Alkermes, Inc.

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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 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.

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VIVITROL must be prepared and administered by a healthcare provider.

Prior to initiating VIVITROL, an opioid-free duration of a minimum of 7-10 days is recommended for patients, to avoid precipitation of opioid withdrawal that may be severe enough to require hospitalization [see Warnings and Precautions (5.3)].

The recommended dose of VIVITROL is 380 mg delivered intramuscularly every 4 weeks or once a month. The injection should be administered by a healthcare provider as an intramuscular (IM) gluteal injection, alternating buttocks for each subsequent injection, using the carton components provided [see How Supplied/Storage and Handling (16)]. The needles provided in the carton are customized needles. VIVITROL must not be injected using any other needle. The needle lengths (either 1.5 or 2 inches) may not be adequate in every patient because of body habitus. Body habitus should be assessed prior to each injection for each patient to assure that needle length is adequate for intramuscular administration. For patients with a larger amount of subcutaneous tissue overlying the gluteal muscle, the administering healthcare provider may utilize the supplied 2-inch needle with needle protection device to help ensure that the injectate reaches the intramuscular mass. For very lean patients, the 1.5-inch needle may be appropriate to prevent the needle contacting the periosteum. Either needle may be used for patients with average body habitus. Healthcare providers should ensure that the VIVITROL injection is given correctly, and should consider alternate treatment for those patients whose body habitus precludes an intramuscular gluteal injection with one of the provided needles.

VIVITROL must not be administered intravenously or subcutaneously.

If a patient misses a dose, he/she should be instructed to receive the next dose as soon as possible.

Pretreatment with oral naltrexone is not required before using VIVITROL.

2.1 Reinitiation of Treatment in Patients Previously Discontinued

There are no data to specifically address reinitiation of treatment. Patients reinitiating treatment with VIVITROL should be opioid-free at the time of dose administration [see Indications and Usage (1), Contraindications (4), and Warnings and Precautions (5.3)].

2.2 Switching From Oral Naltrexone

There are no systematically collected data that specifically address the switch from oral naltrexone to VIVITROL.

2.3 Switching from Buprenorphine, Buprenorphine/Naloxone, or Methadone

There are no systematically collected data that specifically address the switch from buprenorphine or methadone to VIVITROL; however, review of postmarketing case reports have indicated that some patients may experience severe manifestations of precipitated withdrawal when being switched from opioid agonist therapy to opioid antagonist therapy [see Warnings and Precautions (5.3)]. Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as 2 weeks. Healthcare providers should be prepared to manage withdrawal symptomatically with non-opioid medications.

2.4 Directions for Use

To ensure proper dosing, it is important that you follow the preparation and administration instructions outlined in this document.

VIVITROL must be suspended only in the diluent supplied in the carton and must be administered only with one of the administration needles supplied in the carton. The microspheres, diluent, preparation needle, and an administration needle with needle protection device are required for preparation and administration. Two thin-walled 1.5-inch needles with needle protection device and two 2-inch thin-walled needles with needle protection device have been provided to accommodate varying patient body habitus. For patients with a larger amount of subcutaneous tissue overlying the gluteal muscle, the administering healthcare provider may utilize the supplied 2-inch needle with needle protection device to help ensure that the injectate reaches the intramuscular mass. For very lean patients, the 1.5-inch needle may be appropriate to prevent the needle contacting the periosteum. Either needle may be used for patients with average body habitus. A spare administration needle of each size is provided in case of clogging [see How Supplied/Storage and Handling (16)]. Do not substitute any other components for the components of the carton.

Prior to preparation, allow drug to reach room temperature (approximately 45 minutes).

Parenteral products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. A properly mixed suspension will be milky white, will not contain clumps, and will move freely down the wall of the vial [see Directions for Use, illustration below].

Product to be prepared and administered by a healthcare provider.

Keep out of reach of children.

Prepare and administer the VIVITROL suspension using aseptic technique.

WARNING: To reduce the risk of a needlestick:

Do not intentionally disengage the needle protection device. Discard bent or damaged needle into a sharps container and use the spare needle provided. Do not attempt to straighten the needle or engage needle protection device if the needle is bent or damaged. Do not mishandle the needle protection device in a way that could lead to protrusion of the needle. Do not use free hand to press sheath over needle.

THE CARTON SHOULD NOT BE EXPOSED TO TEMPERATURES EXCEEDING 25 °C (77 °F).

The entire carton should be stored in the refrigerator (2-8°C, 36-46°F). Unrefrigerated, VIVITROL microspheres can be stored at temperatures not exceeding 25°C (77°F) for no more than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above 25°C (77°F). VIVITROL should not be frozen.

Parenteral products should be visually inspected for particulate matter and discoloration prior to administration. NEEDLE-PRO® and the color orange applied to the needle protection device are trademarksof the Smiths Medical family of companies.

