MAINTENA 400 mg

Population PK analysis and simulations using a larger pooled dataset of PK data, including the data from the comparative pharmacokinetic study presented in Table 12 and Figure 11, indicated that at steady state ABILIFY ASIMTUFII 960 mg administered every 2 months would result in approximately 25% higher aripiprazole exposure than ABILIFY MAINTENA 400 mg administered once monthly (Figure 11).

Figure 11: Simulated Median and the 5^th to 95^th Percentile of Steady-State Aripiprazole Concentration Time Profile Following Administration of ABILIFY MAINTENA 400 mg (one a month) or ABILIFY ASIMTUFII 960 mg (every 2 months)

Dotted reference lines represent the median C_min,ss following a daily dose of 10 mg oral aripiprazole (94.0 ng/mL), 75^th percentile of C_max,ss following a daily dose of 30 mg oral aripiprazole (534 ng/mL), and 95^th percentile of C_max,ss following a daily dose of 30 mg oral aripiprazole (741 ng/mL).

Absorption: Aripiprazole absorption into the systemic circulation is slow and prolonged following gluteal intramuscular injection administration due to low solubility of aripiprazole particles.

The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over two months following gluteal injection(s) (Figure 10). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with T_max ranging between 1 to 49 days following multiple gluteal administrations of 960 mg.

Distribution: The steady-state volume of distribution of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin.

Metabolism: Aripiprazole is extensively metabolised by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalysed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation. After multiple dose administration of ABILIFY ASIMTUFII, dehydro-aripiprazole, the active metabolite, represents about 29% of aripiprazole AUC in plasma.

CYP2D6 Poor Metabolizers

Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). PMs have about an 80% increase in aripiprazole exposure and about a 30% decrease in exposure to the active metabolite compared to EMs, resulting in about a 60% higher exposure to the total active moieties from a given dose of aripiprazole compared to EMs. The mean elimination half-life for aripiprazole is about 75 hours in EMs and 146 hours in PMs. Based on population PK analyses, clearance of aripiprazole is reduced by approximately 51% to 1.88 L/h in CYP2D6 PMs for all formulations (oral, ABILIFY MAINTENA, and ABILIFY ASIMTUFII), compared to clearance of 3.71 L/h in EMs (see 2 Contraindications; 10.3 Pharmacokinetics, Absorption).

Co-administration of aripiprazole with known inhibitors of CYP2D6, like quinidine in EMs, results in a 112% increase in aripiprazole plasma exposure, and dose adjustment is needed (see 9.4 Drug-Drug Interactions). Aripiprazole does not inhibit or induce the CYP2D6 pathway (see 4.1 Dosing Considerations).

Elimination: After multiple dose administration of 300 mg or 400 mg of ABILIFY MAINTENA, the mean aripiprazole terminal elimination half-life is 29.9-46.5 days.

Special Populations and Conditions

Geriatrics: In formal single-dose pharmacokinetic studies (with oral aripiprazole given in a single dose of 15 mg), aripiprazole clearance was 20% lower in elderly (≥65 years) patients compared to younger adult patients (18 to 64 years). There was no detectable age effect, however, in the population pharmacokinetic analysis in patients with schizophrenia. Also, the pharmacokinetics of aripiprazole after multiple doses in elderly patients appeared similar to that observed in young, healthy subjects (see 7.1.4 Geriatrics, 4.1 Dosing Considerations).

Sex: C_max and AUC of aripiprazole and its active metabolite, dehydro-aripiprazole, are 30 to 40% higher in women than in men, and correspondingly, the apparent oral clearance of aripiprazole is lower in women. These differences, however, are largely explained by differences in body weight (25%) between men and women. No dosage adjustment is recommended based on gender.

In the 32-week open-label study with 266 patients with schizophrenia or bipolar I disorder comparing the pharmacokinetics, safety and tolerability of ABILIFY ASIMTUFII to ABILIFY MAINTENA, gastrointestinal treatment emergent adverse events (i.e., abdominal discomfort, constipation, diarrhea, dyspepsia and nausea), arthralgia, back pain and anxiety were reported more than twice as frequently in women compared to men during treatment with ABILIFY ASIMTUFII.

Ethnic origin: Although no specific pharmacokinetic study was conducted to investigate the effects of race on the disposition of aripiprazole, population pharmacokinetic evaluation of ABILIFY ASIMTUFII showed no evidence of race-related differences on the pharmacokinetics of aripiprazole.

