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:

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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,

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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,

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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,

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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,

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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)].

Recommendations for Use in Renal Impairment

Assess renal function prior to initiation of ACTOPLUS MET and periodically thereafter.

ACTOPLUS MET is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2.

Initiation of ACTOPLUS MET in patients with an eGFR between 30 – 45 mL/min/1.73 m2 is not recommended.

In patients taking ACTOPLUS MET whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.

Discontinue ACTOPLUS MET if the patient's eGFR later falls below 30 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.2)].

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)].

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue ACTOPLUS MET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart ACTOPLUS MET if renal function is stable [see Warnings and Precautions (5.2)].