Takeda Pharmaceuticals America, Inc.

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Takeda Pharmaceuticals America, Inc. Drugs

Azithromycin Monohydrat...

Azithromycin Monohydrate

2.1 Recommended Dosing

The recommended dose of NESINA is 25 mg once daily.

NESINA may be taken with or without food.

2.2 Patients with Renal Impairment

No dose adjustment of NESINA is necessary for patients with mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min).

The dose of NESINA is 12.5 mg once daily for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min).

The dose of NESINA is 6.25 mg once daily for patients with severe renal impairment (CrCl ≥15 to <30 mL/min) or with end-stage renal disease (ESRD) (CrCl <15 mL/min or requiring hemodialysis). NESINA may be administered without regard to the timing of dialysis. NESINA has not been studied in patients undergoing peritoneal dialysis [see Clinical Pharmacology (12.3)].

Because there is a need for dose adjustment based upon renal function, assessment of renal function is recommended prior to initiation of NESINA therapy and periodically thereafter.
Rozerem

Rozerem

2.1 Dosage in Adults

The recommended dose of ROZEREM is 8 mg taken within 30 minutes of going to bed. It is recommended that ROZEREM not be taken with or immediately after a high-fat meal.

The total ROZEREM dose should not exceed 8 mg per day.

2.2 Dosing in Patients with Hepatic Impairment

ROZEREM is not recommended in patients with severe hepatic impairment. ROZEREM should be used with caution in patients with moderate hepatic impairment [see Warnings and Precautions (5.6), Clinical Pharmacology (12.4)].

2.3 Administration with Other Medications

ROZEREM should not be used in combination with fluvoxamine. ROZEREM should be used with caution in patients taking other CYP1A2 inhibiting drugs [see Drug Interactions (7), Clinical Pharmacology (12.5)].
Gabapentin

Gabapentin

The long-term use of colchicine is established for FMF and the prophylaxis of gout flares, but the safety and efficacy of repeat treatment for gout flares has not been evaluated. The dosing regimens for COLCRYS are different for each indication and must be individualized.

The recommended dosage of COLCRYS depends on the patient's age, renal function, hepatic function and use of coadministered drugs [see Dose Modification for Coadministration of Interacting Drugs (2.4)].

COLCRYS tablets are administered orally without regard to meals.

COLCRYS is not an analgesic medication and should not be used to treat pain from other causes.

2.1 Gout Flares

Prophylaxis of Gout Flares

The recommended dosage of COLCRYS for prophylaxis of gout flares for adults and adolescents older than 16 years of age is 0.6 mg once or twice daily. The maximum recommended dose for prophylaxis of gout flares is 1.2 mg/day.

An increase in gout flares may occur after initiation of uric acid-lowering therapy, including pegloticase, febuxostat and allopurinol, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. COLCRYS is recommended upon initiation of gout flare prophylaxis with uric acid-lowering therapy. Prophylactic therapy may be beneficial for at least the first six months of uric acid-lowering therapy.

Treatment of Gout Flares

The recommended dose of COLCRYS for treatment of a gout flare is 1.2 mg (two tablets) at the first sign of the flare followed by 0.6 mg (one tablet) one hour later. Higher doses have not been found to be more effective. The maximum recommended dose for treatment of gout flares is 1.8 mg over a one hour period. COLCRYS may be administered for treatment of a gout flare during prophylaxis at doses not to exceed 1.2 mg (two tablets) at the first sign of the flare followed by 0.6 mg (one tablet) one hour later. Wait 12 hours and then resume the prophylactic dose.

2.2 FMF

The recommended dosage of COLCRYS for FMF in adults is 1.2 mg to 2.4 mg daily.

COLCRYS should be increased as needed to control disease and as tolerated in increments of 0.3 mg/day to a maximum recommended daily dose. If intolerable side effects develop, the dose should be decreased in increments of 0.3 mg/day. The total daily COLCRYS dose may be administered in one to two divided doses.

2.3 Recommended Pediatric Dosage

Prophylaxis and Treatment of Gout Flares

COLCRYS is not recommended for pediatric use in prophylaxis or treatment of gout flares.

FMF

The recommended dosage of COLCRYS for FMF in pediatric patients 4 years of age and older is based on age. The following daily doses may be given as a single or divided dose twice daily:
• Children 4 to 6 years: 0.3 mg to 1.8 mg daily • Children 6 to 12 years: 0.9 mg to 1.8 mg daily • Adolescents older than 12 years: 1.2 mg to 2.4 mg daily
2.4 Dose Modification for Coadministration of Interacting Drugs

Concomitant Therapy

Coadministration of COLCRYS with drugs known to inhibit CYP3A4 and/or P-glycoprotein (P-gp) increases the risk of colchicine-induced toxic effects (Table 1). If patients are taking or have recently completed treatment with drugs listed in Table 1 within the prior 14 days, the dose adjustments are as shown in the table below [see Drug Interactions (7)].
Table 1 COLCRYS Dose Adjustment for Coadministration with Interacting Drugs if no Alternative Available* * For magnitude of effect on colchicine plasma concentrations [ see Pharmacokinetics (12.3)] † When used in combination with Ritonavir, see dosing recommendations for strong CYP3A4 inhibitors [ see Contraindications (4)] ‡ Patients with renal or hepatic impairment should not be given COLCRYS in conjunction with strong CYP3A4 or P-gp inhibitors [ see Contraindications (4)]
Strong CYP3A4 Inhibitors2

Drug

Noted or Anticipated Outcome

Gout Flares

FMF

Prophylaxis of Gout Flares

Treatment of Gout Flares

Original Intended Dosage

Adjusted Dose

Original Intended Dosage

Adjusted Dose

Original Intended Dosage

Adjusted Dose

AtazanavirClarithromycinDarunavir/Ritonavir† IndinavirItraconazole KetoconazoleLopinavir/Ritonavir† NefazodoneNelfinavirRitonavirSaquinavir TelithromycinTipranavir/Ritonavir†

Significant increase in colchicine plasma levels*; fatal colchicine toxicity has been reported with clarithromycin, a strong CYP3A4 inhibitor. Similarly, significant increase in colchicine plasma levels is anticipated with other strong CYP3A4 inhibitors.

