Glipizide and Metformin Hydrochloride

Glipizide and metformin hydrochloride tablets combine glipizide and metformin hydrochloride, 2 antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.

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

Metformin hydrochloride is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

In a single-dose study in healthy subjects, the glipizide and metformin components of glipizide and metformin hydrochloride tablets, 5 mg/500 mg were bioequivalent to coadministered glipizide tablets and metformin hydrochloride tablets. Following administration of a single glipizide and metformin hydrochloride 5 mg/500 mg tablet in healthy subjects with either a 20% glucose solution or a 20% glucose solution with food, there was a small effect of food on peak plasma concentration (C _{ma x}) and no effect of food on area under the curve (AUC) of the glipizide component. Time to peak plasma concentration (T _max) for the glipizide component was delayed 1 hour with food relative to the same tablet strength administered fasting with a 20% glucose solution. C _max for the metformin component was reduced approximately 14% by food whereas AUC was not affected. T _max for the metformin component was delayed 1 hour after food.

Gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. Peak plasma concentrations occur 1 to 3 hours after a single oral dose. Glipizide does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes.

The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets of 500 mg and 1500 mg, and 850 mg 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. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower peak concentration and a 25% lower AUC in plasma and a 35 minute prolongation of time to peak plasma concentration following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98% to 99% 1 hour after either route of administration. The apparent volume of distribution of glipizide after intravenous administration was 11 liters, indicative of localization within the extracellular fluid compartment. In mice, no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labeled drug.

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

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

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

The metabolism and excretion of glipizide may be slowed in patients with impaired hepatic function (see PRECAUTIONS). No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for metformin.

The metabolism and excretion of glipizide may be slowed in patients with impaired renal function (see PRECAUTIONS).

In patients with decreased renal function (based on creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also, see WARNINGS).

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

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and C _max is increased, when compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Metformin treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.

Table 1: Select Mean (± SD) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin

Subject Groups: Metformin Dose (Number of Subjects)	C max (mcg/mL)	T max (hrs)	Renal Clearance (mL/min)
Healthy, Nondiabetic Adults:
500 mg SD (24)	1.03 (± 0.33)	2.75 (± 0.81)	600 (± 132)
850 mg SD (74)	1.60 (± 0.38)	2.64 (± 0.82)	552 (± 139)
850 mg t.i.d. for 19 doses (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 (9)	1.90 (± 0.62)	2.01 (± 1.22)	550 (± 160)
Elderly , 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 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)

No data from pharmacokinetic studies in pediatric subjects are available for glipizide.

After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin C _max and AUC differed < 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.

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

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 comparable in males and females.

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

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).

In a 24 week, double-blind, active-controlled, multicenter international clinical trial, patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with diet and exercise alone (hemoglobin A _1c [HbA _1c] > 7.5% and ≤ 12% and fasting plasma glucose [FPG] < 300 mg/dL) were randomized to receive initial therapy with glipizide 5 mg, metformin 500 mg, glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, or glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg. After 2 weeks, the dose was progressively increased (up to the 12 week visit) to a maximum of 4 tablets daily in divided doses as needed to reach a target mean daily glucose (MDG) of ≤ 130 mg/dL. Trial data at 24 weeks are summarized in Table 2.

Table 2: Active-Controlled Trial of Glipizide and Metformin Hydrochloride Tablets in Patients With Inadequate Glycemic Control on Diet and Exercise Alone: Summary of Trial Data at 24 Weeks

	Glipizide 5 mg Tablets	Metformin 500 mg Tablets	Glipizide and Metformin Hydrochloride Tablets, 2.5 mg/250 mg	Glipizide and Metformin Hydrochloride Tablets, 2.5 mg/500 mg
Mean Final Dose	16.7 mg	1749 mg	7.9 mg/791 mg	7.4 mg/1477 mg
Hemoglobin A 1c (%)	N = 168	N = 171	N = 166	N = 163
Baseline Mean	9.17	9.15	9.06	9.1
Final Mean	7.36	7.67	6.93	6.95
Adjusted Mean Change from Baseline	-1.77	-1.46	-2.15	-2.14
Difference from Glipizide			-0.38	-0.37
Difference from Metformin			-0.70	-0.69
% Patients with Final HbA 1c < 7%	43.5%	35.1%	59.6%	57.1%
Fasting Plasma Glucose (mg/dL)	N = 169	N = 176	N = 170	N = 169
Baseline Mean	210.7	207.4	206.8	203.1
Final Mean	162.1	163.8	152.1	148.7
Adjusted Mean Change from Baseline	-46.2	-42.9	-54.2	-56.5
Difference from Glipizide			-8	-10.4
Difference from Metformin			-11.3	-13.6

