Antidiabetic Agents, Sulfonylurea (Systemic)

This monograph includes information on the following:

1) Acetohexamide
2) Chlorpropamide
3) Gliclazide *
4) Glimepiride 
5) Glipizide  
6) Glyburide
7) Tolazamide  
8) Tolbutamide


INN:
Glyburide—Glibenclamide {12}7

BAN:
Glyburide—Glibenclamide {12}6


JAN:
Glyburide—Glibenclamide {12}5

VA CLASSIFICATION
Acetohexamide
Primary: HS502

Chlorpropamide
Primary: HS502
Secondary: CV900

Gliclazide
Primary: HS502

Glimepiride
Primary: HS502

Glipizide
Primary: HS502

Glyburide
Primary: HS502

Tolazamide
Primary: HS502

Tolbutamide
Primary: HS502


Commonly used brand name(s): Albert Glyburide6; Amaryl4; Apo-Chlorpropamide2; Apo-Glyburide6; Apo-Tolbutamide8; DiaBeta6; Diabinese2; Diamicron3; Dimelor1; Dymelor1; Euglucon6; Gen-Glybe6; Glucotrol5; Glucotrol XL5; Glynase PresTab6; Medi-Glybe6; Micronase6; Novo-Butamide8; Novo-Glyburide6; Novo-Propamide2; Nu-Glyburide6; Orinase8; Tolinase7.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Antidiabetic—Acetohexamide; Chlorpropamide; Gliclazide; Glimepiride; Glipizide; Glyburide; Tolazamide; Tolbutamide;

Antidiuretic—Chlorpropamide;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Diabetes, type 2 (treatment)—Sulfonylureas are indicated as adjunctive therapy to diet and exercise in the treatment and control of certain patients with type 2 diabetes (previously known as non–insulin-dependent diabetes mellitus [NIDDM], adult-onset diabetes, maturity-onset diabetes, ketosis-resistant diabetes, or stable diabetes), which occurs in individuals who produce or secrete insufficient quantities of endogenous insulin or who have developed resistance to endogenous insulin. {12}4 {12}3 {12}2 {12}1 {12}0 {73}9 {73}8 {73}7 {73}6 {73}5 {73}4 {73}3 {73}2 {73}1 {73}0 {81}9 {81}8 {81}7 {81}6 {81}5 An attempt to control diabetes through changes in diet and level of physical activity is usually first-line management before beginning pharmacologic treatment. {81}4 {81}3 {81}2 {81}1 {81}0 {90}9 {90}8 {90}7 {90}6 {90}5 {90}4 {90}3 {90}2 {90}1 {90}0 {90}9 {90}8 Patients not responding adequately to diet alone or patients who require diet plus insulin, especially if they require 40 USP Units or less of insulin a day, may be candidates for therapy with a sulfonylurea as monotherapy or combination therapy. {90}7 {90}6 {90}5 {90}4 {90}3 {90}2 {90}1 {90}0

—Diabetes mellitus, other, associated with certain conditions or syndromes, such as: {238}9    • Endocrine disease, including endocrine overactivity due to Cushing's syndrome, hyperthyroidism, pheochromocytoma, somatostatinoma, or aldosteronoma; or endocrine underactivity due to hypoparathyroidism-hypocalcemia, type I isolated growth hormone deficiency, or multitropic pituitary deficiency or {238}8 {238}7
   • Genetic syndromes, including inborn errors of metabolism, such as glycogen-storage disease type I, or insulin-resistant syndromes, such as muscular dystrophies, late onset proximal myopathy, or Huntington's chorea. {238}6 {238}5
   • Sulfonylureas may be used in conditions causing diabetes mellitus induced by hormones, medications, or chemicals in patients who have functioning pancreatic beta cells when the diabetes cannot be controlled by diet or exercise. {238}4 {238}3


—Combination use of insulin and sulfonylurea agents in patients with type 1 diabetes is controversial because many studies have indicated that sulfonylureas are not effective in the treatment of these patients. {238}2 {238}1 {238}0 {90}9 {90}8 {90}7 {90}6 {90}5 {90}4 {90}3 {90}2 {90}1 {90}0

—Short-term administration of a sulfonylurea or insulin for transient loss of blood glucose control may be sufficient for patients with type 2 diabetes whose blood glucose levels are normally well-controlled with diet. Switching to another sulfonylurea agent may be beneficial if one particular sulfonylurea does not optimally control the diabetes mellitus; however, use of a sulfonylurea should be discontinued if satisfactory reduction of blood glucose concentration is not achieved. {239}9 {239}8 {239}7 {239}6 {239}5 {239}4 {239}3 {239}2 {239}1 {239}0 {90}9 {90}8

—The effectiveness of sulfonylureas in controlling blood glucose can decrease over time. {90}7 {90}6 {90}5 {90}4 If maximum doses of a sulfonylurea fail to control blood glucose, switching to another sulfonylurea or adding metformin to a sulfonylurea treatment regimen may be beneficial in increasing glycemic control and lipoprotein metabolism and may help avoid initiation of insulin therapy. This is especially successful in patients with type 2 diabetes whose blood sugar levels are poorly controlled by insulin alone, in short-term diabetics, or in patients who are 120 to 160% over ideal baseline body weight but who are not excessively insulin-resistant. Glimepiride and metformin may be used concomitantly when diet, exercise and glimepiride or metformin alone do not adequately control blood glucose levels. Combined use of glimepiride and metformin may increase the potential for hypoglycemia.{90}3 Alternatively, low-dose insulin in conjunction with sulfonylureas can help to avoid using large doses of insulin, especially for patients with type 2 diabetes who are obese. {90}2 {90}1 {90}0 {12}9 {12}8 {12}7 {12}6 {12}5 {12}4 However, complications, such as weight gain, the effects of hyperinsulinemia, and an increased risk of hypoglycemia need to be considered. {12}3 {12}2 {12}1 {12}0 {40}9 {40}8 {40}7 {40}6 {40}5 Some patients with type 2 diabetes who are nonobese and who are experiencing secondary sulfonylurea failure may be best treated with insulin. {40}4 {40}3 A sulfonylurea should be discontinued any time it fails to contribute to the lowering of plasma glucose in a patient for whom compliance with proper diet and sulfonylurea dosing has been determined to be adequate. {40}2 {40}1 {40}0 {12}9 {12}8 {12}7

[Diabetes insipidus, central, partial (treatment)]1—Chlorpropamide is also indicated as secondary therapy {12}6 in selected patients to treat partial central diabetes insipidus. Used as an antidiuretic, chlorpropamide has successfully reduced polyuria in about 50% of such treated patients. Chlorpropamide may be used alone or in combination with another agent such as carbamazepine or clofibrate so that the dose of both can be reduced and side effects minimized. Desmopressin is considered the primary treatment for diabetes insipidus. {12}5

Unaccepted
Sulfonylureas are not effective in the treatment of type 1 diabetes (previously known as insulin-dependent diabetes mellitus [IDDM]). {12}4 {12}3

Chlorpropamide is not effective in the treatment of nephrogenic diabetes insipidus.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Table 1. Pharmacology/Pharmacokinetics



Drug
V D
(L/kg)
Protein
binding *
(%)
Biotransformation
(%)
Elimination
half-life
(hrs)
Time
to
peak
(hrs)
Peak serum
concentration
Duration
of
action
(hrs)
Elimination
(%)
Concentration
per mL
Dose
(mg)
Acetohexamide
Hydroxyhexamide
(metabolite)
0.21 {12}2
Very high,
65–90;
Ionic {12}1 {12}0
Hepatic, mainly; {40}9
erythrocytes {40}8 {40}7
1.3 {40}6 {40}5 {40}4
4.6–6 {40}3 {40}2 {40}1
1.5–2 {40}0 {12}9 {12}8
2–6 {12}7 {12}6
47 mcg {12}5
60 mcg {12}4
1000 {12}3
8–24 {12}2 {12}1
Renal: 71 {12}0 {40}9
Fecal: 15 {40}8
Chlorpropamide
0.09–0.27 {40}7
Very high,
>90;
Ionic {40}6
Hepatic {40}5 {40}4 {40}3
36 §
(range, 24–48) {40}2 {40}1
2–4 {40}0 {58}9 {58}8
N/A
N/A
24–72 {58}7 {58}6 {58}5
Renal:
In 96 hours:
Unchanged—6–20
Active and inactive metabolites
Gliclazide
0.2 {58}4
Very high,
94; {58}3
Nonionic
Hepatic {58}2 {58}1
10.4 {58}0
4–6 {67}9
5 mcg {67}8
3 {67}7
24 {67}6
Renal:
Unchanged—<1
Metabolites, conjugates—60–70 {67}5
Fecal: Metabolites, conjugates—10–20 {67}4
Glimepiride
8.8 {67}3
Very high,
> 99.5 {67}2
Hepatic {67}1
5 {67}0
(following a single dose) {73}9
9.2 {73}8
(following multiple doses) {73}7
2–3 {73}6
N/A
N/A
N/A
Renal: 60 {73}5
Fecal: 40 {73}4
Glipizide
0.14–0.16 {73}3 {73}2 {73}1
Very high,
99; {73}0 {12}9 {12}8
Nonionic {12}7
Hepatic
(no first-pass) {12}6 {12}5
2–4 {12}4 {12}3 {12}2 {12}1
  N/A
N/A
  Renal:
Unchanged—<10 {12}0 {40}9 {40}8
Metabolites, inactive, and conjugates—80 {40}7
Fecal: 10 {40}6
immediate release
        1–3 {40}5 {40}4
    12–24 {40}3 {40}2 {40}1
 
extended release
        6–12 {40}0
    24 {40}9
 
Glyburide
0.14–0.16 {40}8
Very high,
99; {40}7
Nonionic {40}6 {40}5 {40}4 {40}3 {40}2
Hepatic {40}1 {40}0
        24 {40}9 {40}8 {40}7 {40}6 {40}5
Renal: 50 {40}4 {40}3 {40}2 {40}1 {40}0
Metabolites, active—2 weak, short-lived {12}9 {12}8 {12}7 {12}6
Biliary: 50 {12}5 {12}4 {12}3 {12}2 {12}1
Nonmicronized
      6–10 # {12}0 {40}9 {40}8
3.4–4.5 {40}7 {40}6 {40}5
87.5 nanograms {40}4 {40}3
5
   
