Pioglitazole and metformin hydrochloride

Tablet · Oral

Prescription (Rx) Biguanide Peroxisome Proliferator Receptor alpha Agonist Peroxisome Proliferator Receptor gamma Agonist

Boxed 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). If congestive heart failure develops while taking pioglitazone and metformin hydrochloride, consider discontinuation of pioglitazone and metformin hydrochloride or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride [see Warnings and Precautions ( 5.1 )].
• Pioglitazone and…

Uses

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 metformin is appropriate. ( 1 , 14 ) Limitations of Use :
• Not for treatment of type 1 diabetes or diabetic ketoacidosis. ( 1 )

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. ( 2.2 )
• Recommended starting dosage in patients with NYHA Class I or Class II congestive heart failure is 15 mg of pioglitazone and 850 mg of metformin HCl orally once daily. ( 2.4 )
• Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). ( 2.2 ) o Contraindicated in patients with eGFR below 30 mL/min o Initiation is not recommended in patients with eGFR between 30 to 45 mL/min o Assess risk/benefit of continuing pioglitazone and metformin hydrochloride if eGFR falls below 45 mL/min o Discontinue if eGFR falls below 30 mL/min
• Monitor patients for adverse events related to fluid retention after initiation and dose increases. ( 2.4 )
• Pioglitazone and metformin hydrochloride may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.6) 2.1 Important Dosage and Administration Information
• Obtain liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) prior to initiating pioglitazone and metformin hydrochloride tablets [see Warnings and Precautions ( 5.5 )].
• Pioglitazone and metformin hydrochloride tablets contain 15 mg of pioglitazone and 850 mg of metformin hydrochloride (HCl) in each tablet.
• Take pioglitazone and metformin hydrochloride tablets with meals to reduce gastrointestinal adverse reactions with metformin [see Adverse Reactions ( 6.1 )].
• If a dose is missed, do not double the next dose 2.2 Recommended Dosage and Administration Recommended Starting Dosage Based on Current Regimen Individualize the starting dosage of pioglitazone and metformin hydrochloride tablets based on the patient's current regimen and the available strength of pioglitazone and metformin hydrochloride tablets (see Table 1). Table 1: Recommended Starting Dosage Based on the Patient’s Current Regimen Current Regimen Starting Dosage of pioglitazone and metformin Hydrochloride tablets (15 mg of pioglitazone and 850 mg of metformin HCl per tablet)* Not treated with either pioglitazone or metformin HCl One tablet orally once daily Metformin HCl One tablet orally once or twice daily. Select a dosage that is as close as possible to the current dosage of metformin HCl Pioglitazone One tablet orally once daily Pioglitazone and metformin HCl Select a dosage that is as close as possible to the current dosage of pioglitazone and metformin HCl while not exceeding three tablets orally per day. *For dosage recommendations for patients with renal impairment and/or congestive heart failure, see Dosage and Administration ( 2.3 , 2.4 ) Dosage Titration for Additional Glycemic Control Titrate the pioglitazone and metformin hydrochloride tablets dosage gradually, as needed, after assessing therapeutic response and tolerability. Pioglitazone and metformin hydrochloride tablets may be increased to a maximum recommended total daily dosage of three tablets per day (45 mg of pioglitazone and 2,550 mg of metformin HCl). Total daily dosages of 2,550 mg of metformin HCl may be taken in divided doses three times a day to reduce gastrointestinal adverse reactions [see Adverse Reactions ( 6.1 )]. 2.3 Recommendations for Use in Patients with Renal Impairment
• Assess renal function prior to initiation of pioglitazone and metformin hydrochloride tablets and periodically thereafter [see Use in Specific Populations ( 8.6 )].
• Pioglitazone and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min.
• Initiation of pioglitazone and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/min is not recommended.
• In patients taking pioglitazone and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy.
• Discontinue pioglitazone and metformin hydrochloride tablets if the patient’s eGFR later falls below 30 mL/min [see Contraindications (4), Warnings and Precautions ( 5.2 )]. 2.4 Recommendations for Congestive Heart Failure Starting Dosage in Patients with NYHA Class I or II Congestive Heart Failure For patients with preexisting NYHA Class I or II congestive heart failure, the recommended starting dosage of pioglitazone and metformin hydrochloride tablets are 15 mg of pioglitazone and 850 mg of metformin [see Boxed Warning and Warnings and Precautions ( 5.1 )]. Monitoring for Fluid Retention and Dosage Modifications for Congestive Heart Failure After initiation of pioglitazone and metformin hydrochloride tablets or with dosage increase, monitor patients carefully for adverse reactions related to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and symptoms of congestive heart failure). If congestive heart failure develops while taking pioglitazone and metformin hydrochloride tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride tablets [see Boxed Warning and Warnings and Precautions ( 5.1 )]. 2.5 Coadministration with Strong CYP2C8 Inhibitors The maximum recommended dosage of pioglitazone and metformin hydrochloride tablets are one tablet (15 mg of pioglitazone and 850 mg of metformin HCl) once daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )].

