Source: FDA, National Drug Code (US) Revision Year: 2019
ACTOPLUS MET XR combines two anti-diabetic medications with different mechanisms of action to improve glycemic control in adults with type 2 diabetes: pioglitazone, a thiazolidinedione, and metformin hydrochloride, a biguanide. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.
Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.
In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.
Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
Metformin 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. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or healthy subjects [except in specific circumstances, see [Warnings and Precautions (5.4)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin [see Clinical Studies (14)].
Patients with lipid abnormalities were included in clinical trials with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in serum triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with pioglitazone [see Warnings and Precautions (5.10) and Adverse Reactions (6.1)].
In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the 15 mg, 30 mg, and 45 mg pioglitazone dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone than in the patients treated with placebo. There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone compared to placebo (Table 14).
Table 14. Lipids in a 26-Week Placebo-Controlled Monotherapy Dose-Ranging Study:
| Placebo | Pioglitazone 15 mg Once Daily | Pioglitazone 30 mg Once Daily | Pioglitazone 45 mg Once Daily | |
|---|---|---|---|---|
| Triglycerides (mg/dL) | N=79 | N=79 | N=84 | N=77 |
| Baseline (mean) | 263 | 284 | 261 | 260 |
| Percent change from baseline (adjusted mean*) | 4.8% | -9.0% † | -9.6% † | -9.3%† |
| HDL Cholesterol (mg/dL) | N=79 | N=79 | N=83 | N=77 |
| Baseline (mean) | 42 | 40 | 41 | 41 |
| Percent change from baseline (adjusted mean*) | 8.1% | 14.1%† | 12.2% | 19.1%† |
| LDL Cholesterol (mg/dL) | N=65 | N=63 | N=74 | N=62 |
| Baseline (mean) | 139 | 132 | 136 | 127 |
| Percent change from baseline (adjusted mean*) | 4.8% | 7.2% | 5.2% | 6.0% |
| Total Cholesterol (mg/dL) | N=79 | N=79 | N=84 | N=77 |
| Baseline (mean) | 225 | 220 | 223 | 214 |
| Percent change from baseline (adjusted mean*) | 4.4% | 4.6% | 3.3% | 6.4% |
* Adjusted for baseline, pooled center, and pooled center by treatment interaction
† p <0.05 versus placebo
In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy studies with metformin (16 weeks and 24 weeks), the results were generally consistent with the data above.
In bioequivalence studies of ACTOPLUS MET XR 15 mg/1000 mg and 30 mg/1000 mg, the AUC and maximum concentration (Cmax) of both the pioglitazone and the extended-release metformin components following a single dose of the combination tablet were bioequivalent to ACTOS 15 mg and 30 mg concomitantly administered with extended-release metformin hydrochloride (FORTAMET) 1000 mg tablets under fed conditions in healthy subjects.
Administration of ACTOPLUS MET XR 30 mg/1000 mg with food resulted in no change in total (AUC) exposure of pioglitazone; however, a decrease in Cmax by approximately 18% was observed. With the extended-release metformin component, there was an increase in Cmax by approximately 98% and AUC exposure by approximately 85% when administered with food. These levels are comparable to exposures obtained with extended release metformin when administered with food. Time to peak serum concentration (Tmax) was prolonged by approximately three and two hours for pioglitazone and extended-release metformin respectively, under fed conditions.
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 7 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, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC.
Cmax, AUC, and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.
Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four hours, but does not alter the extent of absorption (AUC).
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. 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 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 approximately a 40% lower mean Cmax, a 25% lower AUC, and a 35-minute prolongation of Tmax following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
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.
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.
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) and 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.
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.
Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.
The mean serum half-life (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance (CL/F) calculated to be five to seven L/hr.
Renal clearance is approximately 3.5 times greater than creatinine clearance (CLcr) 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 t1/2 of approximately 6.2 hours. In blood, the t1/2 is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Pioglitazone:
The serum t1/2 of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (CLcr 30 to 50 mL/min) and severe (CLcr <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dose adjustment in patients with renal impairment is required.