Hepatic Insufficiency: In a single-dose trial (15 mg of oral aripiprazole) in patients with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C), the AUC of aripiprazole, compared to healthy subjects, increased 31% in mild hepatic impairment, increased 8% in moderate hepatic impairment, and decreased 20% in severe hepatic impairment, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity.

Renal Insufficiency: In patients with severe renal impairment (creatinine clearance <30 mL/min), C_max of aripiprazole (given in a single oral dose of 15 mg) and dehydro-aripiprazole increased by 36% and 53%, respectively, but AUC was 15% lower for aripiprazole and 7% higher for dehydroaripiprazole. Renal excretion of both unchanged aripiprazole and dehydro-aripiprazole is less than 1% of the dose. No dosage adjustment is required in patients with renal impairment.

Smoking: Based on studies utilizing human liver enzymes in vitro, aripiprazole is not a substrate for CYP1A2 and also does not undergo direct glucuronidation. Smoking should, therefore, not have an effect on the pharmacokinetics of aripiprazole. Population pharmacokinetic evaluation of oral aripiprazole has revealed no evidence of clinically relevant effects from smoking on the pharmacokinetics of aripiprazole.

1. 11. Storage, Stability, and Disposal

Store between 15 and 30°C.

Any unused product or waste material should be disposed of in accordance with local requirements.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Proper name: aripiprazole monohydrate

Chemical name: 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy]-3,4 dihydrocarbostyril as monohydrate

Molecular formula and molecular mass: C₂₃H₂₇Cl₂N₃O₂.H₂O

466.40 g/mol

Structural formula: N N CH₂CH₂CH₂CH₂O N H O Cl Cl H₂O.

Physicochemical properties: Aripiprazole monohydrate is a white to off white crystalline powder. Aripiprazole monohydrate is practically insoluble in water. The pKa was determined to be 7.6 (in 20% ethanol solution).

14. Clinical Trials

14.1. Clinical Trials by Indication

The efficacy of ABILIFY ASIMTUFII administered once every two months, for treatment of schizophrenia or bipolar I disorder, is based on clinical trials that demonstrated the efficacy of ABILIFY MAINTENA administered once monthly.

In a clinical study conducted in adult patients with schizophrenia or bipolar I disorder, ABILIFY ASIMTUFII administered once every two months, was shown to provide similar aripiprazole concentrations to ABILIFY MAINTENA, administered monthly, over the dosing interval (see 10.3 Pharmacokinetics.

Schizophrenia

• he efficacy of ABILIFY MAINTENA in achieving and maintaining symptomatic control and delaying relapse in schizophrenia was established in three randomized, double-blind trials. In addition, the efficacy of ABILIFY MAINTENA 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.
• Table 13.

Table 13: Summary of Patient Demographics for Clinical Trials in Acute Schizophrenia and Maintenance Phase of Schizophrenia

Clinical Efficacy in the Acute Phase of Schizophrenia

The efficacy of ABILIFY MAINTENA in adult patients in the acute phase of schizophrenia was established in one short-term (12-week), randomized, double-blind, placebo controlled trial of acutely relapsed adult patients. In this trial, the primary measure used for assessing psychiatric signs and symptoms was the Positive and Negative Syndrome Scale (PANSS). The primary endpoint was the change from baseline to week 10 in PANSS total score. The key secondary endpoint was the Clinical Global Impression-Severity (CGI-S) assessment at week 10.

The inclusion criteria for this short term trial included adult inpatients who met DSM-IV-TR criteria for schizophrenia. In addition, all patients entering the trial must have experienced an acute psychotic episode as defined by both PANSS Total Score ≥ 80 and a PANSS score of > 4 on each of four specific psychotic symptoms (conceptual disorganization, hallucinatory behaviour, suspiciousness/persecution, unusual thought content) at screening and baseline. Patients had a mean PANSS total score of 103 (range 82 to 144) and a CGI-S score of 5.0 (markedly ill) at entry.