Micronized
      4 # {40}2 {40}1
2.3–3.5 {40}0
97.2 nanograms {12}9 {12}8
3
   
Tolazamide **
N/A
Very high,
94; {12}7
Ionic {12}6
Hepatic {12}5
7 {12}4 {12}3
3–4 {12}2
N/A
  10–20 {12}1 {12}0 {40}9 {40}8
Renal: 85 †† {40}7
Metabolites, major—5 metabolites (potency 0–70%) {40}6 {40}5
Fecal: 7 {40}4
Tolbutamide **
0.10 {40}3 {40}2
Very high,
96;
Ionic {40}1
Hepatic {40}0 {85}9
4.5–6.5 {85}8 {85}7 {85}6
3–4 {85}5
N/A
  6–12 {85}4 {85}3 {85}2 {85}1
Renal: 100
Metabolites, inactive—75 {85}0 {12}9
* Primarily to albumin. {12}8 {12}7
 Renal impairment prolongs acetohexamide half-life to 30 hours. {12}6 {12}5
 A primary metabolite for acetohexamide, hydroxyhexamide, accounts for 47 to 60% of dose and is 2.5 times more potent than its parent. {12}4 {12}3 {12}2
§ A randomized crossover study of five phases conducted over a 2- to 3-week period demonstrated that the half-life of chlorpropamide can be affected by the pH of the urine; half-life is 69 ± 26 hours with acidic urine (pH 4.7 to 5.5) and 13 ± 3 hours with basic urine (pH 7.1 to 8.2). {12}1
# Micronized glyburide allows greater solubility, faster absorption, and, therefore, faster elimination; it is not bioequivalent to nonmicronized glyburide; micronized glyburide's area under the plasma concentration–time curve (AUC) is 568 ngohr/mL and nonmicronized glyburide's AUC is 746 ngohr/mL. {12}0 {40}9
** Tolazamide is approximately 5 to 6.7 times more potent than tolbutamide and equal in potency to chlorpropamide on a milligram-per-milligram basis. {40}8
††  The majority of a single dose of tolazamide is eliminated in urine within 24 hours and elimination is complete after 5 days. {40}7 Less active metabolites include carboxytolazamide, hydroxytolazamide, and p-toulene sulfonamide. {40}6


Physicochemical characteristics:

Chemical group—
    Sulfonylurea. {40}5 {40}4 {40}3 {40}2 {40}1 {40}0 {85}9 {85}8 {85}7 {85}6 {85}5 {85}4 {85}3 {85}2 {85}1 {85}0 {67}9 {67}8
    First generation: Acetohexamide, chlorpropamide, tolazamide, tolbutamide. {67}7 {67}6
    Second generation: Gliclazide, glimepiride, glipizide, glyburide. {67}5 {67}4 {67}3
Molecular weight—
    Acetohexamide: 324.4 {67}2
    Chlorpropamide: 276.75 {67}1
    Gliclazide: 323.42 {67}0
    Glimepiride: 490.63 {68}9
    Glipizide: 445.55 {68}8 {68}7
    Glyburide: 494.01 {68}6
    Tolazamide: 311.41 {68}5
    Tolbutamide: 270.35 {68}4

pKa—
    Chlorpropamide: 4.8 {68}3
    Gliclazide: 5.98 {68}2 {68}1 {68}0
    Glipizide: 5.9 {76}9 {76}8
    Glyburide: 5.3 {76}7
    Tolazamide: 3.5, 5.7 {76}6
    Tolbutamide: 5.3 {76}5 {76}4

Mechanism of action/Effect:


Antidiabetic:

Sulfonylureas lower blood glucose in patients with type 2 diabetes by directly stimulating the acute release of insulin from functioning beta cells of pancreatic islet tissue by an unknown process that involves a sulfonylurea receptor on the beta cell. Sulfonylureas inhibit the ATP-potassium channels on the beta cell membrane and potassium efflux, which results in depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin-containing granules by exocytosis, an effect similar to that of glucose. Insulin is a hormone that lowers blood glucose and controls the storage and metabolism of carbohydrates, proteins, and fats. {76}3 {76}2 {76}1 {76}0 Sulfonylureas are effective only in patients whose pancreata are capable of producing insulin. {58}9 {58}8 {58}7 {58}6 {58}5 {58}4 {58}3 {58}2 {58}1 {58}0 {76}9

With chronic sulfonylurea treatment, insulin production is not increased and may return to pretreatment values, {76}8 but insulin efficacy continues and is thought to involve extrapancreatic mechanisms to increase insulin sensitivity in target tissues, such as liver, muscle, and fat as well as in other cells, such as monocytes and erythrocytes. {76}7 {76}6 {76}5 {76}4 {76}3 This can result in a decrease in hepatic glycogenolysis and gluconeogenesis. It is unclear if the sulfonylurea's extrapancreatic actions that increase insulin's efficacy are direct or indirect effects, but it is clear that the mechanism of action is not due to a direct sulfonylurea action on the insulin receptor. {76}2 {76}1 {76}0 {77}9 Because this peripheral effect is not apparent in patients with type 1 diabetes, the evidence suggests that this may not be the clinically significant mechanism of sulfonylurea action in patients with type 2 diabetes either. However, it is clear that tissues of sulfonylurea-treated patients with type 2 diabetes become more responsive to lower concentrations of endogenous insulin. Primary failure of sulfonylurea therapy may occur if beta-cell function is severely impaired. In addition to stimulating insulin secretion through the beta cell–sulfonylurea receptor, gliclazide may have a direct effect on intracellular calcium transport that specifically improves the biphasic response of the beta cell to a meal, that is, the immediate first phase of insulin release as well as the normally delayed second phase. {77}8 {77}7 {77}6 {77}5 {77}4 {77}3 {77}2



Antidiuretic:

Chlorpropamide seems to potentiate the effect of minimal concentrations of antidiuretic hormone present in patients with partial central diabetes insipidus.



Other actions/effects:

Acetohexamide and its more potent major metabolite, hydroxyhexamide, have uricosuric properties. {77}1 Gliclazide, at therapeutic doses, reduces platelet adhesiveness and aggregation by inhibiting arachidonic acid release and thromboxane synthesis, and increasing production of prostacyclin (PGI 2) and release of plasminogen activator, which increases fibrinolysis. {77}0 {69}9 It is also thought that gliclazide and glyburide have protective activity against cardiac arrhythmias because they can stabilize potassium and calcium concentrations by inhibition of the sodium-potassium-ATPase pump transport system. {69}8 {69}7 {69}6 {69}5 {69}4 {69}3 {69}2 {69}1 Tolbutamide and chlorpropamide decrease free water clearance {69}0 while glyburide, glipizide, and tolazamide produce a mild diuresis effect by enhancement of renal free water clearance. {92}9 {92}8 {92}7 {92}6 {92}5 {92}4 {92}3 {92}2 In contrast to glyburide, tolazamide and tolbutamide increase hexose uptake in adipocytes and myocytes. {92}1 Sulfonylureas directly increase the secretion of pancreatic and gastric somatostatin and do not seem to have a direct effect on glucagon. {92}0 {70}9 {70}8 {70}7

Absorption:

Rapidly and well absorbed but may have wide inter- and intra-individual variability. {70}6 {70}5 {70}4 {70}3 {70}2 {70}1 {70}0 {76}9 {76}8 {76}7 {76}6 {76}5 {76}4 {76}3 By impairing gastric motility and gastric emptying, hyperglycemia may significantly delay sulfonylurea absorption; glipizide plasma concentration has been shown to be reduced by 50% with plasma glucose concentrations over 198 mg/dL (11 millimoles/L). {76}2

Chlorpropamide—Food delays absorption of chlorpropamide. {76}1

Gliclazide—Food delays absorption of gliclazide up to 187 minutes; may be best taken 30 minutes before or with a meal. {76}0 {78}9 {78}8

Glimepiride—Food decreases mean peak drug concentrations (C max) and the area under the plasma concentration–time curve (AUC) (by 8% and 9%, respectively) and increases the mean time to reach C max (T max) (by 12%) in healthy volunteers. {78}7 It is recommended that glimepiride be taken with breakfast or the first main meal. {78}6

Glipizide—Food delays absorption of immediate-release glipizide by 40 minutes; therefore, it is recommended that glipizide be taken 30 minutes before a meal. While food had no effect on the lag time of absorption (3 to 4 hours) for extended-release glipizide, administration of glipizide to normal males before a meal high in fat showed a 40% increase in the time to peak serum concentrations; AUC was not affected. {78}5 {78}4 {78}3 {78}2

Glyburide—Bioavailability of nonmicronized glyburide is lowest when given with a high-fat diet compared to fasting or a high-carbohydrate diet. Micronized glyburide is more consistent in its bioavailability and in its T max with regard to all meal types than is the nonmicronized formulation. {78}1 {78}0 Also, micronized glyburide is better absorbed and is effective at a lower dose than is nonmicronized glyburide. {84}9

Tolbutamide—Absorption is unaltered if taken with food but is increased with high pH. {84}8 {84}7


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one of the sulfonylureas may be sensitive to the others also; cross-sensitivity to other sulfonamide- or thiazide-type medications may also occur. {84}6

Carcinogenicity

Acetohexamide—Long-term studies in rats and mice showed no evidence of carcinogenicity. {84}5

Chlorpropamide—Chronic toxicity studies in dogs treated for 6, 13, and 20 months with doses of chlorpropamide greater than 20 times the human dose showed no histological or pathological abnormalities. {84}4

Gliclazide—Specific carcinogenicity studies have not been done in animals; however, long-term toxicity studies have not shown any evidence of drug-related carcinogenicity.