0.6 mg twice a day0.6 mg once a day

0.3 mg once a day0.3 mg once every other day

1.2 mg(2 tablets) followed by 0.6 mg (1 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

0.6 mg(1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 1.2 – 2.4 mg

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

Moderate CYP3A4 Inhibitors

Drug

Noted or Anticipated Outcome

Gout Flares

FMF

Prophylaxis of Gout Flares

Treatment of Gout Flares

Original Intended Dosage

Adjusted Dose

Original Intended Dosage

Adjusted Dose

Original Intended Dosage

Adjusted Dose

Amprenavir† AprepitantDiltiazem Erythromycin Fluconazole Fosamprenavir† (pro-drug ofAmprenavir)Grapefruit juiceVerapamil

Significant increase in colchicine plasma concentration is anticipated. Neuromuscular toxicity has been reported with diltiazem and verapamil interactions.

0.6 mg twice a day0.6 mg once a day

0.3 mg twice a day or 0.6 mg once a day0.3 mg once a day

1.2 mg(2 tablets) followed by 0.6 mg (1 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

1.2 mg(2 tablets) × 1 dose. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 1.2 – 2.4 mg.

Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day)

P-gp Inhibitors‡

Drug

Noted or Anticipated Outcome

Gout Flares

FMF

Prophylaxis of Gout Flares

Treatment of Gout Flares

Original Intended Dosage

Adjusted Dose

Original Intended Dosage

Adjusted Dose

Original Intended Dosage

Adjusted Dose

Cyclosporine Ranolazine

Significant increase in colchicine plasma levels*; fatal colchicine toxicity has been reported with cyclosporine, a P-gp inhibitor. Similarly, significant increase in colchicine plasma levels is anticipated with other P-gp inhibitors.

0.6 mg twice a day0.6 mg once a day

0.3 mg once a day0.3 mg once every other day

1.2 mg(2 tablets) followed by 0.6 mg (1 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

0.6 mg(1 tablet) × 1 dose. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 1.2 – 2.4 mg

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
Table 2 COLCRYS Dose Adjustment for Coadministration with Protease Inhibitors
Protease Inhibitor

Clinical Comment

w/Colchicine - Prophylaxis of Gout Flares

w/Colchicine - Treatment of Gout Flares

w/Colchicine - Treatment of FMF

Atazanavir sulfate(Reyataz)

Patients with renal or hepatic impairment should not be given colchicine with Reyataz.

Original dose

Adjusted dose

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

0.6 mg twice a day0.6 mg once a day

0.3 mg once a day0.3 mg once every other day

Darunavir (Prezista)

Patients with renal or hepatic impairment should not be given colchicine with Prezista/ritonavir.

Original dose

Adjusted dose

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

0.6 mg twice a day0.6 mg once a day

0.3 mg once a day0.3 mg once every other day

Fosamprenavir (Lexiva) with Ritonavir

Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir.

Original dose

Adjusted dose

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

0.6 mg twice a day0.6 mg once a day

0.3 mg once a day0.3 mg once every other day

Fosamprenavir (Lexiva)

Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir.

Original dose

Adjusted dose

1.2 mg (2 tablets) × 1 dose. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day)

0.6 mg twice a day0.6 mg once a day

0.3 mg twice a day or 0.6 mg once a day0.3 mg once a day

Indinavir (Crixivan)

Patients with renal or hepatic impairment should not be given colchicine with Crixivan.

Original dose

Adjusted dose

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

0.6 mg twice a day0.6 mg once a day

0.3 mg once a day0.3 mg once every other day

Lopinavir/Ritonavir (Kaletra)

Patients with renal or hepatic impairment should not be given colchicine with Kaletra.

Original dose

Adjusted dose

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

0.6 mg twice a day0.6 mg once a day

0.3 mg once a day0.3 mg once every other day

Nelfinavir mesylate (Viracept)

Patients with renal or hepatic impairment should not be given colchicine with Viracept.

Original dose

Adjusted dose

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

0.6 mg twice a day0.6 mg once a day

0.3 mg once a day0.3 mg once every other day

Ritonavir (Norvir)

Patients with renal or hepatic impairment should not be given colchicine with Norvir.

Original dose

Adjusted dose

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

0.6 mg twice a day0.6 mg once a day

0.3 mg once a day0.3 mg once every other day

Saquinavir mesylate (Invirase)

Patients with renal or hepatic impairment should not be given colchicine with Invirase/ritonavir.

Original dose

Adjusted dose

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

0.6 mg twice a day0.6 mg once a day

0.3 mg once a day0.3 mg once every other day

Tipranavir (Aptivus)

Patients with renal or hepatic impairment should not be given colchicine with Aptivus/ritonavir.

Original dose

Adjusted dose

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

0.6 mg twice a day0.6 mg once a day

0.3 mg once a day0.3 mg once every other day

Treatment of gout flares with COLCRYS is not recommended in patients receiving prophylactic dose of COLCRYS and CYP3A4 inhibitors.

2.5 Dose Modification in Renal Impairment

Colchicine dosing must be individualized according to the patient's renal function [see Renal Impairment (8.6)].