Remove the carton from refrigeration. Prior to preparation, allow drug to reach room temperature (approximately 45 minutes). To ease mixing, firmly tap the VIVITROL microspheres vial on a hard surface, ensuring the powder moves freely. (see Figure B) Remove flip-off caps from both vials. DO NOT USE IF FLIP-OFF CAPS ARE BROKEN OR MISSING. Wipe the vial tops with an alcohol swab. Place the 1-inch preparation needle on the syringe and withdraw 3.4 mL of the diluent from the diluent vial. Some diluent will remain in the diluent vial. (see Figure B)

Inject the 3.4 mL of diluent into the VIVITROL microsphere vial. (see Figure C)

Mix the powder and diluent by vigorously shaking the vial for approximately 1 minute. (see Figure D)Ensure that the dose is thoroughly suspended prior to proceeding to Step E.A PROPERLY MIXED SUSPENSION WILL BE MILKY WHITE, WILL NOT CONTAIN CLUMPS, AND WILL MOVE FREELY DOWN THE WALLS OF THE VIAL.

Immediately after suspension, withdraw 4.2 mL of the suspension into the syringe using the same preparation needle. (see Figure E) Select the appropriate needle for an intramuscular injection based on patient's body habitus: 1.5-inch TERUMO® Needle 2-inch NEEDLE-PRO® Needle

Remove the preparation needle and replace with appropriately selected administration needle for immediate use. Peel the blister pouch of the selected administration needle open halfway. Grasp sheath using the plastic pouch. Attach the luer connection to the syringe with an easy clockwise twisting motion. (see Figure F) Seat the needle firmly on the needle protection device with a push and clockwise twist.

Pull the sheath away from the needle -do not twist the sheath because it could result in loosening the needle. Prior to injecting, tap the syringe to release any air bubbles, then push gently on the plunger until 4 mL of the suspension remains in the syringe. (see Figure G)THE SUSPENSION IS NOW READY FOR IMMEDIATE ADMINISTRATION.

Using a circular motion, clean the injection site with the alcohol swab. Let the site dry before injecting. Do not touch the site again before giving injections. Administer the suspension by deep intramuscular (IM) injection into a gluteal muscle, alternating buttocks per monthly injection. Remember to aspirate for blood before injection. (see Figure H) If blood aspirates or the needle clogs, do not inject. Change to the spare needle provided in the carton and administer into an adjacent site in the same gluteal region, again aspirating for blood before injection. Inject the suspension in a smooth and continuous motion.VIVITROL must NOT be given intravenously or subcutaneously.

After the injection is administered, cover the needle by pressing the needle protection device against a flat surface using a one-handed motion away from self and others. (see Figure I)

Visually confirm needle is fully engaged into the needle protection device. (see Figure J)DISPOSE OF USED AND UNUSED ITEMS IN PROPER WASTE CONTAINERS.

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VIVITROL must be prepared and administered by a healthcare provider.

Prior to initiating VIVITROL, an opioid-free duration of a minimum of 7-10 days is recommended for patients, to avoid precipitation of opioid withdrawal that may be severe enough to require hospitalization [see Warnings and Precautions (5.3)].

The recommended dose of VIVITROL is 380 mg delivered intramuscularly every 4 weeks or once a month. The injection should be administered by a healthcare provider as an intramuscular (IM) gluteal injection, alternating buttocks for each subsequent injection, using the carton components provided [see How Supplied/Storage and Handling (16)]. The needles provided in the carton are customized needles. VIVITROL must not be injected using any other needle. The needle lengths (either 1.5 or 2 inches) may not be adequate in every patient because of body habitus. Body habitus should be assessed prior to each injection for each patient to assure that needle length is adequate for intramuscular administration. For patients with a larger amount of subcutaneous tissue overlying the gluteal muscle, the administering healthcare provider may utilize the supplied 2-inch needle with needle protection device to help ensure that the injectate reaches the intramuscular mass. For very lean patients, the 1.5-inch needle may be appropriate to prevent the needle contacting the periosteum. Either needle may be used for patients with average body habitus. Healthcare providers should ensure that the VIVITROL injection is given correctly, and should consider alternate treatment for those patients whose body habitus precludes an intramuscular gluteal injection with one of the provided needles.

VIVITROL must not be administered intravenously or subcutaneously.

If a patient misses a dose, he/she should be instructed to receive the next dose as soon as possible.

Pretreatment with oral naltrexone is not required before using VIVITROL.

2.1 Reinitiation of Treatment in Patients Previously Discontinued

There are no data to specifically address reinitiation of treatment. Patients reinitiating treatment with VIVITROL should be opioid-free at the time of dose administration [see Indications and Usage (1), Contraindications (4), and Warnings and Precautions (5.3)].

2.2 Switching From Oral Naltrexone

There are no systematically collected data that specifically address the switch from oral naltrexone to VIVITROL.

2.3 Switching from Buprenorphine, Buprenorphine/Naloxone, or Methadone

There are no systematically collected data that specifically address the switch from buprenorphine or methadone to VIVITROL; however, review of postmarketing case reports have indicated that some patients may experience severe manifestations of precipitated withdrawal when being switched from opioid agonist therapy to opioid antagonist therapy [see Warnings and Precautions (5.3)]. Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as 2 weeks. Healthcare providers should be prepared to manage withdrawal symptomatically with non-opioid medications.

