ACTOPLUS MET XR Film-coated tablet Ref.[10501] Active ingredients: Metformin Metformin and Pioglitazone Pioglitazone

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 Recommendations for Use in Renal Impairment

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

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

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

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

Discontinue ACTOPLUS MET XR if the patient’s eGFR later falls below 30 mL/min/1.73 m² [see Contraindications (4) and Warnings and Precautions (5.12)].

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)].

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue ACTOPLUS MET XR 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 XR if renal function is stable [see Warnings and Precautions (5.2)].

Pioglitazone

During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.

Metformin hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.2)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated metformin from patients in whom metformin overdosage is suspected.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity.