الجرعة وطريقة الإعطاء
2 DOSAGE AND ADMINISTRATION Obtain liver tests before initiation. If abnormal, use caution when treating with ACTOPLUS MET, investigate the probable cause, treat (if possible), and follow appropriately. ( 2.1 ) Take orally with meals to reduce gastrointestinal adverse reactions with metformin ( 2.10 ) Individualize the starting dose based on the patient’s current regimen and titrate the dosage gradually, as needed after assessing therapeutic response and tolerability. The maximum recommended total daily dosage is pioglitazone 45 mg and metformin 2,550 mg. ( 2.2 ) Recommended starting dosage in patients with NYHA Class I or Class II congestive heart failure is 15 mg of pioglitazone and 850 mg of metformin HCl orally once daily. ( 2.4 ) Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). ( 2.2 ) Contraindicated in patients with eGFR below 30 mL/min Initiation is not recommended in patients with eGFR between 30 to 45 mL/min Assess risk/benefit of continuing ACTOPLUS MET if eGFR falls below 45 mL/min Discontinue if eGFR falls below 30 mL/min Monitor patients for adverse events related to fluid retention after initiation and dose increases. ( 2.4 ) ACTOPLUS MET may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.6 ) 2.1 Important Dosage and Administration Information Obtain liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) prior to initiating ACTOPLUS MET [see Warnings and Precautions (5.5) ] . ACTOPLUS MET contains 15 mg of pioglitazone and 850 mg of metformin hydrochloride (HCl) in each tablet. Take ACTOPLUS MET with meals to reduce gastrointestinal adverse reactions with metformin [see Adverse Reactions (6.1) ] . If a dose is missed, do not double the next dose. 2.2 Recommended Dosage and Administration Recommended Starting Dosage Based on Current Regimen Individualize the starting dosage of ACTOPLUS MET based on the patient's current regimen and the available strength of ACTOPLUS MET (see Table 1 ). Table 1: Recommended Starting Dosage Based on the Patient’s Current Regimen Current Regimen Starting Dosage of ACTOPLUS MET (15 mg of pioglitazone and 850 mg of metformin HCl per tablet) For dosage recommendations for patients with renal impairment and/or congestive heart failure, see Dosage and Administration (2.3 , 2.4) Not treated with either pioglitazone or metformin HCl One tablet orally once daily Metformin HCl One tablet orally once or twice daily. Select a dosage that is as close as possible to the current dosage of metformin HCl Pioglitazone One tablet orally once daily Pioglitazone and metformin HCl Select a dosage that is as close as possible to the current dosage of pioglitazone and metformin HCl while not exceeding three tablets orally per day. Dosage Titration for Additional Glycemic Control Titrate the ACTOPLUS MET dosage gradually, as needed, after assessing therapeutic response and tolerability. ACTOPLUS MET may be increased to a maximum recommended total daily dosage of three tablets per day (45 mg of pioglitazone and 2,550 mg of metformin HCl). Total daily dosages of 2,550 mg of metformin HCl may be taken in divided doses three times a day to reduce gastrointestinal adverse reactions [see Adverse Reactions (6.1) ] . 2.3 Recommendations for Use in Patients with Renal Impairment Assess renal function prior to initiation of ACTOPLUS MET and periodically thereafter [see Use in Specific Populations (8.6) ] . ACTOPLUS MET is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min. Initiation of ACTOPLUS MET in patients with an eGFR between 30 to 45 mL/min is not recommended. In patients taking ACTOPLUS MET whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy. Discontinue ACTOPLUS MET if the patient’s eGFR later falls below 30 mL/min [see Contraindications (4) , Warnings and Precautions (5.2) ] . 2.4 Recommendations for Congestive Heart Failure Starting Dosage in Patients with NYHA Class I or II Congestive Heart Failure For patients with preexisting NYHA Class I or II congestive heart failure, the recommended starting dosage of ACTOPLUS MET is 15 mg of pioglitazone and 850 mg of metformin [see Boxed Warning and Warnings and Precautions (5.1) ] . Monitoring for Fluid Retention and Dosage Modifications for Congestive Heart Failure After initiation of ACTOPLUS MET or with dosage increase, monitor patients carefully for adverse reactions related to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and symptoms of congestive heart failure). If congestive heart failure develops while taking ACTOPLUS MET, consider discontinuation of ACTOPLUS MET or dosage reduction of pioglitazone in ACTOPLUS MET [see Boxed Warning and Warnings and Precautions (5.1) ] . 2.5 Coadministration with Strong CYP2C8 Inhibitors The maximum recommended dosage of ACTOPLUS MET 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 ACTOPLUS MET 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 ACTOPLUS MET if renal function is stable [see Warnings and Precautions (5.2) ] .