In this 12-week study (n=339) comparing ABILIFY MAINTENA (n=167) to placebo (n=172), patients were administered 400 mg ABILIFY MAINTENA or placebo on days 0, 28, and 56. The dose could be adjusted down and up within the range of 400 to 300 mg on a one time basis. (For the first two weeks of the study, patients randomized to ABILIFY MAINTENA also received concomitant oral ABILIFY, 10 to 20 mg/day). ABILIFY MAINTENA was superior to placebo in improving the PANSS total score with early onset and sustained efficacy (week 10 scores of -26.8 vs. -11.7 respectively) with a statistical difference at each measured time point, p=<0.0005 at week 1 and p=<0.0001 for all other time points until study completion. The adjusted mean change in PANSS total score over time (Mixed Model of Repeated Measure MMRM) is demonstrated in Figure 12.

Figure 12: Adjusted Mean Change from Baseline in PANSS Total Score – MMRM

ABILIFY MAINTENA also showed improvement in CGI-S score mean changes from baseline that were statistically significant at all post-baseline timepoints (week 10 scores of -1.4 vs. -0.6 at week 10, ABILIFY MAINTENA vs. placebo, respectively).

Clinical Efficacy in the Maintenance Phase of Schizophrenia

The first trial, Trial 1, was a 38-week, randomized, double-blind, active-controlled trial designed to establish the efficacy, safety, and tolerability of ABILIFY MAINTENA 400 mg/300 mg administered as monthly injections compared to once daily oral aripiprazole tablets 10-30 mg as maintenance treatment in adult patients with schizophrenia as defined by DSM-IV-TR criteria and a history of the illness for at least 3 years prior to screening and with a history of relapse and/or exacerbation of symptoms when they were not receiving antipsychotic treatment.

This trial consisted of a screening phase and 3 treatment phases:

• A conversion Phase (4 to 6 weeks) for all patients to achieve a monotherapy target starting dose of 10 or 15 mg oral aripiprazole. A total of 709 patients entered this phase.

• An oral Stabilization Phase (a minimum of 8 weeks and a maximum of 28 weeks in duration) during which patients were stabilized on an oral dose of aripiprazole ranging from 10 mg to 30 mg daily. Stabilization was defined as having all of the following for eight consecutive weeks: an outpatient status, PANSS total score ≤80, CGI-S ≤4 (moderately ill), and CGI-SS score ≤2 (mildly suicidal) on Part 1 and ≤5 (minimally worsened) on Part 2; and a score of ≤4 on each of

  • the following PANSS items: conceptual disorganization, suspiciousness, hallucinatory behaviour, and unusual thought content. A total of 842 patients entered this phase. The majority of patients who were enrolled in the Oral Stabilization Phase were male (518/842, 61.5%), Caucasian (489/842, 58.1%). The mean age was 40.8 years (range, 18 to 60 years). The mean baseline PANSS total score was 63.8 (range, 30 to 110). The mean baseline CGI-S severity and CGI-SS severity scores were 3.4 and 1.0, respectively.
• Double-blind, Active-controlled Phase.

Six-hundred and sixty-two patients eligible for the 38-week Double-Blind, Active-Controlled Phase were randomly assigned in a 2:2:1 ratio to double-blind treatment to one of 3 treatment groups: 1) ABILIFY MAINTENA 400 mg/300 mg, 2) the stabilization dose of oral aripiprazole 10-30 mg, or 3) aripiprazole IM depot 50 mg/25 mg. The aripiprazole IM depot 50 mg/25 mg dose was included as a low dose aripiprazole group to test assay sensitivity for the non-inferiority design. The overall demographic characteristics for randomized patients were similar to those seen in the previous phases; most patients randomized were male (406/662, 61.3%), Caucasian (387/662, 58.5%); the mean age was 41.2 years (range, 18 to 60 years). Baseline disease severity was comparable across the 3 treatment groups. The mean age at first diagnosis of schizophrenia was 28.2, 26.9, and 26.3 years for the ABILIFY MAINTENA 400 mg/300 mg, oral aripiprazole tablets 10-30 mg, and IM depot 50 mg/25 mg groups, respectively. The mean baseline PANSS total score was 58.0, 56.6, and 56.1 for the ABILIFY MAINTENA 400 mg/300 mg, oral aripiprazole tablets 10-30 mg, and IM depot 50 mg/25 mg groups, respectively. The mean baseline CGI-S was 3.1 in both the ABILIFY MAINTENA 400 mg/300 mg and oral aripiprazole tablets 10-30 mg groups, and 3.0 in the IM depot 50 mg/25 mg group. Mean baseline CGI-SS was 1.0 in all 3 treatment groups.

The primary efficacy endpoint, was the estimated proportion of patients experiencing impending relapse by end of Week 26 of the Double-blind, Active-controlled Phase.

