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Pioglitazone Hydrochloride and Metformin Hydrochloride Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 


WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS

Congestive Heart Failure

• Thiazolidinediones, including pioglitazone, which is a component of pioglitazone/metformin, cause or exacerbate congestive heart failure in some patients (see WARNINGS).

• After initiation of pioglitazone/metformin, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone/metformin must be considered [see Warnings and Precautions].

• Pioglitazone/metformin is not recommended in patients with symptomatic heart failure.

• Initiation of pioglitazone/metformin in patients with established NYHA Class III or IV heart failure is contraindicated (see CONTRAINDICATIONS and WARNINGS).

Lactic Acidosis

• Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure [see Warnings and Precautions].

• The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate [see Warnings and Precautions].

• If acidosis is suspected, pioglitazone/metformin should be discontinued and the patient hospitalized immediately [see Warnings and Precautions].



1. DESCRIPTION

Pioglitazone/metformin tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: pioglitazone hydrochloride and metformin hydrochloride. The concomitant use of pioglitazone and metformin has been previously approved based on clinical trials in patients with type 2 diabetes inadequately controlled on metformin. Additional efficacy and safety information about pioglitazone and metformin monotherapies may be found in the prescribing information for each individual drug.

Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the α-glucosidase inhibitors. The molecule 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 empirical formula: C19H20N2O3S•HCl - Molecular weight: 392.90 daltons

Pioglitazone hydrochloride is an odorless white crystalline powder. 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 hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:

Metformin HCl empirical formula: C4H11N5•HCl - Molecular weight: 165.62

Metformin hydrochloride 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 is 6.68.

Pioglitazone/metformin is available as a tablet for oral administration containing 15 mg pioglitazone hydrochloride (as the base) with 500 mg metformin hydrochloride (15 mg/500 mg) or 15 mg pioglitazone hydrochloride (as the base) with 850 mg metformin hydrochloride (15 mg/850 mg) formulated with the following excipients: povidone USP, microcrystalline cellulose NF, croscarmellose sodium NF, magnesium stearate NF, hypromellose 2910 USP, polyethylene glycol 8000 NF, titanium dioxide USP, and talc USP.

2. INDICATIONS AND USAGE

Pioglitazone/metformin is 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.

Important Limitations of Use

Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. Pioglitazone/metformin should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. Use caution in patients with liver disease [see Warnings and Precautions].

3. DOSAGE AND ADMINISTRATION

3.1 Recommendations for All Patients

Pioglitazone/metformin should be taken with meals to reduce the gastrointestinal side effects associated with metformin.

If therapy with a combination tablet containing pioglitazone and metformin is considered appropriate the recommended starting dose is:

• 15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,

• for patients with New York Heart Association (NYHA) Class I or Class II congestive heart failure: 15 mg/500 mg or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,

• for patients inadequately controlled on metformin monotherapy: 15 mg/500 mg twice daily or 15 mg/850 mg once or twice daily (depending on the dose of metformin already being taken) and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,

• for patients inadequately controlled on pioglitazone monotherapy: 15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability.

• for patients who are changing from combination therapy of pioglitazone plus metformin as separate tablets: Pioglitazone/metformin should be taken at doses that are as close as possible to the dose of pioglitazone and metformin already being taken.

Pioglitazone/metformin may be titrated up to a maximum daily dose of 45 mg of pioglitazone and 2550 mg of metformin.

Metformin doses above 2000 mg may be better tolerated given 3 times a day.

After initiation of pioglitazone/metformin or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions]. Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating pioglitazone/metformin. Routine periodic monitoring of liver tests during treatment with pioglitazone/metformin is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of pioglitazone/metformin or who are found to have abnormal liver tests while taking pioglitazone/metformin should be managed as described under Warnings and Precautions [see Warnings and Precautions].

3.2 Concomitant Use with an Insulin Secretagogue or Insulin

If hypoglycemia occurs in a patient co-administered pioglitazone/metformin and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient co-administered pioglitazone/metformin and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

3.3 Coadministration with Strong CYP2C8 Inhibitors

Coadministration of pioglitazone (one of the ingredients in pioglitazone/metformin) and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone/metformin is 15 mg/850 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions].

4. CONTRAINDICATIONS

Initiation of pioglitazone/metformin in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see BOXED WARNING).

In addition, pioglitazone/metformin is contraindicated in patients with:

1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females], or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS, Metformin hydrochloride and PRECAUTIONS, General: Metformin hydrochloride).

2. Known hypersensitivity to pioglitazone, metformin or any other component of pioglitazone/metformin.

3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Pioglitazone/metformin should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function (see PRECAUTIONS, General: Metformin hydrochloride).