After 24 weeks, treatment with glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg and 2.5 mg/500 mg resulted in significantly greater reduction in HbA _1c compared to glipizide and metformin therapy. Also, glipizide and metformin hydrochloride tablet, 2.5 mg/250 mg therapy resulted in significant reductions in FPG versus metformin therapy.

Increases above fasting glucose and insulin levels were determined at baseline and final study visits by measurement of plasma glucose and insulin for 3 hours following a standard mixed liquid meal. Treatment with glipizide and metformin hydrochloride tablets lowered the 3 hour postprandial glucose AUC, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. Compared to baseline, glipizide and metformin hydrochloride tablets enhanced the postprandial insulin response, but did not significantly affect fasting insulin levels.

There were no clinically meaningful differences in changes from baseline for all lipid parameters between glipizide and metformin hydrochloride tablet therapy and either metformin therapy or glipizide therapy. The adjusted mean changes from baseline in body weight were: glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, -0.4 kg; glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg, -0.5 kg; glipizide, -0.2 kg; and metformin, -1.9 kg. Weight loss was greater with metformin than with glipizide and metformin hydrochloride tablets.

In an 18 week, double-blind, active-controlled U.S. clinical trial, a total of 247 patients with type 2 diabetes not adequately controlled (HbA _1c ≥ 7.5% and ≤ 12% and FPG < 300 mg/dL) while being treated with at least one-half the maximum labeled dose of a sulfonylurea (e.g., glyburide 10 mg, glipizide 20 mg) were randomized to receive glipizide (fixed dose, 30 mg), metformin (500 mg), or glipizide and metformin hydrochloride tablets, 5 mg/500 mg. The doses of metformin and glipizide and metformin hydrochloride tablets were titrated (up to the 8 week visit) to a maximum of 4 tablets daily as needed to achieve MDG ≤ 130 mg/dL. Trial data at 18 weeks are summarized in Table 3.

Table 3: Glipizide and Metformin Hydrochloride Tablets in Patients With Inadequate Glycemic Control on Sulfonylurea Alone: Summary of Trial Data at 18 Weeks

	Glipizide 5 mg Tablets	Metformin 500 mg Tablets	Glipizide and Metformin Hydrochloride Tablets, 5 mg/500 mg
Mean Final Dose	30.0 mg	1927 mg	17.5 mg/1747 mg
Hemoglobin A 1c (%)	N = 79	N = 71	N = 80
Baseline Mean	8.87	8.61	8.66
Final Adjusted Mean	8.45	8.36	7.39
Difference from Glipizide			-1.06
Difference from Metformin			-0.98
% Patients with Final HbA 1c < 7%	8.9%	9.9%	36.3%
Fasting Plasma Glucose (mg/dL)	N = 82	N = 75	N = 81
Baseline Mean	203.6	191.3	194.3
Adjusted Mean Change from Baseline	7	6.7	-30.4
Difference from Glipizide			-37.4
Difference from Metformin			-37.2

After 18 weeks, treatment with glipizide and metformin hydrochloride tablets at doses up to 20 mg/2000 mg per day resulted in significantly lower mean final HbA _1c and significantly greater mean reductions in FPG compared to glipizide and metformin therapy. Treatment with glipizide and metformin hydrochloride tablets lowered the 3 hour postprandial glucose AUC, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. Glipizide and metformin hydrochloride tablets did not significantly affect fasting insulin levels.

There were no clinically meaningful differences in changes from baseline for all lipid parameters between glipizide and metformin hydrochloride tablet therapy and either metformin therapy or glipizide therapy. The adjusted mean changes from baseline in body weight were: glipizide and metformin hydrochloride tablets, 5 mg/500 mg, -0.3 kg; glipizide, -0.4 kg; and metformin, -2.7 kg. Weight loss was greater with metformin than with glipizide and metformin hydrochloride tablets.