Metformin hydrochloride:
In patients with decreased renal function, the plasma and blood t1/2 of metformin is prolonged and the renal clearance is decreased [see Dosage and Administration (2.2), Contraindications (4) and Warnings and Precautions (5.2)].
Pioglitazone:
Compared with healthy controls, subjects with impaired hepatic function (Child-Turcotte-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III and M-IV) mean Cmax but no change in the mean AUC values. Therefore, no dose 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 XR with caution in patients with liver disease [see Warnings and Precautions (5.5)].
Metformin hydrochloride:
No pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment [see Warnings and Precautions (5.5)].
Pioglitazone:
In healthy elderly subjects, Cmax of pioglitazone was not significantly different, but AUC values were approximately 21% higher than those achieved in younger subjects. The mean t1/2 of pioglitazone was also prolonged in elderly subjects (about ten hours) as compared to younger subjects (about seven hours). 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 CL/F is decreased, the t1/2 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.
Pioglitazone:
Safety and efficacy of pioglitazone in pediatric patients have not been established. ACTOPLUS MET XR is not recommended for use in pediatric patients [see Use in Specific Populations (8.4)].
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), all with normal renal function.
Pioglitazone:
The mean Cmax and AUC values of pioglitazone were increased 20% to 60% in women compared to men. 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 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.
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 metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).
Specific pharmacokinetic drug interaction studies with ACTOPLUS MET XR have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.
Pioglitazone:
Table 15. Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs:
| Coadministered Drug | ||||||||
|---|---|---|---|---|---|---|---|---|
| Pioglitazone Dosage Regimen (mg) * | Name and Dose Regimens | Change in AUC † | Change in Cmax† | |||||
| 45 mg (N=12) | Warfarin ‡ | |||||||
| Daily loading then maintenance doses based PT and INR values Quick’s Value=35 ± 5% | R-Warfarin | • ↓3% | R-Warfarin | ↓2% | ||||
| S-Warfarin | ↓1% | S-Warfarin | ↑1% | |||||
| 45 mg (N=12) | Digoxin | |||||||
| 0.200 mg twice daily (loading dose) then 0.250 mg daily (maintenance dose, 7 days) | ↑15% | ↑17% | ||||||
| 45 mg daily for 21 days (N=35) | Oral Contraceptive | |||||||
| [Ethinyl Estradiol (EE) 0.035 mg plus 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 | |||||||
| 1000 mg single dose on Day 8 | ↓3% | ↓5% | ||||||
| 45 mg (N=21) | Midazolam | |||||||
| 7.5 mg single dose on Day 15 | ↓26% | ↓26% | ||||||
| 45 mg (N=24) | Ranitidine | |||||||
| 150 mg twice daily for 7 days | ↑1% | ↓1% | ||||||
| 45 mg daily for 4 days (N=24) | Nifedipine ER | |||||||
| 30 mg daily for 4 days | ↓13% | ↓17% | ||||||
| 45 mg (N=25) | Atorvastatin Ca | |||||||
| 80 mg daily for 7 days | ↓14% | ↓23% | ||||||
| 45 mg (N=22) | Theophylline | |||||||
| 400 mg twice daily for 7 days | ↑2% | ↑5% | ||||||
* Daily for 7 days unless otherwise noted
† % change (with/without coadministered drug and no change=0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively
‡ Pioglitazone had no clinically significant effect on prothrombin time
Table 16. Effect of Coadministered Drugs on Pioglitazone Systemic Exposure:
| Coadministered Drug and Dosage Regimen | Pioglitazone | ||
|---|---|---|---|
| Dose Regimen (mg)* | Change in AUC † | Change in Cmax † | |
| Gemfibrozil 600 mg twice daily for 2 days (N=12) | 15 mg single dose | ↑3.2-fold ‡ | ↑6% |
| Ketoconazole 200 mg twice daily for 7 days (N=28) | 45 mg | ↑34% | ↑14% |
| Rifampin 600 mg daily 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 Ca 80 mg daily for 7 days (N=24) | 45 mg | ↓24% | ↓31% |
| Theophylline 400 mg twice daily for 7 days (N=22) | 45 mg | ↓4% | ↓2% |
| Topiramate 96 mg twice daily for 7 days § (N=26) | 30 mg § | ↓15% ¶ | 0% |
* Daily for 7 days unless otherwise noted
† Mean ratio (with/without coadministered drug and no change=1-fold) % change (with/without coadministered drug and no change=0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.
