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These highlights do not include all the information needed to use PIOGLITAZONE AND METFORMIN HYDROCHLORIDE
TABLETS safely and effectively. See full prescribing information for PIOGLITAZONE AND METFORMIN HYDROCHLORIDE TABLETS. PIOGLITAZONE AND METFORMIN HYDROCHLORIDE Tablets , for oral use Initial U.S. Approval: 2005 · Torrent Pharmaceuticals Limited
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 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 embryo-fetal 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 embryo-fetal 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 HCl 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 2,000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively.
Safety and effectiveness of pioglitazone and metformin hydrochloride in pediatric patients have not been established.
Pioglitazone and metformin hydrochloride is 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)].
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, 1,068 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), Dosage and Administration (2.2)].
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.
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.
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 is 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 B12 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.
Trademarks are the property of their respective owners.
Dispense with Medication Guide available at: https://torrentpharma.com/pi/usa/products/
Dispense with Medication Guide available at: https://torrentpharma.com/pi/usa/products/
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MEDICATION GUIDE PIOGLITAZONE AND METFORMIN HYDROCHLORIDE (PYE o GLI ta zone and met FOR min HYE-droe-KLOR-ide) TABLETS, USP |
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Read this Medication Guide carefully before you start taking pioglitazone and metformin hydrochloride tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about pioglitazone and metformin hydrochloride tablets, ask your healthcare provider or pharmacist. |
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What is the most important information I should know about pioglitazone and metformin hydrochloride tablets ? Pioglitazone and metformin hydrochloride tablets can cause serious side effects, including:
Before you start taking pioglitazone and metformin hydrochloride tablets: Tell your healthcare provider if you have ever had heart failure or have problems with your kidneys Call your healthcare provider right away if you have any of the following:
These may be symptoms of heart failure.
Stop taking pioglitazone and metformin hydrochloride tablets and call your healthcare provider right away if you have any of the following symptoms, which could be signs of lactic acidosis:
Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your healthcare provider if you have any of the following, because you have a higher chance for getting lactic acidosis with pioglitazone and metformin hydrochloride tablets if you:
The best way to keep from having a problem with lactic acidosis from metformin is to tell your healthcare provider if you have any of the problems in the list above. Your healthcare provider may decide to stop your pioglitazone and metformin hydrochloride tablets for a while if you have any of these things. Pioglitazone and metformin hydrochloride tablets can have other serious side effects. See “What are the possible side effects of pioglitazone and metformin hydrochloride tablets?” |
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What are pioglitazone and metformin hydrochloride tablets? Pioglitazone and metformin hydrochloride tablets are prescription medicine that contains 2 diabetes medicines, pioglitazone (ACTOS) and metformin hydrochloride (GLUCOPHAGE). Pioglitazone and metformin hydrochloride tablets are used along with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes. Pioglitazone and metformin hydrochloride tablets are not for people with type 1 diabetes. Pioglitazone and metformin hydrochloride tablets are not for people with diabetic ketoacidosis (increased ketones in your blood or urine). It is not known if pioglitazone and metformin hydrochloride tablets are safe and effective in children under the age of 18. Pioglitazone and metformin hydrochloride tablets are not recommended for use in children. |
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Who should not take pioglitazone and metformin hydrochloride tablets? See “What is the most important information I should know about pioglitazone and metformin hydrochloride tablets?”. Do not take pioglitazone and metformin hydrochloride tablets if you:
o swelling of your face, lips, throat and other areas on o difficulty with swallowing or your skin breathing o raised, red areas on your skin (hives) o skin rash, itching, flaking or peeling
Tell your healthcare provider before taking pioglitazone and metformin hydrochloride tablets if you have any of these conditions. |
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What should I tell my healthcare provider before taking pioglitazone and metformin hydrochloride tablets? Before you take pioglitazone and metformin hydrochloride tablets, tell your healthcare provider if you:
are going to have dye injected into a vein for an x-ray, CAT scan, heart study, or other type of scanning
Tell your healthcare provider about all the medicines you take, including prescription and over the counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist before you start a new medicine. They will tell you if it is okay to take pioglitazone and metformin hydrochloride tablets with other medicines. Pioglitazone and metformin hydrochloride tablets may affect the way other medicines work, and other medicines may affect how pioglitazone and metformin hydrochloride tablets work. Contact your healthcare provider before you start or stop other types of medicines. |
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How should I take pioglitazone and metformin hydrochloride tablets?