Glimepiride—A 24-month study in rats given doses approximately 340 times the maximum recommended human dose based on body surface area showed no evidence of carcinogenicity. {84}3

Glipizide—Large-dose studies using up to 75 times the maximum human dose in rats and in mice for 20 and 18 months, respectively, showed no evidence of drug-related carcinogenicity. {84}2 {84}1 {84}0

Glyburide—An 18-month study in rats given doses of up to 300 mg per kg of body weight (mg/kg) a day and a 2-year oncogenicity study in mice showed no evidence of drug-related carcinogenicity. {67}9 {67}8 {67}7 {67}6

Tolazamide—A 103-week study in rats and mice at both low and high doses showed no evidence of carcinogenicity. {67}5

Tolbutamide—A 78-week study in male and female rats and mice showed no evidence of carcinogenicity. {67}4

Mutagenicity

Acetohexamide—Sister chromatid exchange testing showed no evidence of mutagenicity. {67}3

Chlorpropamide—The micronucleus test in one strain of Swiss mice given chlorpropamide doses of 200, 400, 800, and 1600 mg/kg (32 times greater than the therapeutic adult dose) showed no evidence of mutagenicity. {67}2 However, three strains of mice showed positive results when evaluated using the Salmonella /microsome test. The results are questionable because negative results were also shown in rats and Chinese hamsters. Although an increase in chromosomal breakage has not been observed in treated mammals, Chinese hamsters, rats, or mice, the sister chromatin exchange showed a positive reaction with Chinese hamster cells in vivo and in vitro ; however, spontaneous breakage in this study was not even doubled in extremely high doses. It is difficult to assign a cause-and-effect explanation to the slightly positive results in these animal studies. {67}1 {67}0

Gliclazide—The Ames test, human lymphocyte test, and micronucleus test did not reveal mutagenicity.

Glimepiride—A series of in vitro and in vivo studies, including the Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, and mouse micronucleus test, showed no evidence of mutagenicity. {68}9

Glipizide—Bacterial and in vivo mutagenicity testing showed no evidence of mutagenicity. {68}8 {68}7 {68}6

Glyburide—Testing with the Ames test, DNA damage/alkaline elution assay, and the micronucleus test (at doses 60 to 240 times the average human therapeutic dose) showed no evidence of mutagenicity. {68}5 {68}4 {68}3 {68}2 {68}1 {68}0

Tolbutamide—The Ames test {76}9 and the micronucleus test in mice (at doses of 500 mg/kg) showed no evidence of mutagenicity. {76}8

Pregnancy/Reproduction
Fertility—

Acetohexamide, tolazamide, tolbutamide

Studies in humans have not been done.

Studies in animals have not been done. {76}7 {76}6



Chlorpropamide

Studies in humans have not been done. {76}5

Studies in rats treated with high doses of chlorpropamide (125 mg/kg) for 6 to 12 months showed varying degrees of spermatogenesis suppression. {76}4



Gliclazide

Studies in humans have not been done.

Studies in female rats and the first generation offspring of treated male and female rats showed no evidence of impaired fertility.



Glimepiride

Studies in humans have not been done. {76}3

Studies in male mice and male and female rats given more than 1700 times and approximately 4000 times, respectively, the maximum recommended human dose based on body surface area showed no evidence of impaired fertility. {76}2



Glipizide

Studies in humans have not been done. {76}1

Studies in male and female rats given 75 times the maximum human dose showed no evidence of impaired fertility. {76}0 {58}9



Glyburide

Studies in humans have not been done. {58}8 {58}7 {58}6

Studies in rats and rabbits given 500 times the human dose have not shown evidence of impaired fertility. {58}5 {58}4


Pregnancy—
Chlorpropamide crosses the placenta; glyburide does not significantly cross the placenta, and it is not known whether other sulfonylureas cross the placenta. {58}3 {58}2 {58}1 {58}0 Use of insulin rather than sulfonylurea antidiabetic agents during pregnancy allows for the maintenance of blood glucose concentrations that are as close to normal as possible. Abnormal blood glucose concentrations in the mother have been associated with a higher incidence of congenital abnormalities {76}9 {76}8 {76}7 {76}6 {76}5 {76}4 {76}3 {76}2 during early pregnancy, and with increased perinatal morbidity and mortality later in pregnancy. {76}1 {76}0 {77}9 Adequate and well-controlled studies in humans have not been done to determine whether sulfonylureas are teratogenic. It remains possible that sulfonylureas cause congenital malformations if they cross the placenta, but current data leave unresolved the issue of whether the abnormalities are due to poor glucose control or to sulfonylurea treatment. {77}8 {77}7 {77}6 {77}5 Generally, sulfonylureas are not recommended during pregnancy. {77}4 {77}3 {77}2 In the rare case that sulfonylureas are used during pregnancy, they should be discontinued to allow an interval before delivery appropriate for the particular sulfonylurea being used because of the risk that they will cause insulin release and hypoglycemia in the neonate at delivery. {77}1 {77}0 {69}9 {69}8 {69}7


Acetohexamide

Adequate and well-controlled studies in humans have not been done.

Acetohexamide has been shown to be teratogenic in animal studies when large doses were administered. {69}6 {69}5

FDA Pregnancy Category C. {69}4



Chlorpropamide

Chlorpropamide crosses the placenta. {69}3 Adequate and well-controlled studies have not been done in humans. Low doses (250 mg a day or less) of chlorpropamide have been used in pregnant women without adverse effects. {69}2 {69}1 The manufacturer recommends discontinuing chlorpropamide at least 1 month before the expected delivery date. {69}0

Using an in vitro method and whole embryo mouse culture, one study compared growth differences between untreated embryos and those bathed in hypoglycemic and euglycemic chlorpropamide-treated rat serums. The teratologic evaluation of the treated early somite mouse embryos showed malformations and growth retardation at doses similar to human therapeutic concentrations, which suggested that the teratogenicity was due to chlorpropamide and not to hypoglycemia; untreated mouse embryos showed normal development. {76}9

FDA Pregnancy Category C. {76}8



Gliclazide

Studies in humans have not been done. Gliclazide is not recommended for use during pregnancy. {76}7

No teratogenic effects were found in studies of mice and rabbits. Embryotoxicity was not seen in studies of rats. However, a significant decrease in offspring viability at 48 hours was seen when pregnant females were treated up to delivery. It is unclear how this relates to the use of gliclazide or if it applies to humans. {76}6



Glimepiride

Studies in humans have not been done. {76}5

No evidence of teratogenicity was found in rats following oral administration of glimepiride at doses approximately 4000 times the maximum recommended human dose based on body surface area, or in rabbits following administration of glimepiride at doses approximately 60 times the maximum recommended human dose based on body surface area. {76}4 However, glimepiride use has been associated with intrauterine death in rats administered doses 50 times the human dose based on body surface area, and in rabbits administered doses 0.1 time the human dose based on body surface area. {76}3 This fetotoxicity, observed only at doses inducing maternal hypoglycemia, has been similarly noted with other sulfonylureas and is believed to be directly related to the hypoglycemic action of glimepiride. {76}2

FDA Pregnancy Category C. {76}1



Glipizide

Studies in humans have not been done. Glipizide should be discontinued at least 1 month before the expected delivery date. {76}0 {78}9 {78}8

Studies in rats have shown glipizide to be fetotoxic at all doses from 5 to 50 mg/kg; the fetotoxicity is thought to be due to the pharmacologic hypoglycemic effect during the perinatal period. {78}7 {78}6 {78}5 No teratogenic effects were found in studies in rats and rabbits. {78}4 {78}3 {78}2

FDA Pregnancy Category C. {78}1 {78}0 {92}9



Glyburide

Glyburide does not significantly cross the placenta according to an in vitro study using human placentas. {92}8 Studies in humans have not been done. Use should be discontinued at least 2 weeks before the expected delivery date. {92}7 {92}6 {92}5 {92}4

Studies in rats and rabbits given up to 500 times the human dose have produced no evidence of teratogenicity. {92}3 {92}2

FDA Pregnancy Category B (Micronase, Glynase PresTab). {92}1 {92}0 {70}9

FDA Pregnancy Category C (DiaBeta). {70}8



Tolazamide

Studies in humans have not been done. Use should be discontinued at least 2 weeks before the expected delivery date. {70}7

Studies in rats given 10 times the human dose have shown tolazamide to cause reduced litter sizes. No teratogenic effects were found. High doses of 100 mg/kg a day also produced reduced litter sizes and increased perinatal mortality in pups. {70}6

FDA Pregnancy Category C. {70}5



Tolbutamide

Studies in humans have not been done. Use should be discontinued at least 2 weeks before the expected delivery date. {70}4

Studies in rats given doses of tolbutamide that were 25 to 100 times greater than the human dose have shown teratogenic effects, such as ocular and bone abnormalities, and increased mortality in the offspring. {70}3 {70}2 {70}1 Repeat studies in rabbits showed no teratogenic effects. {70}0 {84}9 {84}8

FDA Pregnancy Category C. {84}7


Delivery—

Prolonged severe hypoglycemia lasting for 4 to 10 days has been reported in neonates born to mothers who were receiving a sulfonylurea antidiabetic agent at the time of delivery. This effect has been reported more frequently with those agents with longer half-lives, such as chlorpropamide. {84}6 {84}5 {84}4 {84}3 {84}2 {84}1 {84}0 {12}9 {12}8 {12}7 If sulfonylureas are used during pregnancy, they should be discontinued according to the manufacturer's labeling.