Clcr in mL/minute may be estimated from serum creatinine (mg/dL) determination using the following formula:

[140-age (years) × weight (kg)]Clcr = --------------------------------------- × 0.85 for female patients 72 × serum creatinine (mg/dL)

Gout Flares

Prophylaxis of Gout Flares

For prophylaxis of gout flares in patients with mild (estimated creatinine clearance [Clcr] 50 to 80 mL/min) to moderate (Clcr 30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg/day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring [see Clinical Pharmacology (12.3) and Renal Impairment (8.6)].

Treatment of Gout Flares

For treatment of gout flares in patients with mild (Clcr 50 to 80 mL/min) to moderate (Clcr 30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every two weeks. For patients with gout flares requiring repeated courses, consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (one tablet). For these patients, the treatment course should not be repeated more than once every two weeks [see Clinical Pharmacology (12.3) and Renal Impairment (8.6)].

Treatment of gout flares with COLCRYS is not recommended in patients with renal impairment who are receiving COLCRYS for prophylaxis.

FMF

Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing dialysis. For these patients, the dosage should be reduced [see Clinical Pharmacology (12.3)]. Patients with mild (Clcr 50 to 80 mL/min) and moderate (Clcr 30 to 50 mL/min) renal impairment should be monitored closely for adverse effects of COLCRYS. Dose reduction may be necessary. For patients with severe renal failure (Clcr less than 30 mL/min), start with 0.3 mg/day; any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine [see Renal Impairment (8.6)]. For patients undergoing dialysis, the total recommended starting dose should be 0.3 mg (half tablet) per day. Dosing can be increased with close monitoring. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine [see Clinical Pharmacology (12.3) and Renal Impairment (8.6)].

2.6 Dose Modification in Hepatic Impairment

Gout Flares

Prophylaxis of Gout Flares

For prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment [see Hepatic Impairment (8.7)].

Treatment of Gout Flares

For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, for the treatment of gout flares in patients with severe impairment, while the dose does not need to be adjusted, a treatment course should be repeated no more than once every two weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy [see Hepatic Impairment (8.7)].

Treatment of gout flares with COLCRYS is not recommended in patients with hepatic impairment who are receiving COLCRYS for prophylaxis.

FMF

Patients with mild to moderate hepatic impairment should be monitored closely for adverse effects of colchicine. Dose reduction should be considered in patients with severe hepatic impairment [see Hepatic Impairment (8.7)].
Edarbyclor

Edarbyclor

2.1 Dosing Information

The recommended starting dose of Edarbyclor is 40/12.5 mg taken orally once daily. Most of the antihypertensive effect is apparent within 1 to 2 weeks. The dosage may be increased to 40/25 mg after 2 to 4 weeks as needed to achieve blood pressure goals. Edarbyclor doses above 40/25 mg are probably not useful.

Edarbyclor may be used to provide additional blood pressure lowering for patients not adequately controlled on ARB or diuretic monotherapy treatment. Patients not controlled with azilsartan medoxomil 80 mg may have an additional systolic / diastolic clinic blood pressure reduction of 13/6 mm Hg when switched to Edarbyclor 40/12.5 mg. Patients not controlled with chlorthalidone 25 mg may have an additional clinic blood pressure reduction of 10/7 mm Hg when switched to Edarbyclor 40/12.5 mg.

Edarbyclor may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals.

Patients titrated to the individual components (azilsartan medoxomil and chlorthalidone) may instead receive the corresponding dose of Edarbyclor.

Edarbyclor may be taken with or without food [see Clinical Pharmacology (12.3)].

Edarbyclor may be administered with other antihypertensive agents as needed.

2.2 Prior to Dosing

Correct any volume depletion prior to administration of Edarbyclor, particularly in patients with impaired renal function or those treated with high doses of diuretics [see Warnings and Precautions (5.2)].

Patients who experience dose-limiting adverse reactions on chlorthalidone may be switched to Edarbyclor, initially with a lower dose of chlorthalidone [see Warnings and Precautions (5.4)].

2.3 Handling Instructions

As Edarbyclor is moisture sensitive, dispense and store Edarbyclor in its original container to protect Edarbyclor from light and moisture.
Edarbi

Edarbi

2.1 Recommended Dose

The recommended dose in adults is 80 mg taken orally once daily. Consider a starting dose of 40 mg for patients who are treated with high doses of diuretics.

If blood pressure is not controlled with Edarbi alone, additional blood pressure reduction can be achieved by taking Edarbi with other antihypertensive agents.

Edarbi may be taken with or without food [see Clinical Pharmacology (12.3)].

2.2 Handling Instructions

Do not repackage Edarbi. Dispense and store Edarbi in its original container to protect Edarbi from light and moisture.

2.3 Special Populations

No initial dose adjustment is recommended for elderly patients, patients with mild-to-severe renal impairment, end-stage renal disease, or mild-to-moderate hepatic dysfunction. Edarbi has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].
Amitiza

Amitiza

Take Amitiza orally with food and water. Swallow capsules whole and do not break apart or chew. Physicians and patients should periodically assess the need for continued therapy.

2.1 Chronic Idiopathic Constipation and Opioid-induced Constipation

The recommended dose is 24 mcg twice daily orally with food and water.

Dosage in patients with hepatic impairment

For patients with moderately impaired hepatic function (Child-Pugh Class B), the recommended starting dose is 16 mcg twice daily. For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg twice daily. If this dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.2 Irritable Bowel Syndrome with Constipation

The recommended dose is 8 mcg twice daily orally with food and water.