Impending relapse was defined as meeting any or all of the following 4 criteria:

1. 1)

   Clinical Global Impression of Improvement (CGI-I) of ≥ 5 (minimally worse)

   AND

   • an increase on any of the following individual Positive and Negative Syndrome Scale (PANSS) items (conceptual disorganization, hallucinatory behaviour, suspiciousness, unusual thought content) to a score > 4 with an absolute increase of ≥ 2 on that specific item since randomization OR
   • an increase on any of the following individual PANSS items (conceptual disorganization, hallucinatory behaviour, suspiciousness, unusual thought content) to a score > 4 and an absolute increase of ≥ 4 on the combined 4 PANSS items (conceptual disorganization, hallucinatory behaviour, suspiciousness, unusual thought content) since randomization.
2. 2) Hospitalization due to worsening of psychotic symptoms (including partial hospitalization programs), but excluding hospitalization for psychosocial reasons
3. 3) Clinical Global Impression of Severity of Suicide (CGI-SS) of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2
4. 4) Violent behaviour resulting in clinically relevant self-injury, injury to another person, or property damage.

The estimated proportion of patients experiencing impending relapse by end of Week 26 for the ABILIFY MAINTENA 400 mg/300 mg group was 7.12%, which was statistically significantly lower than in the aripiprazole IM depot 50 mg/25 mg group (21.80%; p = 0.0006). Thus, superiority of ABILIFY MAINTENA 400 mg/300 mg over the aripiprazole IM depot 50 mg/25 mg was established and the validity of the trial design was confirmed. The proportion of patients who met the stability criteria at endpoint in the Double-blind, Active-controlled Phase was 89.8% (237/264) in the ABILIFY MAINTENA 400 mg/300 mg group compared with 75.2% (97/129) in the aripiprazole IM depot 50 mg/25 mg group.

The Kaplan-Meier curves of the secondary efficacy endpoint time from randomization to impending relapse during the 38-week, double-blind treatment phase for ABILIFY MAINTENA 400 mg/300 mg, oral aripiprazole 10-30mg group, and aripiprazole IM depot 50 mg/25 mg groups are shown in Figure 13. The aripiprazole IM depot 50 mg/25 mg group had a 3.158-fold higher risk of relapse than the ABILIFY MAINTENA 400 mg/300 mg group (95% CI = 1.813, 5.502). As shown below, ABILIFY MAINTENA significantly delayed time to impending relapse.

*ARIP IMD = ABILIFY MAINTENA; ORAL ARIP = oral aripiprazole;

Figure 13: Kaplan-Meier Product Limit Plot for Time to Exacerbation of Psychotic

Symptoms/Impending Relapse*

The second trial, Trial 2, was a 52-week, randomized-withdrawal, double-blind, placebo-controlled trial conducted in adult patients with a current diagnosis of schizophrenia as defined by DSM-IV-TR criteria and a history of the illness for at least 3 years prior to screening and with a history of relapse and/or exacerbation of symptoms when they were not receiving antipsychotic treatment. This trial consisted of a screening phase and 4 treatment phases:

• A 4-6 week open-label, oral conversion phase for patients on antipsychotic medications other than aripiprazole. A total of 633 patients entered this phase.
• An open-label, oral aripiprazole stabilization phase (target dose of 10 mg to 30 mg once daily). A total of 710 patients entered this phase. Patients were 18 to 60 years old (mean 40 years) and 60% were male. The mean PANSS total score was 66 (range 33 to 124). The mean CGI-S score was 3.5 (mildly to moderately ill). Prior to the next phase, stabilization was required. Stabilization was defined as having all of the following for four consecutive weeks: an outpatient status, PANSS total score ≤80, CGI-S ≤4 (moderately ill), and CGI-SS score ≤2 (mildly suicidal) on Part 1 and ≤5 (minimally worsened) on Part 2; and a score of ≤4 on each of the following PANSS items: conceptual disorganization, suspiciousness, hallucinatory behaviour, and unusual thought content.
• A 12-week uncontrolled, single-blind ABILIFY MAINTENA stabilization phase (treatment with 400 mg of ABILIFY MAINTENA given every 4 weeks in conjunction with oral aripiprazole [10 mg to 20 mg/day] for the first 2 weeks). The dose of ABILIFY MAINTENA may have been decreased to 300 mg due to adverse reactions. A total of 576 patients entered this phase. The mean PANSS total score was 59 (range 30 to 80) and the mean CGI-S score was 3.2 (mildly ill). Prior to the next phase, stabilization was required (see above for the definition of stabilization) for 12 consecutive weeks.
• A double-blind, placebo-controlled randomized-withdrawal phase to observe for relapse (defined as in trial 1). A total of 403 patients were randomized 2:1 to the same dose of ABILIFY MAINTENA they were receiving at the end of the stabilization phase, (400 mg or 300 mg administered once every 4 weeks) or placebo. Patients had a mean PANSS total score of 55 (range 31 to 80) and a CGI-S score of 2.9 (mildly ill) at entry. The dose could be adjusted up and down or down and up within the range of 300 to 400 mg on a one time basis.