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to 1 of 4 treatment groups ( Diabetes 19 (Suppl. 2):747-830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glipizide and of alternative modes of therapy.

Although only 1 drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

In a double-blind 24 week clinical trial involving glipizide and metformin hydrochloride tablets as initial therapy, a total of 172 patients received glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, 173 received glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg, 170 received glipizide, and 177 received metformin. The most common clinical adverse events in these treatment groups are listed in Table 4.

Table 4: Clinical Adverse Events > 5% in any Treatment Group, by Primary Term, in Initial Therapy Study

Adverse Event	Number (%) of Patients
Glipizide 5 mg Tablets N = 170	Metformin 500 mg Tablets N = 177	Glipizide and Metformin Hydrochloride Tablets, 2.5 mg/250 mg N = 172	Glipizide and Metformin Hydrochloride Tablets, 2.5 mg/500 mg N = 173
Upper respiratory infection	12 (7.1)	15 (8.5)	17 (9.9)	14 (8.1)
Diarrhea	8 (4.7)	15 (8.5)	4 (2.3)	9 (5.2)
Dizziness	9 (5.3)	2 (1.1)	3 (1.7)	9 (5.2)
Hypertension	17 (10.0)	10 (5.6)	5 (2.9)	6 (3.5)
Nausea/vomiting	6 (3.5)	9 (5.1)	1 (0.6)	3 (1.7)

In a double-blind 18 week clinical trial involving glipizide and metformin hydrochloride tablets as second-line therapy, a total of 87 patients received glipizide and metformin hydrochloride tablets, 84 received glipizide, and 75 received metformin. The most common clinical adverse events in this clinical trial are listed in Table 5.

Table 5: Clinical Adverse Events > 5% in any Treatment Group, by Primary Term, in Second-Line Therapy Study

	Number (%) of Patients
Adverse Event	Glipizide 5 mg Tablets N = 84	Metformin 500 mg Tablets N = 75	Glipizide and Metformin Hydrochloride Tablets, 5 mg/500 mg N = 87
Diarrhea	11 (13.1)	13 (17.3)	16 (18.4)
Headache	5 (6.0)	4 (5.3)	11 (12.6)
Upper respiratory infection	11 (13.1)	8 (10.7)	9 (10.3)
Musculoskeletal pain	6 (7.1)	5 (6.7)	7 (8.0)
Nausea/vomiting	5 (6.0)	6 (8.0)	7 (8.0)
Abdominal pain	7 (8.3)	5 (6.7)	5 (5.7)
UTI	4 (4.8)	6 (8.0)	1 (1.1)

In a controlled initial therapy trial of glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg and 2.5 mg/500 mg the numbers of patients with hypoglycemia documented by symptoms (such as dizziness, shakiness, sweating, and hunger) and a fingerstick blood glucose measurement ≤ 50 mg/dL were 5 (2.9%) for glipizide, 0 (0%) for metformin, 13 (7.6%) for glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, and 16 (9.3%) for glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg. Among patients taking either glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg or glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg, 9 (2.6%) patients discontinued glipizide and metformin hydrochloride tablets due to hypoglycemic symptoms and 1 required medical intervention due to hypoglycemia. In a controlled second-line therapy trial of glipizide and metformin hydrochloride tablets, 5 mg/500 mg, the numbers of patients with hypoglycemia documented by symptoms and a fingerstick blood glucose measurement ≤ 50 mg/dL were 0 (0%) for glipizide, 1 (1.3%) for metformin, and 11 (12.6%) for glipizide and metformin hydrochloride tablets. One (1.1%) patient discontinued glipizide and metformin hydrochloride tablet therapy due to hypoglycemic symptoms and none required medical intervention due to hypoglycemia (see PRECAUTIONS).

