Pioglitazone Hcl And Metformin Hcl

FDA Drug Information • Also known as: Pioglitazone Hcl And Metformin Hcl

Brand Names: Pioglitazone Hcl And Metformin Hcl
Route: ORAL
Dosage Form: TABLET
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: CONGESTIVE HEART FAILURE and LACTIC ACIDOSIS See full prescribing information for complete boxed warning. 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. (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 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. (5.1)

Pioglitazone and metformin hydrochloride tablets are not recommended in patients with symptomatic heart failure. (5.1)

Initiation of pioglitazone and metformin hydrochloride tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated. (4, 5.1) Lactic Acidosis

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate:pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL. (5.2)

Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information. (5.2)

If lactic acidosis is suspected, discontinue pioglitazone and metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.2) 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)] .

Pioglitazone and metformin hydrochloride tablets are not recommended in patients with symptomatic heart failure [see Warnings and Precautions (5.1)] .

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (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 [see Warnings and Precautions (5.2)] .

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.2), Drug Interactions (7), Use in Specific Populations (8.6, 8.7)] .

If metformin-associated lactic acidosis is suspected, immediately discontinue pioglitazone and metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.2)] .

Description

11 DESCRIPTION Pioglitazone and metformin hydrochloride tablets, USP are a thiazolidinediones and biguanide combination product that contains two oral antidiabetic medications: pioglitazone HCl and metformin HCl. 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 hydrochloride ( N,N -dimethylimidodicarbonimidic diamide HCl), USP 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 HCl 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 HCl is 6.68. The structural formula is as shown: Pioglitazone and metformin hydrochloride tablets, USP are available as a tablet for oral administration containing 15 mg pioglitazone (as the base) with 500 mg metformin hydrochloride (15 mg/500 mg) or 15 mg pioglitazone (as the base) with 850 mg metformin hydrochloride (15 mg/850 mg) formulated with the following excipients: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide. 1 2

What Is Pioglitazone Hcl And Metformin Hcl Used For?

1 INDICATIONS AND USAGE Pioglitazone and metformin hydrochloride tablets, are a combination of pioglitazone, a thiazolidinedione agonist of peroxisome proliferator receptor gamma, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: Not recommended for treatment of type 1 diabetes or diabetic ketoacidosis. ( 1 ) 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 are not recommended to treat type 1 diabetes mellitus or diabetic ketoacidosis.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION

Obtain liver tests before initiation. If abnormal, use caution when treating with pioglitazone and metformin hydrochloride tablets, 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 tablets 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 tablets 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 contains 15 mg of pioglitazone and 500 mg of metformin hydrochloride (HCl) and 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...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS Most common adverse reactions (>5%) are upper respiratory tract infection, edema, diarrhea, headache and weight gain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are discussed elsewhere in the labeling:

Congestive heart failure [see Boxed Warning, Warnings and Precautions (5.1)]

Lactic acidosis [see Boxed Warning, Warnings and Precautions (5.2)]

Edema [see Warnings and Precautions (5.3)]

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] 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 8,500 patients with type 2 diabetes mellitus have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2,605 patients with type 2 diabetes mellitus and macrovascular disease treated with pioglitazone from the PROactive clinical trial. In these trials, over 6,000 patients have been treated with pioglitazone for six months or longer, over 4,500 patients have been treated with pioglitazone for one year or longer, and over 3,000 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 2. 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...

Drug Interactions

7 DRUG INTERACTIONS

Strong CYP2C8 inhibitors (e.g., gemfibrozil): Limit pioglitazone and metformin hydrochloride tablets 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 (t1/2) 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 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...

Contraindications

4 CONTRAINDICATIONS

In patients with established New York Heart Association (NYHA) Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride tablets initiation [see Boxed Warning]. ( 4 )

In patients with severe renal impairment: (eGFR below 30 mL/min). ( 4 )

In patients with a history of serious hypersensitivity to pioglitazone, metformin HCl, or any of the excipients in pioglitazone and metformin hydrochloride tablets. ( 4 )

In patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis. ( 4 ) 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)] .

Pregnancy and Breastfeeding

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 2,000 mg clinical dose, based on body surface area (see Data) . The estimated background risk of major birth defects is 6 to 10% in women with pregestational diabetes with a HbA1c >7 and has been reported to be as high as 20 to 25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 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 postmarketing studies have not reported a clear association with metformin...

Overdosage

10 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 HCl 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Pioglitazone and metformin hydrochloride tablets, USP are available in 15 mg pioglitazone (as the base)/500 mg metformin HCl and 15 mg pioglitazone (as the base)/850 mg metformin HCl tablets as follows: 15 mg/500 mg tablet: white to off-white colored, capsule shaped, biconvex, film coated tablets debossed with "15/500" on one side and "1280" on other side, available in: Bottles of 60 NDC 13668-280-60 Bottles of 180 NDC 13668-280-33 Bottles of 500 NDC 13668-280-05 Bottles of 1000 NDC 13668-280-10 15 mg/850 mg tablet: white to off-white colored, capsule shaped, biconvex, film coated tablets debossed with "15/850" on one side and "1281" on other side, available in: Bottles of 60 NDC 13668-281-60 Bottles of 180 NDC 13668-281-33 Bottles of 500 NDC 13668-281-05 Bottles of 750 NDC 13668-281-49 Storage Store at 20° to 25° C (68° to 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.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.