Otsuka America Pharmaceutical, Inc.

2.1 Adjunctive Treatment of Major Depressive Disorder

The recommended starting dosage for REXULTI as adjunctive treatment is 0.5 mg or 1 mg once daily, taken orally with or without food [see Clinical Pharmacology (12.3)].

Titrate to 1 mg once daily, then up to the target dosage of 2 mg once daily. Dosage increases should occur at weekly intervals based on the patient’s clinical response and tolerability. The maximum recommended daily dosage is 3 mg. Periodically reassess to determine the continued need and appropriate dosage for treatment.

2.2 Treatment of Schizophrenia

The recommended starting dosage for REXULTI is 1 mg once daily on Days 1 to 4, taken orally with or without food [see Clinical Pharmacology (12.3)].

The recommended target REXULTI dosage is 2 mg to 4 mg once daily. Titrate to 2 mg once daily on Day 5 through Day 7, then to 4 mg on Day 8 based on the patient’s clinical response and tolerability. The maximum recommended daily dosage is 4 mg. Periodically reassess to determine the continued need and appropriate dosage for treatment.

2.3 Dosage Adjustments for Hepatic Impairment

For patients with moderate to severe hepatic impairment (Child-Pugh score ≥7), the maximum recommended dosage is 2 mg once daily for patients with MDD, and 3 mg once daily for patients with schizophrenia [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.4 Dosage Adjustments for Renal Impairment

For patients with moderate, severe or end-stage renal impairment (creatinine clearance CLcr<60 mL/minute), the maximum recommended dosage is 2 mg once daily for patients with MDD and 3 mg once daily for patients with schizophrenia [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].

2.5 Dosage Modifications for CYP2D6 Poor Metabolizers and for Concomitant use with CYP Inhibitors or Inducers

Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 1). If the coadministered drug is discontinued, adjust the REXULTI dosage to its original level. If the coadministered CYP3A4 inducer is discontinued, reduce the REXULTI dosage to the original level over 1 to 2 weeks [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Table 1: Dosage Adjustments of REXULTI for CYP2D6 Poor Metabolizers and for Concomitant Use with CYP3A4 and CYP2D6 Inhibitors and/or CYP3A4 Inducers

Factors

Adjusted REXULTI Dosage

CYP2D6 Poor Metabolizers

CYP2D6 poor metabolizers

Administer half of the usual dose

Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors

Administer a quarter of the usual dose

Patients Taking CYP2D6 Inhibitors and/or CYP3A4 Inhibitors

Strong CYP2D6 inhibitors*

Administer half of the usual dose

Strong CYP3A4 inhibitors

Administer half of the usual dose

Strong/moderate CYP2D6 inhibitors with strong/moderate CYP3A4 inhibitors

Administer a quarter of the usual dose

Patients Taking CYP3A4 Inducers

Strong CYP3A4 inducers

Double usual dose over 1 to 2 weeks

*In clinical trials examining the adjunctive use of REXULTI in the treatment of MDD, dosage was not adjusted for strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine). Thus, CYP considerations are already factored into general dosing recommendations and REXULTI may be administered without dosage adjustment in patients with MDD.

2.1 Dosage Overview for the Treatment of Schizophrenia

ABILIFY MAINTENA is only to be administered by intramuscular injection by a healthcare professional. The recommended starting and maintenance dose of ABILIFY MAINTENA is 400 mg monthly (no sooner than 26 days after the previous injection).

For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ABILIFY MAINTENA. Due to the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability.

After the first ABILIFY MAINTENA injection, administer oral aripiprazole (10 mg to 20 mg) for 14 consecutive days to achieve therapeutic aripiprazole concentrations during initiation of therapy. For patients already stable on another oral antipsychotic (and known to tolerate aripiprazole), after the first ABILIFY MAINTENA injection, continue treatment with the antipsychotic for 14 consecutive days to maintain therapeutic antipsychotic concentrations during initiation of therapy.

If there are adverse reactions with the 400 mg dosage, consider reducing the dosage to 300 mg once monthly.