The trial design included two pre-specified interim analyses for efficacy in order to minimize continued exposure to placebo and the risk of relapse: the first was to occur after accrual of 50% of the 125 targeted impending relapse events (64 events) and the second was to occur after 75% accrual of the events (94 events). A Data Monitoring Committee (DMC) was responsible for ongoing safety monitoring and evaluation of efficacy from the pre-specified interim analyses. Since the first pre-specified interim analysis showed statistically significant superiority of ABILIFY MAINTENA over IM placebo in time to impending relapse, the study was terminated early.

The final efficacy analysis included 403 randomized patients and 80 “exacerbation of psychosis/impending relapse” events. In this analysis, time to impending relapse was significantly delayed with ABILIFY MAINTENA compared with IM placebo (p < 0.0001; log-rank test).

Similar results were observed at the interim analysis, with a significantly longer time to impending relapse with ABILIFY MAINTENA compared with placebo (log-rank test, P<.0001 and significantly lower relapse rates with ABILIFY MAINTENA (9.6% n=22/230) than placebo (36.8%; n=42/114; HR=4.72, 95% CI, 2.81-7.94).

The Kaplan-Meier curves of the time from randomization to impending relapse during the double-blind treatment phase for ABILIFY MAINTENA and placebo groups are shown in Figure 14.

The key secondary efficacy endpoint, proportion of patients meeting the impending relapse criteria, was significantly lower in the ABILIFY MAINTENA 400 mg/300 mg group (interim analysis: 9.6%; final analysis:10.0%) than in the placebo group (interim analysis: 36.8%; final analysis: 39.6%).

Figure 14: Kaplan-Meier Product Limit Plot for Time to Exacerbation of Psychotic Symptoms/Impending Relapse

Bipolar I Disorder

The efficacy of ABILIFY MAINTENA as maintenance treatment in adults with bipolar I disorder was demonstrated in a 52-week multicenter, randomized, double-blind, placebo-controlled trial of patients with bipolar I disorder who were currently experiencing a manic episode at trial entry. An additional 52-week open label trial was conducted to primarily assess the safety of ABILIFY MAINTENA. In addition, the efficacy of ABILIFY MAINTENA in the treatment of patients with bipolar I disorder was established, in part, on the basis of efficacy data from trials with the oral formulation of aripiprazole.

The trial design is summarized below in

Table 14.

Table 14: Summary of Subject Demographics for the Phase 3 Clinical Trial

Clinical Efficacy in Maintenance Treatment of Bipolar I Disorder

The safety and efficacy of ABILIFY MAINTENA as maintenance treatment in adults with bipolar I disorder aged 18 to 65 years was demonstrated in a 52-week multicenter, randomized, double-blind, placebo-controlled trial (Trial 31-08-250) of patients who met DSM-IV-TR criteria for bipolar I disorder and who were currently experiencing a manic episode at trial entry.

This trial consisted of a screening phase and 4 treatment phases:

• An oral conversion phase (4 to 6 weeks) for all patients to achieve a monotherapy target starting dose of 15 mg/day oral aripiprazole. A total of 466 patients entered this phase.

