The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride 500 to 1500 mg and 850 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 hydrochloride, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL.
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 (Cmax ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax ) following administration of a single 850 mg tablet of metformin hydrochloride with food, compared to the same tablet strength administered fasting.
The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride 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 4) 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 3) [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 in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax 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 4). [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].
|a All doses given fasting except the first 18 doses of the multiple dose studies b Peak plasma concentrationc Time to peak plasma concentrationd Combined results (average means) of five studies: mean age 32 years (range 23 to 59 years)e Kinetic study done following dose 19, given fastingf Elderly subjects, mean age 71 years (range 65 to 81 years)g CLcr = creatinine clearance normalized to body surface area of 1.73 m2|
|Subject Groups: Metformin Hydrochloride Tablets dosea (number of subjects)||Cmax b (mcg/mL)||Tmax c (hrs)||Renal Clearance (mL/min)|
|Healthy, nondiabetic adults: 500 mg single dose (24)850 mg single dose (74)d 850 mg three times daily for 19 dosese (9)||1.03 (±0.33)1.60 (±0.38)2.01 (±0.42)||2.75 (±0.81)2.64 (±0.82)1.79 (±0.94)||600 (±132)552 (±139)642 (±173)|
|Adults with type 2 diabetes mellitus: 850 mg single dose (23)850 mg three times daily for 19 dosese (9)||1.48 (±0.5)1.90 (±0.62)||3.32 (±1.08)2.01 (±1.22)||491 (±138)550 (±160)|
|Elderlyf , healthy nondiabetic adults:850 mg single dose (12)||2.45 (±0.70)||2.71 (±1.05)||412 (±98)|
|Renal-impaired adults: 850 mg single dose Mild (CLcrg 61 to 90 mL/min) (5)Moderate (CLcr 31 to 60 mL/min) (4)Severe (CLcr 10 to 30 mL/min) (6)||1.86 (±0.52) 4.12 (±1.83) 3.93 (±0.92)||3.20 (±0.45) 3.75 (±0.50) 4.01 (±1.10)||384 (±122)108 (±57)130 (±90)|
After administration of a single oral metformin hydrochloride 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.
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
|* All metformin and coadministered drugs were given as single doses † AUC = AUC(INF) ‡ Ratio of arithmetic means§ At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h|
|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||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|
|* All metformin and coadministered drugs were given as single doses† AUC = AUC(INF) unless otherwise noted‡ Ratio of arithmetic means, p-value of difference <0.05§ AUC(0-24 hr) reported¶ Ratio of arithmetic means|
|Coadministered Drug||Dose of Coadministered Drug *||Dose of Metformin *||Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00|
|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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