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What are the possible side effects of pioglitazone and metformin hydrochloride tablets? Pioglitazone and metformin hydrochloride tablets may cause serious side effects, including:
o shaking or feeling jittery o change in vision o change in mood o sweating o hunger o confusion o fast heartbeat o headache o dizziness
o nausea or vomiting o stomach pain o unusual or unexplained tiredness o loss of appetite o dark urine o yellowing of your skin or the whites of your eyes
o blood or a red color in your urine o an increased need to urinate o pain while you urinate
Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the side effects of pioglitazone and metformin hydrochloride tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
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How should I store pioglitazone and metformin hydrochloride tablets?
Keep pioglitazone and metformin hydrochloride tablets and all medicines out of the reach of children. |
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General information about the safe and effective use of pioglitazone and metformin hydrochloride tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use pioglitazone and metformin hydrochloride tablets for a condition for which it was not prescribed. Do not give pioglitazone and metformin hydrochloride tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about pioglitazone and metformin hydrochloride tablets that is written for health professionals. |
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What are the ingredients in pioglitazone and metformin hydrochloride tablets? Active Ingredients: pioglitazone hydrochloride, USP and metformin hydrochloride, USP Inactive Ingredients: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide Trademarks are the property of their respective owners. For more information, call 1-800-912-9561. |
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[image: MM4] Manufactured by: Torrent Pharmaceuticals LTD., India. Manufactured for: Torrent Pharma INC., Basking Ridge, NJ07920 8099814 Revised: March 2025 |
This Medication Guide has been approved by the U.S. Food and Drug Administration.
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:
[image: MM1]Pioglitazone HCl, USP is an odorless white crystalline powder that has a molecular formula of C 19H 20N 2O 3S•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 4H 11N 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:
[image: MM2]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.
Pioglitazone and Metformin Hydrochloride Tablets - 15 mg / 500 mg
[image: MM5]
Pioglitazone and Metformin Hydrochloride Tablets - 15 mg / 850 mg
[image: MM6]
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.
What it looks like
Photos of the product and/or packaging supplied by the manufacturer.
Package codes (NDC)
- 13668-280-05
- 13668-280-10
- 13668-280-33
- 13668-280-60
- 13668-280-74
- 13668-281-05
- 13668-281-33
- 13668-281-49
- 13668-281-60
- 13668-281-74
Full prescribing information (for healthcare professionals)
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 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 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)].
• 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), Warnings and Precautions (5.1)].
Lactic Acidosis
• 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)].
SPL UNCLASSIFIED SECTION
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.
2.5 Coadministration with Strong CYP2C8 Inhibitors
The maximum recommended dosage of pioglitazone and metformin hydrochloride tablet is 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)] .
2.6 Discontinuation for Iodinated Contrast Imaging Procedures
Discontinue pioglitazone and metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min; 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 pioglitazone and metformin hydrochloride tablets if renal function is stable [see Warnings and Precautions (5.2)].
SPL UNCLASSIFIED SECTION
• 15 mg of pioglitazone and 500 mg of metformin HCl tablets, USP: white to off-white colored, capsule shaped, biconvex, film coated tablets debossed with “15/500” on one side and “1280” on other side.
• 15 mg of pioglitazone and 850 mg of metformin HCl tablets, USP: white to off-white colored, capsule shaped, biconvex, film coated tablets debossed with “15/850” on one side and “1281” on other side.
SPL UNCLASSIFIED SECTION
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)].
SPL UNCLASSIFIED SECTION
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 B12 Levels [see Warnings and Precautions (5.9]
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Pioglitazone and metformin hydrochloride tablets combine 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, 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.
12.2 Pharmacodynamics
Pioglitazone
Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2 diabetes mellitus, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin [see Clinical Studies (14)].
Patients with lipid abnormalities were included in clinical trials with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in serum triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with pioglitazone [see Adverse Reactions (6.1)].
In a 26 week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the 15 mg, 30 mg, and 45 mg pioglitazone dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone compared to placebo (see Table 17).