• An oral stabilization phase (a minimum of 2 weeks and a maximum of 8 weeks in duration) during which patients were stabilized on an oral dose of aripiprazole ranging from 15 mg to 30 mg daily. Stabilization was defined as having all of the following stability criteria at one biweekly visit in order to proceed to ABILIFY MAINTENA stabilization phase: outpatient status, YMRS total score ≤ 12, MADRS total score ≤ 12, no active suicidality; with active suicidality defined as a score of 4 or more on the MADRS item 10 OR an answer of “yes” on question 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS). A total of 632 patients entered this

  • phase of which 265 patients entered the oral stabilization phase directly.
• ABILIFY MAINTENA Stabilization Phase (a minimum of 12 weeks and a maximum of 28 weeks in duration) during which patients were stabilized on ABILIFY MAINTENA 400 mg or 300 mg, as dictated by tolerability. Oral dosing with aripiprazole continued for the first 2 weeks following the injection to maintain therapeutic plasma concentrations. Stabilization was defined as having all of the following for eight consecutive weeks: an outpatient status, YMRS total score ≤ 12, MADRS total score ≤ 12, no active suicidality; with active suicidality defined as a score of 4 or more on the MADRS item 10 OR an answer of “yes” on question 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS). A total of 425 patients entered this phase. The mean baseline YMRS total score was 5.8 (range, 0 to 28). The mean baseline MADRS total score was 3.7 (range, 0 to 28). The mean baseline CGI-BP-S overall score was 2.1 (range, 1 to 5). Patients who demonstrated stability for 8 consecutive weeks were randomized into the double-blind, placebo- controlled treatment phase.
• A randomized, double-blind, placebo-controlled phase (52 weeks). Two hundred sixty-six (266) patients eligible for the 52-week double-blind, placebo-controlled phase were randomly assigned in a 1:1 ratio to double-blind treatment with either the last stabilization dose of ABILIFY MAINTENA from the previous phase or placebo. During this phase, a single decrease to ABILIFYMAINTENA 300 mg was permitted for tolerability, as was a single return to the original 400 mg dose if required. The mean baseline YMRS total score was 2.9, and 2.6 for the ABILIFY MAINTENA 400 mg/300 mg and placebo groups, respectively. The mean baseline MADRS total score was 3.0 and 2.4 for the ABILIFY MAINTENA 400 mg/300 mg and placebo groups, respectively. The mean baseline CGI-BP-S score was 1.5 and 1.4 for the ABILIFY MAINTENA 400 mg/300 mg and placebo groups, respectively.

The primary efficacy endpoint of this trial was the time from randomization to recurrence of any mood episode during the double-blind, placebo-controlled phase.

The time to recurrence of any mood episode was significantly longer in patients randomized to the ABILIFY MAINTENA group compared to placebo-treated patients. A total of 103 mood events were observed during the double-blind treatment phase: 35 occurred during ABILIFY MAINTENA treatment and 68 occurred during placebo treatment (26.5% vs 51.1%, p < 0.0001). The hazard ratio from the Cox proportional hazard model for the ABILIFY MAINTENA to placebo comparison was 0.451 (95% CI = 0.299, 0.678), patients in the ABILIFY MAINTENA group had less than half the risk of experiencing recurrence of any mood episode compared with patients in the placebo group. Thus, superiority of ABILIFY MAINTENA over placebo was established. The analysis of the primary efficacy endpoint is shown in the Kaplan-Meier curves below (Figure 15).

n = number of patients at risk of recurrence

ARIP IMD = Aripiprazole IM depot (ABILIFY MAINTENA)

Figure 15: Kaplan-Meier Curves of Time to Recurrence for any Mood Episode

Secondary and other efficacy endpoints were generally supportive of the primary efficacy outcome.

ABILIFY MAINTENA as maintenance treatment in adults with bipolar I disorder was assessed in a 52-week multicentre, open-label trial (n=464, Trial 31-08-252). Safety and tolerability were supportive of the results observed in the double-blind, placebo-controlled study.

16. Non-Clinical Toxicology

General toxicology

Intramuscular Aripiprazole

The toxicological profile for aripiprazole administered to experimental animals by intramuscular injection is generally similar to that seen following oral administration at comparable plasma levels of the drug. With intramuscular injection, however, injection-site tissue reactions were observed that consisted of localized inflammation, swelling, scabbing and foreign-body reactions to deposited drug. These effects gradually resolved with discontinuation of dosing. In dogs, repeated intramuscular dosing of the two-month aripiprazole prolonged release injectable suspension administered once every 4 weeks over a period of 52 weeks produced no clinical evidence of significant local irritation, and resulted in a slight foreign-body type of localized granulomatous inflammatory reaction to deposited drug at the injection site.

