Pioglitazone hydrochloride and metformin hydrochloride tablets
In bioequivalence studies of pioglitazone hydrochloride and metformin hydrochloride tablets 15 mg/500 mg and 15 mg/850 mg, the area under the curve (AUC) and maximum concentration (Cmax ) of both the pioglitazone and the metformin component following a single dose of the combination tablet were bioequivalent to pioglitazone hydrochloride tablets 15 mg concomitantly administered with Glucophage (500 mg or 850 mg respectively) tablets under fasted conditions in healthy subjects.
Administration of pioglitazone hydrochloride and metformin hydrochloride tablets 15 mg/850 mg with food resulted in no change in overall exposure of pioglitazone. With metformin there was no change in AUC; however, mean peak serum concentration of metformin was decreased by 28% when administered with food. A delayed time to peak serum concentration was observed for both components (1.9 hours for pioglitazone and 0.8 hours for metformin) under fed conditions. These changes are not likely to be clinically significant.
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.
Maximum serum concentration (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 hydrochloride, peak concentrations of pioglitazone were observed within 2 hours. Food slightly delays the time to peak serum concentration (Tmax ) to 3 to 4 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. 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.
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 apparent volume of distribution (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. 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.
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. 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 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.
Excretion and Elimination
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 its metabolites (M-III and M-IV) range 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.
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.
The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dose adjustment in patients with renal impairment is required.
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 (4) and Warnings and Precautions (5.2)]. Because metformin is contraindicated in patients with renal impairment, pioglitazone hydrochloride and metformin hydrochloride tablets are also contraindicated in these patients.
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 peak concentrations 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 pioglitazone hydrochloride and metformin hydrochloride tablets with caution in patients with liver disease [see Warnings and Precautions (5.4)].
No pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment. Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Pioglitazone hydrochloride and metformin hydrochloride tablets is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.4)].
In healthy elderly subjects, peak serum concentrations of pioglitazone are not significantly different, but AUC values are approximately 21% higher than those achieved in younger subjects. The mean terminal half-life values of pioglitazone were also longer in elderly subjects (about 10 hours) as compared to younger subjects (about 7 hours). These changes were not of a magnitude that would be considered clinically relevant.
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.
As is true for all patients, pioglitazone hydrochloride and metformin hydrochloride tablets treatment should not be initiated in geriatric patients unless measurement of creatinine clearance demonstrates that renal function is not reduced [see Warnings and Precautions (5.2)].
Safety and efficacy of pioglitazone in pediatric patients have not been established. Pioglitazone hydrochloride and metformin hydrochloride tablets is not recommended for use in pediatric patients [see Use in Specific Populations (8.4)].
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.
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 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.
Pharmacokinetic data among various ethnic groups are not available.
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 pioglitazone hydrochloride and metformin hydrochloride tablets have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.
|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) then0.250 mg daily (maintenance dose, 7 days)||↑ 15%||↑ 17%|
|45 mg daily for 21 days(N = 35)||Oral Contraceptive|
|[Ethinyl Estradiol (EE) 0.035 mg plusNorethindrone (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%|
|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)||30 mg single dose||↑ 3.4-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%|
|Coadministered Drug||Dose of Coadministered Drug *||Dose of Metformin *||Geometric Mean Ratio(ratio with/without coadministered drug)No effect = 1.00|
|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§|
|Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination: use with caution [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: use with caution [see Warnings and Precautions (5) and Drug Interactions (7)].|
|Topiramate||100 mg ¶||500 mg ¶||1.25¶||1.17|
|Coadministered Drug||Dose of Coadministered Drug *||Dose of Metformin *||Geometric Mean Ratio(ratio with/without coadministered drug) No effect = 1.00|
|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|