5. MECHANISM OF ACTION

Pioglitazone/metformin combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: pioglitazone hydrochloride, a member of the thiazolidinedione class, and metformin hydrochloride, a member of the biguanide class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.

Pioglitazone hydrochloride

Pioglitazone is a thiazolidinedione antidiabetic agent 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. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent agonist for peroxisome proliferatoractivated 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.

Pharmacological studies indicate that pioglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels.

Since 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 hydrochloride

Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, 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. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS, General: Metformin hydrochloride) 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of pioglitazone/metformin or its individual components in pregnant women. Animal studies using pioglitazone show increased rates of post-implantation loss, delayed development, reduced fetal weights, and delayed parturition at doses 10 to 40 times the maximum recommended human dose. Pioglitazone/metformin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pioglitazone

Clinical Considerations: Abnormal blood glucose concentrations during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality. Most experts recommend the use of insulin during pregnancy to maintain blood glucose concentrations as close to normal as possible for patients with diabetes.

Animal Data: In animal reproductive studies, pregnant rats and rabbits received pioglitazone at doses up to approximately 17 (rat) and 40 (rabbit) times the maximum recommended human oral dose (MRHD) based on body surface area (mg/m2); no teratogenicity was observed. Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more times the MRHD (mg/m2 basis). No functional or behavioral toxicity was observed in rat offspring. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses approximately 2 or more times the MRHD (mg/m2 basis). In rabbits, embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m2 basis).

Metformin hydrochloride

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times a human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, metformin should not be used during pregnancy unless clearly needed.

6.2 Labor and Delivery

The effect of pioglitazone/metformin on labor and delivery in humans is not known.

6.3 Nursing Mothers

No studies have been conducted with the combined components of pioglitazone/metformin. In studies performed with the individual components, both pioglitazone and metformin are secreted in the milk of lactating rats. It is not known whether pioglitazone and/or metformin is secreted in human milk. Because many drugs are excreted in human milk, pioglitazone/metformin should not be administered to a breastfeeding woman. If pioglitazone/metformin is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

6.4 Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

Pioglitazone/metformin is not recommended for the treatment of diabetes in pediatric patients based on adverse effects observed with pioglitazone in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see Warnings and Precautions].

6.5 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 2 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 ³ 65 years old and 22 (2.1%) were ≥ 75 years old.

In PROactive, 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. These clinical experiences have not identified differences in effectiveness and safety between the elderly (≥ 65 years) and younger patients although small sample sizes for patients ≥ 75 years old limit conclusions.

Metformin hydrochloride

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. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, pioglitazone/metformin should only be used in patients with normal renal function [see Contraindications, Warnings and Precautions]. Because aging is associated with reduced renal function, pioglitazone/metformin should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of pioglitazone/metformin [see Warnings and Precautions and Dosage and Administration].

7. WARNINGS AND PRECAUTIONS

7.1 Congestive Heart Failure

Pioglitazone

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. Patients treated with pioglitazone/metformin should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone/metformin must be considered [see Boxed Warning, Contraindications, and Adverse Reactions].

7.2 Lactic Acidosis

Metformin hydrochloride

Lactic Acidosis: Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with pioglitazone/metformin and, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate concentrations (> 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 μg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is approximately 0.03 cases/1000 patientyears, with approximately 0.015 fatal cases/1000 patient-years. In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/ surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Pioglitazone/metformin treatment should not be initiated in any patient unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, because alcohol potentiates the effects of metformin on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids [see Warnings and Precautions]. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may frequently cause dose-dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis [see Drug Interactions].

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. Patients should be educated to promptly report these symptoms should they occur. If present, pioglitazone/metformin should be withdrawn until lactic acidosis is ruled out. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling [see Warnings and Precautions].

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery [see Contraindications and Warnings and Precautions].

7.3 Edema

In controlled clinical trials with pioglitazone, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose related [see Adverse Reactions]. In postmarketing experience, reports of new onset or worsening of edema have been received.

Pioglitazone/metformin should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, pioglitazone/metformin should be used with caution in patients at risk for congestive heart failure. Patients treated with pioglitazone/metformin should be monitored for signs and symptoms of congestive heart failure [see Boxed Warning, Warnings and Precautions].

7.4 Hepatic Effects

There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date [see Adverse Reactions].

Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating pioglitazone/metformin therapy.

In patients with abnormal liver tests, pioglitazone/metformin should be initiated with caution.

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than three times the upper limit of the reference range), pioglitazone/metformin treatment should be interrupted and investigation done to establish the probable cause. Pioglitazone/metformin should not be restarted in these patients without another explanation for the liver test abnormalities.

Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury, and should not be restarted on pioglitazone/metformin. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with pioglitazone/metformin can be used with caution.

Because impaired hepatic function has been associated with some cases of lactic acidosis pioglitazone/metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

7.5 Fractures

In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone/metformin and attention should be given to assessing and maintaining bone health according to current standards of care.

7.6 Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In two 3-year trials in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) cases on placebo.

A five-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk for bladder cancer in subjects ever exposed to pioglitazone, compared to subjects never exposed to pioglitazone (HR 1.2 [95% CI 0.9 – 1.5]). Compared to never exposure, a duration of pioglitazone therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9 – 2.1]), which reached statistical significance after more than 24 months of pioglitazone use (HR 1.4 [95% CI 1.03 – 2.0]). Interim results from this study suggested that taking pioglitazone longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of 3 cases in 10,000 (from approximately 7 in 10,000 [without pioglitazone] to approximately 10 in 10,000 [with pioglitazone]).

There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, pioglitazone/metformin should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone/metformin should be considered in patients with a prior history of bladder cancer.

7.7 Hypoglycemia

Patients receiving pioglitazone/metformin in combination with insulin or other anti-diabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant anti-diabetic medication may be necessary to reduce the risk of hypoglycemia [see Dosage and Administration].

Hypoglycemia can also occur when caloric intake is deficient or when strenuous exercise is not compensated by caloric supplement. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

7.8 Macular Edema

Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.

Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.

Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings [see Adverse Reactions].

7.9 Ovulation

Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking pioglitazone/metformin [see Use in Specific Populations]. This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with pioglitazone/metformin is recommended.

7.10 Monitoring of Renal Function

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Therefore, pioglitazone/metformin is contraindicated in patients with renal impairment.

Before initiation of therapy with pioglitazone/metformin and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated (e.g., elderly), renal function should be assessed more frequently and pioglitazone/metformin discontinued if evidence of renal impairment is present.

Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution.

Radiological studies and surgical procedures:

Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin [see Contraindications]. Therefore, in patients in whom any such study is planned, pioglitazone/metformin should be discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

7.11 Hypoxic States

Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients receiving pioglitazone/metformin therapy, the drug should be promptly discontinued.

7.12 Surgical Procedures

Use of pioglitazone/metformin should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

7.13 Alcohol Intake

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving pioglitazone/metformin.

7.14 Vitamin B12 Levels

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on pioglitazone/metformin and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at two- to three-year intervals may be useful.

7.15 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone/metformin or any other oral anti-diabetic drug.

8. ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

• Congestive heart failure [see Boxed Warning and Warnings and Precautions]

• Lactic acidosis [see Boxed Warning and Warnings and Precautions]

• Edema [see Warnings and Precautions]

• Fractures [see Warnings and Precautions]

8.1 Clinical Studies 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 have been treated with pioglitazone in randomized, double-blind, controlled clinical trials. This includes 2605 high-risk patients with type 2 diabetes treated with pioglitazone from the PROactive clinical trial. Over 6000 patients have been treated for 6 months or longer, and over 4500 patients for one year or longer. Over 3000 patients have received pioglitazone for at least 2 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 1. 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

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 2. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone.

Table 2. 16 to 24 Week Clinical Trials of Pioglitazone Add-on to Metformin

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/Metformin Clinical Trial

Table 3 summarizes the incidence and types of adverse reactions reported in a controlled, 24-week double-blind clinical trial of pioglitazone/metformin dosed twice-daily in patients with inadequate glycemic control on diet and exercise (N=600).

Table 3. Adverse Events (≥5% for Pioglitazone/Metformin) Reported by Patients with Inadequate Glycemic Control on Diet and Exercise in a 24-Week Double-Blind Clinical Trial of Pioglitazone/Metformin Administered Twice Daily

In this 24-week trial, abdominal pain was reported in 2.0% of patients in the pioglitazone/metformin group, 1.6% in the pioglitazone monotherapy group and 3.3% in the metformin monotherapy group.

Common Adverse Events: PROactive Trial

A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 4. 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.

Table 4. PROactive Trial: Incidence and Types of Adverse Events Reported in >5% of Patients Treated with Pioglitazone and More Commonly than Placebo

Mean duration of patient follow-up was 34.5 months.

Congestive Heart Failure: A summary of the incidence of adverse events related to congestive heart failure is provided in Table 5 for the 16- to 24-week add-on to metformin trials. None of the events were fatal.