Dosage in patients with hepatic impairment

For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg once daily. If this dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response. Dosage adjustment is not required for patients with moderately impaired hepatic function (Child-Pugh Class B) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Dexilant

Dexilant

2.1 Recommended Dose

DEXILANT is available as capsules in 30 mg and 60 mg strengths for adult use. Directions for use in each indication are summarized in Table 1.
* Controlled studies did not extend beyond 6 months.
Table 1. DEXILANT Dosing Recommendations

Indication

Recommended Dose

Frequency

Healing of EE

60 mg

Once daily for up to 8 weeks

Maintenance of Healed EE and relief of heartburn

30 mg

Once daily*

Symptomatic Non-Erosive GERD

30 mg

Once daily for 4 weeks

2.2 Hepatic Impairment

No adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). Consider a maximum daily dose of 30 mg for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.3 Important Administration Information
• DEXILANT can be taken without regard to food. • DEXILANT should be swallowed whole. • DEXILANT should not be chewed.
For patients who have difficulty swallowing capsules, follow the instructions below for administration:

Administration with Applesauce
• Place one tablespoon of applesauce into a clean container. • Open capsule. • Sprinkle intact granules on applesauce. • Swallow applesauce and granules immediately. Do not chew granules. Do not save the applesauce and granules for later use.
Administration with Water in an Oral Syringe
• Open the capsule and empty the granules into a clean container with 20 mL of water. • Withdraw the entire mixture into a syringe. • Gently swirl the syringe in order to keep granules from settling. • Administer the mixture immediately into the mouth. Do not save the water and granule mixture for later use. • Refill the syringe with 10 mL of water, swirl gently, and administer. • Refill the syringe again with 10 mL of water, swirl gently, and administer.
Administration with Water via a Nasogastric Tube (≥16 French)
• Open the capsule and empty the granules into a clean container with 20 mL of water. • Withdraw the entire mixture into a catheter-tip syringe. • Swirl the syringe gently in order to keep the granules from settling, and immediately inject the mixture through the nasogastric tube into the stomach. Do not save the water and granule mixture for later use. • Refill the syringe with 10 mL of water, swirl gently, and flush the tube. • Refill the syringe again with 10 mL of water, swirl gently, and administer.
Actos

Actos

2.1 Recommendations for All Patients

ACTOS should be taken once daily and can be taken without regard to meals.

The recommended starting dose for patients without congestive heart failure is 15 mg or 30 mg once daily.

The recommended starting dose for patients with congestive heart failure (NYHA Class I or II) is 15 mg once daily.

The dose can be titrated in increments of 15 mg up to a maximum of 45 mg once daily based on glycemic response as determined by HbA1c.

After initiation of ACTOS or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.5)].

Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating ACTOS. Routine periodic monitoring of liver tests during treatment with ACTOS is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of ACTOS or who are found to have abnormal liver tests while taking ACTOS should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

2.2 Concomitant Use with an Insulin Secretagogue or Insulin

If hypoglycemia occurs in a patient co-administered ACTOS and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient co-administered ACTOS and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

2.3 Concomitant Use with Strong CYP2C8 Inhibitors

Coadministration of ACTOS and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of ACTOS is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Actoplus Met Xr

Actoplus Met Xr

2.1 Recommendations for All Patients

ACTOPLUS MET XR should be taken with meals to reduce the gastrointestinal side effects associated with metformin.

If therapy with a combination tablet containing pioglitazone and extended-release metformin is considered appropriate the recommended starting dose is:
• 15 mg/1000 mg or 30 mg/1000 mg once daily and gradually titrated as needed, after assessing adequacy of therapeutic response and tolerability, • for patients with NYHA Class I or Class II congestive heart failure: 15 mg/1000 mg or 30 mg/1000 mg once daily and gradually titrated as needed, after assessing adequacy of therapeutic response and tolerability. • for patients inadequately controlled on metformin monotherapy: 15 mg/1000 mg twice daily or 30 mg/1000 mg once daily (depending on the dose of metformin already being taken) and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, • for patients inadequately controlled on pioglitazone monotherapy: 15 mg/1000 mg twice daily or 30 mg/1000 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability. • for patients who are changing from combination therapy of pioglitazone plus metformin as separate tablets: ACTOPLUS MET XR should be taken at doses that are as close as possible to the dose of pioglitazone and metformin already being taken.
ACTOPLUS MET XR may be titrated up to a maximum daily dose of 45 mg/2000 mg of pioglitazone/extended-release metformin.

Metformin doses above 2000 mg may be better tolerated given three times a day.

Patients should be informed that ACTOPLUS MET XR must be swallowed whole and not chewed, cut, or crushed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

After initiation of ACTOPLUS MET XR or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)]. Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating ACTOPLUS MET XR. Routine periodic monitoring of liver tests during treatment with ACTOPLUS MET XR is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of ACTOPLUS MET XR or who are found to have abnormal liver tests while taking ACTOPLUS MET XR should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

2.2 Concomitant Use with an Insulin Secretagogue or Insulin

If hypoglycemia occurs in a patient coadministered ACTOPLUS MET XR and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient coadministered ACTOPLUS MET XR and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

2.3 Concomitant Use with Strong CYP2C8 Inhibitors

Coadministration of pioglitazone (one of the ingredients in ACTOPLUS MET XR) and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure by approximately 3-fold. Therefore, the maximum recommended dose of ACTOPLUS MET XR is 15 mg/1000 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Uloric

Uloric

2.1 Recommended Dose

For treatment of hyperuricemia in patients with gout, ULORIC is recommended at 40 mg or 80 mg once daily.

The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended.

ULORIC can be taken without regard to food or antacid use [see Clinical Pharmacology (12.3)].