2.2 Dosage Adjustments for Missed Doses

If the second or third doses are missed:

If the fourth or subsequent doses are missed:

2.3 Dosage Adjustments for Cytochrome P450 Considerations

Dosage adjustments are recommended in patients who are CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days (see Table 1). Dosage adjustments for 200 mg and 160 mg are obtained only by using the 300 mg or 400 mg strength vials for intramuscular deltoid or gluteal injection.

If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the ABILIFY MAINTENA dosage may need to be increased [see DOSAGE AND ADMINISTRATION (2.1)].

Avoid the concomitant use of CYP3A4 inducers with ABILIFY MAINTENA for greater than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels.

Dosage adjustments are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days.

CYP2D6 Poor Metabolizers

Known CYP2D6 Poor Metabolizers

300 mg

Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors

200 mg1

Patients Taking 400 mg of ABILIFY MAINTENA

Strong CYP2D6 or CYP3A4 inhibitors

300 mg

CYP2D6 and CYP3A4 inhibitors

200 mg1

CYP3A4 inducers

Avoid use

Patients Taking 300 mg of ABILIFY MAINTENA

Strong CYP2D6 or CYP3A4 inhibitors

200 mg1

CYP2D6 and CYP3A4 inhibitors

160 mg1

CYP3A4 inducers

Avoid use

ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe (2.5), and 2) Vials (2.6).

2.4 Different Aripiprazole Formulations and Kits

There are two aripiprazole formulations for intramuscular use with different dosages, dosing frequencies, and indications. ABILIFY MAINTENA is a long-acting aripiprazole formulation with 4 week dosing intervals indicated for the treatment of schizophrenia. In contrast, aripiprazole injection (9.75 mg per vial) is a short-acting formulation indicated for agitation in patients with schizophrenia or mania. Do not substitute these products. Refer to the prescribing information for aripiprazole injection for more information about aripiprazole injection.

ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe available in 300 mg or 400 mg strength syringes [see DOSAGE AND ADMINISTRATION (2.5)], and 2) Single-use vials available in 300 mg or 400 mg strength vials [see DOSAGE AND ADMINISTRATION (2.6)].

The 200 mg and 160 mg dosage adjustments are obtained only by using the 300 mg or 400 mg strength vials.

2.5 Pre-filled Dual Chamber Syringe: Preparation and Administration Instructions

Preparation Prior to Reconstitution

For deep intramuscular deltoid or gluteal injection by healthcare professionals only. Do not administer by any other route. Inject full syringe contents immediately following reconstitution. Administer once monthly.

Lay out and confirm that components listed below are provided in the kit:

Reconstitution of Lyophilized Powder in Pre-filled Dual Chamber Syringe

Reconstitute at room temperature.

Figure 1

Figure 2

Injection Procedure

Use appropriate aseptic techniques throughout injection procedure. For deep intramuscular injection only.

Figure 3

Figure 4

For deltoid administration:

For gluteal administration:

Figure 5

Figure 6

Figure 7

Disposal Procedure

Figure 8

2.6 Vial: Preparation and Administration Instructions

Preparation Prior to Reconstitution

For deep intramuscular injection by healthcare professionals only. Do not administer by any other route. Inject immediately after reconstitution. Administer once monthly.

400 mg Vial

300 mg Vial

Dose

Sterile Water for Injection

Dose

Sterile Water for Injection

400 mg

1.9 mL

300 mg

1.5 mL

Important: There is more Sterile Water for Injection in the vial than is needed to reconstitute ABILIFY MAINTENA (aripiprazole) for extended-release injectable suspension. The vial will have excess Sterile Water for Injection; discard any unused portion.

Reconstitution of Lyophilized Powder in Vial

Figure 9

Figure 10

Figure 11

Figure 12

Preparation Prior to Injection

Figure 13

Figure 14

Figure 15

Dose

Volume to Inject

Dose

Volume to Inject

400 mg

2 mL

---

---

300 mg

1.5 mL

300 mg

1.5 mL

200 mg

1 mL

200 mg

1 mL

160 mg

0.8 mL

160 mg

0.8 mL

Figure 16

Figure 17

Injection Procedure

For deltoid administration:

For gluteal administration:

Figure 18

Slowly inject the recommended volume as a single intramuscular injection into the deltoid or gluteal muscle. Do not massage the injection site.