Side Effects Overview
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Congestive heart failure [see Boxed Warning , Warnings and Precautions (5.1) ] Lactic acidosis [see Boxed Warning , Warnings and Precautions (5.2) ] Edema [see Warnings and Precautions (5.3) ] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.4) ] Hepatic Effects [see Warnings and Precautions (5.5) ] Urinary Bladder Tumors [see Warnings and Precautions (5.6) ] Fractures [see Warnings and Precautions (5.7) ] Macular Edema [see Warnings and Precautions (5.8 ] Vitamin B 12 Levels [see Warnings and Precautions (5.9 ] Most common adverse reactions (>5%) are upper respiratory tract infection, edema, diarrhea, headache and weight gain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327 and the ACTOPLUS MET website at: www.actoplusmet.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pioglitazone Over 8,500 patients with type 2 diabetes mellitus have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2,605 patients with type 2 diabetes mellitus and macrovascular disease treated with pioglitazone from the PROactive clinical trial. In these trials, over 6,000 patients have been treated with pioglitazone for six months or longer, over 4,500 patients have been treated with pioglitazone for one year or longer, and over 3,000 patients have been treated with pioglitazone for at least two years. In six pooled 16 to 26 week placebo-controlled monotherapy and 16 to 24 week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3.0%). In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone and 0.6% of patients treated with placebo. Common Adverse Events: 16 to 26 Week Monotherapy Trials A summary of the incidence and type of common adverse events reported in three pooled 16 to 26 week placebo-controlled monotherapy trials of pioglitazone is provided in Table 2. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse events were related to the pioglitazone dose. Table 2: Three Pooled 16 to 26 Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence >5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo % of Patients Placebo N=259 Pioglitazone N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Pharyngitis 0.8 5.1 Common Adverse Events: 16 to 24 Week Add-on Combination Therapy Trials A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone add-on to metformin is provided in Table 3. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone. Table 3: 16 to 24 Week Clinical Trials of Pioglitazone Add-on to Metformin Note: The preferred terms of edema peripheral, generalized edema, pitting edema, and fluid retention were combined to form the aggregate term of “edema.” 16 Week Placebo-Controlled Trial Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Pioglitazone + Metformin than in Patients Treated with Placebo + Metformin % of Patients Placebo + Metformin N=160 Pioglitazone 30 mg + Metformin N=168 Edema 2.5 6.0 Headache 1.9 6.0 24 Week Non-Controlled Double-Blind Trial Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Metformin than in Patients Treated with Pioglitazone 30 mg + Metformin % of Patients Pioglitazone 30 mg + Metformin N=411 Pioglitazone 45 mg + Metformin N=416 Upper Respiratory Tract Infection 12.4 13.5 Edema 5.8 13.9 Headache 5.4 5.8 Weight Increased 2.9 6.7 Common Adverse Events: 24 Week ACTOPLUS MET Clinical Trial Table 4 summarizes the incidence and types of adverse reactions reported in a controlled, 24 week double-blind clinical trial of ACTOPLUS MET dosed twice daily in patients with inadequate glycemic control on diet and exercise (N=600). Table 4: Adverse Events (≥5% for ACTOPLUS MET) Reported by Patients with Inadequate Glycemic Control on Diet and Exercise in a 24 Week Double-Blind Clinical Trial of ACTOPLUS MET Administered Twice Daily % of Patients ACTOPLUS MET 15/850 mg Twice Daily N=201 Pioglitazone 15 mg Twice Daily N=190 Metformin 850 mg Twice Daily N=209 Diarrhea 9.0 2.6 15.3 Headache 5.5 2.6 4.8 In this 24 week trial, abdominal pain was reported in 2.0% of patients in the ACTOPLUS MET 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 5. 