2.2 Special Populations

No dose adjustment is necessary when administering ULORIC in patients with mild to moderate renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended.

No dose adjustment is necessary in patients with mild to moderate hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.3 Uric Acid Level

Testing for the target serum uric acid level of less than 6 mg/dL may be performed as early as two weeks after initiating ULORIC therapy.

2.4 Gout Flares

Gout flares may occur after initiation of ULORIC due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of ULORIC. Prophylactic therapy may be beneficial for up to six months [see Clinical Studies (14.1)].

If a gout flare occurs during ULORIC treatment, ULORIC need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient [see Warnings and Precautions (5.1)].
Sodium Fluoride F 18

Sodium Fluoride F 18

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

The recommended adult oral dose is 30 mg PREVACID, 1 g amoxicillin, and 500 mg clarithromycin administered together twice daily (morning and evening) for 10 or 14 days (see INDICATIONS AND USAGE).

PREVPAC is not recommended in patients with creatinine clearance less than 30 mL/min.
Entyvio

Entyvio

2.1 Important Administration Instructions

Administer ENTYVIO as an intravenous infusion over 30 minutes. Do not administer as an intravenous push or bolus. ENTYVIO lyophilized powder must be reconstituted with Sterile Water for injection and diluted in 250 mL of sterile 0.9% Sodium Chloride injection prior to administration [see Dosage and Administration (2.4)]. After the infusion is complete, flush with 30 mL of sterile 0.9% Sodium Chloride injection.

ENTYVIO should be administered by a healthcare professional prepared to manage hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and medical support measures should be available for immediate use. Observe patients during infusion and until the infusion is complete.

2.2 Prior to Administration of ENTYVIO

Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines.

2.3 Dosage in Adults with Ulcerative Colitis or Crohn’s Disease

The recommended dosage of ENTYVIO in adults with ulcerative colitis or Crohn's disease is 300 mg administered by intravenous infusion at zero, two and six weeks and then every eight weeks thereafter.

Discontinue therapy in patients who show no evidence of therapeutic benefit by Week 14.

2.4 Reconstitution and Dilution Instructions

Reconstitution Instructions

Reconstitute ENTYVIO at room temperature. ENTYVIO should be reconstituted and prepared by a trained medical professional using aseptic technique by the following procedure:
1. Remove the flip-off cap from the single-dose vial and wipe with alcohol swab. Reconstitute ENTYVIO vial containing lyophilized powder with 4.8 mL of Sterile Water for injection, using a syringe with a 21 to 25 gauge needle. 2. Insert the syringe needle into the vial through the center of the stopper and direct the stream of Sterile Water for injection to the glass wall of the vial to avoid excessive foaming. 3. Gently swirl the vial for at least 15 seconds to dissolve the lyophilized powder. Do not vigorously shake or invert. 4. Allow the solution to sit for up to 20 minutes at room temperature to allow for reconstitution and for any foam to settle; the vial can be swirled and inspected for dissolution during this time. If not fully dissolved after 20 minutes, allow another 10 minutes for dissolution. Do not use the vial if the drug product is not dissolved within 30 minutes. 5. Visually inspect the reconstituted ENTYVIO solution for particulate matter and discoloration prior to administration. Solution should be clear or opalescent, colorless to light brownish yellow and free of visible particulates. Do not administer reconstituted solution showing uncharacteristic color or containing particulates. 6. Prior to withdrawing the reconstituted ENTYVIO solution from the vial, gently invert vial three times. 7. Withdraw 5 mL (300 mg) of reconstituted ENTYVIO solution using a syringe with a 21 to 25 gauge needle. Discard any remaining portion of the reconstituted solution in the vial.
Dilution Instructions

Add the 5 mL (300 mg) of reconstituted ENTYVIO solution to 250 mL of sterile 0.9% Sodium Chloride and gently mix the infusion bag. Do not add other medicinal products to the prepared infusion solution or intravenous infusion set. Once reconstituted and diluted, use the infusion solution as soon as possible.

Storage

If necessary, the infusion solution may be stored for up to four hours at 2° to 8°C (36º to 46ºF). Do not freeze. Discard any unused portion of the infusion solution.
Lovastatin

Lovastatin

PREVACID is available as a capsule and an orally disintegrating tablet, and is available in 15 mg and 30 mg strengths. Directions for use specific to the route and available methods of administration for each of these dosage forms is presented below. PREVACID should be taken before eating. PREVACID products SHOULD NOT BE CRUSHED OR CHEWED. In the clinical trials, antacids were used concomitantly with PREVACID.

2.1 Recommended Dose
Indication Recommended Dose Frequency * Please refer to amoxicillin and clarithromycin full prescribing information for CONTRAINDICATIONS and WARNINGS, and for information regarding dosing in elderly and renally-impaired patients. † Controlled studies did not extend beyond indicated duration. ‡ For patients who do not heal with PREVACID for 8 weeks (5 to 10%), it may be helpful to give an additional 8 weeks of treatment. If there is a recurrence of erosive esophagitis, an additional 8 week course of PREVACID may be considered. § The PREVACID dose was increased (up to 30 mg twice daily) in some pediatric patients after 2 or more weeks of treatment if they remained symptomatic. For pediatric patients unable to swallow an intact capsule please see Administration Options. ¶ Controlled studies did not extend beyond 12 months # Varies with individual patient. Recommended adult starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Dosages up to 90 mg twice daily have been administered. Daily dose of greater than 120 mg should be administered in divided doses. Some patients with Zollinger-Ellison Syndrome have been treated continuously with PREVACID for more than 4 years.
Duodenal Ulcers

  Short-Term Treatment

15 mg

Once daily for 4 weeks

  Maintenance of Healed

15 mg

Once daily

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence*

  Triple Therapy:

    PREVACID

30 mg

Twice daily (q12h) for 10 or 14 days

    Amoxicillin

1 gram

Twice daily (q12h) for 10 or 14 days

    Clarithromycin

500 mg

Twice daily (q12h) for 10 or 14 days

  Dual Therapy:

    PREVACID

30 mg

Three times daily (q8h) for 14 days

    Amoxicillin

1 gram

Three times daily (q8h) for 14 days

Benign Gastric Ulcer

  Short-Term Treatment

30 mg

Once daily for up to 8 weeks

NSAID-associated Gastric Ulcer

  Healing

30 mg

Once daily for 8 weeks†

  Risk Reduction

15 mg

Once daily for up to 12 weeks†

Gastroesophageal Reflux Disease (GERD)

  Short-Term Treatment of Symptomatic GERD

15 mg

Once daily for up to 8 weeks

  Short-Term Treatment of Erosive Esophagitis

30 mg

Once daily for up to 8 weeks‡

Pediatric

(1 to 11 years of age)Short-Term Treatment of Symptomatic GERD and Short-Term Treatment of Erosive Esophagitis

  ≤ 30 kg

15 mg

Once daily for up to 12 weeks§

  > 30 kg

30 mg

Once daily for up to 12 weeks§

(12 to 17 years of age)Short-Term Treatment of Symptomatic GERD

  Nonerosive GERD

15 mg

Once daily for up to 8 weeks

  Erosive Esophagitis

30 mg

Once daily for up to 8 weeks

Maintenance of Healing of Erosive Esophagitis

15 mg

Once daily¶

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

60 mg

Once daily#

Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose.

2.2 Special Populations

Renal impairment patients and geriatric patients do not require dosage adjustment. However, consider dose adjustment in patients with severe liver impairment [see Use in Specific Populations (8.5, 8.6 and 8.7)].

2.3 Important Administration Information

Administration Options

PREVACID Delayed-Release Capsules – Oral Administration
• PREVACID Delayed-Release Capsules should be swallowed whole. • Alternatively, for patients who have difficulty swallowing capsules, PREVACID Delayed-Release Capsules can be opened and administered as follows: • Open capsule. • Sprinkle intact granules on one tablespoon of either applesauce, ENSURE pudding, cottage cheese, yogurt or strained pears. • Swallow immediately. • PREVACID Delayed-Release Capsules may also be emptied into a small volume of either apple juice, orange juice or tomato juice and administered as follows: • Open capsule. • Sprinkle intact granules into a small volume of either apple juice, orange juice or tomato juice (60 mL – approximately 2 ounces). • Mix briefly. • Swallow immediately. • To ensure complete delivery of the dose, the glass should be rinsed with two or more volumes of juice and the contents swallowed immediately.
PREVACID Delayed-Release Capsules – Nasogastric Tube (≥16 French) Administration
• For patients who have a nasogastric tube in place, PREVACID Delayed-Release Capsules can be administered as follows: • Open capsule. • Mix intact granules into 40 mL of apple juice. DO NOT USE OTHER LIQUIDS. • Inject through the nasogastric tube into the stomach. • Flush with additional apple juice to clear the tube.
USE IN OTHER FOODS AND LIQUIDS HAS NOT BEEN STUDIED CLINICALLY AND IS THEREFORE NOT RECOMMENDED.

PREVACID SoluTab Delayed-Release Orally Disintegrating Tablets
• PREVACID SoluTab should not be broken or cut. • PREVACID SoluTab should not be chewed. • Place the tablet on the tongue and allow it to disintegrate, with or without water, until the particles can be swallowed. • The tablet typically disintegrates in less than 1 minute. • Alternatively, for children or other patients who have difficulty swallowing tablets, PREVACID SoluTab can be delivered in two different ways. PREVACID SoluTab – Oral Syringe For administration via oral syringe, PREVACID SoluTab can be administered as follows: ▪ Place a 15 mg tablet in oral syringe and draw up 4 mL of water, or place a 30 mg tablet in oral syringe and draw up 10 mL of water. ▪ Shake gently to allow for a quick dispersal. ▪ After the tablet has dispersed, administer the contents within 15 minutes. ▪ Refill the syringe with approximately 2 mL (5 mL for the 30 mg tablet) of water, shake gently, and administer any remaining contents. PREVACID SoluTab – Nasogastric Tube (≥8 French) Administration For administration via a nasogastric tube, PREVACID SoluTab can be administered as follows: ▪ Place a 15 mg tablet in a syringe and draw up 4 mL of water, or place a 30 mg tablet in a syringe and draw up 10 mL of water. ▪ Shake gently to allow for a quick dispersal. ▪ After the tablet has dispersed, inject through the nasogastric tube into the stomach within 15 minutes. ▪ Refill the syringe with approximately 5 mL of water, shake gently, and flush the nasogastric tube.
Haloperidol

Haloperidol

2.1 Recommendations for All Patients
• Healthcare providers should individualize the starting dose of KAZANO based on the patient's current regimen. • KAZANO should be taken twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin. KAZANO tablets must not be split before swallowing. • Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin HCl. • The following doses are available: 12.5 mg alogliptin and 500 mg metformin HCl 12.5 mg alogliptin and 1000 mg metformin HCl
Actoplus Met

Actoplus Met

2.1 Recommendations for All Patients

ACTOPLUS MET should be taken with meals to reduce the gastrointestinal side effects associated with metformin.