Dosage forms and strengths

• Pioglitazone and Metformin hydrochloride tablets, USP 15 mg/500 mg: White to off-white coloured, capsule shaped, film-coated tablets debossed with 'C27' on one side and plain on the other side.
• Pioglitazone and Metformin hydrochloride tablets USP 15 mg/850 mg: White to off-white coloured, capsule shaped, film-coated tablets debossed with 'C28' on one side and plain on the other side. Tablets: 15 mg pioglitazone/500 mg metformin HCl and 15 mg pioglitazone/850 mg metformin HCl ( 3 )

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)]. Pioglitazone and metformin hydrochloride tablets is 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 )].

Warnings and precautions

• Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms. ( 5.1 )
• Edema: Dose-related edema may occur. ( 5.3 )
• Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination with pioglitazone and metformin hydrochloride. ( 5.4 )
• Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt pioglitazone and metformin hydrochloride and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart pioglitazone and metformin hydrochloride if liver injury is confirmed and no alternate etiology can be found. ( 5.5 )
• Urinary Bladder Tumors: May increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. ( 5.6 )
• Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. ( 5.7 )
• Macular edema: Postmarketing reports. Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes. ( 5.8 )
• Vitamin B 12 deficiency: Metformin may lower vitamin B 12 levels. Monitor hematologic parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. ( 5.9 )) 5.1 Congestive Heart Failure Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Observe patients for signs and symptoms of congestive heart failure. If congestive heart failure develops while taking pioglitazone and metformin hydrochloride tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets,or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride tablets, [see Boxed Warning, Contraindications ( 4 ), Adverse Reactions ( 6.1 )]. 5.2 Lactic Acidosis Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate: pyruvate ratio, and metformin plasma levels generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of pioglitazone and metformin hydrochloride tablets. In pioglitazone and metformin hydrochloride-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue pioglitazone and metformin hydrochloride and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )].
• Before initiating pioglitazone and metformin hydrochloride tablets, obtain an eGFR.
• P ioglitazone and metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30mL/min /1.73 m2. Initiation of pioglitazone and metformin hydrochloride tablets is not recommended in patients with eGFR between 30 to 45 mL/min [see contraindications ( 4 )].
• Obtain an eGFR at least annually in all patients taking pioglitazone and metformin hydrochloride tablets. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
• In patients taking pioglitazone and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit and risk of continuing therapy. Drug Interactions The concomitant use of pioglitazone and metformin hydrochloride tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g. cationic drugs) [see Drug Interactions ( 7 )]. Therefore, consider more frequent monitoring of patients.

