Following a single oral dose of metformin hydrochloride extended-release tablets, C max is achieved with a median value of 7 hours and a range of 4 to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride tablets, however, the extent of absorption (as measured by AUC) is comparable to metformin hydrochloride tablets.
At steady state, the AUC and C max are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 to 2,000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4 and 1.8 mcg/mL for 500, 1,000, 1,500, and 2,000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets at a 2,000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1,000 mg twice daily. After repeated administration of metformin hydrochloride extended-release tablets, metformin did not accumulate in plasma.
Effect of food: Food decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (T max ) following administration of a single 850 mg tablet of metformin hydrochloride with food, compared to the same tablet strength administered fasting.
Although the extent of metformin absorption (as measured by AUC) from the metformin hydrochloride extended-release tablets increased by approximately 50% when given with food, there was no effect of food on C max and T max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended-release tablets.
The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.
Renal clearance (see Table 3) 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.
In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 2) [See Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)] .
Limited data from controlled pharmacokinetic studies of metformin hydrochloride tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 3) . [See Warnings and Precautions (5.1) and Use in Specific Populations (8.5)] .
|Subject Groups: Metformin Hydrochloride Tablets Dose * (number of subjects)||C max †(mcg/mL)||T max ‡(hrs)||Renal Clearance (mL/min)|
|Healthy, nondiabetic adults:|
|500 mg single dose (24)||1.03 (± 0.33)||2.75 (± 0.81)||600 (± 132)|
|850 mg single dose (74) §||1.60 (± 0.38)||2.64 (± 0.82)||552 (± 139)|
|850 mg three times daily for 19 doses ¶ (9)||2.01 (± 0.42)||1.79 (± 0.94)||642 (± 173)|
|Adults with type 2 diabetes mellitus:|
|850 mg single dose (23)||1.48 (± 0.5)||3.32 (± 1.08)||491 (± 138)|
|850 mg three times daily for 19 doses ¶ (9)||1.90 (± 0.62)||2.01 (± 1.22)||550 (± 160)|
|Elderly #, healthy nondiabetic adults:|
|850 mg single dose (12)||2.45 (± 0.70)||2.71 (± 1.05)||412 (± 98)|
|850 mg single dose|
|Mild (CL cr Þ 61 to 90 mL/min) (5)||1.86 (± 0.52)||3.20 (± 0.45)||384 (± 122)|
|Moderate (CL cr 31 to 60 mL/min) (4)||4.12 (± 1.83)||3.75 (± 0.50)||108 (± 57)|
|Severe (CL cr 10 to 30 mL/min) (6)||3.93 (± 0.92)||4.01 (± 1.10)||130 (± 90)|
After administration of a single oral metformin hydrochloride 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), all with normal renal function.
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).
No studies of metformin pharmacokinetic parameters according to race have been performed.
In Vivo Assessment of Drug Interactions
|Coadministered Drug||Dose of Coadministered Drug *||Dose of Metformin *||Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00|
|AUC †||C max|
|No dosing adjustments required for the following:|
|Glyburide||5 mg||850 mg||metformin||0.91 ‡||0.93 ‡|
|Furosemide||40 mg||850 mg||metformin||1.09 ‡||1.22 ‡|
|Nifedipine||10 mg||850 mg||metformin||1.16||1.21|
|Propranolol||40 mg||850 mg||metformin||0.90||0.94|
|Ibuprofen||400 mg||850 mg||metformin||1.05 ‡||1.07 ‡|
|Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [See Warnings and Precautions (5.1) and Drug Interactions (7).]|
|Cimetidine||400 mg||850 mg||metformin||1.40||1.61|
|Carbonic anhydrase inhibitors may cause metabolic acidosis [See Warnings and Precautions (5.1) and Drug Interactions (7).]|
|Topiramate||100 mg §||500 mg §||metformin||1.25 §||1.17|
|Coadministered Drug||Dose of Coadministered Drug *||Dose of Metformin *||Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00|
|AUC †||C max|
|No dosing adjustments required for the following:|
|Glyburide||5 mg||850 mg||glyburide||0.78 ‡||0.63 ‡|
|Furosemide||40 mg||850 mg||furosemide||0.87 ‡||0.69 ‡|
|Nifedipine||10 mg||850 mg||nifedipine||1.10 §||1.08|
|Propranolol||40 mg||850 mg||propranolol||1.01 §||1.02|
|Ibuprofen||400 mg||850 mg||ibuprofen||0.97 ¶||1.01 ¶|
|Cimetidine||400 mg||850 mg||cimetidine||0.95 §||1.01|
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