If therapy with a combination tablet containing pioglitazone and metformin is considered appropriate the recommended starting dose is:

15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,

for patients with New York Heart Association (NYHA) Class I or Class II congestive heart failure: 15 mg/500 mg or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,

for patients inadequately controlled on metformin monotherapy: 15 mg/500 mg twice daily or 15 mg/850 mg once or twice daily (depending on the dose of metformin already being taken) and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,

for patients inadequately controlled on pioglitazone monotherapy: 15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,

for patients who are changing from combination therapy of pioglitazone plus metformin as separate tablets: ACTOPLUS MET should be taken at doses that are as close as possible to the dose of pioglitazone and metformin already being taken.

ACTOPLUS MET may be titrated up to a maximum daily dose of 45 mg of pioglitazone and 2550 mg of metformin.

Metformin doses above 2000 mg may be better tolerated given three times a day.

After initiation of ACTOPLUS MET or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)]. Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating ACTOPLUS MET. Routine periodic monitoring of liver tests during treatment with ACTOPLUS MET is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of ACTOPLUS MET or who are found to have abnormal liver tests while taking ACTOPLUS MET should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

2.2 Concomitant Use with an Insulin Secretagogue or Insulin

If hypoglycemia occurs in a patient coadministered ACTOPLUS MET and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient coadministered ACTOPLUS MET and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

2.3 Concomitant Use with Strong CYP2C8 Inhibitors

Coadministration of pioglitazone (one of the ingredients in ACTOPLUS MET) and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of ACTOPLUS MET is 15 mg/850 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Duetact

Duetact

2.1 Recommendations for All Patients

DUETACT should be taken once daily with the first main meal.

DUETACT tablets are available as a 30 mg pioglitazone plus 2 mg glimepiride or a 30 mg pioglitazone plus 4 mg glimepiride tablet. If therapy with a combination tablet containing pioglitazone and glimepiride is considered appropriate the recommended starting dose is:
• 30 mg/2 mg or 30 mg/4 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, • for patients inadequately controlled on glimepiride monotherapy: 30 mg/2 mg or 30 mg/4 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, • for patients inadequately controlled on pioglitazone monotherapy: 30 mg/2 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, • for patients who are changing from combination therapy of pioglitazone plus glimepiride as separate tablets: DUETACT should be taken at doses that are as close as possible to the dose of pioglitazone and glimepiride already being taken, • for patients currently on a different sulfonylurea monotherapy or switching from combination therapy of pioglitazone plus a different sulfonylurea (e.g., glyburide, glipizide, chlorpropamide, tolbutamide, acetohexamide): 30 mg/2 mg once daily and adjusted after assessing adequacy of therapeutic response. Observe for hypoglycemia for one to two weeks due to the potential overlapping drug effect. • for patients with systolic dysfunction, the lowest approved dose of DUETACT should be prescribed only after titration from 15 mg to 30 mg of pioglitazone has been safely tolerated.
After initiation of DUETACT or with dose increase, monitor patients carefully for hypoglycemia and adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.7)].

Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating DUETACT. Routine periodic monitoring of liver tests during treatment with DUETACT is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of DUETACT or who are found to have abnormal liver tests while taking DUETACT should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

2.2 Concomitant Use with an Insulin Secretagogue or Insulin

If hypoglycemia occurs in a patient coadministered DUETACT and an insulin secretagogue, the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient coadministered DUETACT and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

2.3 Concomitant Use with Strong CYP2C8 Inhibitors

Coadministration of pioglitazone and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors. If gemfibrozil or other CYP2C8 inhibitors need to co-administered, patients should switch to individual components of DUETACT because the minimum dose of pioglitazone in DUETACT exceeds 15 mg [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

2.4 Concomitant Use with Colesevelam

When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, DUETACT should be administered at least four hours prior to colesevelam [see Drug Interactions (7.6) and Clinical Pharmacology (12.3)].
Brintellix

Brintellix

2.1 General Instruction for Use

The recommended starting dose is 10 mg administered orally once daily without regard to meals. Dosage should then be increased to 20 mg/day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the United States. The efficacy and safety of doses above 20 mg/day have not been evaluated in controlled clinical trials. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses [see Clinical Studies (14)].

2.2 Maintenance/Continuation/Extended Treatment

It is generally agreed that acute episodes of major depression should be followed by several months or longer of sustained pharmacologic therapy. A maintenance study of BRINTELLIX demonstrated that BRINTELLIX decreased the risk of recurrence of depressive episodes compared to placebo.

2.3 Discontinuing Treatment

Although BRINTELLIX can be abruptly discontinued, in placebo-controlled trials patients experienced transient adverse reactions such as headache and muscle tension following abrupt discontinuation of BRINTELLIX 15 mg/day or 20 mg/day. To avoid these adverse reactions, it is recommended that the dose be decreased to 10 mg/day for one week before full discontinuation of BRINTELLIX 15 mg/day or 20 mg/day [see Adverse Reactions (6)].

2.4 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of therapy with BRINTELLIX to avoid the risk of Serotonin Syndrome [see Warnings and Precautions (5.2)]. Conversely, at least 21 days should be allowed after stopping BRINTELLIX before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4)].

2.5 Use of BRINTELLIX with Other MAOIs such as Linezolid or Methylene Blue

Do not start BRINTELLIX in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4)].

In some cases, a patient already receiving BRINTELLIX therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, BRINTELLIX should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 21 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with BRINTELLIX may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)].

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with BRINTELLIX is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)].

2.6 Use of BRINTELLIX in Known CYP2D6 Poor Metabolizers or in Patients Taking Strong CYP2D6 Inhibitors

The maximum recommended dose of BRINTELLIX is 10 mg/day in known CYP2D6 poor metabolizers. Reduce the dose of BRINTELLIX by one-half when patients are receiving a CYP2D6 strong inhibitor (e.g., bupropion, fluoxetine, paroxetine, or quinidine) concomitantly. The dose should be increased to the original level when the CYP2D6 inhibitor is discontinued [see Drug Interactions (7.3)].