Breast-feeding

Chlorpropamide and tolbutamide are distributed into human breast milk and potentially may cause hypoglycemia in the infant. Glimepiride is distributed into the milk of rats. {12}6 It is not known whether acetohexamide, gliclazide, glipizide, glyburide, or tolazamide is distributed into breast milk. {12}5 {12}4 {12}3 {12}2 {12}1 {12}0 {40}9 {40}8 {40}7 {40}6 {40}5 {40}4 {40}3

Chlorpropamide: {40}2 Chlorpropamide has been found to be distributed into breast milk at a concentration of 5 mcg per mL after 5 hours for a single 500-mg dose (after 5 hours, blood concentration for a single dose of 250 mg chlorpropamide is 30 mcg per mL); therefore, its use during breast-feeding is not recommended. {40}1 Its effect on the nursing infant is not known. {40}0

Glimepiride: Glimepiride is distributed into the milk of rats in significant concentrations. The offspring of rats exposed to high concentrations during pregnancy developed skeletal abnormalities after nursing. Use of glimepiride during breast-feeding is not recommended. {68}9

Tolbutamide: Tolbutamide was distributed into breast milk at a concentration averaging 3 and 18 mcg per mL in two patients taking 500 mg twice a day (milk:plasma ratio of 0.09 and 0.4, respectively). The effect on the nursing infants is not known. The American Academy of Pediatrics considers tolbutamide to be compatible with breast-feeding. {68}8 {68}7

Pediatrics

Oral antidiabetic agents are not effective in type 1 (juvenile-onset) diabetes. Because type 2 diabetes occurs rarely in this age group, very little or no published pediatrics-specific information is available. Safety and efficacy have not been established. {68}6 {68}5 {68}4 {68}3 {68}2 {68}1 {68}0 {69}9 {69}8 {69}7 {69}6 {69}5 {69}4


Geriatrics


In general, no overall difference in safety or efficacy was apparent in persons over 65 years of age when compared to persons younger than 65 years of age taking sulfonylureas for type 2 diabetes. {69}3 {69}2 Lower doses are used initially because of possible increased sensitivity to these agents due to age-related metabolism and excretion changes; the steady state concentration of extended-release glipizide has been delayed for 1 or 2 days in elderly patients. {69}1 {69}0 {70}9 The risk of adverse reactions is relatively low when other factors for toxicity, including liver and kidney disease and known drug interactions, are considered. Special counseling with emphasis on hydration, diet, and exercise may be necessary because of the greater risk of hypoglycemia in this age group. Special instruction to recognize hypoglycemia may be needed because early warning adrenergic symptoms of hypoglycemia (such as sweating, weakness, tachycardia, and nervousness) are absent in many patients. Hypoglycemia manifests as neurological symptoms (such as headache, irritability, mental confusion, unusual tiredness, and drowsiness) and may be more prolonged and severe in the elderly. Combining antidiabetic agents (sulfonylureas with metformin or insulin) or using long-acting sulfonylureas, such as chlorpropamide and glyburide, is most often associated with hypoglycemia in elderly patients and is not generally recommended; {70}8 shorter-acting sulfonylureas cause fewer problems. Also, instructions may be needed to help the patient monitor urine or blood glucose if visual problems are present. {70}7 {70}6 {70}5 {70}4

Geriatric patients may be more likely to develop a reversible syndrome of inappropriate antidiuretic hormone (SIADH) from the use of chlorpropamide. The incidence of SIADH is rare and occurs with greater incidence when thiazides are taken concurrently with chlorpropamide than when chlorpropamide is taken alone (10% versus 3%, respectively). In one study, women over 70 years of age were affected 10 times more often than women under 60 years of age when thiazides were used concurrently with chlorpropamide. It is not thought to be a gender-oriented effect. SIADH has been rarely reported with tolbutamide. {70}3 {70}2

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
There is an increased chance of hypoglycemia occurring if more than one hypoglycemia-causing agent is used concurrently with sulfonylureas. {70}1 {70}0 {81}9 {81}8 {81}7 {81}6 {81}5 If the need exists to administer any medications that may affect metabolic or glycemic control of type 2 diabetes, blood glucose concentrations should be monitored by the patient or health care professional. This is particularly important when any medication is added to or removed from an established drug regimen. Subsequent adjustments in diet or antidiabetic agent dosage or both may be necessary; these adjustments may differ depending on the severity of the diabetes. {81}4

» Alcohol {81}3 {81}2 {81}1 {81}0 {84}9 {84}8 {84}7 {84}6 {84}5 {84}4 {84}3 {84}2 {84}1 {84}0 {85}9 {85}8 {85}7 {85}6 {85}5 {85}4    (a disulfiram-like reaction, which is characterized primarily by flushing of the face, neck, and arms, may occur with any of the sulfonylureas when alcohol is ingested concurrently but has not been reported with glipizide; risk is lowest with tolbutamide and glyburide and highest with chlorpropamide; it has occurred 12 hours after a single 250-mg dose of chlorpropamide and 40 mL of 18% alcohol {85}3 {85}2 {85}1 {85}0 {86}9 {86}8 {86}7)

    (the risk of hypoglycemia may be increased or prolonged when moderate or large amounts of alcohol have been consumed concurrently with sulfonylurea antidiabetic agents; {86}6 {86}5 small amounts of alcohol taken with meals do not usually result in hypoglycemia {86}4 {86}3 {86}2 {86}1)


Allopurinol    (increased risk of hypoglycemia due to inhibition of renal tubular secretion of chlorpropamide; closer monitoring required {86}0)


Angiotensin-converting enzyme inhibitors, {103}9 {103}8 such as:
Captopril {103}7 or
Enalapril {103}6    (the mechanism of enhanced hypoglycemia that occurs rarely is unknown; concurrent use need not be avoided and may be advantageous in the treatment of type 2 diabetes; however, the dosage of the sulfonylurea may need to be modified in some patients {103}5 {103}4 {103}3 {103}2 {103}1)


» Anticoagulants, coumarin- or indandione-derivative {103}0 {90}9 {90}8 {90}7 {90}6 {90}5 {90}4 {90}3 {90}2 {90}1 {90}0 {81}9 {81}8 {81}7 {81}6 {81}5 {81}4 {81}3 {81}2 {81}1 {81}0 {81}9 {81}8 {81}7 {81}6    (the mechanism is not completely known; however, mutual interactions of both agents have increased their anticoagulant and hypoglycemic effects. A hypoglycemic effect may be partially due to the decrease in hepatic metabolism of sulfonylureas caused by anticoagulants, which can prolong the half-life of the sulfonylureas twofold to threefold. An increased protein binding displacement of anticoagulants by sulfonylureas has been found to prolong prothrombin times; however, because of the increase in the metabolism of dicumarol that can shorten its half-life by as much as 50%, an increase, decrease, or no effect on coagulation may result. Although these effects have been reported specifically for chlorpropamide, tolbutamide, and dicumarol, concurrent use of all sulfonylurea antidiabetic agents with anticoagulants should be well-monitored and dosage adjustments of both agents may be required {81}5 {81}4 {81}3 {81}2 {81}1 {81}0)

    (glipizide and glyburide have lower plasma concentrations than other sulfonylureas and exhibit only nonionic plasma protein binding; therefore, they may be less susceptible to displacement from plasma proteins by other medications that exhibit ionic binding to plasma proteins; studies have not been done and caution is still warranted {81}9 {81}8 {81}7)


» Antifungals, azole, systemic, {81}6 {81}5 {81}4 {81}3 {81}2 {81}1 {81}0 {81}9 {81}8 such as:
Miconazole {81}7 {81}6 {81}5 {81}4 {81}3 {81}2 {81}1 {81}0 {81}9 {81}8 {81}7 {81}6 {81}5 {81}4
Fluconazole {81}3 {81}2    (severe hypoglycemia has been reported shortly after concurrent use of tolbutamide, glyburide, and glipizide with these oral azole antifungal agents. In one study, glipizide and fluconazole increased the area under the plasma concentration–time curve [AUC] of glipizide 56.9% [range, 35–81%]. Also, hypoglycemia has been reported for gliclazide taken concurrently with miconazole, but not with fluconazole {81}1)


Appetite suppressants    (when appetite suppressants and a concurrent dietary regimen are used, blood glucose concentrations may be altered in patients with diabetes; dosage adjustment of the antidiabetic agent may be necessary during and after therapy)


» Asparaginase {81}0 {81}9 {81}8 or
» Corticosteroids {81}7 {81}6 {81}5 {81}4 {81}3 {81}2 {81}1 {81}0 {03}9 {03}8 {03}7 {03}6 {03}5 {03}4 {03}3 {03}2 {03}1 {03}0 {81}9 {81}8 {81}7 {81}6 or
» Diuretics, thiazide {81}5 {81}4 {81}3 {81}2 {81}1 {81}0 {66}9 {66}8 {66}7 {66}6 {66}5 {66}4 {66}3 {66}2 {66}1 {66}0 {110}9 {110}8 {110}7 {110}6 {110}5 {110}4 {110}3 {110}2 or
» Lithium {110}1 {110}0 {243}9    (these medications have intrinsic hyperglycemic activity in both diabetic and nondiabetic patients; dosage of the sulfonylurea may need to be modified during and after treatment. Some studies of lithium have reported hypoglycemia {243}8 {243}7 {243}6 {243}5 {243}4 {243}3)

    (concurrent treatment using thiazides with chlorpropamide, and more rarely with tolbutamide, may increase the chance of hyponatremia and hypo-osmolality, especially in patients over 70 years of age {243}2 {243}1)


Barbiturates {243}0 {81}9 {81}8 {81}7 {81}6 {81}5 {81}4 {81}3    (chlorpropamide may prolong the effect of barbiturates {81}2 and barbiturates may prolong the effect of gliclazide; other sulfonylureas may also exhibit these effects; dosage adjustment of the sulfonylurea or the barbiturate may be necessary {81}1)