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* Adjusted for baseline, pooled center, and pooled center by treatment interaction |
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† p < 0.05 vs placebo |
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| Table 17: Lipids in a 26 Week Placebo - Controlled Monotherapy Dose - Ranging Study | ||||
| Placebo | Pioglitazone 15 mg Once Daily | Pioglitazone 30 mg Once Daily | Pioglitazone 45 mg Once Daily | |
| Triglycerides ( mg / dL ) | N=79 | N=79 | N=84 | N=77 |
| Baseline (mean) | 263 | 284 | 261 | 260 |
| Percent change from baseline (adjusted mean*) | 4.8% | -9.0% † | -9.6% † | -9.3% † |
| HDL Cholesterol ( mg / dL ) | N=79 | N=79 | N=83 | N=77 |
| Baseline (mean) | 42 | 40 | 41 | 41 |
| Percent change from baseline (adjusted mean*) | 8.1% | 14.1% † | 12.2% | 19.1% † |
| LDL Cholesterol ( mg / dL ) | N=65 | N=63 | N=74 | N=62 |
| Baseline (mean) | 139 | 132 | 136 | 127 |
| Percent change from baseline (adjusted mean*) | 4.8% | 7.2% | 5.2% | 6.0% |
| Total Cholesterol ( mg / dL ) | N=79 | N=79 | N=84 | N=77 |
| Baseline (mean) | 225 | 220 | 223 | 214 |
| Percent change from baseline (adjusted mean*) | 4.4% | 4.6% | 3.3% | 6.4% |
In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy studies with metformin (16 weeks and 24 weeks), the results were generally consistent with the data above.
12.3 Pharmacokinetics
Absorption
Pioglitazone and metformin hydrochloride tablets
In bioequivalence studies of pioglitazone and metformin hydrochloride tablets 15 mg/500 mg and
15 mg/850 mg, the area under the curve (AUC) and maximum concentration (Cmax) of both the pioglitazone and the metformin component following a single dose of the combination tablet were bioequivalent to ACTOS 15 mg concomitantly administered with metformin HCl immediate release (500 mg or 850 mg, respectively) tablets under fasted conditions in healthy subjects.
Administration of pioglitazone and metformin hydrochloride tablets 15 mg/850 mg with food resulted in no change in overall exposure of pioglitazone. With metformin there was no change in AUC; however, mean peak serum concentration of metformin was decreased by 28% when administered with food. A delayed time to peak serum concentration was observed for both components (1.9 hours for pioglitazone and 0.8 hours for metformin) under fed conditions. These changes are not likely to be clinically significant.
Pioglitazone
Following once-daily administration of pioglitazone, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within seven days. At steady state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady state, in both healthy volunteers and patients with type 2 diabetes mellitus, pioglitazone comprises approximately 30 to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20 to 25% of the total AUC.
Cmax, AUC, and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.
Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four hours, but does not alter the extent of absorption (AUC).
Metformin HCl
The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50 to 60%. Studies using single oral doses of metformin tablets of 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
Food decreases the rate and extent of metformin absorption, as shown by a 40% lower mean Cmax, a 25% lower AUC, and a 35 minute prolongation of Tmax following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Distribution
Pioglitazone
The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. M-III and M-IV are also extensively bound (>98%) to serum albumin.
Metformin HCl
The Vd/F of metformin following single oral doses of 850 mg immediate-release metformin averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.
Elimination
Metabolism
Pioglitazone
Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major circulating active metabolites in humans.
In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone which include CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms, including the mainly extrahepatic CYP1A1. In vivo study of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor, showed that pioglitazone is a CYP2C8 substrate [see Dosage and Administration (2.3), Drug Interactions (7.1)]. Urinary
6-ßhydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.
Metformin HCl
Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.
Excretion
Pioglitazone
Following oral administration, approximately 15 to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.
The mean serum half-life (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be five to seven L/hr.
Metformin HCl
Renal clearance is approximately 3.5 times greater than creatinine clearance (CrCl), which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination t1/2 of approximately 6.2 hours. In blood, the elimination t1/2 is approximately
17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Specific Populations
Geriatric Patients
Pioglitazone
In healthy elderly subjects, Cmax of pioglitazone was not significantly different, but AUC values were approximately 21% higher than those achieved in younger subjects. The mean t½ of pioglitazone was also prolonged in elderly subjects (about ten hours) as compared to younger subjects (about seven hours). These changes are not considered clinically relevant.
Metformin HCl
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total CL/F is decreased, the t½ is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
Pediatric Patients
Pioglitazone
Safety and efficacy of pioglitazone in pediatric patients have not been established. Pioglitazone and metformin hydrochloride is not recommended for use in pediatric patients [see Use in Specific Populations (8.4)].
Metformin HCl
After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), and all with normal renal function.