2.7 Use of BRINTELLIX in Patients Taking Strong CYP Inducers

Consider increasing the dose of BRINTELLIX when a strong CYP inducer (e.g., rifampin, carbamazepine, or phenytoin) is coadministered for greater than 14 days. The maximum recommended dose should not exceed three times the original dose. The dose of BRINTELLIX should be reduced to the original level within 14 days, when the inducer is discontinued [see Drug Interactions (7.3)].
Contrave

Contrave

2.1 Recommended Dosing

CONTRAVE dosing should be escalated according to the following schedule:

Morning Dose

Evening Dose

Week 1

1 tablet

None

Week 2

1 tablet

1 tablet

Week 3

2 tablets

1 tablet

Week 4 – Onward

2 tablets

2 tablets

A total daily dosage of two CONTRAVE 8 mg/90 mg tablets twice daily (32 mg/360 mg) is reached at the start of Week 4.

CONTRAVE should be taken by mouth in the morning and in the evening. The tablets should not be cut, chewed, or crushed. Total daily doses greater than 32 mg/360 mg per day (two tablets twice daily) are not recommended. In clinical trials, CONTRAVE was administered with meals. However, CONTRAVE should not be taken with a high-fat meal because of a resulting significant increase in bupropion and naltrexone systemic exposure [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

Patients may develop elevated blood pressure or heart rate during CONTRAVE treatment; the risk may be greater during the initial three months of therapy [see Warnings and Precautions (5.6)]. Because patients with hypertension may be at increased risk for developing blood pressure elevations, such patients should be monitored for this potential effect when initiating treatment with CONTRAVE.

Response to therapy should be evaluated after 12 weeks at the maintenance dosage. If a patient has not lost at least 5% of baseline body weight, discontinue CONTRAVE, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.

BMI is calculated by dividing weight (in kg) by height (in meters) squared. A BMI chart for determining BMI based on height and weight is provided in Table 1.

Table 1. BMI Conversion Chart

Weight

(lb)

125

130

135

140

145

150

155

160

165

170

175

180

185

190

195

200

205

210

215

220

225

(kg)

56.8

59.1

61.4

63.6

65.9

68.2

70.5

72.7

75.0

77.3

79.5

81.8

84.1

86.4

88.6

90.9

93.2

95.5

97.7

100. 0

102. 3

Height

(in)

(cm)

58

147.3

26

27

28

29

30

31

32

34

35

36

37

38

39

40

41

42

43

44

45

46

47

59

149.9

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

43

44

45

46

60

152.4

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

61

154.9

24

25

26

27

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

62

157.5

23

24

25

26

27

27

28

29

30

31

32

33

34

35

36

37

38

38

39

40

41

63

160.0

22

23

24

25

26

27

28

28

29

30

31

32

33

34

35

36

36

37

38

39

40

64

162.6

22

22

23

24

25

26

27

28

28

29

30

31

32

33

34

34

35

36

37

38

39

65

165.1

21

22

23

23

24

25

26

27

28

28

29

30

31

32

33

33

34

35

36

37

38

66

167.6

20

21

22

23

23

24

25

26

27

27

28

29

30

31

32

32

33

34

35

36

36

67

170.2

20

20

21

22

23

24

24

25

26

27

27

28

29

30

31

31

32

33

34

35

35

68

172.7

19

20

21

21

22

23

24

24

25

26

27

27

28

29

30

30

31

32

33

34

34

69

175.3

18

19

20

21

21

22

23

24

24

25

26

27

27

28

29

30

30

31

32

33

33

70

177.8

18

19

19

20

21

22

22

23

24

24

25

26

27

27

28

29

29

30

31

32

32

71

180.3

17

18

19

20

20

21

22

22

23

24

24

25

26

27

27

28

29

29

30

31

31

72

182.9

17

18

18

19

20

20

21

22

22

23

24

24

25

26

27

27

28

29

29

30

31

73

185.4

17

17

18

19

19

20

20

21

22

22

23

24

24

25

26

26

27

28

28

29

30

74

188.0

16

17

17

18

19

19

20

21

21

22

23

23

24

24

25

26

26

27

28

28

29

75

190.5

16

16

17

18

18

19

19

20

21

21

22

23

23

24

24

25

26

26

27

28

28

76

193.0

15

16

16

17

18

18

19

20

20

21

21

22

23

23

24

24

25

26

26

27

27

2.2 Dose Adjustment in Patients with Renal Impairment

In patients with moderate or severe renal impairment, the maximum recommended daily dose for CONTRAVE is two tablets (one tablet each morning and evening). CONTRAVE is not recommended for use in patients with end-stage renal disease. There is a lack of adequate information to guide dosing in patients with mild renal impairment [see Use in Specific Population (8.6) and Clinical Pharmacology (12.3)].

2.3 Dose Adjustment in Patients with Hepatic Impairment

In patients with hepatic impairment, the maximum recommended daily dose of CONTRAVE is one tablet in the morning [see Use in Specific Population (8.7) and Clinical Pharmacology (12.3)].

2.4 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Antidepressant

At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with CONTRAVE. Conversely, at least 14 days should be allowed after stopping CONTRAVE before starting an MAOI antidepressant [see Contraindications (4) and Drug Interactions (7.1)].

2.5 Concomitant Use with CYP2B6 Inhibitors

During concomitant use with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel), the maximum recommended daily dose of CONTRAVE is two tablets (one tablet each morning and evening) [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)].

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