» Beta-adrenergic blocking agents, including ophthalmics, if significant absorption occurs {81}0 {66}9 {66}8 {66}7 {66}6 {66}5 {66}4 {66}3 {66}2 {66}1 {66}0 {110}9 {110}8 {110}7 {110}6 {110}5 {110}4 {110}3 {110}2 {110}1 {110}0 {243}9 {243}8 {243}7 {243}6    (beta-adrenergic blocking agents may decrease the hypoglycemic effects of sulfonylureas to some extent by inhibition of insulin secretion, modification of carbohydrate metabolism, and increased peripheral insulin resistance, leading to hyperglycemia; an adjustment in dose may be required. Other mechanisms that control the normal physiological response to a fall in blood glucose may be affected also, such as a blocked catecholamine-mediated response to hypoglycemia [glycogenolysis and mobilization of glucose], thereby prolonging the time it takes to achieve euglycemia and increasing the risk of a severe hypoglycemic reaction. Selective beta 1-adrenergic blocking agents [such as acebutolol, atenolol, betaxolol, bisoprolol, and metoprolol] exhibit the above actions to a lesser extent; however, any of the agents can blunt some of the symptoms of developing hypoglycemia, such as increased heart rate or tremors [increased sweating and blood pressure may not be altered], making detection of this complication more difficult {243}5 {243}4 {243}3 {243}2 {243}1 {243}0 {66}9 {66}8 {66}7)


» Cimetidine {66}6 {66}5 {66}4 {66}3 {66}2 {66}1 {66}0 {81}9 {81}8 or
» Ranitidine {81}7 {81}6 {81}5 {81}4 {81}3 {81}2    (these agents, in therapeutic doses, can significantly decrease the postprandial rise in blood glucose and increase the hypoglycemic effects of glipizide, gliclazide, and glyburide in patients with diabetes; also, cimetidine has decreased tolbutamide's elimination {81}1 and increased absorption of tolbutamide and glyburide; ranitidine did not affect glyburide's AUC; {81}0 {66}9 {66}8 {66}7 {66}6 {66}5 close monitoring for dose adjustments of sulfonylureas may be needed when these agents are added or withdrawn {66}4 {66}3 {66}2 {66}1 {66}0 {81}9 {81}8 {81}7 {81}6 {81}5 {81}4 {81}3 {81}2)


» Cyclosporine {81}1 {81}0    (glipizide may significantly increase the plasma concentration of cyclosporine by reducing its metabolism; dose reduction of cyclosporine may be necessary; similar effects may be possible with other sulfonylureas)


» Fluoroquinolones, {81}9 {81}8 {81}7 {81}6 {81}5 such as ciprofloxacin {81}4 {81}3 {81}2    (use of glyburide with ciprofloxacin has caused hypoglycemia; since the mechanism is not understood, similar effects with other sulfonylurea antidiabetic agents should be considered when these medications are used together {81}1 {81}0 {101}9 {101}8 {101}7)


» Guanethidine {101}6 {101}5 {101}4 or
» Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline {101}3 {101}2 {101}1 {101}0 {15}9 {15}8 {15}7 {15}6 {15}5 {15}4 {15}3 {15}2 {15}1 {15}0 {15}9 {15}8 {15}7 {15}6 {15}5 {15}4 {15}3 {15}2 {15}1 or
» Quinidine {15}0 or
» Quinine {15}9 or
» Salicylates, in large doses {15}8 {15}7 {15}6 {15}5 {15}4 {15}3 {15}2 {15}1 {15}0 {15}9 {15}8 {15}7 {15}6 {15}5 {15}4 {15}3 {15}2 {15}1 {15}0 {15}9 {15}8 {15}7    (these medications have intrinsic hypoglycemic activity in both diabetic and nondiabetic patients, possibly severe with quinine, quinidine, or salicylates in high doses but unlikely with low doses of salicylates. Also, salicylates may interfere with chlorpropamide's renal excretion. Salicylate dose may need to be reduced {15}6 {15}5 {15}4 {15}3)


Hemolytics, other (see Appendix II )    (concurrent use may increase the incidence of sulfonylurea-induced hemolysis through a possible additive effect; reported cases of hemolysis effects have rarely occurred with chlorpropamide or tolbutamide and have not been reported with other sulfonylureas {15}2)


Hepatic enzyme inducers, such as:
Rifabutin {15}1
Rifampin {15}0 {15}9 {15}8 {15}7 {15}6 {15}5    (metabolism of sulfonylureas may be increased due to stimulation of hepatic microsomal enzymes; dosage adjustments may be necessary during and after concurrent treatment {15}4 {15}3 {15}2 {15}1 {15}0 {15}9)

    (drug interaction data for rifabutin are not available; it is structurally related to rifampin but appears to be a less potent enzyme inducer of the hepatic cytochrome P450 system than is rifampin. It is recommended that patients taking rifabutin concurrently with sulfonylurea antidiabetic agents be monitored since the significance of possible drug interactions is not known {15}8 {15}7 {15}6 {15}5 {15}4)


Hepatic enzyme inhibitors, such as:
» Chloramphenicol {15}3 {15}2 {15}1 {15}0 {15}9 {15}8 {15}7 {15}6 {15}5 {15}4 {15}3 {15}2 {15}1 {15}0 {15}9 {15}8 {15}7 {15}6 {15}5 {15}4    (metabolism of sulfonylureas may be decreased due to inhibition of hepatic microsomal enzymes; dosage adjustments may be necessary during and after concurrent use {15}3 {15}2 {15}1 {15}0)

    (also, with concurrent use, chlorpropamide's half-life has increased up to 146 hours; this may be partially due to interference with renal excretion of chlorpropamide by chloramphenicol {15}9 {15}8 {15}7 {15}6)


Highly protein-bound medications {15}5 {15}4 {15}3 {15}2 {15}1 {15}0 {15}9 {15}8 {15}7 {15}6 such as:
Anti-inflammatory drugs, nonsteroidal (NSAIDs), {15}5 {15}4 {15}3 {15}2 {15}1 {15}0 {43}9 {43}8 {43}7 {43}6 {43}5 {43}4 {43}3 {43}2 such as phenylbutazone {43}1 {43}0 {15}9 {15}8 {15}7 {15}6 {15}5 {15}4 {15}3 {15}2 {15}1 {15}0 {42}9 {42}8 {42}7
Clofibrate {42}6 {42}5 {42}4 {42}3 {42}2 {42}1 {42}0 {15}9 {15}8 {15}7 {15}6 {15}5 {15}4 {15}3 {15}2 {15}1 {15}0
Probenecid {18}9 {18}8 {18}7 {18}6 {18}5 {18}4 {18}3 {18}2 {18}1 {18}0 {16}9 {16}8 {16}7 {16}6 {16}5 {16}4 {16}3 {16}2 {16}1 {16}0
Sulfinpyrazone {16}9 {16}8 {16}7 {16}6
Sulfonamides {16}5 {16}4 {16}3 {16}2 {16}1 {16}0 {16}9 {16}8 {16}7 {16}6 {16}5 {16}4 {16}3 {16}2 {16}1 {16}0 {16}9 {16}8 {16}7 {16}6 {16}5 {16}4 {16}3 {16}2    (these medications enhance the hypoglycemic effects of sulfonylureas when given concurrently; the mechanism is unknown but may be due to displacement of sulfonylureas from protein binding sites and alterations in their renal excretion; concurrent use need not be avoided; however, the dosage of the sulfonylurea may need to be modified in some patients {16}1 {16}0 {45}9 {45}8 {45}7 {45}6 {45}5 {45}4 {45}3 {45}2 {45}1)

    (clofibrate also shows intrinsic hypoglycemic effects by causing increased insulin sensitivity and has been used advantageously in the treatment of diabetes mellitus; also, clofibrate has intrinsic antidiuretic effects that have been used to treat diabetes insipidus; this effect may be lessened with concurrent use of glyburide or increased with concurrent use of chlorpropamide or tolbutamide {45}0 {12}9 {12}8 {12}7 {12}6 {12}5)

    (sulfinpyrazone and phenylbutazone have been shown to inhibit the hepatic metabolism of tolbutamide; {12}4 they also inhibit the renal excretion of acetohexamide but not of glyburide; the effect on other sulfonylureas by NSAIDs [other than ibuprofen, naproxen, sulindac, and tolmetin, which do not affect sulfonylureas] is not known {12}3 {12}2 {12}1)

    (NSAIDs inhibit synthesis of prostaglandin E, which inhibits endogenous insulin secretion; this increases basal insulin secretion, the response to a glucose load, and the hypoglycemic effect of insulin secretion; dosage adjustment of each medication used may be necessary following chronic use of NSAIDs {12}0 {14}9 {14}8 {14}7 {14}6)

    (glipizide and glyburide have lower plasma concentrations than other sulfonylureas and exhibit nonionic plasma protein binding only; therefore, these sulfonylureas may be less susceptible to displacement from plasma proteins by other medications that exhibit ionic binding to plasma proteins {14}5 {14}4 {14}3)


Hyperglycemia-causing agents, such as:
Anticonvulsants, hydantoin {14}2 {14}1 {14}0 {16}9 {16}8 {16}7 {16}6 {16}5 {16}4 {16}3 {16}2 {16}1 {16}0 {45}9 {45}8
Calcium channel blocking agents {45}7 {45}6 {45}5 {45}4 {45}3 {45}2 {45}1 {45}0 {45}9 {45}8 {45}7 {45}6
Clonidine {45}5 {45}4
Danazol {45}3
Dextrothyroxine {45}2
Diazoxide, parenteral {45}1 {45}0 {45}9 {45}8
Estrogens {45}7 {45}6 {45}5 {45}4 {45}3 {45}2 {45}1 {45}0 {45}9 {45}8 {45}7 {45}6 {45}5
Estrogen–progestin-containing oral contraceptives {45}4 {45}3 {45}2 {45}1 {45}0 {45}9 {45}8 {45}7 {45}6 {45}5 {45}4 {45}3 {45}2 {45}1 {45}0 {16}9 {16}8 {16}7 {16}6 {16}5 {16}4
Furosemide {16}3 {16}2 {16}1 {16}0 {60}9 {60}8 {60}7
Glucagon {60}6 {60}5 {60}4
Growth hormone {60}3 {60}2
Isoniazid {60}1 {60}0 {16}9 {16}8 {16}7 {16}6 {16}5 {16}4 {16}3 {16}2 {16}1 {16}0 {16}9 {16}8
Morphine {16}7 {16}6
Niacin {16}5 {16}4 {16}3 {16}2 {16}1 {16}0 {16}9 {16}8 {16}7 {16}6 {16}5 {16}4 {16}3 {16}2 {16}1 {16}0 {16}9 {16}8 {16}7 {16}6 {16}5
Phenothiazines, such as chlorpromazine {16}4 {16}3 {16}2 {16}1 {16}0 {15}9 {15}8 {15}7 {15}6 {15}5 {15}4 {15}3 {15}2 {15}1 {15}0 {16}9
Sympathomimetic agents, {16}8 {16}7 {16}6 {16}5 {16}4 {16}3 {16}2 {16}1 {16}0 {60}9 {60}8 {60}7 {60}6 {60}5 such as beta-adrenergic agonists {60}4 {60}3 {60}2 {60}1 {60}0 {83}9 {83}8 {83}7
Thyroid hormones {83}6 {83}5 {83}4 {83}3 {83}2 {83}1 {83}0 {46}9 {46}8 {46}7 {46}6 {46}5 {46}4 {46}3 {46}2    (these medications may change many factors that affect the metabolic control of glucose concentrations and, unless the changes can be controlled with diet, may necessitate an increased sulfonylurea dose and regular monitoring {46}1 {46}0)