Disposal Procedure

DOSAGE AND ADMINISTRATION: Supra Sulfa®III Boluses (Sulfamethazine Sustained Release Boluses) are designed to be administered orally to beef cattle and non-lactating dairy cattle (See Warning). Supra Sulfa® III Boluses should be given according to the following dosage schedule:

This bolus may be divided for better approximation of correct dose; however, care should be taken not to crush the bolus. Care should also be taken to ensure the entire dose has been swallowed by the animal. Observe animals following administration to ensure boluses are not regurgitated. Lubricate bolus before dosing animals.

Supra Sulfa®III Boluses are designed to provide a therapeutic sulfamethazine level in approximately 6 hours, and persist in providing this level of 72 hours (3 days). After 72 hours, all animals should be reexamined for persistence of observable disease signs. If signs are present, consult a veterinarian. It is strongly recommended that a second dose be given to provide for an additional 72 hours of therapy particularly in those more severe cases. The dosage schedule should be used at each 72-hour interval.

2.1 Initial Dosing Information

2.2 Preparation and Administration Precautions

DO NOT USE POLYCARBONATE SYRINGES OR POLYCARBONATE FILTER NEEDLES WITH BUSULFEX.

Use an administration set with minimal residual hold-up volume (2-5 cc) for product administration.

BUSULFEX is a cytotoxic drug. Follow applicable special handling and disposal procedures. Skin reactions may occur with accidental exposure. Use gloves when preparing BUSULFEX. If BUSULFEX or diluted BUSULFEX solution contacts the skin or mucosa, wash the skin or mucosa thoroughly with water.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration whenever the solution and container permit. Do not use if particulate matter is seen in the BUSULFEX vial.

2.3 Preparation for Intravenous Administration

BUSULFEX must be diluted prior to intravenous infusion with either 0.9% Sodium Chloride Injection, USP (normal saline) or 5% Dextrose Injection, USP (D5W). The diluent quantity should be 10 times the volume of BUSULFEX, so that the final concentration of busulfan is approximately 0.5 mg per mL. Calculation of the dose for a 70 kg patient would be performed as follows:

To prepare the final solution for infusion, add 9.3 mL of BUSULFEX to 93 mL of diluent (normal saline or D5W) as calculated below:

(9.3 mL BUSULFEX) x (10) =93 mL of either diluent plus the 9.3 mL of BUSULFEX to yield a final concentration of busulfan of 0.54 mg per mL (9.3 mL x 6 mg per mL ÷ 102.3 mL =0.54 mg per mL).

All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood while wearing gloves and protective clothing.

DO NOT put the BUSULFEX into an intravenous bag or large-volume syringe that does not contain normal saline or D5W. Always add the BUSULFEX to the diluent, not the diluent to the BUSULFEX. Mix thoroughly by inverting several times.

Infusion pumps should be used to administer the diluted BUSULFEX solution. Set the flow rate of the pump to deliver the entire prescribed BUSULFEX dose over two hours. Prior to and following each infusion, flush the indwelling catheter line with approximately 5 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. DO NOT infuse concomitantly with another intravenous solution of unknown compatibility. WARNING: RAPID INFUSION OF BUSULFEX HAS NOT BEEN TESTED AND IS NOT RECOMMENDED.

2.1 Usual Dosage in Adults

Patients should be in a hospital for initiation and re-initiation of therapy to evaluate the therapeutic response and because too rapid correction of hyponatremia can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death.

The usual starting dose for SAMSCA is 15 mg administered once daily without regard to meals. Increase the dose to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium. Do not administer SAMSCA for more than 30 days to minimize the risk of liver injury [see Warnings and Precautions (5.2)].

