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ARISTADA (aripiprazole lauroxil) extended-release injectable suspension, for intramuscular

2016-01-03 08:14:14 来源: 作者: 【大中小】浏览:527次评论:0条

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ARISTADA ™ safely and effectively. See full prescribing information for ARISTADA ™.
ARISTADA ™ (aripiprazole lauroxil) extended-release injectable suspension, for intramuscular use
Initial U.S. Approval: 2015
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. (5.1)
ARISTADA is not approved for the treatment of patients with dementia-related psychosis. (5.1)

INDICATIONS AND USAGE

ARISTADA is an atypical antipsychotic indicated for the treatment of schizophrenia (1).
DOSAGE AND ADMINISTRATION

To be administered by intramuscular injection in the deltoid (441 mg dose only) or gluteal (441 mg, 662 mg or 882 mg) muscle by a healthcare professional (2.1).
For patients naïve to aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA (2.1).
ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly or 882 mg dose every 6 weeks (2.1).
In conjunction with the first ARISTADA injection, administer treatment with oral aripiprazole for 21 consecutive days (2.1).
Dosing regimen adjustments may be required for missed doses (2.2).
Dose adjustments are required for 1) known CYP2D6 poor metabolizers and 2) for patients taking CYP3A4 inhibitors, CYP2D6 inhibitors, or CYP3A4 inducers for more than 2 weeks (2.4).

DOSAGE FORMS AND STRENGTHS

For extended-release injectable suspension: 441 mg, 662 mg or 882 mg single-use pre-filled syringe (3)
CONTRAINDICATIONS

Known hypersensitivity to aripiprazole (4)
WARNINGS AND PRECAUTIONS

Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemia attack, including fatalities) (5.2).
Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.3).
Tardive Dyskinesia: Discontinue if clinically appropriate (5.4).
Metabolic Changes: Monitor for hyperglycemia, dyslipidemia, and weight gain (5.5).
Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope (5.6).
Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count. Consider discontinuation if clinically significant decline in WBC in the absence of other causative factors (5.7).
Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.8).
Potential for Cognitive and Motor Impairment: Use caution when operating machinery (5.9).

ADVERSE REACTIONS

Most commonly observed adverse reaction with ARISTADA (incidence ≥5% and at least twice that for placebo) was akathisia (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Alkermes, Inc. at 1-866-274-7823 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates in women exposed during the third trimester of pregnancy (8.1).

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 10/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

1. INDICATIONS AND USAGE

2. DOSAGE AND ADMINISTRATION

2.1. Treatment of Schizophrenia

2.2. Missed Doses

2.3. Early Dosing

2.4. Dose Adjustments for CYP450 Considerations

2.5. Instructions for Use

3. DOSAGE FORMS AND STRENGTHS

4. CONTRAINDICATIONS

5. WARNINGS AND PRECAUTIONS

5.1. Increased Mortality in Elderly Patients with Dementia-related Psychosis

5.2. Cerebrovascular Adverse Reactions, Including Stroke

5.3. Neuroleptic Malignant Syndrome

5.4. Tardive Dyskinesia

5.5. Metabolic Changes

5.6. Orthostatic Hypotension

5.7. Leukopenia, Neutropenia, and Agranulocytosis

5.8. Seizures

5.9. Potential for Cognitive and Motor Impairment

5.10. Body Temperature Regulation

5.11. Dysphagia

6. ADVERSE REACTIONS

6.1. Clinical Studies Experience

6.2. Postmarketing Experience

7. DRUG INTERACTIONS

7.1. Drugs Having Clinically Important Interactions with ARISTADA

7.2. Drugs Having No Clinically Important Interactions with ARISTADA

8. USE IN SPECIFIC POPULATIONS

8.1. Pregnancy

8.2. Lactation

8.4. Pediatric Use

8.5. Geriatric Use

8.6. CYP2D6 Poor Metabolizers

8.7. Hepatic and Renal Impairment

8.8. Other Specific Populations

10. OVERDOSAGE

10.1. Human Experience

10.2. Management of Overdosage

11. DESCRIPTION

12. CLINICAL PHARMACOLOGY

12.1. Mechanism of Action

12.2. Pharmacodynamics

12.3. Pharmacokinetics

13. NONCLINICAL TOXICOLOGY

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2. Animal Toxicology and/or Pharmacology

14. Clinical Studies

16. HOW SUPPLIED/ STORAGE AND HANDLING

16.1. How Supplied

16.2. Storage

17. PATIENT COUNSELING INFORMATION

*: Sections or subsections omitted from the full prescribing information are not listed.

1. INDICATIONS AND USAGE

ARISTADA is indicated for treatment of schizophrenia [see Clinical Studies (14)].