Table 5. Treatment–Emergent Adverse Events of Congestive Heart Failure (CHF) Patients Treated with Pioglitazone or Placebo Added on to Metformin

 

Table 6. Treatment–Emergent Adverse Events of Congestive Heart Failure (CHF)

 

Table 7. Treatment–Emergent Adverse Events of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with Pioglitazone or Glyburide

Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 8.

Table 8. Treatment–Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive Trial

Cardiovascular Safety: In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 months.

The primary objective of this trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, non-fatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with pioglitazone and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).

Although there was no statistically significant difference between pioglitazone and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with pioglitazone. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9.

Table 9. PROactive: Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint

CABG = coronary artery bypass grafting; PCI = percutaneous intervention

Weight Gain: Dose-related weight gain occurs when pioglitazone is used alone or in combination with other anti-diabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Tables 10, 11 and 12 summarize the changes in body weight with pioglitazone and placebo in the 16- to 26-week randomized, doubleblind monotherapy and 16- to 24-week combination add-on therapy trials, the PROactive trial, and the 24-week pioglitazone/metformin trial.

Table 10. Weight Changes (kg) from Baseline during Randomized, Double-Blind Clinical Trials

 

Table 11. Median Change in Body Weight in Patients Treated with Pioglitazone Versus Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial

Note: Median exposure for both Pioglitazone and Placebo was 2.7 years.

 

Table 12. Weight Changes (kg) from Baseline during Double-Blind Clinical Trial with Pioglitazone/Metformin in Patients with Inadequate Glycemic Control on Diet and Exercise

Note: Trial duration of 24 weeks.

Edema: Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure.

In the 24-week pioglitazone/metformin trial, edema was reported in 3.0% of patients in the pioglitazone/metformin group, 4.2% in the pioglitazone monotherapy group and 1.4% in the metformin monotherapy group.

A summary of the frequency and types of edema adverse events occurring in clinical investigations of pioglitazone is provided in Table 13.

Table 13. Adverse Events of Edema in Patients Treated with Pioglitazone

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of "edema."

 

Table 14. Adverse Events of Edema in Patients in the PROactive Trial

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of "edema."

Hepatic Effects: There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, 3-year trial comparing pioglitazone to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every 8 weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with pioglitazone and 9/1046 (0.9%) patients treated with glyburide developed ALT values > three times the upper limit of the reference range. None of the patients treated with pioglitazone in the pioglitazone controlled clinical trial database to date have had a serum ALT > three times the upper limit of the reference range and a corresponding total bilirubin > two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.

Hypoglycemia: In the pioglitazone clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing.

In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with pioglitazone 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with pioglitazone 15 mg, 15.4% with pioglitazone 30 mg, and 4.8% with placebo.

The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to pioglitazone 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% vs. 13.4%) and in the 24-week add-on to insulin trial (47.8% vs. 43.5%).

Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving pioglitazone 30 mg (0.9%) in the 24-week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient's usual activities) that did not require hospitalization. These patients were receiving pioglitazone 45 mg in combination with sulfonylurea (n=2) or pioglitazone 30 mg or 45 mg in combination with insulin (n=12).

Urinary Bladder Tumors: Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In two 3-year trials in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) cases on placebo. There are too few events of bladder cancer to establish causality.

Metformin hydrochloride

In a double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141 patients received metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin than placebo-treated patients, are listed in Table 15. In this trial, diarrhea led to discontinuation of study medication in 6% of patients treated with metformin.

Table 15. Most Common Adverse Reactions (> 5.0%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy*

* Reactions that were more common in metformin than placebo-treated patients.

8.2 Laboratory Abnormalities

Hematologic Effects: Pioglitazone may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and are not likely to be associated with any clinically significant hematologic effects.

Vitamin B12 concentrations: Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on pioglitazone/metformin and any apparent abnormalities should be appropriately investigated and managed [see Warnings and Precautions].

Creatine Phosphokinase: During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in 9 (0.2%) patients treated with pioglitazone (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive pioglitazone, two patients were noted to have the CPK elevation on the last day of dosing, and one patient discontinued pioglitazone due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown.

8.3 Postmarketing Experience

Pioglitazone

The following adverse reactions have been identified during post-approval use of pioglitazone. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• New onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions].

• Fatal and non-fatal hepatic failure [see Warnings and Precautions].

Postmarketing reports of congestive heart failure have been reported in patients treated with pioglitazone, both with and without previously known heart disease and both with and without concomitant insulin administration.

In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning and Warnings and Precautions].

9. OVERDOSAGE

Pioglitazone hydrochloride

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.

In the event of overdosage, appropriate supportive treatment should be initiated according to patient’s clinical signs and symptoms.