2.4 Directions for Use

To ensure proper dosing, it is important that you follow the preparation and administration instructions outlined in this document.

VIVITROL must be suspended only in the diluent supplied in the carton and must be administered only with one of the administration needles supplied in the carton. The microspheres, diluent, preparation needle, and an administration needle with needle protection device are required for preparation and administration. Two thin-walled 1.5-inch needles with needle protection device and two 2-inch thin-walled needles with needle protection device have been provided to accommodate varying patient body habitus. For patients with a larger amount of subcutaneous tissue overlying the gluteal muscle, the administering healthcare provider may utilize the supplied 2-inch needle with needle protection device to help ensure that the injectate reaches the intramuscular mass. For very lean patients, the 1.5-inch needle may be appropriate to prevent the needle contacting the periosteum. Either needle may be used for patients with average body habitus. A spare administration needle of each size is provided in case of clogging [see How Supplied/Storage and Handling (16)]. Do not substitute any other components for the components of the carton.

Prior to preparation, allow drug to reach room temperature (approximately 45 minutes).

Parenteral products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. A properly mixed suspension will be milky white, will not contain clumps, and will move freely down the wall of the vial [see Directions for Use, illustration below].

Product to be prepared and administered by a healthcare provider.

Keep out of reach of children.

Prepare and administer the VIVITROL suspension using aseptic technique.

WARNING: To reduce the risk of a needlestick:

Do not intentionally disengage the needle protection device. Discard bent or damaged needle into a sharps container and use the spare needle provided. Do not attempt to straighten the needle or engage needle protection device if the needle is bent or damaged. Do not mishandle the needle protection device in a way that could lead to protrusion of the needle. Do not use free hand to press sheath over needle.

THE CARTON SHOULD NOT BE EXPOSED TO TEMPERATURES EXCEEDING 25 °C (77 °F).

The entire carton should be stored in the refrigerator (2-8°C, 36-46°F). Unrefrigerated, VIVITROL microspheres can be stored at temperatures not exceeding 25°C (77°F) for no more than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above 25°C (77°F). VIVITROL should not be frozen.

Parenteral products should be visually inspected for particulate matter and discoloration prior to administration. NEEDLE-PRO®and the color orange applied to the needle protection device are trademarksof the Smiths Medical family of companies.

Remove the carton from refrigeration. Prior to preparation, allow drug to reach room temperature (approximately 45 minutes). To ease mixing, firmly tap the VIVITROL microspheres vial on a hard surface, ensuring the powder moves freely. (see Figure B) Remove flip-off caps from both vials. DO NOT USE IF FLIP-OFF CAPS ARE BROKEN OR MISSING. Wipe the vial tops with an alcohol swab. Place the 1-inch preparation needle on the syringe and withdraw 3.4 mL of the diluent from the diluent vial. Some diluent will remain in the diluent vial. (see Figure B)

Inject the 3.4 mL of diluent into the VIVITROL microsphere vial. (see Figure C)

Mix the powder and diluent by vigorously shaking the vial for approximately 1 minute. (see Figure D)Ensure that the dose is thoroughly suspended prior to proceeding to Step E.A PROPERLY MIXED SUSPENSION WILL BE MILKY WHITE, WILL NOT CONTAIN CLUMPS, AND WILL MOVE FREELY DOWN THE WALLS OF THE VIAL.

Immediately after suspension, withdraw 4.2 mL of the suspension into the syringe using the same preparation needle. (see Figure E) Select the appropriate needle for an intramuscular injection based on patient's body habitus: 1.5-inch TERUMO®Needle 2-inch NEEDLE-PRO®Needle

Remove the preparation needle and replace with appropriately selected administration needle for immediate use. Peel the blister pouch of the selected administration needle open halfway. Grasp sheath using the plastic pouch. Attach the luer connection to the syringe with an easy clockwise twisting motion. (see Figure F) Seat the needle firmly on the needle protection device with a push and clockwise twist.

Pull the sheath away from the needle -do not twist the sheath because it could result in loosening the needle. Prior to injecting, tap the syringe to release any air bubbles, then push gently on the plunger until 4 mL of the suspension remains in the syringe. (see Figure G)THE SUSPENSION IS NOW READY FOR IMMEDIATE ADMINISTRATION.

Using a circular motion, clean the injection site with the alcohol swab. Let the site dry before injecting. Do not touch the site again before giving injections. Administer the suspension by deep intramuscular (IM) injection into a gluteal muscle, alternating buttocks per monthly injection. Remember to aspirate for blood before injection. (see Figure H) If blood aspirates or the needle clogs, do not inject. Change to the spare needle provided in the carton and administer into an adjacent site in the same gluteal region, again aspirating for blood before injection. Inject the suspension in a smooth and continuous motion.VIVITROL must NOT be given intravenously or subcutaneously.

After the injection is administered, cover the needle by pressing the needle protection device against a flat surface using a one-handed motion away from self and others. (see Figure I)

Visually confirm needle is fully engaged into the needle protection device. (see Figure J)DISPOSE OF USED AND UNUSED ITEMS IN PROPER WASTE CONTAINERS.