Acute Toxicity

The acute oral toxicity of aripiprazole was determined in rats and monkeys. The estimated median lethal oral dose in male and female rats was 953 and 705 mg/kg, respectively, and in monkeys was greater than 2000 mg/kg for both sexes. Clinical signs consistent with pharmacologically mediated central nervous (CNS) depression and extrapyramidal side effects were noted in both species. In rats, clinical signs included decreased spontaneous motor activity, crouching, prone position, ataxia, tremors, convulsions, straub tail, catalepsy, ptosis, and coldness to touch. In monkeys, principal drug-related effects included impaired motor activity, hyporeactivity to external stimuli, tremors, catalepsy, closed eyes, crouching, and prone and/or lateral position.

Short- and Long-Term Toxicity

The repeat-dose oral toxicity of aripiprazole in rats was evaluated in a 13-week study (2, 6, or 20 mg/kg/day), a 52-week study (1, 3, or 10 mg/kg/day), a 4-week study (60 or 100 mg/kg/day), and a 26-week (6 month) study (10, 30, or 60 mg/kg/day). The repeat-oral dose toxicity of aripiprazole in monkeys was evaluated in a 13-week study (0.5, 1, 5, or 25 mg/kg/day), a 52-week study (0.5, 5, or 25 mg/kg/day), and a 39-week study (25, 50, or 75 mg/kg/day).

Aripiprazole did not cause life-threatening toxicity when given to rats at doses up to 60 mg/kg/day for 6 months or to monkeys at doses up to 75 mg/kg/day for 9 months.

CNS-related clinical signs in rats were postdose hypoactivity and ptosis and predose hyperactivity at 30 and 60 mg/kg/day in the 26-week study. Morphological changes reflective of exaggerated pharmacology or considered secondary to drug-related increases (females) or decreases (males) in serum prolactin levels were observed microscopically in the pituitary, ovaries, female reproductive tract, mammary gland, epididymides, and/or testes. These changes included atrophy of the pars intermedia of the pituitary gland, mammary gland hyperplasia (females) or atrophy (males), vaginal mucification, persistent ovarian corpora lutea, uterine atrophy, minimal to moderate testicular atrophy, and increased numbers of exfoliated germinal epithelial cells in epididymides. Drug-related direct target organ changes were limited to dose-related increased incidence and/or severity of alveolar macrophages (pulmonary histiocytosis) in lungs at all doses after 4 and 26 weeks, and minimally increased lipofuscin pigment accumulation in the adrenal cortex at 30 and 60 mg/kg/day and in the ovaries at 60 mg/kg/day after 26 weeks. In addition, an increased incidence of inflammation of the prostatic ampullary gland was seen at 30 and 60 mg/kg/day after 26 weeks. All pituitary, reproductive organ and mammary gland changes were reversible. The pulmonary histiocytosis was partially reversible. In the 52-week toxicity study in rats, which was conducted at lower doses than given in the 26-week toxicity study, NOAEL for effects was established at 1 (female) or 3 mg/kg/day (male).

In monkeys, the principal pharmacologically-mediated CNS signs (e.g., impaired motor activity, hyporeactivity, tremors, catalepsy, and abnormal posture) were most prominent during the first 1 to 2 weeks of dosing, were generally mild and transient at 5 mg/kg/day, and decreased in incidence and severity with continued dosing at 25 mg/kg/day. Similar CNS-related clinical signs were noted in the 39-week toxicity study primarily during the first 4 weeks at 25 mg/kg/day and throughout the dosing period at 50 and 75 mg/kg/day. No life-threatening clinical signs were occurred at doses up to 75 mg/kg/day/day for 39 weeks or 25 mg/kg/day for 52 weeks. Gallsand (muddy substance, granular material) in bile was noted at 25 mg/kg/day after 13 weeks, and dose-related incidence of gallsand or gallstones (calculi) were observed in gallbladder at ≥ 25 mg/kg/day in the 39- and 52-week studies. Gallsand at 25 and 125 mg/kg/day and a gallstone at 125 mg/kg/day were also seen in the 4-week toxicity study. Minimal focal hepatolithiasis was observed at in the subscapular parenchyma (proximal to gallbladder) of liver in 2 monkeys given 50 mg/kg/day and in 1 monkey given 75 mg/kg/day for 39 weeks. There were no correlative alterations in liver functions tests. The gallsand and gallstones were considered a consequence of concentration and precipitation of sulfate conjugates, which, due to their limited solubility, precipitate out in the bile, or hydroxy metabolites of aripiprazole in the terminal biliary tree and gallbladder. No other target organs of toxicity were identified in monkeys. There was no evidence of other target organ toxicity at any dose level. In the 13-week toxicity study, drug-related changes at 25 mg/kg/day were reversible or improved during the 4-week postdose period. In the 52-week toxicity study in monkeys, which was conducted at lower doses than given in the 39-week toxicity study, the NOAEL for effects was established at 0.5 mg/kg/day.