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 5: 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. % of Patients Placebo N=2,633 Pioglitazone N=2,605 Hypoglycemia 18.8 27.3 Edema 15.3 26.7 Cardiac Failure 6.1 8.1 Pain in Extremity 5.7 6.4 Back Pain 5.1 5.5 Chest Pain 5.0 5.1 Congestive Heart Failure A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16 to 24 week add-on to metformin trials. None of the events were fatal. Table 6: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) Patients Treated with Pioglitazone or Placebo Added on to Metformin Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double-Blind Trial (24 weeks) Placebo + Metformin N=160 Pioglitazone 30 mg + Metformin N=168 Pioglitazone 30 mg + Metformin N=411 Pioglitazone 45 mg + Metformin N=416 At least one congestive heart failure event 0 1 (0.6%) 0 1 (0.2%) Hospitalized 0 1 (0.6%) 0 1 (0.2%) Table 7: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) Patients Treated with Pioglitazone or Placebo Added on to a Sulfonylurea Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double-Blind Trial (24 weeks) Placebo + Sulfonylurea N=187 Pioglitazone 15 mg + Sulfonylurea N=184 Pioglitazone 30 mg + Sulfonylurea N=189 Pioglitazone 30 mg + Sulfonylurea N=351 Pioglitazone 45 mg + Sulfonylurea N=351 At least one congestive heart failure event 2 (1.1%) 0 0 1 (0.3%) 6 (1.7%) Hospitalized 2 (1.1%) 0 0 0 2 (0.6%) Patients Treated with Pioglitazone or Placebo Added on to Insulin Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double-Blind Trial (24 weeks) Placebo + Insulin N=187 Pioglitazone 15 mg + Insulin N=191 Pioglitazone 30 mg + Insulin N=188 Pioglitazone 30 mg + Insulin N=345 Pioglitazone 45 mg + Insulin N=345 At least one congestive heart failure event 0 2 (1.0%) 2 (1.1%) 3 (0.9%) 5 (1.4%) Hospitalized 0 2 (1.0%) 1 (0.5%) 1 (0.3%) 3 (0.9%) Patients Treated with Pioglitazone or Placebo Added on to Metformin Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double-Blind Trial (24 weeks) Placebo + Metformin N=160 Pioglitazone 30 mg + Metformin N=168 Pioglitazone 30 mg + Metformin N=411 Pioglitazone 45 mg + Metformin N=416 At least one congestive heart failure event 0 1 (0.6%) 0 1 (0.2%) Hospitalized 0 1 (0.6%) 0 1 (0.2%) Table 8: 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 Number (%) of Subjects Pioglitazone N=262 Glyburide N=256 Death due to cardiovascular causes (adjudicated) 5 (1.9%) 6 (2.3%) Overnight hospitalization for worsening CHF (adjudicated) 26 (9.9%) 12 (4.7%) Emergency room visit for CHF (adjudicated) 4 (1.5%) 3 (1.2%) Patients experiencing CHF progression during study 35 (13.4%) 21 (8.2%) Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 9. Table 9: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive Trial Number (%) of Patients Placebo N=2,633 Pioglitazone N=2,605 At least one hospitalized congestive heart failure event 108 (4.1%) 149 (5.7%) Fatal 22 (0.8%) 25 (1.0%) Hospitalized, nonfatal 86 (3.3%) 124 (4.7%) Cardiovascular Safety In the PROactive trial, 5,238 patients with type 2 diabetes mellitus and a history of macrovascular disease were randomized to pioglitazone (N=2,605), force-titrated up to 45 mg daily or placebo (N=2,633) 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, nonfatal 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 (HR = 0.90; 95% CI: 0.80, 1.02; p=0.10). Although there was no statistically significant difference between pioglitazone and placebo for the three 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 10. Table 10: PROactive Trial: Number of First and Total Events for Each Component Within the Cardiovascular Composite Endpoint CABG = coronary artery bypass grafting; PCI = percutaneous intervention. Cardiovascular Events Placebo N=2,633 Pioglitazone N=2,605 First Events n (%) Total events n First Events n (%) Total events n Any event 572 (21.7) 900 514 (19.7) 803 All-cause mortality 122 (4.6) 186 110 (4.2) 177 Nonfatal myocardial infarction (MI) 118 (4.5) 157 105 (4.0) 131 Stroke 96 (3.6) 119 76 (2.9) 92 Acute coronary syndrome 63 (2.4) 78 42 (1.6) 65 Cardiac intervention (CABG/PCI) 101 (3.8) 240 101 (3.9) 195 Major leg amputation 15 (0.6) 28 9 (0.3) 28 Leg revascularization 57 (2.2) 92 71 (2.7) 115 Weight Gain Dose-related weight gain occurs when pioglitazone is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Tables 11, 12, and 13 summarize the changes in body weight with pioglitazone and placebo in the 16 to 26 week randomized, double-blind monotherapy and 16 to 24 week combination add-on therapy trials, the PROactive trial, and the 24 week ACTOPLUS MET trial. Table 11: Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical Trials Control Group (Placebo) Pioglitazone 15 mg Pioglitazone 30 mg Pioglitazone 45 mg Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Monotherapy (16 to 26 weeks) -1.4 (-2.7, 0.0) N=256 0.9 (-0.5, 3.4) N=79 1.0 (-0.9, 3.4) N=188 2.6 (0.2, 5.4) N=79 Combination Therapy (16 to 24 weeks) Sulfonylurea -0.5 (-1.8, 0.7) N=187 2.0 (0.2, 3.2) N=183 3.1 (1.1, 5.4) N=528 4.1 (1.8, 7.3) N=333 Metformin -1.4 (-3.2, 0.3) N=160 N/A 0.9 (-1.3, 3.2) N=567 1.8 (-0.9, 5.0) N=407 Insulin 0.2 (-1.4, 1.4) N=182 2.3 (0.5, 4.3) N=190 3.3 (0.9, 6.3) N=522 4.1 (1.4, 6.8) N=338 Table 12: Median Change in Body Weight in Patients Treated with Pioglitazone vs 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. Placebo Pioglitazone Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Change from baseline to final visit (kg) -0.5 (-3.3, 2.0) N=2,581 +3.6 (0.0, 7.5) N=2,560 Table 13: Weight Changes (kg) from Baseline During Double-Blind Clinical Trial with ACTOPLUS MET in Patients with Inadequate Glycemic Control on Diet and Exercise Note: Trial duration of 24 weeks. ACTOPLUS MET 15/850 mg Twice Daily Pioglitazone 15 mg Twice Daily Metformin 850 mg Twice Daily Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Change from baseline to final visit (kg) 1.00 (-1.0, 3.0) N=198 1.35 (-0.7, 4.1) N=178 -1.00 (-2.6, 0.4) N=203 Edema Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is co-existing congestive heart failure. In the 24 week ACTOPLUS MET trial, edema was reported in 3.0% of patients in the ACTOPLUS MET 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 14. Table 14: 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.” Number (%) of Patients Placebo Pioglitazone 15 mg Pioglitazone 30 mg Pioglitazone 45 mg Monotherapy (16 to 26 weeks) 3 (1.2%) N=259 2 (2.5%) N= 81 13 (4.7%) N= 275 11 (6.5%) N=169 Combined Therapy (16 to 24 weeks) Sulfonylurea 4 (2.1%) N=187 3 (1.6%) N=184 61 (11.3%) N=540 81 (23.1%) N=351 Metformin 4 (2.5%) N=160 N/A 34 (5.9%) N=579 58 (13.9%) N=416 Insulin 13 (7.0%) N=187 24 (12.6%) N=191 109 (20.5%) N=533 90 (26.1%) N=345 Table 15: 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.” Number (%) of Patients Placebo N=2,633 Pioglitazone N=2,605 419 (15.9%) 712 (27.3%) Hepatic Effects There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, three 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 eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1,051 (0.3%) patients treated with pioglitazone and 9/1,046 (0.9%) patients treated with glyburide developed ALT values greater than 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 greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than 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 [see Nonclinical Toxicology (13.1) ] . During the three-year PROactive clinical trial, 14 patients out of 2,605 (0.54%) randomized to pioglitazone and 5 out of 2,633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and 2 (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR = 1.00; [95% CI: 0.59 1.72]) [see Warnings and Precautions (5.6) ] . Metformin HCl In a double-blind clinical study of metformin in patients with type 2 diabetes mellitus, a total of 141 patients received metformin therapy (up to 2,550 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 16. In this trial, diarrhea led to discontinuation of study medication in 6% of patients treated with metformin. Table 16: 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. Adverse Reaction Metformin Monotherapy (n=141) Placebo (n=145) % of Patients Diarrhea 53.2 11.7 Nausea/Vomiting 25.5 8.3 Flatulence 12.1 5.5 Asthenia 9.2 5.5 Indigestion 7.1 4.1 Abdominal Discomfort 6.4 4.8 Headache 5.7 4.8 Laboratory Abnormalities Pioglitazone 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 four 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. 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 nine (0.2%) patients treated with pioglitazone (values of 2,150 to 11,400 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. Metformin Vitamin B 12 Concentrations In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of pioglitazone and/or metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Pioglitazone Cardiac Disorders: Rapid increases in weight, edema, congestive heart failure with and without previously known heart disease or concomitant insulin administration Eye Disorders: New onset or worsening diabetic macular edema with decreased visual acuity Hepatobiliary Disorders: Fatal and nonfatal hepatic failure Metformin Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury.
