GLUCOPHAGE (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, 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. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

12.3 Pharmacokinetics

Absorption
The absolute bioavailability of a GLUCOPHAGE 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of GLUCOPHAGE 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 GLUCOPHAGE, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL.

Following a single oral dose of GLUCOPHAGE XR, Cmax 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 GLUCOPHAGE, however, the extent of absorption (as measured by AUC) is comparable to GLUCOPHAGE.

At steady state, the AUC and C max are less than dose proportional for GLUCOPHAGE XR within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4 and 1.8 mcg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from GLUCOPHAGE XR at a 2000 mg once-daily dose is similar to the same total daily dose administered as GLUCOPHAGE tablets 1000 mg twice daily. After repeated administration of GLUCOPHAGE XR, 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 GLUCOPHAGE with food, compared to the same tablet strength administered fasting.
Although the extent of metformin absorption (as measured by AUC) from the GLUCOPHAGE XR tablet 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 GLUCOPHAGE XR.

Distribution
The apparent volume of distribution (V/F) of metformin following single oral doses of GLUCOPHAGE 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.
Metabolism
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.
Elimination
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.

Specific Populations

Renal Impairment
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)]
Hepatic Impairment
No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [See Warnings and Precautions (5.1) and Use in Specific Populations (8.7)]

Geriatrics Limited data from controlled pharmacokinetic studies of GLUCOPHAGE 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)]

Table 4: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of GLUCOPHAGE

Subject Groups: GLUCOPHAGE dose a

(number of subjects)

C max b

(mcg/mL)

T max c

(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) d 1.60 (±0.38) 2.64 (±0.82) 552 (±139)
850 mg three times daily for 19 doses e (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 e (9) 1.90 (±0.62) 2.01 (±1.22) 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 (CLcr g 61-90 mL/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122)
Moderate (CLcr 31-60 mL/min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57)
Severe (CLcr 10-30 mL/min) (6) 3.93 (±0.92) 4.01 (±1.10) 130 (±90)

a All doses given fasting except the first 18 doses of the multiple dose studies
b Peak plasma concentration
c Time to peak plasma concentration
d Combined results (average means) of five studies: mean age 32 years (range 23-59 years)
e Kinetic study done following dose 19, given fasting
f Elderly subjects, mean age 71 years (range 65-81 years)
g CLcr = creatinine clearance normalized to body surface area of 1.73 m 2

Pediatrics
After administration of a single oral GLUCOPHAGE 500 mg tablet with food, geometric mean metformin C max and AUC differed less than 5% between pediatric type 2 diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function.

Gender
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).

Race
No studies of metformin pharmacokinetic parameters according to race have been performed.

Drug Interactions In Vivo Assessment of Drug Interactions

Table 5: 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 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 Drug Interactions (7)]
Cimetidine 400 mg 850 mg metformin 1.40 1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis [See 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)
‡ Ratio of arithmetic means § At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0 -12h

Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure

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

* 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

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2019. All Rights Reserved.