During initiation and titration, frequently monitor for changes in serum electrolytes and volume. Avoid fluid restriction during the first 24 hours of therapy. Patients receiving SAMSCA should be advised that they can continue ingestion of fluid in response to thirst [see Warnings and Precautions (5.1)].

2.2 Drug Withdrawal

Following discontinuation from SAMSCA, patients should be advised to resume fluid restriction and should be monitored for changes in serum sodium and volume status.

2.3 Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors

CYP 3A Inhibitors

Tolvaptan is metabolized by CYP 3A, and use with strong CYP 3A inhibitors causes a marked (5‑fold) increase in exposure [see Contraindications (4.4)]. The effect of moderate CYP 3A inhibitors on tolvaptan exposure has not been assessed. Avoid co-administration of SAMSCA and moderate CYP 3A inhibitors [see Warnings and Precautions (5.5), Drug Interactions (7.1)].

CYP 3A Inducers

Co-administration of SAMSCA with potent CYP 3A inducers (e.g., rifampin) reduces tolvaptan plasma concentrations by 85%. Therefore, the expected clinical effects of SAMSCA may not be observed at the recommended dose. Patient response should be monitored and the dose adjusted accordingly [see Warnings and Precautions (5.5), Drug Interactions (7.1)].

P-gp Inhibitors

Tolvaptan is a substrate of P-gp. Co-administration of SAMSCA with inhibitors of P-gp (e.g., cyclosporine) may necessitate a decrease in SAMSCA dose [see Warnings and Precautions (5.5), Drug Interactions (7.1)].

    There are two regimens for DACOGEN administration. With either regimen it is recommended that patients be treated for a minimum of 4 cycles; however, a complete or partial response may take longer than 4 cycles. 

    Complete blood counts and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle.  Liver chemistries and serum creatinine should be obtained prior to initiation of treatment.

2.1 Treatment Regimen – Option 1

    DACOGEN is administered at a dose of 15 mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days.  This cycle should be repeated every 6 weeks.  Patients may be premedicated with standard anti-emetic therapy.

    If hematologic recovery (ANC ≥ 1,000/μL and platelets ≥ 50,000/μL) from a previous DACOGEN treatment cycle requires more than 6 weeks, then the next cycle of DACOGEN therapy should be delayed and dosing temporarily reduced by following this algorithm:

2.2 Treatment Regimen – Option 2

    DACOGEN is administered at a dose of 20 mg/m2 by continuous intravenous infusion over 1 hour repeated daily for 5 days.  This cycle should be repeated every 4 weeks.  Patients may be premedicated with standard anti-emetic therapy.  

    If myelosuppression is present, subsequent treatment cycles of DACOGEN should be delayed until there is hematologic recovery (ANC ≥ 1,000/μL platelets ≥ 50,000/μL ).

2.3 Patients with Non-hematologic Toxicity

    Following the first cycle of DACOGEN treatment, if any of the following non-hematologic toxicities are present, DACOGEN treatment should not be restarted until the toxicity is resolved:  1) serum creatinine ≥ 2 mg/dL; 2) SGPT, total bilirubin ≥ 2 times ULN; 3) and active or uncontrolled infection.

2.4 Instructions for Intravenous Administration

    DACOGEN is a cytotoxic drug and caution should be exercised when handling and preparing DACOGEN.  Procedures for proper handling and disposal of antineoplastic drugs should be applied.  Several guidances on this subject have been published.1,,,4

    DACOGEN should be aseptically reconstituted with 10 mL of Sterile Water for Injection (USP); upon reconstitution, each mL contains approximately 5.0 mg of decitabine at pH 6.7-7.3.  Immediately after reconstitution, the solution should be further diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final drug concentration of 0.1 - 1.0 mg/mL.  Unless used within 15 minutes of reconstitution, the diluted solution must be prepared using cold (2˚C - 8˚C) infusion fluids and stored at 2˚C - 8˚C (36˚F - 46˚F) for up to a maximum of 4 hours until administration.

    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Do not use if there is evidence of particulate matter or discoloration.