2. DOSAGE AND ADMINISTRATION

2.1. Treatment of Schizophrenia

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

Depending on individual patient's needs, treatment with ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, which corresponds to 300 mg, 450 mg and 600 mg of aripiprazole, respectively. Treatment may also be initiated with the 882 mg dose every 6 weeks [see Clinical Pharmacology (12.3)].

Administer ARISTADA either in the deltoid muscle (441 mg dose only) or gluteal muscle (441 mg, 662 mg or 882 mg).

Table 1: ARISTADA Dosing Frequency and Site of Injection
Dose	Dosing Frequency	Site of Intramuscular Injection
441 mg	Monthly	Deltoid or Gluteal
662 mg	Monthly	Gluteal
882 mg	Monthly or every 6 weeks	Gluteal

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

Table 2: ARISTADA Doses Based on Oral Aripiprazole Total Daily Dose
Oral Aripiprazole Dose	Intramuscular ARISTADA Dose
10 mg per day	441 mg per month
15 mg per day	662 mg per month
20 mg or higher per day	882 mg per month

In conjunction with the first ARISTADA injection, administer treatment with oral aripiprazole for 21 consecutive days.

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

2.2. Missed Doses

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

Table 3: Recommendation for Concomitant Oral Aripiprazole Supplementation Following Missed Dosesa
Dose of Patient's Last ARISTADA Injection	Length of Time Since Last Injection
Dose of Patient's Last ARISTADA Injection	No Oral Supplementation Required	Supplement with 7 Days Oral Aripiprazole	Supplement with 21 Days Oral Aripiprazole
a The patient should supplement with the same dose of oral aripiprazole as when the patient began ARISTADA (see Table 2).
Monthly 441 mg	≤ 6 weeks	> 6 and ≤ 7 weeks	> 7 weeks
Monthly 662 mg	≤ 8 weeks	> 8 and ≤ 12 weeks	> 12 weeks
Monthly 882 mg	≤ 8 weeks	> 8 and ≤ 12 weeks	> 12 weeks
882 mg every 6 weeks	≤ 8 weeks	> 8 and ≤ 12 weeks	> 12 weeks

2.3. Early Dosing

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

2.4. Dose Adjustments for CYP450 Considerations

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

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

No dosage changes recommended for ARISTADA, if CYP450 modulators are added for less than 2 weeks.
Make dose changes to ARISTADA if CYP450 modulators are added for greater than 2 weeks (see Table 4).

Table 4: ARISTADA Dose Adjustments with Concomitant CYP450 Modulator Use
Concomitant Medicine	Dose Change for ARISTADAa
a For the 882 mg dose administered every 6 weeks, the next lower strength should be 441 mg administered every 4 weeks.
Strong CYP3A4 Inhibitor	Reduce the dose of ARISTADA to the next lower strength. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated. For patients known to be poor metabolizers of CYP2D6: Reduce dose to 441 mg from 662 mg or 882 mg. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated.
Strong CYP2D6 Inhibitor	Reduce the dose of ARISTADA to the next lower strength. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated. For patients known to be poor metabolizers of CYP2D6: No dose adjustment required.
Both Strong CYP3A4 Inhibitor and Strong CYP2D6 Inhibitor	Avoid use for patients at 662 mg or 882 mg dose. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated.
CYP3A4 Inducers	No dose adjustment for 662 mg and 882 mg dose, increase the 441 mg dose to 662 mg.

2.5. Instructions for Use

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

A | 5 ML SYRINGE containing ARISTADA sterile aqueous suspension

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

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

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

1. TAP and SHAKE the syringe.

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

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

2. SELECT the injection needle.

2a. Select injection site.

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

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

3. ATTACH the injection needle.

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

4. PRIME the syringe to remove air.

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

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

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

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

3. DOSAGE FORMS AND STRENGTHS

ARISTADA is a white to off-white aqueous extended-release suspension provided in a single-use pre-filled syringe for intramuscular injection in the deltoid or gluteal muscle at the 441 mg dose strength and in the gluteal muscle at dose strengths of 662 mg and 882 mg.

ARISTADA is available as described in Table 6.

Table 6: Presentations of ARISTADA
Dose Strength	Volume	Inject Intramuscularly	Color Label
441 mg	1.6 mL	Deltoid or Gluteal Muscle	Light Blue
662 mg	2.4 mL	Gluteal Muscle Only	Green
882 mg	3.2 mL	Gluteal Muscle Only	Burgundy

4. CONTRAINDICATIONS

ARISTADA is contraindicated in patients with a known hypersensitivity reaction to aripiprazole. Hypersensitivity reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions (6)].

5. WARNINGS AND PRECAUTIONS

5.1. Increased Mortality in Elderly Patients with Dementia-related Psychosis

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

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

5.2. Cerebrovascular Adverse Reactions, Including Stroke

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

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