Glucovance

[Glyburide/Metformin]

Healthy, nondiabetic adults:
500 mg SD d (24) 1.03 (± 0.33) 2.75 (± 0.81) 600 (± 132)
850 mg SD (74) e 1.60 (± 0.38) 2.64 (± 0.82) 552 (± 139)
850 mg t. i. d. for 19 doses f (9) 2.01 (± 0.42) 1.79 (± 0.94) 642 (± 173)

Adults with type 2 diabetes:
850 mg SD (23) 1.48 (± 0.5) 3.32 (± 1.08) 491 (± 138)
850 mg t. i. d. for 19 doses f (9) 1.90 (± 0.62) 2.01 (± 1.22) 550 (± 160)

Elderly g , healthy nondiabetic adults:
850 mg SD (12) 2.45 (± 0.70) 2.71 (± 1.05) 412 (± 98)

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Renal-impaired adults: 850 mg SD
Mild (CL cr h 61-90 mL/ min) (5) 1.86 (± 0.52) 3.20 (± 0.45) 384 (± 122)
Moderate (CL cr 31-60 mL/ min) (4) 4.12 (± 1.83) 3.75 (± 0.50) 108 (± 57)
Severe (CL cr 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 SD = single dose
e Combined results (average means) of five studies: mean age 32 years (range 23-59 years)
f Kinetic study done following dose 19, given fasting
g Elderly subjects, mean age 71 years (range 65-81 years)
h CL cr = creatinine clearance normalized to body surface area of 1.73 m 2

Pediatrics

No data from pharmacokinetic studies in pediatric subjects are available for either glyburide or metformin.

Gender

There is no information on the effect of gender on the pharmacokinetics of glyburide. Metformin pharmacokinetic parameters did not differ significantly in subjects with or without 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 com-parable in males and females.

Race

No information is available on race differences in the pharmacokinetics of glyburide. 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).

Clinical Studies

Initial Therapy

In a 20-week, double-blind, multicenter U. S. clinical trial, a total of 806 drug-naive patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with diet and exercise alone (baseline fasting plasma glucose [FPG] <240 mg/ dL, baseline hemoglobin A 1c [HbA 1c ] between 7% and 11%), were randomized to receive initial therapy with placebo, 2.5 mg glyburide, 500 mg met-formin, GLUCOVANCE 1.25 mg/ 250 mg, or GLUCOVANCE (Glyburide and Metformin HCl Tablets) 2.5 mg/ 500 mg. After four weeks, the dose was progressively increased (up to the eight-week visit) to a maximum of four tablets daily as needed to reach a target FPG of 126 mg/ dL. Trial data at 20 weeks are summarized in Table 2.

a p< 0.001
b p< 0.05
c p= NS

Treatment with GLUCOVANCE resulted in significantly greater reduction in HbA 1c and postprandial plasma glucose (PPG) compared to glyburide, metformin, or placebo. Also, GLUCOVANCE therapy resulted in greater reduction in FPG compared to glyburide, metformin, or placebo, but the differences from glyburide and metformin did not reach statistical significance.

Changes in the lipid profile associated with GLUCOVANCE treatment were similar to those seen with glyburide, metformin, and placebo. The double-blind placebo-controlled trial described above restricted enrollment to patients with HbA 1c <11% or FPG <240 mg/ dL. Screened patients ineligible for the first trial because of HbA 1c and/ or FPG exceeding these limits were treated directly with GLUCOVANCE 2.5 mg/ 500 mg in an open-label uncontrolled protocol. In this study, three out of 173 patients (1.7%) discontinued because of inadequate therapeutic response. Across the group of 144 patients who completed 26 weeks of treatment, mean HbA 1c was reduced from a baseline of 10.6% to 7.1%. The mean baseline FPG was 283 mg/ dL and was reduced to 164 and 161 mg/ dL after 2 and 26 weeks, respectively. The mean final titrated dose of GLUCOVANCE was 7.85 mg/ 1569 mg (equivalent to approximately three GLUCOVANCE 2.5 mg/ 500 mg tablets per day).

Second Line Therapy

In a 16-week, double-blind, active-controlled U. S. clinical trial, a total of 639 patients with type 2 diabetes not adequately controlled (mean baseline HbA 1c 9.5%, mean baseline FPG 213 mg/ dL)
while being treated with at least one-half the maximum dose of a sulfonylurea (e. g., glyburide 10 mg, glipizide 20 mg) were randomized to receive glyburide (fixed dose, 20 mg), metformin (500 mg), GLUCOVANCE 2.5 mg/ 500 mg, or GLUCOVANCE 5 mg/ 500 mg. The doses of metformin and GLUCOVANCE were titrated to a maximum of four tablets daily as needed to achieve FPG <140 mg/ dL. Trial data at 16 weeks are summarized in Table 3.

a p< 0.001
After 16 weeks, there was no significant change in the mean HbA 1c in the patients randomized to glyburide or to metformin therapy. Treatment with GLUCOVANCE at doses up to 20 mg/ 2000 mg per day resulted in significant lowering of HbA 1c , FPG, and PPG from baseline compared to glyburide or metformin alone.

In a 24-week, double-blind, multicenter U. S. clinical trial, patients with type 2 diabetes not ade-quately controlled on current oral antihyperglycemic therapy (either monotherapy or combination therapy) were first switched to open label GLUCOVANCE 2.5 mg/ 500 mg tablets and titrated to a maximum daily dose of 10 mg/ 2000 mg. A total of 365 patients inadequately controlled (HbA 1c >7.0% and 10%) after 10 to 12 weeks of a daily GLUCOVANCE dose of at least 7.5 mg/ 1500 mg were randomized to receive add-on therapy with rosiglitazone 4 mg or placebo once daily. After eight weeks, the rosiglitazone dose was increased to a maximum of 8 mg daily as needed to reach a target mean daily glucose of 126 mg/ dL or HbA 1c <7%. Trial data at 24 weeks or at the last prior visit are summarized in Table 4.

a Adjusted for the baseline mean difference
b p< 0.001
For patients who did not achieve adequate glycemic control on GLUCOVANCE, the addition of rosiglitazone, compared to placebo, resulted in significant lowering of HbA 1c and FPG.

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