Side effects

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 ( 5.6 )]
• Fractures [see Warnings and Precautions ( 5.7 )]
• Macular Edema [see Warnings and Precautions ( 5.8 ]
• Vitamin B 12 Levels [see Warnings and Precautions ( 5.9 ] Most common adverse reactions (>5%) are upper respiratory tract infection, edema, diarrhea, headache and weight gain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pioglitazone Over 8500 patients with type 2 diabetes mellitus have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes mellitus and macrovascular disease treated with pioglitazone from the PROactive clinical trial. In these trials, over 6000 patients have been treated with pioglitazone for six months or longer, over 4500 patients have been treated with pioglitazone for one year or longer, and over 3000 patients have been treated with pioglitazone for at least two years. In six pooled 16- to 26-week placebo-controlled monotherapy and 16- to 24-week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3.0%). In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone and 0.6% of patients treated with placebo. Common Adverse Events: 16- to 26-Week Monotherapy Trials A summary of the incidence and type of common adverse events reported in three pooled 16- to 26-week placebo-controlled monotherapy trials of pioglitazone is provided in Table 1. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse events were related to the pioglitazone dose. Table 2. Three Pooled 16- to 26-Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence > 5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo % of Patients Placebo N=259 Pioglitazone N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Pharyngitis 0.8 5.1 Common Adverse Events: 16- to 24-Week Add-on Combination Therapy Trials A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone add-on to metformin is provided in Table 3. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone. Table 3. 16- to 24-Week Clinical Trials of Pioglitazone Add-on to Metformin 16-Week Placebo-Controlled Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone + Metformin than in Patients Treated with Placebo + Metformin % of Patients Placebo + Metformin N=160 Pioglitazone 30 mg + Metformin N=168 Edema 2.5 6.0 Headache 1.9 6.0 24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Metformin than in Patients Treated with Pioglitazone 30 mg + Metformin % of Patients Pioglitazone 30 mg + Metformin N=411 Pioglitazone 45 mg + Metformin N=416 Upper Respiratory Tract Infection 12.4 13.5 Edema 5.8 13.9 Headache 5.4 5.8 Weight Increased 2.9 6.7 Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.” Common Adverse Events: 24-Week pioglitazone and metformin hydrochloride Clinical Trial Table 4 summarizes the incidence and types of adverse reactions reported in a controlled, 24-week double-blind clinical trial of pioglitazone and metformin hydrochloride dosed twice daily in patients with inadequate glycemic control on diet and exercise (N=600). Table 4. Adverse Events (≥5% for pioglitazone and metformin hydrochloride) Reported by Patients with Inadequate Glycemic Control on Diet and Exercisein a 24-Week Double-Blind Clinical Trial of Pioglitazone and Metformin Hydrochloride Administered Twice Daily % of Patients P ioglitazone and Metformin Hydrochloride 15/850 mg Twice Daily N=201 Pioglitazone 15 mg Twice Daily N=190 Metformin 850 mg Twice Daily N=209 Diarrhea 9.0 2.6 15.3 Headache 5.5 2.6 4.8 In this 24-week trial, abdominal pain was reported in 2.0% of patients in the pioglitazone and metformin hydrochloride group, 1.6% in the pioglitazone monotherapy group and 3.3% in the metformin monotherapy group.

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. ( 7.4 )
• Alcohol: Warn patients against excessive alcohol intake. ( 7.5 )
• Use of insulin secretagogues or insulin use may increase the risk for hypoglycemia and may require dose reduction. ( 7.6 )
• Topiramate may decrease pioglitazone concentrations. ( 7.8 ) 7.1 Strong CYP2C8 Inhibitors An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t 1/2 ) of pioglitazone. Therefore, the maximum recommended dosage of pioglitazone and metformin hydrochloride tablets is 15 mg of pioglitazone and 850 mg of metformin HCl once daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors [ see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )]. 7.2 CYP2C8 Inducers An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with pioglitazone and metformin hydrochloride tablets, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dosage of pioglitazone and metformin hydrochloride tablets, (45 mg of pioglitazone and 2,550 mg of metformin HCl) [see Clinical Pharmacology ( 12.3 )]. 7.3 Carbonic Anhydrase Inhibitors Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with pioglitazone and metformin hydrochloride tablets may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients. 7.4 Drugs that Reduce Metformin Clearance Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology ( 12.3 )]. Consider the benefits and risks of concomitant use. 7.5 Alcohol Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving pioglitazone and metformin hydrochloride tablets. 7.6 Insulin Secretagogues or Insulin Coadministration of pioglitazone and metformin hydrochloride tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. 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 7.7 Drugs Affecting Glycemic Control Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving pioglitazone and metformin hydrochloride tablets, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving pioglitazone and metformin hydrochloride tablets, the patient should be observed closely for hypoglycemia 7.8 Topiramate A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate [see Clinical Pharmacology ( 12.3 )]. The clinical relevance of this decrease is unknown; however, when pioglitazone and metformin hydrochloride and topiramate are used concomitantly, monitor patients for adequate glycemic control.

