metaglip

DESCRIPTION
METAGLIP™ (glipizide and metformin HCl) Tablets contains two oral antihyperglycemicdrugs used in the management of type 2 diabetes, glipizide and metformin hydrochloride metaglip.

Glipizide is an oral antihyperglycemic drug of the sulfonylurea class metaglip. Thechemical name for glipizide is 1-cyclohexyl-3-[[ p -[2-(5-methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea metaglip. Glipizide is a whitish, odorless powder with a molecular formula of C 21 H 27N 5 O 4 S, a molecular weight of 445.55 and a pK a of 5.9 metaglip. It is insoluble inwater and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide metaglip. The structural formula is represented below metaglip.

Metformin hydrochloride is an oral antihyperglycemic drug used in the managementof type 2 diabetes metaglip. Metformin hydrochloride ( N , N -dimethylimidodicarbonimidicdiamide mono-hydrochloride) is not chemically or pharmacologically related tosulfonylureas, thiazolidinediones, or (alpha)-glucosidase inhibitors metaglip. It isa white to off-white crystalline compound with a molecular formula of C 4 H12 ClN 5 (monohydrochloride) and a molecular weight of 165.63 metaglip. Metformin hydrochlorideis freely soluble in water and is practically insoluble in acetone, ether, andchloroform metaglip. The pK a of metformin is 12.4 metaglip. The pH of a 1% aqueous solution ofmetformin hydrochloride is 6.68 metaglip. The structural formula is as shown:

METAGLIP is available for oral administration in tablets containing 2.5 mgglipizide with 250 mg metformin hydrochloride, 2.5 mg glipizide with 500 mgmetformin hydrochloride, and 5 mg glipizide with 500 mg metformin hydrochloride metaglip. In addition, each tablet contains the following inactive ingredients: microcrystallinecellulose, povidone, croscarmellose sodium, and magnesium stearate metaglip. The tabletsare film coated, which provides color differentiation metaglip.

CLINICAL PHARMACOLOGY
Mechanism of Action
METAGLIP (glipizide and metformin HCl) combines glipizide and metformin hydrochloride,two antihyperglycemic agents with complementary mechanisms of action, to improveglycemic control in patients with type 2 diabetes metaglip.

Glipizide appears to lower blood glucose acutely by stimulating the releaseof insulin from the pancreas, an effect dependent upon functioning beta cellsin the pancreatic islets metaglip. Extrapancreatic effects may play a part in the mechanismof action of oral sulfonylurea hypoglycemic drugs metaglip. The mechanism by which glipizidelowers blood glucose during long-term administration has not been clearly established metaglip. In man, stimulation of insulin secretion by glipizide in response to a mealis undoubtedly of major importance metaglip. Fasting insulin levels are not elevatedeven on long-term glipizide administration, but the postprandial insulin responsecontinues to be enhanced after at least 6 months of treatment metaglip.

Metformin hydrochloride is an antihyperglycemic agent that improves glucosetolerance in patients with type 2 diabetes, lowering both basal and postprandialplasma glucose metaglip. Metformin hydrochloride decreases hepatic glucose production,decreases intestinal absorption of glucose, and improves insulin sensitivityby increasing peripheral glucose uptake and utilization metaglip.

Pharmacokinetics
Absorption and Bioavailability

METAGLIP

In a single dose study in healthy subjects, the glipizide and metformin componentsof METAGLIP 5 mg/500 mg were bioequivalent to coadministered GLUCOTROL ®and GLUCOPHAGE ® (metformin hydrochloride) metaglip. Following administration ofa single METAGLIP 5 mg/500 mg tablet in healthy subjects with either a 20% glucosesolution or a 20% glucose solution with food, there was a small effect of foodon peak plasma concentration (C max ) and no effect of food on area under thecurve (AUC) of the glipizide component metaglip. Time to peak plasma concentration (Tmax ) for the glipizide component was delayed 1 hour with food relative to thesame tablet strength administered fasting with a 20% glucose solution metaglip. C maxfor the metformin component was reduced approximately 14% by food whereas AUCwas not affected metaglip. T max for the metformin component was delayed 1 hour afterfood metaglip.

Glipizide

Gastrointestinal absorption of glipizide is uniform, rapid, and essentiallycomplete metaglip. Peak plasma concentrations occur 1-3 hours after a single oral dose metaglip. Glipizide does not accumulate in plasma on repeated oral administration metaglip. Totalabsorption and disposition of an oral dose was unaffected by food in normalvolunteers, but absorption was delayed by about 40 minutes metaglip.

Metformin hydrochloride

The absolute bioavailability of a 500 mg metformin hydrochloride tablet givenunder fasting conditions is approximately 50-60% metaglip. Studies using single oraldoses of metformin tablets of 500 mg and 1500 mg, and 850 mg to 2550 mg, indicatethat there is a lack of dose proportionality with increasing doses, which isdue to decreased absorption rather than an alteration in elimination metaglip. Food decreasesthe extent of and slightly delays the absorption of metformin, as shown by approximatelya 40% lower peak concentration and a 25% lower AUC in plasma and a 35-minuteprolongation of time to peak plasma concentration following administration ofa single 850 mg tablet of metformin with food, compared to the same tablet strengthadministered fasting metaglip. The clinical relevance of these decreases is unknown metaglip.