    (hyperglycemic effects have resulted with doses greater than 100 mg of chlorpromazine; other phenothiazines or lower doses of chlorpromazine have not had this effect. However, caution may be warranted for concurrent use of phenothiazines with sulfonylureas {47}9 {47}8)

    (isoniazid usually causes hyperglycemia, but hypoglycemia has occurred in some patients with diabetes who are taking tolbutamide; a decrease in the dose of tolbutamide is then warranted {47}7 {47}6)

    (beta-adrenergic agonists increase risk of hyperglycemia by increasing glycogenolysis. If given during pregnancy, these agents may cause hypoglycemia in the fetus, independent of maternal blood glucose concentrations, by causing a depletion of fetal glycogen stores; sulfonylurea dose adjustment may be necessary if these agents are given together during pregnancy {47}5 {47}4 {47}3)


Hypoglycemia-causing agents, such as:
Anabolic steroids {47}2 {47}1 {47}0
Androgens {48}9 {48}8 {48}7
Bromocriptine {48}6
Disopyramide {48}5 {48}4
Pyridoxine {48}3
Tetracycline {48}2 {48}1 {48}0 {75}9
Theophylline {75}8    (these medications may change metabolic control of glucose concentrations and, unless the changes can be controlled with diet, may necessitate a decreased sulfonylurea dose; patients susceptible to hypoglycemia should be monitored closely)


Insulin {75}7 {75}6    (sulfonylurea agents chronically stimulate the pancreatic beta cell to release insulin and increase receptor and tissue sensitivity to insulin; although concurrent use of the medications with insulin may increase the hypoglycemic response, the effect may be unpredictable)

    (although the combination has been used to treat a select group of patients with diabetes whose condition is not well-controlled with either agent alone, many studies have shown there is generally no additional benefit from using oral agents for the treatment of type 1 diabetes {75}5 {75}4 {75}3)


» Octreotide {75}2 {75}1    (octreotide suppresses pancreatic insulin and counterregulatory hormones, such as glucagon and growth hormone, and delays or lowers glucose absorption from the gastrointestinal tract; depending on the dose, concurrent use with sulfonylureas may cause hypoglycemia or hyperglycemia so that dose adjustment of the sulfonylurea may be needed; octreotide has been used beneficially for sulfonylurea overdose or insulinomas {75}0 {83}9 {83}8)


» Pentamidine {83}7 {83}6 {83}5    (pentamidine has a toxic effect on pancreatic beta cells resulting in a biphasic effect on glucose concentration, i.e., initial insulin release and hypoglycemia followed by hypoinsulinemia and hyperglycemia with continued use of pentamidine; dose alterations and continued use of sulfonylureas should be considered {83}4 {83}3 {83}2)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Blood urea nitrogen (BUN) {83}1 {83}0    (acetohexamide produces a reaction with diacetyl and falsely elevates results of this test {71}9 {71}8)


Creatinine, serum {71}7 {71}6 {71}5 {71}4 {71}3 {71}2    (acetohexamide has significantly increased the creatinine concentration for some laboratory tests by as much as 2.2 or 3.3 mg/dL and as little as 0.3 mg/dL for others {71}1 {71}0 {16}9)


Protein, total, serum    (tolbutamide interferes with sulfosalicylic acid test by causing turbidity {16}8 {16}7)


» Sodium iodide I 123 {16}6 {16}5 or
» Sodium iodide I 131 {16}4 {16}3    (tolbutamide may decrease thyroidal uptake of I 123 or I 131; withdrawal of tolbutamide 1 week or longer before reactive iodine uptake test is necessary to prevent interference {16}2 {16}1)

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) {16}0 {60}9 or
Alkaline phosphatase {60}8 {60}7 {60}6 or
Aspartate aminotransferase (AST [SGOT]) {60}5 {60}4 {60}3 {60}2 {60}1 or
Lactate dehydrogenase (LDH) {60}0 {83}9 {83}8    (values may be mildly increased, usually are not associated with clinical symptoms, and may be due to the sulfonylurea or to the underlying diabetes; however, hepatitis or cholestatic jaundice is caused rarely by sulfonylureas and should be considered with high values {83}7 {83}6 {83}5 {83}4)


Bile, urine or
Bilirubin, urine    (concentrations may be mildly increased and usually do not present with clinical symptoms; however, hepatitis or cholestatic jaundice is caused rarely by sulfonylureas and should be considered with high values {83}3)


C-peptide, serum    (increased concentration for the first three months of sulfonylurea treatment; can return to pretreatment values long-term [18 months in one study] {83}2)


Osmolality, urine {83}1 {83}0 or
Sodium, serum {16}9 {16}8 {16}7 {16}6    (may be decreased with acetohexamide, gliclazide, glipizide, glyburide, or tolazamide because of their slight diuretic effect {16}5 {16}4 {16}3)

    (chlorpropamide increases osmolality because of its antidiuretic effect and has caused dilutional hyponatremia {16}2 {16}1 {16}0)

    (sodium may also decrease in response to hyperglycemia; each 100 mg/dL [5.51 mmol/L] increase in blood glucose decreases serum sodium by 1.6 mEq/L {60}9)


Uric acid, serum    (concentrations are considerably reduced by use of acetohexamide due to its mild uricosuric effect {60}8)


Urine collection, 24-hour {60}7 {60}6    (quantity is mildly increased due to normal slight diuretic response by acetohexamide, gliclazide, glipizide, glyburide, or tolazamide {60}5)

    (quantity is decreased with chlorpropamide due to its antidiuretic effect {60}4 {60}3)


For gliclazide
Factors VIII, XI {60}2    (concentrations may be decreased {60}1 {60}0)


Tissue plasminogen activator {83}9 {83}8    (concentrations may be increased {83}7 {83}6)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:

For all oral sulfonylurea antidiabetic agents:
» Acidosis, significant or
» Burns, severe or
» Diabetic coma {83}5 {83}4 {83}3 {83}2 {83}1 or
» Diabetic ketoacidosis, with or without coma {83}0 {18}9 {18}8 {18}7 {18}6 {18}5 {18}4 {18}3 {18}2 {18}1 {18}0 {60}9 {60}8 {60}7 {60}6 {60}5 {60}4 {60}3 or
» Hyperosmolar nonketotic coma {60}2 {60}1 {60}0 {16}9 or
» Surgery, major {16}8 {16}7 {16}6 {16}5 {16}4 {16}3 {16}2 {16}1 {16}0 {16}9 {16}8 {16}7 {16}6 {16}5 {16}4 {16}3 or
» Trauma, severe {16}2 {16}1 {16}0 {16}9 {16}8 {16}7 {16}6 {16}5 {16}4 {16}3 {16}2 {16}1 {16}0 {80} {81} {210} or
» Any other condition that causes severe blood glucose fluctuations or
» Any other condition in which insulin needs change rapidly     (fluctuations in blood glucose concentrations associated with certain disease states are more closely controlled by titration of insulin dosing, possibly on a short-term basis, rather than with oral antidiabetic agents, such as sulfonylureas)


Risk-benefit should be considered when the following medical problems exist

For all oral sulfonylurea antidiabetic agents:
Allergy to sulfonylurea antidiabetic agents, sulfonamides, or thiazide-type diuretics {03} {11} {14} {15} {16} {40} {56} {58} {60} {67} {73} {77} {79} {81}
» Diarrhea, severe {62} or
» Gastroparesis {26} or
» Intestinal obstruction {62} or
» Vomiting, prolonged {62} or
» Other conditions causing delayed food absorption {26}    (delayed stomach emptying or intestinal movement or vomiting may require modification of a sulfonylurea dose or a change to insulin therapy)


» Hepatic disease {06} {12} {15} {40} {44} {52} {56} {58} {60} {67} {73} {77} {79} {80} {81}    (sulfonylureas that are extensively metabolized in the liver should not be used when there is hepatic impairment; hypoglycemia that develops may be more severe when these sulfonylureas are being used {52} {97} {101} {107})


» Hyperglycemia-causing conditions, such as:
Female hormone changes or
Fever, {06} {12} {15} {40} {73} high or
Hyperadrenalism, not optimally controlled {58} {81} {211} or
Infection, severe {06} {12} {15} {16} {40} {44} {52} {56} {57} {58} {60} {67} {73} {77} {79} or
Psychological stress {11} {12} {21} {40} {52} {130} {210}    (these conditions, by increasing blood glucose, may increase the need for more frequent glucose monitoring and for a permanent or temporary dose increase for sulfonylureas or a change to insulin if blood glucose is uncontrolled {11} {21} {130} {210})