Among the most common clinical adverse events in the initial therapy trial were diarrhea and nausea/vomiting; the incidences of these events were lower with both glipizide and metformin hydrochloride tablets dosage strengths than with metformin therapy. There were 4 (1.2%) patients in the initial therapy trial who discontinued glipizide and metformin hydrochloride tablet therapy due to gastrointestinal (GI) adverse events. Gastrointestinal symptoms of diarrhea, nausea/vomiting, and abdominal pain were comparable among glipizide and metformin hydrochloride tablets, glipizide and metformin in the second-line therapy trial. There were 4 (4.6%) patients in the second-line therapy trial who discontinued glipizide and metformin hydrochloride tablet therapy due to GI adverse events.

Cholestatic and hepatocellular forms of liver injury accompanied by jaundice have been reported rarely in association with glipizide; glipizide and metformin hydrochloride tablets should be discontinued if this occurs.

To report SUSPECTED ADVERSE EVENTS, contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

Overdosage of sulfonylureas, including glipizide, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery. Clearance of glipizide from plasma would be prolonged in persons with liver disease. Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit.

Overdose of metformin hydrochloride has occurred, including ingestion of amounts > 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Dosage of glipizide and metformin hydrochloride tablets USP must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glipizide/2000 mg metformin. Glipizide and metformin hydrochloride tablets USP should be given with meals and should be initiated at a low dose, with gradual dose escalation as described below, in order to avoid hypoglycemia (largely due to glipizide), reduce GI side effects (largely due to metformin), and permit determination of the minimum effective dose for adequate control of blood glucose for the individual patient.

With initial treatment and during dose titration, appropriate blood glucose monitoring should be used to determine the therapeutic response to glipizide and metformin hydrochloride tablets USP and to identify the minimum effective dose for the patient. Thereafter, HbA _1c should be measured at intervals of approximately 3 months to assess the effectiveness of therapy. The therapeutic goal in all patients with type 2 diabetes is to decrease FPG, PPG, and HbA _1c to normal or as near normal as possible. Ideally, the response to therapy should be evaluated using HbA _1c, which is a better indicator of long-term glycemic control than FPG alone.

No studies have been performed specifically examining the safety and efficacy of switching to glipizide and metformin hydrochloride tablet therapy in patients taking concomitant glipizide (or other sulfonylurea) plus metformin. Changes in glycemic control may occur in such patients, with either hyperglycemia or hypoglycemia possible. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring.

When colesevelam is coadministered with glipizide ER, maximum plasma concentration and total exposure to glipizide is reduced. Therefore, glipizide and metformin hydrochloride tablets should be administered at least 4 hours prior to colesevelam.
Glipizide and Metformin Hydrochloride Tablets in Patients with Inadequate Glycemic Control on Diet and Exercise Alone

For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose of glipizide and metformin hydrochloride tablets USP is 2.5 mg/250 mg once a day with a meal. For patients whose FPG is 280 mg/dL to 320 mg/dL a starting dose of glipizide and metformin hydrochloride tablets USP, 2.5 mg/500 mg twice daily should be considered. The efficacy of glipizide and metformin hydrochloride tablets USP in patients whose FPG exceeds 320 mg/dL has not been established. Dosage increases to achieve adequate glycemic control should be made in increments of 1 tablet per day every 2 weeks up to maximum of 10 mg/1000 mg or 10 mg/2000 mg glipizide and metformin hydrochloride tablets USP per day given in divided doses. In clinical trials of glipizide and metformin hydrochloride tablets USP as initial therapy, there was no experience with total daily doses > 10 mg/2000 mg per day.

For patients not adequately controlled on either glipizide (or another sulfonylurea) or metformin alone, the recommended starting dose of glipizide and metformin hydrochloride tablets USP is 2.5 mg/500 mg or 5 mg/500 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of glipizide and metformin hydrochloride tablets USP should not exceed the daily doses of glipizide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day.

Patients previously treated with combination therapy of glipizide (or another sulfonylurea) plus metformin may be switched to glipizide and metformin hydrochloride tablets USP, 2.5 mg/500 mg or 5 mg/500 mg; the starting dose should not exceed the daily dose of glipizide (or equivalent dose of another sulfonylurea) and metformin already being taken. The decision to switch to the nearest equivalent dose or to titrate should be based on clinical judgment. Patients should be monitored closely for signs and symptoms of hypoglycemia following such a switch and the dose of glipizide and metformin hydrochloride tablets USP should be titrated as described above to achieve adequate control of blood glucose.