Male and Female Patients
Pioglitazone
The mean Cmax and AUC values of pioglitazone were increased 20 to 60% in females compared to males. In controlled clinical trials, HbA1c decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%). Because therapy should be individualized for each patient to achieve glycemic control, no dosage adjustment is recommended based on gender alone.
Metformin HCl
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.
Racial or Ethnic Groups
Pioglitazone
Pharmacokinetic data among various ethnic groups are not available.
Metformin HCl
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Blacks or African Americans (n=51), and Hispanics or Latinos (n=24).
Patients with Renal Impairment
Pioglitazone
The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (CrCl 30 to 50 mL/min) and severe (CrCl <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dosage adjustment in patients with renal impairment is required.
Metformin HCl
In patients with decreased renal function, the plasma and blood t1/2 of metformin is prolonged and the renal clearance is decreased [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.2)].
Patients with Hepatic Impairment
Pioglitazone
Compared with healthy controls, subjects with impaired hepatic function (Child-Turcotte-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III, and M-IV) mean Cmax but no change in the mean AUC values. Therefore, no dosage adjustment in patients with hepatic impairment is required.
There are postmarketing reports of liver failure with pioglitazone and clinical trials have generally excluded patients with serum ALT >2.5 times the upper limit of the reference range. Use pioglitazone and metformin hydrochloride tablets with caution in patients with liver disease [see Warnings and Precautions (5.5)].
Metformin HCl
No pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment [see Warnings and Precautions (5.5)].
Drug Interaction Studies
Specific pharmacokinetic drug interaction studies with pioglitazone and metformin hydrochloride tablets have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.
Pioglitazone
|
* Daily for 7 days unless otherwise noted |
|||||
|
†% change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively |
|||||
|
‡Pioglitazone had no clinically significant effect on prothrombin time |
|||||
| Table 18: Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs | |||||
| Coadministered Drug | |||||
| Pioglitazone Dosage Regimen ( mg )* | Name and Dose Regimens | Change in AUC † | Change in C m a x † | ||
| 45 mg (N = 12) | Warfarin ‡ | ||||
| Daily loading then maintenance doses based PT and INR values Quick's Value = 35 ± 5% | R-Warfarin | ↓3% | R-Warfarin | ↓2% | |
| S-Warfarin | ↓1% | S-Warfarin | ↑1% | ||
| 45 mg (N = 12) | Digoxin | ||||
| 0.200 mg twice daily (loading dose) then 0.250 mg daily (maintenance dose, 7 days) | ↑15% | ↑17% | |||
| 45 mg daily for 21 days (N = 35) | Oral Contraceptive | ||||
| [Ethinyl Estradiol (EE) 0.035 mg plus | EE | ↓11% | EE | ↓13% | |
| Norethindrone (NE) 1 mg] for 21 days | NE | ↑3% | NE | ↓7% | |
| 45 mg (N = 23) | Fexofenadine | ||||
| 60 mg twice daily for 7 days | ↑30% | ↑37% | |||
| 45 mg (N = 14) | Glipizide | ||||
| 5 mg daily for 7 days | ↓3% | ↓8% | |||
| 45 mg daily for 8 days (N = 16) | Metformin | ||||
| 1000 mg single dose on Day 8 | ↓3% | ↓5% | |||
| 45 mg (N = 21) | Midazolam | ||||
| 7.5 mg single dose on Day 15 | ↓26% | ↓26% | |||
| 45 mg (N = 24) | Ranitidine | ||||
| 150 mg twice daily for 7 days | ↑1% | ↓1% | |||
| 45 mg daily for 4 days (N = 24) | Nifedipine ER | ||||
| 30 mg daily for 4 days | ↓13% | ↓17% | |||
| 45 mg (N = 25) | Atorvastatin Calcium | ||||
| 80 mg daily for 7 days | ↓14% | ↓23% | |||
| 45 mg (N = 22) | Theophylline | ||||
| 400 mg twice daily for 7 days | ↑2% | ↑5% |
|
*Daily for 7 days unless otherwise noted |
|||
|