» Hyperthyroidism, not optimally controlled {16} {58} {60}    (hyperthyroidism aggravates diabetes mellitus by increasing plasma glycogen concentrations and glucose absorption and by impairing glucose tolerance; thyroid hormone has dose-dependent biphasic effects on glycogenolysis and gluconeogenesis; hyperthyroidism can make glycemic control difficult until the patient is euthyroid; patients with this condition may require an increased dose of the sulfonylurea until euthyroidism is achieved {55} {211})


» Hypoglycemia-causing conditions, such as:
Adrenal insufficiency, not optimally controlled {06} {12} {15} {40} {44} {52} {56} {57} {58} {60} {67} {77} {73} {79} {80} {81} {209} or
Debilitated physical condition {06} {12} {15} {40} {44} {52} {56} {58} {59} {60} {67} {73} {77} {79} {80} {81} {209} {210} or
Malnutrition {06} {12} {15} {40} {44} {52} {56} {58} {59} {60} {67} {73} {77} {79} {80} {81} {210} or
Pituitary insufficiency, not optimally controlled {06} {12} {15} {40} {44} {52} {57} {73} {80} {81} {209}    (these conditions, which inherently predispose patients to the risk of developing hypoglycemia, increase the patient's risk of developing severe hypoglycemia with concurrent treatment of sulfonylurea antidiabetic agents; reduced sulfonylurea dose or more frequent monitoring may be required for patients with these conditions {09} {12} {44} {58} {60} {62} {80} {81})


Hypothyroidism, not optimally controlled    (sulfonylurea metabolism may be reduced with hypothyroidism and may mildly aggravate this underlying condition, which already exhibits reduced glucose absorption and altered glucose and lipoprotein metabolism [tolbutamide has goitrogenic properties]; low doses of a sulfonylurea may be needed when hypothyroid conditions exist, and an increase in sulfonylurea dosing may be required when initiating thyroid treatment; euglycemic control may be difficult until the patient is euthyroid {55} {209} {211} {212} {213} {215})


» Renal function impairment {06} {12} {15} {40} {44} {52} {56} {58} {60} {67} {73} {77} {79} {80} {81}    (use of sulfonylureas increases the risk of possibly prolonged hypoglycemia with renal function impairment {12} {60} {80} {81})

    (the elimination half-lives of all the sulfonylureas are increased with renal function impairment, especially where tubular involvement predominates or if azotemia is present, but less so if the glomerular filtration rate is mildly reduced; sulfonylureas with longer half-lives, such as acetohexamide and chlorpropamide, are not recommended since renal excretion is important in the elimination of chlorpropamide and the active metabolite of acetohexamide [hydroxyhexamide]; weakly active metabolites of tolazamide and glyburide may also accumulate, particularly in those patients with a creatinine clearance of less than 30 mL/min [0.5 mL/sec]; sulfonylureas with shorter half-lives, such as gliclazide, glipizide, or tolbutamide, should present fewer problems but should be used cautiously in renal impairment {11} {27} {97} {101} {125} {137})


For chlorpropamide or tolbutamide:
» Congestive heart failure {220}    (fluid retention, caused rarely by chlorpropamide and even less often by tolbutamide, may result in hyponatremia and precipitate congestive heart failure in the elderly when other risk factors for congestive heart failure are present {209} {216} {220})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood glucose determinations {03} {06} {12} {14} {15} {16} {40} {44} {52} {73} {79} {80} {81}    (blood or plasma glucose reflects the current degree of metabolic control and should be routinely self-monitored by the patient at home and by the physician [every 3 months, or more often when patient is not stabilized] to confirm that blood glucose concentration is maintained within agreed-upon targets by the selected diet and dosing regimen; this is particularly important during dosage adjustments. Self-monitoring of blood glucose by the patient may require testing multiple times during the day or once to several times a week {03} {14} {16} {228})

    (caution in interpreting blood glucose concentrations is needed because normal whole blood glucose values are approximately 15% lower than plasma glucose values; glucose values are also laboratory- and method-specific. Normal fasting whole blood glucose for adults of all ages is 65 to 95 mg/dL [3.6 to 5.3 mmol/L]. Normal fasting serum glucose is 70 to 105 mg/dL [3.9 to 5.8 mmol/L] for adults younger than 60 years of age and 80 to 115 mg/dL [4.4 to 6.4 mmol/L] for adults 60 years of age or older. For pregnant women with diabetes, a normal fasting serum glucose is less than 105 mg/dL [5.8 mmol/L] and a fasting whole blood glucose is less than 120 mg/dL [6.7 mmol/L]. Goals of conventional sulfonylurea antidiabetic therapy are based on the absence of symptoms of hyperglycemia and hypoglycemia {224} {225} {226})

    (capillary blood glucose measurement provides important information when done properly, but caution is warranted because of potential errors in technique and readings; it has been suggested that the values be relied upon only if the reported glucose concentration for patients in whom diabetes is stable is between 75 mg/dL and 325 mg/dL [4.12 mmol/L and 17.88 mmol/L, respectively] {227} {229})


» Complete blood count (CBC) {231} {232}    (leukopenia, agranulocytosis, thrombocytopenia, and hemolytic and aplastic anemias have occurred rarely with sulfonylureas {03} {12} {14} {15} {16} {40} {56} {58} {80} {81})


Glucose, urine {03} {06} {14} {15} {16} {40} {52} {73} {79} {80} {81} or
Ketones, urine    (if blood glucose concentrations exceed 200 mg/dL [11.1 mmol/L], monitoring of urine for the presence of glucose and ketones may be necessary; normalization of glucose in the urine generally lags quantitatively behind serum glucose concentrations; test methods are generally capable of detecting serum glucose concentrations greater than 180 mg/dL [10 mmol/L] {224} {225} {226})


» Glycosylated hemoglobin (hemoglobin A 1c) determinations {03} {06} {12} {14} {15} {16} {40} {44} {52} {73} {80} {81}    (hemoglobin A 1c values [normal whole blood hemoglobin A 1c is approximately 4 to 6% of total hemoglobin; specific values are laboratory-dependent] reflect the metabolic control over the preceding 3 months, but assessment of this parameter does not eliminate the need for daily blood glucose monitoring. Hemoglobin A 1c may be falsely elevated in patients whose diabetes is unstable when the intermediate precursor is elevated [e.g., in alcoholism] and falsely lowered in conditions of shortened red blood cell lifespan [e.g., in anemia and acute or chronic blood loss] or in patients with hemoglobinopathies [e.g., sickle cell disease] {224} {225} {226} {227} {228} {229})


Osmolarity determinations, plasma or
Sodium concentrations, serum    (may be necessary with use of chlorpropamide or tolbutamide, especially for the elderly or when thiazide diuretics are being taken concurrently)


pH measurements, serum or
Potassium concentrations, serum    (determinations may be important if patient is hypoglycemic and ketoacidotic )




Side/Adverse Effects

Note: It has been suggested by some studies, including the University Group Diabetes Program (UGDP), that certain sulfonylurea antidiabetic agents increase cardiovascular mortality in diabetic patients, a population that already has a greater risk of cardiovascular disease and mortality when blood glucose is not controlled. {44} {52} {108} Other studies have not reached a similar conclusion and have in fact suggested that control of elevated blood glucose with sulfonylurea antidiabetic agents may lessen the danger of cardiovascular disease and mortality. {01} {02} {172} Despite questions regarding the interpretation of the results and the adequacy of the experimental design, the findings of the UGDP study provide an adequate basis for caution, especially for certain high risk patients with coronary artery disease, congestive heart failure, or angina pectoris. If sulfonylurea treatment is necessary, glyburide or gliclazide may be the preferred sulfonylureas for use in patients at risk for conditions causing cardiac hypoxia. {108} {172} {216} {217} {218} {219} {220} {221} The patient should be informed of the potential risks and advantages of sulfonylurea antidiabetic agents and of alternative modes of therapy. {03} {06} {12} {14} {15} {16} {40} {44} {52} {56} {57} {58} {60} {61} {73} {80} {81} {82}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hypoglycemia—mild, including nocturnal hypoglycemia (anxiety; behavior change similar to drunkenness; blurred vision; cold sweats; confusion; cool pale skin; difficulty in concentrating; drowsiness; excessive hunger; fast heartbeat; headache; nausea; nervousness; nightmares; restless sleep; shakiness; slurred speech; unusual tiredness or weakness){12}{44}{67}{79}{80}{81}{104}{204}{205}
    
weight gain {02}{11}{234}

Note: Predisposing factors related to diet, exercise, age, or concurrent use of other hypoglycemia-causing drugs (including insulin) increase the chances of hypoglycemic episodes occurring. The occurrence of a recent episode of hypoglycemia may lessen the symptoms of a second episode. In the elderly, hypoglycemia symptoms are variable and harder to identify. Furthermore, nocturnal hypoglycemia may be asymptomatic in 33% or more of affected patients. {202} {235} Hypoglycemic episodes are experienced by 20% of the patients taking sulfonylureas every 6 months (6% experiencing monthly episodes). {09} {192}
Weight gain is greater with combination use of insulin and sulfonylureas than with sulfonylurea therapy alone. Gliclazide alone, or metformin in combination with sulfonylureas, usually results in less weight gain than other sulfonylureas and has exhibited a weight loss effect. {11} {19} {193} {234}


Incidence less frequent
    
Erythema multiforme or exfoliative dermatitis (peeling of skin; skin redness, itching, or rash){06}{12}{30}{40}{44}{52}{57}{81}{104}{209}{233}{236}
    
hypoglycemia—severe (coma; seizures){06}{09}{12}{15}{40}{44}{56}{58}{60}{67}{73}{77}{79}{81}{104}{192}
For chlorpropamide or, rarely, tolbutamide
    
Dilutional hyponatremia, hypo-osmolality, or syndrome of inappropriate antidiuretic hormone (SIADH) (depression; dizziness; headache; lethargy; nausea; swelling or puffiness of face, ankles, or hands with occasional progression to seizures, coma, or stupor){06}{12}{14}{15}{16}{40}{52}{57}{73}{80}{81}{82}{209}{233}