Use in specific populations

• Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. ( 8.3 )
• Pediatrics: Safety and effectiveness have not been established. ( 8.4 )
• Geriatric Use: Assess renal function more frequently. ( 8.5 )
• Hepatic Impairment: Avoid use in patients with hepatic impairment.( 8.7 ) 8.1 Pregnancy Risk Summary Limited data with pioglitazone and metformin hydrochloride or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [ see Data ]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [ see Clinical Considerations ]. In animal reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5- and 35-times the 45 mg clinical dose, respectively, based on body surface area. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- to 6-times, respectively, a 2000 mg clinical dose, based on body surface area [ see Data ]. The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Pioglitazone and Metformin HCl Animal reproduction studies were not conducted with the combined products in pioglitazone and metformin hydrochloride tablets. The following data are based on studies conducted with the individual components of pioglitazone and metformin hydrochloride tablets. Pioglitazone Pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (~5-times the 45 mg clinical dose), but delayed parturition and reduced embryofetal viability at 40 and 80 mg/kg, or ≥9-times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35-times the 45 mg clinical dose), but reduced embryofetal viability at 160 mg/kg, or ~69-times the 45 mg clinical dose, by body surface area. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or ≥2-times the 45 mg clinical dose, by body surface area. Metformin HCl Metformin hydrochloride did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- to 6-times a 2000 mg clinical dose based on body surface area (mg/m 2 ) for rats and rabbits, respectively. 8.2 Lactation Risk Summary There is no information regarding the presence of pioglitazone and metformin hydrochloride or pioglitazone in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone is present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. Limited published studies report that metformin is present in human milk [ see Data ]. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for pioglitazone and metformin hydrochloride and any potential adverse effects on the breastfed infant from pioglitazone and metformin hydrochloride or from the underlying maternal condition. Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone and metformin hydrochloride tablets, may result in ovulation in some anovulatory women. 8.4 Pediatric Use Safety and effectiveness of pioglitazone and metformin hydrochloride tablets in pediatric patients have not been established.

Pregnancy

8.1 Pregnancy Risk Summary Limited data with pioglitazone and metformin hydrochloride or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [ see Data ]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [ see Clinical Considerations ]. In animal reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5- and 35-times the 45 mg clinical dose, respectively, based on body surface area. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- to 6-times, respectively, a 2000 mg clinical dose, based on body surface area [ see Data ]. The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Pioglitazone and Metformin HCl Animal reproduction studies were not conducted with the combined products in pioglitazone and metformin hydrochloride tablets. The following data are based on studies conducted with the individual components of pioglitazone and metformin hydrochloride tablets. Pioglitazone Pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (~5-times the 45 mg clinical dose), but delayed parturition and reduced embryofetal viability at 40 and 80 mg/kg, or ≥9-times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35-times the 45 mg clinical dose), but reduced embryofetal viability at 160 mg/kg, or ~69-times the 45 mg clinical dose, by body surface area. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or ≥2-times the 45 mg clinical dose, by body surface area. Metformin HCl Metformin hydrochloride did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- to 6-times a 2000 mg clinical dose based on body surface area (mg/m 2 ) for rats and rabbits, respectively.

Pediatric use

8.4 Pediatric Use Safety and effectiveness of pioglitazone and metformin hydrochloride tablets in pediatric patients have not been established. Pioglitazone and metformin hydrochloride tablets are not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see Warnings and Precautions ( 5.1 , 5.3 , 5.6 , 5.7 )].

Geriatric use

8.5 Geriatric Use Pioglitazone A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16- to 26-week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16- to 24- week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65 years old and 22 (2.1%) were ≥75 years old. In PROactive Trial, 1068 patients (41.0%) treated with pioglitazone were ≥65 years old and 42 (1.6%) were ≥75 years old. In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients [see Clinical Pharmacology ( 12.3 )]. Although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old. Metformin HCl Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [ see Warnings and Precautions( 5.2 )and Dosage and Administration ( 2.2 ) ].

Overdosage

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. Metformin HCl Overdose of metformin HCl 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. In the event of overdosage, contact the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.

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 synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown: Pioglitazone HCl USP is an odorless white crystalline powder that has a molecular formula of C 19 H 20 N 2 O 3 S
• HCl and a molecular weight of 392.90 daltons. It is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. Metformin HCl USP (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white crystalline powder with a molecular formula of C 4 H 11 N 5
• HCl and a molecular weight of 165.62. Metformin hydrochloride USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride USP is 6.68. The structural formula is as shown: Pioglitazone and metformin HCl tablets USP are available as a tablet for oral administration containing 15 mg pioglitazone (as the base) with 500 mg metformin HCl USP (15 mg/500 mg) or 15 mg pioglitazone (as the base) with 850 mg metformin HCl USP (15 mg/850 mg) formulated with the following excipients: Croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc and titanium dioxide. FDA approved dissolution test specifications complies with USP Test-1. metpio metpio

Mechanism of action

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. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes mellitus, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes mellitus. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Metformin HCl Metformin HCl improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or healthy subjects [except in specific circumstances, see Warnings and Precautions ( 5.4 )] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