Genotoxicity

The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, 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 a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without 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 in vivo micronucleus assay in mice; however, the response was due to a mechanism considered not relevant to humans.

Carcinogenicity

Lifetime carcinogenicity studies were conducted in ICR mice and in Sprague-Dawley (SD) and F344 rats. Oral aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2 to 5 and 0.3 to 3 times the MRHD based on mg/m², respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day (3 to 19 times the MRHD based on mg/m²). Aripiprazole did not induce tumors in male mice or rats. In female mice, the incidences of pituitary gland adenomas, mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.1 to 0.9 times human exposure at MRHD based on AUC). 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 MRHD based on AUC) and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (10 times human exposure at MRHD based on AUC).

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- 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.

Reproductive and developmental toxicology

In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits. Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the maximum recommended human dose [MRHD] on a mg/m² basis) 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 and 30 mg/kg). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased bodyweights (10 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 and 30 mg/kg and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, and 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, 9, 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 maternal toxicity. Pregnant rabbits were treated with oral doses of 10, 30, and 100 mg/kg/day (2, 3, and 11 times human exposure at MRHD based on AUC) 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 and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30 and 100 mg/kg), and minor skeletal variations (100 mg/kg). In pregnant rabbits receiving aripiprazole injection intravenously (3, 10, 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 MRHD based on AUC. In a study in which rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the MRHD on a mg/m² basis) 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, 8, and 20 mg/kg/day) from day 6 of gestation through day 20 postpartum, an increase in stillbirths was seen at 8 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 behavioural and reproductive development.

Impairment of Fertility

Female rats were treated with oral doses of 2, 6, and 20 mg/kg/day (0.6, 2, and 6 times the MRHD on a mg/m² basis) 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 and 20 mg/kg and decreased fetal weight was seen at 20 mg/kg.

Male rats were treated with oral doses of 20, 40, and 60 mg/kg/day (6, 13, and 19 times the MRHD on a mg/m² basis) 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 and 60 mg/kg, but no impairment of fertility was seen.

Special toxicology

Adrenocortical Changes in Rats

A series of investigative studies were conducted in rats to determine the mechanism for the aripiprazole-related adrenocortical changes after sub-chronic and chronic dosing. The data from these studies supported the conclusion that the female rat-specific adrenocortical tumorigenic response at 60 mg/kg/day in the oral carcinogenicity study was secondary to aripiprazole-related adrenocortical cytotoxicity and consequent increased cell proliferation. The female specificity of the adrenocortical tumorigenic response was considered a consequence of the earlier onset and greater severity of the adrenocortical cytotoxic changes. The adrenocortical cytotoxic and tumorigenic effects have no established clinical relevance since they occurred at a dose 10 times human exposure at the MRHD based on AUC.

Retinal Degeneration in Rats

Aripiprazole produced retinal degeneration in albino Sprague-Dawley (SD) rats in a 26-week chronic toxicity study at a dose of 60 mg/kg and in a 2-year carcinogenicity study at doses of 40 and 60 mg/kg. The 40 and 60 mg/kg doses are 7 to 10 times human exposure at the MRHD based on AUC. In a subsequent 18-month investigative study in albino SD and pigmented Long-Evans (LE) rats administered 60 mg/kg/day aripiprazole, pharmacologically mediated hyperactivity occurred in both rat strains early in the study predisposing the animals to increased light exposure. Time-dependent retinal degeneration with electroretinographic and morphologic features consistent with spontaneous light-induced retinal degeneration was observed in albino SD rats, whereas there was no evidence of light-induced retinal injury in pigmented LE rats at any timepoint despite comparable systemic exposures to aripiprazole. This was due to the photoprotective effect of ocular melanin pigment in LE rats. Therefore, the retinal degeneration observed in albino SD rats after chronic dosing at high doses of aripiprazole was considered to be a consequence of drug-related, pharmacologically mediated hyperactivity during the animal room light phase, resulting in increased light exposure rather than a direct drug effect on the retina. Light-induced retinal degeneration in albino SD rats has no established clinical relevance.