‡ The half-life of pioglitazone increased from 8.3 hours to 22.7 hours in the presence of gemfibrozil [see Dosage and Administration (2.3) and Drug Interactions (7.1)]
§ Indicates duration of concomitant administration with highest twice-daily dose of topiramate from Day 14 onwards over the 22 days of study
¶ Additional decrease in active metabolites; 60% for M-III and 16% for M-IV
Metformin hydrochloride:
Table 17. Effect of Coadministered Drug on Plasma Metformin Systemic Exposure:
| Coadministered Drug | Dose of Coadministered Drug* | Dose of Metformin* | Geometric Mean Ratio (ratio with/without coadministered drug) No effect=1.00 | |
|---|---|---|---|---|
| AUC† | Cmax | |||
| No dosing adjustments required for the following: | ||||
| Glyburide | 5 mg | 500 mg § | 0.98 ‡ | 0.99 ‡ |
| Furosemide | 40 mg | 850 mg | 1.09 ‡ | 1.22 ‡ |
| Nifedipine | 10 mg | 850 mg | 1.16 | 1.21 |
| Propranolol | 40 mg | 850 mg | 0.90 | 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) and Drug Interactions (7)]. | ||||
| Cimetidine | 400 mg | 850 mg | 1.40 | 1.61 |
| Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) and Drug Interactions (7)]. | ||||
| Topiramate | 100 mg ¶ | 500 mg ¶ | 1.25 ¶ | 1.17 |
* All metformin and coadministered drugs were given as single doses
† AUC=AUC0–∞
‡ Ratio of arithmetic means
§ Metformin hydrochloride extended-release tablets, 500 mg
¶ At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC=AUC0-12h
Table 18. Effect of Metformin on Coadministered Drug Systemic Exposure:
| Coadministered Drug | Dose of Coadministered Drug* | Dose of Metformin* | Geometric Mean Ratio (ratio with/without coadministered drug) No effect=1.00 | |
|---|---|---|---|---|
| AUC† | Cmax | |||
| No dosing adjustments required for the following: | ||||
| Glyburide | 5 mg | 500 mg § | 0.78 ‡ | 0.63 ‡ |
| Furosemide | 40 mg | 850 mg | 0.87 ‡ | 0.69 ‡ |
| Nifedipine | 10 mg | 850 mg | 1.10 § | 1.08 |
| Propranolol | 40 mg | 850 mg | 1.01 § | 0.94 |
| Ibuprofen | 400 mg | 850 mg | 0.97 ¶ | 1.01 ¶ |
| Cimetidine | 400 mg | 850 mg | 0.95 § | 1.01 |
* All metformin and coadministered drugs were given as single doses
† AUC=AUC0–∞
‡ Ratio of arithmetic means, p-value of difference <0.05
§ AUC0-24 hr reported
¶ Ratio of arithmetic means
No animal studies have been conducted with ACTOPLUS MET XR. The following data are based on findings in studies performed with pioglitazone or metformin individually.
A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder of male rats. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). Urinary calculi with subsequent irritation and hyperplasia were postulated as the mechanism for bladder tumors observed in male rats. A two-year mechanistic study in male rats utilizing dietary acidification to reduce calculi formation was completed in 2009. Dietary acidification decreased but did not abolish the hyperplastic changes in the bladder. The presence of calculi exacerbated the hyperplastic response to pioglitazone but was not considered the primary cause of the hyperplastic changes.