التحذيرات والاحتياطات
5 WARNINGS AND PRECAUTIONS Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms. ( 5.1 ) Edema: Dose-related edema may occur. ( 5.3 ) Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination with ACTOPLUS MET. ( 5.4 ) Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt ACTOPLUS MET and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart ACTOPLUS MET if liver injury is confirmed and no alternate etiology can be found. ( 5.5 ) Urinary Bladder Tumors: May increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. ( 5.6 ) Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. ( 5.7 ) Macular edema: Postmarketing reports. Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes. ( 5.8 ) Vitamin B 12 deficiency: Metformin may lower vitamin B 12 levels. Monitor hematologic parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. ( 5.9 ) 5.1 Congestive Heart Failure Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Observe patients for signs and symptoms of congestive heart failure. If congestive heart failure develops while taking ACTOPLUS MET, consider discontinuation of ACTOPLUS MET or dosage reduction of pioglitazone in ACTOPLUS MET [see Boxed Warning , Contraindications (4) , Adverse Reactions (6.1) ] . 5.2 Lactic Acidosis Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio, and metformin plasma levels generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of ACTOPLUS MET. In ACTOPLUS MET-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue ACTOPLUS MET and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.3) , Clinical Pharmacology (12.3) ]. Before initiating ACTOPLUS MET, obtain an eGFR. ACTOPLUS MET is contraindicated in patients with an eGFR less than 30 mL/min. Initiation of ACTOPLUS MET is not recommended in patients with eGFR between 30 to 45 mL/min [see Contraindications (4) ] . Obtain an eGFR at least annually in all patients taking ACTOPLUS MET. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. In patients taking ACTOPLUS MET whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy . Drug Interactions The concomitant use of ACTOPLUS MET with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs) [see Drug Interactions (7) ]. Therefore, consider more frequent monitoring of patients. Age 65 or Greater The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5) ]. Radiological Studies with Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop ACTOPLUS MET 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 hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart ACTOPLUS MET if renal function is stable. Surgery and Other Procedures Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. ACTOPLUS MET should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue ACTOPLUS MET. Excessive Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving ACTOPLUS MET. Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of ACTOPLUS MET in patients with clinical or laboratory evidence of hepatic disease. 5.3 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 (6.1) ] . In postmarketing experience, reports of new onset or worsening of edema have been received. ACTOPLUS MET 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, ACTOPLUS MET should be used with caution in patients at risk for congestive heart failure. Patients treated with ACTOPLUS MET should be monitored for signs and symptoms of congestive heart failure [see Boxed Warning , Warnings and Precautions (5.1) ] . 5.4 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dosage of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with ACTOPLUS MET [see Drug Interactions (7.6 , 7.7) ] . 5.5 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 (6.1) ] . Patients with type 2 diabetes mellitus 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 ACTOPLUS MET therapy. In patients with abnormal liver tests, ACTOPLUS MET 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 clinically significant liver enzyme elevations (serum ALT greater than three times the ULN) and if abnormal liver tests persist or worsen, ACTOPLUS MET should be interrupted and investigation done to establish the probable cause. ACTOPLUS MET should not be restarted in these patients without another explanation for the liver test abnormalities. 5.6 Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the two year carcinogenicity study [see Nonclinical Toxicology (13.1) ] . In addition, during the three year PROactive clinical trial, 14 patients out of 2,605 (0.54%) randomized to pioglitazone and 5 out of 2,633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and 2 (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo [Hazard Ratio (HR) = 1.00; (95% Confidence Interval (CI) : 0.59, 1.72)]. Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone, while others did. A large prospective10 year observational cohort study conducted in the United States (U.S) found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to pioglitazone, compared to those never exposed to pioglitazone [HR = 1.06; (95% CI: 0.89, 1.26)]. A retrospective cohort study conducted with data from the United Kingdom found a statistically significant association between ever exposure to pioglitazone and bladder cancer [HR = 1.63; (95% CI: 1.22, 2.19)]. Associations between cumulative dose or cumulative duration of exposure to pioglitazone and bladder cancer were not detected in some studies including the 10 year observational study in the U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies preclude conclusive interpretations of the observational data. Pioglitazone may be associated with an increase in the risk of urinary bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, ACTOPLUS MET should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with ACTOPLUS MET should be considered in patients with a prior history of bladder cancer. 5.7 Fractures In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5,238 patients with type 2 diabetes mellitus and a history of macrovascular disease were randomized to pioglitazone (N=2,605), force-titrated up to 45 mg daily or placebo (N=2,633) 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 ACTOPLUS MET and attention should be given to assessing and maintaining bone health according to current standards of care. 5.8 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 (6.1) ] . 5.9 Vitamin B 12 Levels In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on ACTOPLUS MET and manage any abnormalities [see Adverse Reactions (6.1) ] .
