Pioglitazone and Metformin Hydrocholride

PIOGLITAZONE AND METFORMIN HYDROCHOLRIDE- pioglitazone hydrochloride and metformin hydrochloride tablet, film coated
Teva Pharmaceuticals USA

WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS

Congestive Heart Failure

Thiazolidinediones, including pioglitazone, which is a component of pioglitazone and metformin hydrochloride tablets, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)].
After initiation of pioglitazone and metformin hydrochloride tablets, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone and metformin hydrochloride tablets must be considered [see Warnings and Precautions (5.1)].
Pioglitazone and metformin hydrochloride tablets are not recommended in patients with symptomatic heart failure.
Initiation of pioglitazone and metformin hydrochloride tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].

Lactic Acidosis

Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure [see Warnings and Precautions (5.2)].
The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate[see Warnings and Precautions (5.2)].
If acidosis is suspected, pioglitazone and metformin hydrochloride tablets should be discontinued and the patient hospitalized immediately [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

Pioglitazone and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate [see Clinical Studies (14)].

1.2 Important Limitations of Use

Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. Pioglitazone and metformin hydrochloride tablets should not be used to treat type 1 diabetes or diabetic ketoacidosis, as they would not be effective in these settings.

Use caution in patients with liver disease [see Warnings and Precautions (5.4)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommendations for All Patients

Pioglitazone and metformin hydrochloride tablets 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: pioglitazone and metformin hydrochloride tablets should be taken at doses that are as close as possible to the dose of pioglitazone and metformin already being taken.

Pioglitazone and metformin hydrochloride tablets 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 pioglitazone and metformin hydrochloride tablets 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 pioglitazone and metformin hydrochloride tablets. Routine periodic monitoring of liver tests during treatment with pioglitazone and metformin hydrochloride tablets are not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of pioglitazone and metformin hydrochloride tablets or who are found to have abnormal liver tests while taking pioglitazone and metformin hydrochloride tablets should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ] .

2.2 Concomitant Use with an Insulin Secretagogue or Insulin

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

If hypoglycemia occurs in a patient coadministered pioglitazone and metformin hydrochloride tablets 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 Coadministration with Strong CYP2C8 Inhibitors

Coadministration of pioglitazone (one of the ingredients in pioglitazone and metformin hydrochloride tablets) and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone and metformin hydrochloride tablets 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) ] .

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