Overview
11 DESCRIPTION Pioglitazone and metformin HCl tablets USP are a thiazolidinediones and biguanide combination product that contains two oral antidiabetic medications: pioglitazone hydrochloride USP and metformin hydrochloride USP. Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon, and the compound is...
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pioglitazone and metformin hydrochloride tablets combines two antihyperglycemic agents: pioglitazone and metformin. Pioglitazone Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver.
Indications
- 1 INDICATIONS & 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 Limitations of Use Pioglitazone and metformin hydrochloride tablets is not recommended to treat type 1 diabetes mellitus or diabetic ketoacidosis. Pioglitazone and metformin hydrochloride tablets are a thiazolidinedione and biguanide combination product 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...
Common Doses
- 45 mg
- 550 mg
- 15 mg
- 850 mg
Dosage
2 DOSAGE AND ADMINISTRATION • Obtain liver tests before initiation. If abnormal, use caution when treating with pioglitazone and metformin hydrochloride, investigate the probable cause, treat (if possible), and follow appropriately. ( 2.1 ) • Take orally with meals to reduce gastrointestinal adverse reactions with metformin ( 2.1 ) • Individualize the starting dose based on the patient’s current regimen and titrate the dosage gradually, as needed after assessing therapeutic response and tolerability. The maximum recommended total daily dosage is pioglitazone 45 mg and metformin 2,550 mg. ( 2.
Black Box Warning
WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS FULL PRESCRIBING INFORMATION WARNING: CONGESTIVE HEART FAILURE and LACTIC ACIDOSIS Congestive Heart Failure • Thiazolidinediones, including pioglitazone, which is a component of pioglitazone and metformin hydrochloride, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions ( 5.1 )]. • After initiation of pioglitazone and metformin hydrochloride, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema).
Contraindications
- 4 CONTRAINDICATIONS Pioglitazone and metformin hydrochloride tablets are contraindicated in patients with: • Established NYHA Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride tablets initiation [see Boxed Warning]. • Severe renal impairment (eGFR below 30 mL/min) [see Warnings and Precautions (5.2)]. • A history of serious hypersensitivity to pioglitazone, metformin HCl, or any of the excipients in pioglitazone and metformin hydrochloride tablets. • Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.2)].
Side Effects
- 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Congestive heart failure [see Boxed Warning, and Warnings and Precautions ( 5.1 )] • Lactic acidosis [see Boxed Warning and Warnings, and Precautions ( 5.2 )] • Edema [see Warnings and Precautions ( 5.3 )] • Fractures [see Warnings and Precautions ( 5.7 )] • Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions ( 5.4 )] • Hepatic Effects [see Warnings and Precautions ( 5.5 )] • Urinary Bladder Tumors [see Warnings and Precautions ( 5.
Interactions
- 7 DRUG INTERACTIONS • Strong CYP2C8 inhibitors (e.g., gemfibrozil): Limit pioglitazone and metformin hydrochloride dose to 15 mg/850 mg daily. ( 7.1 ) • CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. ( 7.2 ) • Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. ( 7.3 ) • Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine), may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. ( 7.