الحرائك الدوائية
12.3 Pharmacokinetics Absorption ACTOPLUS MET In bioequivalence studies of ACTOPLUS MET 15 mg/500 mg and 15 mg/850 mg, the area under the curve (AUC) and maximum concentration (C max ) 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 ACTOPLUS MET 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. C max , AUC, and trough serum concentrations (C min ) 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, T max of pioglitazone was within two hours. Food delays the T max 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 1500 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 C max , a 25% lower AUC, and a 35 minute prolongation of T max 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 6ß-hydroxycortisol/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 (t ½ ) 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 t ½ of approximately 6.2 hours. In blood, the elimination t ½ 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, C max of pioglitazone was not significantly different, but AUC values were approximately 21% higher than those achieved in younger subjects. The mean t ½ 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 t ½ is prolonged, and C max 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. ACTOPLUS MET 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 C max 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 C max 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 t 1/2 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 C max 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 ACTOPLUS MET 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 ACTOPLUS MET have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components. Pioglitazone Table 18: Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs Coadministered Drug Pioglitazone Dosage Regimen (mg) Daily for 7 days unless otherwise noted. Name and Dose Regimens Change in AUC % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively. Change in C max 45 mg (N = 12) Warfarin Pioglitazone had no clinically significant effect on prothrombin time. 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 Norethindrone (NE) 1 mg] for 21 days EE ↓11% EE ↓13% 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 1,000 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% Table 19: Effect of Coadministered Drugs on Pioglitazone Systemic Exposure Coadministered Drug and Dosage Regimen Pioglitazone Dose Regimen (mg) Daily for 7 days unless otherwise noted. Change in AUC 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. Change in C max Gemfibrozil 600 mg twice daily for 2 days (N = 12) 15 mg single dose ↑3.2-fold 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) , Drug Interactions (7.1) ] . ↑6% Ketoconazole 200 mg twice daily for 7 days (N = 28) 45 mg ↑34% ↑14% Rifampin 600 mg daily for 5 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 Indicates duration of concomitant administration with highest twice-daily dose of topiramate from Day 14 onwards over the 22 days of study. 30 mg ↓15% Additional decrease in active metabolites; 60% for M-III and 16% for M-IV. 0% (N = 26) Metformin HCl Table 20: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin and coadministered drugs were given as single doses. Dose of Metformin Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.00 AUC AUC = AUC 0–∞ . C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg Metformin HCl extended-release tablets, 500 mg. 0.98 Ratio of arithmetic means. 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 0.90 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) , Drug Interactions (7) ] . Cimetidine 400 mg 850 mg 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) , Drug Interactions (7) ] . Topiramate 100 mg At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h 500 mg 1.25 1.17 Table 21: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin and coadministered drugs were given as single doses. Dose of Metformin Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.00 AUC AUC = AUC 0–∞ . C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg AUC 0-24 hr reported. 0.78 Ratio of arithmetic means, p-value of difference <0.05. 0.63 Furosemide 40 mg 850 mg 0.87 0.69 Nifedipine 10 mg 850 mg 1.10 1.08 Propranolol 40 mg 850 mg 1.01 0.94 Ibuprofen 400 mg 850 mg 0.97 Ratio of arithmetic means. 1.01 Cimetidine 400 mg 850 mg 0.95 1.01