Recommendations for Use in Renal Impairment
Assess renal function prior to initiation of glipizide and metformin hydrochloride tablets and periodically thereafter.
Glipizide and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2.
Initiation of glipizide and metformin hydrochloride tablets in patients with an eGFR between 30 and 45 mL/minute/1.73 m2 is not recommended.
In patients taking glipizide and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.
Discontinue glipizide and metformin hydrochloride tablets if the patient’s eGFR later falls below 30 mL/minute/1.73 m2. (See WARNINGS.)
Discontinuation for Iodinated Contrast Imaging Procedure
Discontinue glipizide and metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart glipizide and metformin hydrochloride tablets if renal function is stable.

Q1. Why do I need to take glipizide and metformin hydrochloride tablets?

Your doctor has prescribed glipizide and metformin hydrochloride tablets to treat your type 2 diabetes. This is also known as non-insulin-dependent diabetes mellitus.

Q2. What is type 2 diabetes?

People with diabetes are not able to make enough insulin and/or respond normally to the insulin their body does make. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems, including kidney damage, amputations, and blindness. Diabetes is also closely linked to heart disease. The main goal of treating diabetes is to lower your blood sugar to a normal level.

Q3. Why is it important to control type 2 diabetes?

The main goal of treating diabetes is to lower your blood sugar to a normal level. Studies have shown that good control of blood sugar may prevent or delay complications, such as heart disease, kidney disease, or blindness.

Q4. How is type 2 diabetes usually controlled?

High blood sugar can be lowered by diet and exercise, a number of oral medications, and insulin injections. Before taking glipizide and metformin hydrochloride tablets you should first try to control your diabetes by exercise and weight loss. Even if you are taking glipizide and metformin hydrochloride tablets, you should still exercise and follow the diet recommended for your diabetes.

Q5. Does glipizide and metformin hydrochloride tablets work differently from other glucose-control medications?

Yes, it does. Glipizide and metformin hydrochloride tablets combine 2 glucose-lowering drugs, glipizide and metformin. These 2 drugs work together to improve the different metabolic defects found in type 2 diabetes. Glipizide lowers blood sugar primarily by causing more of the body’s own insulin to be released, and metformin lowers blood sugar, in part, by helping your body use your own insulin more effectively. Together, they are efficient in helping you to achieve better glucose control.

Q6. What happens if my blood sugar is still too high?

When blood sugar cannot be lowered enough by glipizide and metformin hydrochloride tablets, your doctor may prescribe injectable insulin or take other measures to control your diabetes.

Q7. Can glipizide and metformin hydrochloride tablets cause side effects?

Glipizide and metformin hydrochloride tablets, like all blood sugar-lowering medications, can cause side effects in some patients. Most of these side effects are minor. However, there are also serious, but rare, side effects related to glipizide and metformin hydrochloride tablets (see Question Nos. 9 to 13).

Q8. What are the most common side effects of glipizide and metformin hydrochloride tablets?

The most common side effects of glipizide and metformin hydrochloride tablets are normally minor ones such as diarrhea, nausea, and upset stomach. If these side effects occur, they usually occur during the first few weeks of therapy. Taking your glipizide and metformin hydrochloride tablets with meals can help reduce these side effects.

Symptoms of hypoglycemia (low blood sugar), such as lightheadedness, dizziness, shakiness, or hunger may occur. The risk of hypoglycemic symptoms increases when meals are skipped, too much alcohol is consumed, or heavy exercise occurs without enough food. Following the advice of your doctor can help you to avoid these symptoms.

Q9. Are there any serious side effects that glipizide and metformin hydrochloride tablets can cause?

People who have a condition known as glucose-6-phosphate dehydrogenase (G6PD) deficiency and who take glipizide and metformin hydrochloride tablets may develop hemolytic anemia (fast breakdown of red blood cells). G6PD deficiency usually runs in families. Tell your doctor if you or any members of your family have been diagnosed with G6PD deficiency before you start taking glipizide and metformin hydrochloride tablets.

Glipizide and metformin hydrochloride tablets rarely cause serious side effects. The most serious side effect that glipizide and metformin hydrochloride tablets can cause is called lactic acidosis.

Q10. What is lactic acidosis and can it happen to me?