The relevance to humans of the bladder findings in the male rat cannot be excluded.
A two-year carcinogenicity study was also conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m2). No drug-induced tumors were observed in any organ.
Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.
No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately nine times the maximum recommended human oral dose based on mg/m2).
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times a human daily dose of 2000 mg of the metformin component of ACTOPLUS MET XR based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose of the metformin component of ACTOPLUS MET XR based on body surface area comparisons.
Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2).
There have been no clinical efficacy studies conducted with ACTOPLUS MET XR. However, the efficacy and safety of the separate components have been previously established and the coadministration of the separate components has been evaluated for efficacy and safety in two clinical studies. These clinical studies established an added benefit of pioglitazone in patients with inadequately controlled type 2 diabetes while on metformin therapy. Bioequivalence of ACTOPLUS MET XR with coadministered pioglitazone and extended-release metformin tablets was demonstrated for both tablet strengths of ACTOPLUS MET XR [see Clinical Pharmacology (12.3)].
Two clinical trials were conducted with pioglitazone in combination with metformin. Both trials included patients with type 2 diabetes on any dose of metformin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn at least 3 weeks prior to starting study treatment.
In the first trial, 328 patients were randomized to receive either 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their current metformin regimen. Treatment with pioglitazone as add-on to metformin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to metformin (see Table 19).
Table 19. Glycemic Parameters in a 16 Week Placebo-Controlled, Add-on to Metformin Trial:
| Placebo + Metformin | Pioglitazone 30 mg + Metformin | |
|---|---|---|
| Total Population | ||
| HbA1c (%) | N=153 | N=161 |
| Baseline (mean) | 9.8 | 9.9 |
| Change from baseline (adjusted mean*) | 0.2 | -0.6 |
| Difference from placebo + metformin (adjusted mean*) 95% Confidence Interval | -0.8 † (-1.2, -0.5) | |
| Fasting Plasma Glucose (mg/dL) | N=157 | N=165 |
| Baseline (mean) | 260 | 254 |
| Change from baseline (adjusted mean*) | -5 | -43 |
| Difference from placebo + metformin (adjusted mean*) 95% Confidence Interval | -38† (-49, -26) | |
* Adjusted for baseline, pooled center, and pooled center by treatment interaction
† p ≤0.05 versus placebo + metformin
In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their current metformin regimen. The mean reduction from baseline at Week 24 in HbA1c was 0.8% for the 30 mg dose and 1.0% for the 45 mg dose (see Table 20). The mean reduction from baseline at Week 24 in FPG was 38 mg/dL for the 30 mg dose and 51 mg/dL for the 45 mg dose.
Table 20. Glycemic Parameters in a 24 Week Add-on to Metformin Study:
| Pioglitazone 30 mg + Metformin | Pioglitazone 45 mg + Metformin | |
|---|---|---|
| Total Population | ||
| HbA1c (%) | N=400 | N=398 |
| Baseline (mean) | 9.9 | 9.8 |
| Change from baseline (adjusted mean*) | -0.8 | -1.0 |
| Difference from 30 mg daily Pioglitazone + Metformin (adjusted mean*) (95% CI) | -0.2 (-0.5, 0.1) | |
| Fasting Plasma Glucose (mg/dL) | N=398 | N=399 |
| Baseline (mean) | 233 | 232 |
| Change from baseline (adjusted mean *) | -38 | -51 |
| Difference from 30 mg daily Pioglitazone + Metformin (adjusted mean*) (95% CI) | -12 † (-21, -4) | |
95% CI = 95% confidence interval
* Adjusted for baseline, pooled center, and pooled center by treatment interaction
† p ≤0.05 versus 30 mg daily pioglitazone + metformin
The therapeutic effect of pioglitazone in combination with metformin was observed in patients regardless of the metformin dose.
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