Distribution
Glipizide

Protein binding was studied in serum from volunteers who received either oralor intravenous glipizide and found to be 98-99% one hour after either routeof administration metaglip. The apparent volume of distribution of glipizide after intravenousadministration was 11 liters, indicative of localization within the extracellularfluid compartment metaglip. In mice, no glipizide or metabolites were detectable autoradiographicallyin the brain or spinal cord of males or females, nor in the fetuses of pregnantfemales metaglip. In another study, however, very small amounts of radioactivity weredetected in the fetuses of rats given labeled drug metaglip.

Metformin hydrochloride

The apparent volume of distribution (V/F) of metformin following single oraldoses of 850 mg averaged 654 ± 358 L metaglip. Metformin is negligibly bound toplasma proteins metaglip. Metformin partitions into erythrocytes, most likely as a functionof time metaglip. At usual clinical doses and dosing schedules of metformin, steady stateplasma concentrations of metformin are reached within 24-48 hours and are generally<1 µg/mL metaglip. During controlled clinical trials, maximum metformin plasmalevels did not exceed 5 µg/mL, even at maximum doses metaglip.

Metabolism and Elimination
Glipizide

The metabolism of glipizide is extensive and occurs mainly in the liver metaglip. Theprimary metabolites are inactive hydroxylation products and polar conjugatesand are excreted mainly in the urine metaglip. Less than 10% unchanged glipizide is foundin the urine metaglip. The half-life of elimination ranges from 2-4 hours in normal subjects,whether given intravenously or orally metaglip. The metabolic and excretory patternsare similar with the two routes of administration, indicating that first-passmetabolism is not significant metaglip.

Metformin hydrochloride

Intravenous single-dose studies in normal subjects demonstrate that metforminis excreted unchanged in the urine and does not undergo hepatic metabolism (nometabolites have been identified in humans) nor biliary excretion metaglip. Renal clearance(see Table 1 ) is approximately 3.5 times greater than creatinine clearance,which indicates that tubular secretion is the major route of metformin elimination metaglip. Following oral administration, approximately 90% of the absorbed drug is eliminatedvia the renal route within the first 24 hours, with a plasma elimination half-lifeof approximately 6.2 hours metaglip. In blood, the elimination half-life is approximately17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution metaglip.

Special Populations
Patients With Type 2 Diabetes

In the presence of normal renal function, there are no differences betweensingle- or multiple-dose pharmacokinetics of metformin between patients withtype 2 diabetes and normal subjects (see Table 1 ), nor is there any accumulationof metformin in either group at usual clinical doses metaglip.

Hepatic Insufficiency
The metabolism and excretion of glipizide may be slowed in patients with impairedhepatic function (see PRECAUTIONS ) metaglip. No pharmacokinetic studies have been conductedin patients with hepatic insufficiency for metformin metaglip.

Renal Insufficiency
The metabolism and excretion of glipizide may be slowed in patients with impairedrenal function (see PRECAUTIONS ) metaglip.

In patients with decreased renal function (based on creatinine clearance),the plasma and blood half-life of metformin is prolonged and the renal clearanceis decreased in proportion to the decrease in creatinine clearance (see Table1 ; also, see WARNINGS ) metaglip.

Geriatrics
There is no information on the pharmacokinetics of glipizide in elderly patients metaglip.

Limited data from controlled pharmacokinetic studies of metformin in healthyelderly subjects suggest that total plasma clearance is decreased, the half-lifeis prolonged, and C max is increased, compared to healthy young subjects metaglip. Fromthese data, it appears that the change in metformin pharmacokinetics with agingis primarily accounted for by a change in renal function (see Table 1 ) metaglip. Metformintreatment should not be initiated in patients >/=80 years of age unless measurementof creatinine clearance demonstrates that renal function is not reduced metaglip.

Table 1: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following
Single or Multiple Oral Doses of Metformin Subject Groups: Metformin
Dose a (Number of Subjects) C max b
(µg/mL) T max c
(hrs) Renal Clearance
(mL/min)
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 metaglip. for 19 doses f (9) 2.01 (±0.42) 1.79 (±0.94) 642(±173)
Adults with Type 2 Diabetes:
850 mg SD (23)
850 mg t.i.d metaglip. for 19 doses f (9)

1.48 (±0.5)
1.90 (±0.62)

3.32 (±1.08)
2.01 (±1.22)

491 (±138)
550 (±160)
Elderly g , Healthy Nondiabetic Adults:
850 mg SD (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98)
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 (range23-59 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 foreither glipizide or metformin metaglip.

Gender
There is no information on the effect of gender on the pharmacokinetics of glipizide metaglip.

Metformin pharmacokinetic parameters did not differ significantly in subjectswith or without type 2 diabetes when analyzed according to gender (males = 19,females = 16) metaglip. Similarly, in controlled clinical studies in patients with type2 diabetes, the antihyperglycemic effect of metformin was comparable in malesand females metaglip.

Race
No information is available on race differences in the pharmacokinetics of glipizide metaglip.

No studies of metformin pharmacokinetic parameters according to race have beenperformed metaglip. In controlled clinical studies of metformin in patients with type2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks(n=51), and Hispanics (n=24) metaglip.

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