How supplied

Pioglitazone and metformin hydrochloride tablets, USP 15 mg / 500 mg: White to off-white coloured, capsule shaped, film-coated tablets debossed with 'C27' on one side and plain on the other side. NDC: 72162-2497-2: 180 Tablets in a BOTTLE NDC: 72162-2497-6: 60 Tablets in a BOTTLE Storage: Store at 20º to 25º C (68º to 77º F); excursions permitted to 15º to 30º C (59º to 86º F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504

Patient information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).
• Congestive Heart Failure : Inform patients of the signs and symptoms of heart failure. Instruct patients who experience an unusually rapid increase in weight or edema, shortness of breath, or other symptoms of heart failure while on pioglitazone and metformin hydrochloride tablets to immediately report these symptoms to their healthcare provider. [see Warnings and Precautions ( 5.1 )].
• Lactic Acidosis : Explain to patients the risks of lactic acidosis, its symptoms and conditions that predispose to its development, as noted in the Warnings and Precautions ( 5.2 ) section. Advise patients to discontinue pioglitazone and metformin hydrochloride tablets immediately and to promptly notify their healthcare professional if unexplained hyperventilation, myalgia, gastrointestinal symptoms, malaise, unusual somnolence, or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about the importance of regular testing of renal function while receiving pioglitazone and metformin hydrochloride tablets. Inform patients about the importance of regular testing of renal function and hematologic parameters when receiving treatment with pioglitazone and metformin hydrochloride tablets Instruct patients to inform their doctor that they are taking pioglitazone and metformin hydrochloride tablets prior to any surgical or radiological procedure, as temporary discontinuation of pioglitazone and metformin hydrochloride tablets may be required until renal function has been confirmed to be normal.
• Edema : Inform patients that pioglitazone and metformin hydrochloride tablets use can lead to new-onset or worsening of edema. Instruct patients to immediately report symptoms of rapid weight increase or worsening edema to their healthcare provider [see Warnings and Precautions ( 5.3 )].
• Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues : Inform patients that the risk of hypoglycemia is increased when pioglitazone and metformin hydrochloride tablets are used with insulin or insulin secretagogues (such as a sulfonylurea). Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions ( 5.4 )].
• Hepatic Effects : Instruct patients to promptly stop taking pioglitazone and metformin hydrochloride tablets and seek immediate medical advice if they experience signs or symptoms of liver injury (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine) [see Warnings and Precautions ( 5.5 )].
• Urinary Bladder Tumors : Advise patients to promptly report any hematuria, dysuria or urinary urgency that develops or increases during treatment as these may be due to bladder cancer [see Warnings and Precautions ( 5.6) ] .
• Fractures : Inform female patients about the risk of fractures while taking pioglitazone and metformin hydrochloride tablets. Provide them with information on factors that may contribute to fracture risk [see Warnings and Precautions ( 5.7 )].
• Macular Edema : Educate patients on the signs and symptoms of macular edema and advise them to seek medical attention from an ophthalmologist if they experience symptoms of macular edema [see Warnings and Precautions ( 5.8 )] .
• Vitamin B 12 Levels : Inform patients about the importance of obtaining regular hematological laboratory monitoring while receiving pioglitazone and metformin hydrochloride tablets [see Warnings and Precautions ( 5.9 )].
• Females of Reproductive Age : Inform female patients that treatment with pioglitazone and metformin hydrochloride tablets may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations ( 8.3 )]
• Missed Dosage : Instruct patients if a dose is missed, not to double their next dose. Manufactured for: Macleods Pharma USA, INC, Princeton, NJ 08540 Manufactured by: Macleods Pharmaceutical Ltd. Baddi, Himachal Pradesh-174101 INDIA Trademarks are the property of their respective owners. Revised: May 2025

Label text from the FDA structured product label by Bryant Ranch Prepack (revised May 15, 2025). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Pioglitazole and metformin hydrochloride NDC products (2)

NDCStrength & formLabelerType
72162-2497Pioglitazone Hydrochloride 15 mg/1; Metformin Hydrochloride 500 mg/1
Tablet		Bryant Ranch PrepackANDA
72162-2498Pioglitazone Hydrochloride 15 mg/1; Metformin Hydrochloride 850 mg/1
Tablet		Bryant Ranch PrepackANDA

Frequently asked questions

What is Pioglitazole and metformin hydrochloride used for?

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…

What are the side effects of Pioglitazole and metformin hydrochloride?

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… See the full label for the complete list.

Who makes Pioglitazole and metformin hydrochloride?

Pioglitazole and metformin hydrochloride is listed by 1 labeler in the FDA NDC directory, including Bryant Ranch Prepack.