Lactic acidosis is caused by a buildup of lactic acid in the blood. Lactic acidosis associated with metformin is rare and has occurred mostly in people whose kidneys were not working normally. Lactic acidosis has been reported in about 1 in 33,000 patients taking metformin over the course of a year. Although rare, if lactic acidosis does occur, it can be fatal in up to half the cases.

It’s also important for your liver to be working normally when you take glipizide and metformin hydrochloride tablets. Your liver helps remove lactic acid from your bloodstream.

Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally.

There is no evidence that glipizide and metformin hydrochloride tablets cause harm to the kidneys or liver.

Q11. Are there other risk factors for lactic acidosis?

Your risk of developing lactic acidosis from taking glipizide and metformin hydrochloride tablets is very low as long as your kidneys and liver are healthy. However, some factors can increase your risk because they can affect kidney and liver function. You should discuss your risk with your doctor.

You should not take glipizide and metformin hydrochloride tablets if:

• You have chronic kidney or liver problems
• You have congestive heart failure which is treated with medications, e.g., digoxin (Lanoxin ^®) or furosemide (Lasix ^®)
• You drink alcohol excessively (all the time or short-term “binge” drinking)
• You are seriously dehydrated (have lost a large amount of body fluids)
• You are going to have certain x-ray procedures with injectable contrast agents
• You are going to have surgery
• You develop a serious condition, such as a heart attack, severe infection, or stroke
• You are ≥ 80 years of age and have NOT had your kidney function tested

Q12. What are the symptoms of lactic acidosis?

Some of the symptoms include: feeling very weak, tired or uncomfortable; unusual muscle pain; trouble breathing; unusual or unexpected stomach discomfort; feeling cold; feeling dizzy or lightheaded; or suddenly developing a slow or irregular heartbeat.

If you notice these symptoms, or if your medical condition has suddenly changed, stop taking glipizide and metformin hydrochloride tablets and call your doctor right away. Lactic acidosis is a medical emergency that must be treated in a hospital.

Q13. What does my doctor need to know to decrease my risk of lactic acidosis?

Tell your doctor if you have an illness that results in severe vomiting, diarrhea, and/or fever, or if your intake of fluids is significantly reduced. These situations can lead to severe dehydration, and it may be necessary to stop taking glipizide and metformin hydrochloride tablets temporarily.

You should let your doctor know if you are going to have any surgery or specialized x-ray procedures that require injection of contrast agents. Glipizide and metformin hydrochloride tablet therapy will need to be stopped temporarily in such instances.

Q14. Can I take glipizide and metformin hydrochloride tablets with other medications?

Remind your doctor that you are taking glipizide and metformin hydrochloride tablets when any new drug is prescribed or a change is made in how you take a drug already prescribed.

Glipizide and metformin hydrochloride tablets may interfere with the way some drugs work and some drugs may interfere with the action of glipizide and metformin hydrochloride tablets.

Q15. What if I become pregnant while taking glipizide and metformin hydrochloride tablets?

Tell your doctor if you plan to become pregnant or have become pregnant. As with other oral glucose-control medications, you should not take glipizide and metformin hydrochloride tablets during pregnancy.

Usually your doctor will prescribe insulin while you are pregnant. As with all medications, you and your doctor should discuss the use of glipizide and metformin hydrochloride tablets if you are nursing a child.

Q16. How do I take glipizide and metformin hydrochloride tablets?

Your doctor will tell you how many glipizide and metformin hydrochloride tablets to take and how often.

This should also be printed on the label of your prescription. You will probably be started on a low dose of glipizide and metformin hydrochloride tablets and your dosage will be increased gradually until your blood sugar is controlled.

Q17. Where can I get more information about glipizide and metformin hydrochloride tablets?

This leaflet is a summary of the most important information about glipizide and metformin hydrochloride tablets.

If you have any questions or problems, you should talk to your doctor or other healthcare provider about type 2 diabetes as well as glipizide and metformin hydrochloride tablets and its side effects. There is also a leaflet (package insert) written for health professionals that your pharmacist can let you read.

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.

Manufactured For:
AvKARE
Pulaski, TN 38478
Mfg. Rev.12/20
AV Rev. 03/25 (M)