†Mean ratio (with/without coadministered drug and no change = 1-fold) % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively |
|||
|
‡The half-life of pioglitazone increased from 8.3 hours to 22.7 hours in the presence of gemfibrozil [see Dosage and Administration (2.3) and Drug Interactions (7.1)] |
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|
§Indicates duration of concomitant administration with highest twice-daily dose of topiramate from Day 14 onwards over the 22 days of study |
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|
¶Additional decrease in active metabolites; 60% for M-III and 16% for M-IV |
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| Table 19: Effect of Coadministered Drugs on Pioglitazone Systemic Exposure | |||
|
Coadministered Drug and
Dosage Regimen |
Pioglitazone | ||
|
Dose Regimen
(mg)* |
Change
in AUC † |
Change
in C max † |
|
| Gemfibrozil 600 mg twice daily for 2 days (N = 12) |
15-mg single dose |
↑3.2-fold‡ | ↑6% |
| Ketoconazole 200 mg twice daily for 7 days (N = 28) |
45 mg | ↑34% | ↑14% |
| Rifampin 600 mg daily for5 days (N = 10) |
30-mg single dose |
↓54% | ↓5% |
| Fexofenadine 60 mg twice daily for 7 days (N = 23) |
45 mg | ↑1% | 0% |
| Ranitidine 150 mg twice daily for 4 days (N = 23) |
45 mg | ↓13% | ↓16% |
| Nifedipine ER 30 mg daily for 7 days (N = 23) |
45 mg | ↑5% | ↑4% |
| Atorvastatin Calcium 80 mg daily for 7 days (N = 24) |
45 mg | ↓24% | ↓31% |
| Theophylline 400 mg twice daily for 7 days (N = 22) |
45 mg | ↓4% | ↓2% |
| Topiramate 96 mg twice daily for 7 days § (N = 26) |
30 mg § | ↓15% ¶ | 0% |
Metformin HCl
|
*All metformin and coadministered drugs were given as single doses |
||||
|
†AUC = AUC 0 to ∞ |
||||
|
‡Ratio of arithmetic means |
||||
|
§Metformin HCl extended-release tablets, 500 mg |
||||
|
¶At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0 to 12h |
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| Table 20: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure | ||||
|
Coadministered
Drug |
Dose of Coadministered Drug* |
Dose of
Metformin* |
Geometric Mean Ratio
(ratio with/without coadministered drug) No effect = 1.00 |
|
| AUC † | Cmax | |||
| No dosing adjustments required for the following: | ||||
| Glyburide | 5 mg | 500 mg § | 0.98 ‡ | 0.99 ‡ |
| Furosemide | 40 mg | 850 mg | 1.09 ‡ | 1.22 ‡ |
| Nifedipine | 10 mg | 850 mg | 1.16 | 1.21 |
| Propranolol | 40 mg | 850 mg | 0.9 | 0.94 |
| Ibuprofen | 400 mg | 850 mg | 1.05 ‡ | 1.07 ‡ |
| Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see Warnings and Precautions (5) and Drug Interactions (7)] . | ||||
| Cimetidine | 400 mg | 850 mg | 1.4 | 1.61 |
| Carbonic anhydrase inhibitors may cause metabolic acidosis: use with caution [see Warnings and Precautions (5) and Drug Interactions (7)] . | ||||
| Topiramate | 100 mg ¶ | 500 mg ¶ | 1.25 ¶ | 1.17 |
|
*All metformin and coadministered drugs were given as single doses |
||||
|
†AUC = AUC 0 to ∞ |
||||
|
‡Ratio of arithmetic means, p-value of difference <0.05 |
||||
|
§AUC 0 to 24hr reported |
||||
|
¶Ratio of arithmetic means |
||||
| Table 21: Effect of Metformin on Coadministered Drug Systemic Exposure | ||||
|
Coadministered
Drug |
Dose of Coadministered Drug * |
Dose of
Metformin * |
Geometric Mean Ratio
(ratio with/without coadministered drug) No effect = 1.00 |
|
| AUC † | C max | |||
| No dosing adjustments required for the following: | ||||
| Glyburide | 5 mg | 500 mg § | 0.78 ‡ | 0.63 ‡ |
| Furosemide | 40 mg | 850 mg | 0.87 ‡ | 0.69 ‡ |
| Nifedipine | 10 mg | 850 mg | 1.1 § | 1.08 |
| Propranolol | 40 mg | 850 mg | 1.01 § | 0.94 |
| Ibuprofen | 400 mg | 850 mg | 0.97 ¶ | 1.01 ¶ |
| Cimetidine | 400 mg | 850 mg | 0.95 § | 1.01 |
13 NONCLINICAL TOXICOLOGY
14 CLINICAL STUDIES
SPL UNCLASSIFIED SECTION
[image: MM3]
Manufactured by:
Torrent Pharmaceuticals LTD., India.
Manufactured for:
Torrent Pharma INC., Basking Ridge, NJ 07920
8099813 Revised: March 2025