Metformin hydrochloride

Overdose of metformin hydrochloride 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, Metformin hydrochloride). 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.

10. DRUG INTERACTIONS

10.1 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 of pioglitazone. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and Administration].

10.2 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, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for pioglitazone.

10.3 Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase.

10.4 Cationic Drugs

Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of ACTOPLUS MET and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

10.5 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 ACTOPLUS MET, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving ACTOPLUS MET, the patient should be observed closely for hypoglycemia.

11. PHARMACOKINETICS

Absorption

Pioglitazone/Metformin

In bioequivalence studies of pioglitazone/metformin 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 pioglitazone 15 mg concomitantly administered with metformin (500 mg or 850 mg respectively) tablets under fasted conditions in healthy subjects.

Administration of pioglitazone/metformin 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 hydrochloride

Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.

Metformin hydrochloride

The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50% - 60%. Studies using single oral doses of metformin tablets of 500 mg to 1500 mg, and 850 mg to 2550 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. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration, a 25% lower AUC in plasma concentration versus time curve, and a 35 minute prolongation of time to peak plasma concentration 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 hydrochloride

The mean apparent volume of distribution (V/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. Metabolites M-III and M-IV also are extensively bound (> 98%) to serum albumin.

Metformin hydrochloride

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 - 48 hours and are generally <1 μg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.

Metabolism, Elimination and Excretion

Pioglitazone hydrochloride

Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC.

In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions, Pioglitazone hydrochloride). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

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 of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr.

Metformin hydrochloride

Intravenous single-dose studies in normal 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. Renal clearance is approximately 3.5 times greater than creatinine clearance 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 half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations

Renal Insufficiency:

Pioglitazone hydrochloride

The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects.

Metformin hydrochloride

In patients with decreased renal function (based on creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see CONTRAINDICATIONS and WARNINGS, Metformin hydrochloride, also see metformin prescribing information). Since metformin is contraindicated in patients with renal impairment, pioglitazone/metformin is also contraindicated in these patients.

Hepatic Insufficiency:

Pioglitazone hydrochloride

Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values.

Therapy with pioglitazone/metformin should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal (see PRECAUTIONS, General: Pioglitazone hydrochloride).

Metformin hydrochloride

No pharmacokinetic studies of metformin have been conducted in subjects with hepatic insufficiency.

Elderly:

Pioglitazone hydrochloride

In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant.

Metformin hydrochloride

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life 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 (see metformin prescribing information, Special Populations, Geriatrics).

Pioglitazone/metformin treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS, Metformin hydrochloride and DOSAGE AND ADMINISTRATION; also see metformin prescribing information).

Pediatrics:

Pioglitazone hydrochloride

Pharmacokinetic data in the pediatric population are not available.

Metformin hydrochloride

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.

Gender:

Pioglitazone hydrochloride

As monotherapy and in combination with sulfonylurea, metformin, or insulin, pioglitazone improved glycemic control in both males and females. The mean Cmax and AUC values were increased 20% to 60% in females. In controlled clinical trials, hemoglobin A1C (A1C) decreases from baseline were generally greater for females than for males (average mean difference in A1C 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Ethnicity:

Pioglitazone

Pharmacokinetic data among various ethnic groups are not available.

Metformin hydrochloride

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of immediate-release metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: ACTOPLUS MET, by TAKEDA PHARMS.

b) Generic drugs: Pioglitazone hydrochloride and metformin hydrochloride, by Mylan.

2) How Supplied:

Pioglitazone Hydrochloride and Metformin Hydrochloride Tablets (by Mylan) are available in 15 mg pioglitazone hydrochloride, USP (as the base)/500 mg metformin hydrochloride, USP and 15 mg pioglitazone hydrochloride, USP (as the base)/850 mg metformin hydrochloride, USP tablets.

The 15 mg/500 mg tablets are white to off-white film-coated, oval, unscored tablets debossed with MYLAN on one side of the tablet and P155 on the other side. They are available as follows:

NDC 0378-1550-91, bottles of 60 tablets

NDC 0378-1550-80, bottles of 180 tablets

NDC 0378-1550-10, bottles of 1000 tablets

The 15 mg/850 mg tablets are white to off-white film-coated, oval, unscored tablets debossed with MYLAN on one side of the tablet and P157 on the other side. They are available as follows:

NDC 0378-1575-91, bottles of 60 tablets

NDC 0378-1575-80, bottles of 180 tablets

NDC 0378-1575-05, bottles of 500 tablets

3) Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Keep container tightly closed, and protect from moisture and humidity.

Rx only

Rev 05/12