Note: The incidence of severe hypoglycemia episodes is 0.22 episodes per 1000 patient-years. It occurs more often with long-acting sulfonylureas, such as chlorpropamide or glyburide, when other predisposing factors or conditions are present, and can be relapsing and prolonged; glyburide results in a higher fatality rate than does chlorpropamide. {09} {57} {99} {100} {191} {192} {204} {205} {237}



Incidence rare
    
Anemia, aplastic or hemolytic (continuing and unexplained tiredness or weakness, headache, shortness of breath brought on by exercise){03}{06}{12}{14}{15}{16}{27}{28}{31}{32}{40}{44}{52}{57}{58}{60}{67}{73}{77}{79}{80}{81}{209}{237}
    
blood dyscrasias, specifically, agranulocytosis, leukopenia, pancytopenia (fever and sore throat; pale skin; unusual bleeding or bruising; unusual tiredness or weakness){03}{06}{12}{14}{15}{16}{30}{40}{44}{52}{56}{57}{58}{60}{67}{73}{77}{79}{80}{81}{236}{237}
    
cholestasis, cholestatic jaundice, hepatic function impairment, hepatic porphyria, hepatitis, or porphyria cutanea tarda (dark urine; fluid-filled skin blisters; itching of the skin; light-colored stools; sensitivity to the sun; skin thinness; yellow eyes or skin){06}{12}{14}{15}{16}{27}{40}{44}{52}{56}{58}{60}{67}{73}{77}{79}{80}{81}{209}{233}{236}{237}
    
eosinophilia (blood in sputum; chest pain; chills; general feeling of ill health; increased production of sputum; increased sweating; shortness of breath){27}{30}{33}{209}
    
thrombocytopenia (unusual bleeding or bruising){06}{12}{15}{27}{30}{31}{32}{52}{56}{58}{60}{67}{73}{77}{79}{209}{237}

Note: Sulfonylurea-induced blood dyscrasias and dermatologic conditions generally occur within the initial six weeks of therapy and are thought to be hypersensitivity reactions. {57} {209} {233}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Changes in sense of taste {16}{209}
    
dizziness {14}{15}{44}{52}{77}{80}
    
drowsiness {14}{52}{80}
    
gastrointestinal disturbances (constipation; diarrhea; flatulence; heartburn; loss of or increase in appetite; nausea; stomach pain, fullness, or discomfort; vomiting){06}{12}{14}{15}{16}{27}{30}{33}{40}{44}{52}{56}{58}{60}{67}{73}{77}{79}{80}{81}{104}{120}{236}
    
headache {14}{15}{16}{44}{52}{77}{80}
    
polyuria (increased volume of urine and frequency of urination){80}

Incidence less frequent or rare
    
Blurred vision and/or changes in accommodation (difficulty in focusing the eyes){12}{40}{44}{67}{73}{81}
    
photosensitivity (increased sensitivity of skin to sunlight){06}{12}{15}{40}{44}{52}{56}{58}{60}{67}{73}{77}{81}{233}

Note: Blurred vision and/or changes in accommodation may be more pronounced when therapy is initiated and are thought to be caused by changes in blood glucose concentration. {12} {40} {44} {73} {81}






Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Antidiabetic Agents, Sulfonylurea (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to sulfonylurea antidiabetic agents, sulfonamides, or thiazide diuretics

Pregnancy—Chlorpropamide crosses the placenta. Sulfonylureas should not be used during pregnancy, especially when insulin is available. In the rare cases that a sulfonylurea is used, chlorpropamide and glipizide should be discontinued at least 1 month before delivery date and other sulfonylureas stopped at least 2 weeks before delivery date. Importance of controlling and monitoring blood glucose concentrations before, during, and after pregnancy by adjusting antidiabetic agent dosing in order to help prevent maternal and fetal problems, including fetal macrosomnia, anomalies, and hyperglycemia





Breast-feeding—Chlorpropamide and tolbutamide are distributed into human breast milk, and their effect on breast-fed infants is not known; some physicians believe that tolbutamide is compatible with breast-feeding; it is not known whether other sulfonylureas are distributed into human breast milk





Use in the elderly—The elderly may be more susceptible to hypoglycemia, especially when treated with glyburide and chlorpropamide or when other hypoglycemia-causing agents are concurrently being prescribed along with sulfonylureas; also, the elderly have a higher risk of developing hyponatremia or a reversible syndrome of inappropriate antidiuretic hormone when treated with chlorpropamide
Other medications, especially alcohol; asparaginase; azole antifungals; beta-adrenergic blocking agents; chloramphenicol; cimetidine; corticosteroids; coumarin- or indandione-derivative anticoagulants; cyclosporine; fluoroquinolones; guanethidine; lithium; MAO inhibitors including furazolidone, procarbazine, and selegiline; octreotide; pentamidine; quinidine; quinine; ranitidine; salicylates, large doses; or thiazide diuretics
Other medical problems, especially conditions causing delayed food absorption including gastroparesis, intestinal obstruction, prolonged vomiting, or severe diarrhea; conditions that cause severe blood glucose fluctuations or rapidly change insulin needs including diabetic coma, diabetic ketoacidosis, hyperosmolar nonketotic coma, major surgery, severe burns, severe trauma, or significant acidosis; hyperglycemia-causing conditions including female hormone changes, high fever, hyperadrenalism that is not optimally controlled, psychological stress, or severe infection; hypoglycemia-causing conditions including adrenal or pituitary insufficiency that is not optimally controlled, debilitated physical condition, hepatic disease, hyperthyroidism that is not optimally controlled, malnutrition; or renal function impairment; in addition, for chlorpropamide or tolbutamide, congestive heart failure

Proper use of this medication
» Compliance with therapy, including not taking more or less medication than directed

» Importance of adherence to recommended regimens for diet, exercise, glucose monitoring, and sick-day management

For extended-release glipizide tablets
Swallowing tablets whole without breaking, crushing, or chewing

Patient may notice empty shell in stool left over after medication is absorbed

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress
»
Carefully following special instructions of health care team
Discussing use of alcohol and tobacco

Not taking other medications unless discussed with physician

Getting counseling for family members to help them assist the patient with diabetes; also, special counseling for pregnancy planning and contraception

Making travel plans to include preparedness for diabetic emergencies and keeping meal times near the usual times with changing time zones

Wearing sunscreen and protective clothing to protect against sunburn and photosensitivity
» Preparing for and understanding what to do in case of an emergency by carrying medical history and current medication list, wearing medical identification, keeping quick-acting sugar and nonexpired glucagon kit and needles close by

» Recognizing symptoms of hypoglycemia: anxiety; behavior change similar to drunkenness; blurred vision; cold sweats; confusion; cool, pale skin; difficulty in concentrating; drowsiness; excessive hunger; fast heartbeat; headache; nausea; nervousness; nightmares; restless sleep; shakiness; slurred speech; and unusual tiredness and weakness

» Recognizing what brings on symptoms of hypoglycemia, such as delaying or missing a meal or snack, exercising more than usual, drinking significant amounts of alcohol, taking certain medications, using too much antidiabetic medication, such as insulin or sulfonylurea, or illness, including vomiting or diarrhea

» Knowing what to do if symptoms of hypoglycemia occur, such as eating glucose tablets or gel, corn syrup, honey, or sugar cubes; or drinking fruit juice, nondiet soft drink, or sugar dissolved in water; also, eating small snack, such as crackers or half sandwich, when scheduled meal is longer than 1 hour away; not eating foods high in fat, such as chocolate, since fat slows gastric emptying; or using glucagon injection if the patient becomes unconscious

» Recognizing symptoms of hyperglycemia and ketoacidosis: blurred vision; drowsiness; dry mouth; flushed, dry skin; fruit-like breath odor; increased urination (frequency and volume); ketones in urine; loss of appetite; stomachache, nausea, or vomiting; tiredness; troubled breathing (rapid and deep); unconsciousness; and unusual thirst

» Recognizing what brings on symptoms of hyperglycemia, such as diarrhea, fever, or infection; not taking enough or skipping a dose of insulin; exercising less than usual; or overeating or not following meal plan

» Knowing what to do if symptoms of hyperglycemia occur, such as checking blood glucose and contacting a member of the health care team


Side/adverse effects
Signs of potential side effects, especially mild or severe hypoglycemia; weight gain; erythema multiforme or exfoliative dermatitis; aplastic or hemolytic anemia; blood dyscrasias; cholestasis, cholestatic jaundice, hepatic function impairment, hepatic porphyria, hepatitis, or porphyria cutanea tarda; eosinophilia; and thrombocytopenia; in addition, for chlorpropamide or, rarely, tolbutamide—dilutional hyponatremia, hypo-osmolality, or syndrome of inappropriate antidiuretic hormone (SIADH)


General Dosing Information
There is little evidence that one sulfonylurea is more effective in lowering blood glucose than another, especially between first and second generation sulfonylureas. Some pharmacokinetic differences between sulfonylureas may result in small qualitative and temporal differences that may make one medication more suitable in a certain situation. For instance, glyburide (possibly due to its longer duration of action and effect on hepatic glucose suppression) and gliclazide exert a better effect on fasting blood glucose than does glipizide, which results in lowered nocturnal and morning blood glucose; glipizide has greater postprandial insulin release and lower postprandial blood glucose concentrations. Overall, the resulting reduction in blood glucose concentration is similar between sulfonylureas. {02} {27} {28} {191}

Conservative initial and maintenance doses may be required in patients with medical problems that make them more sensitive to effects of sulfonylureas. {03}

Secondary failure of oral antidiabetic therapy may occur in certain patients. This may be due to increasing severity of diabetes or to diminished responsiveness to the medication. {06} {12} {15} {19} {20} {21} {22} {23} {24} {40} {44} {52} {73} {80} {81} {190} {193}

When adding a sulfonylurea to an insulin regimen that is poorly controlled with insulin alone, the insulin dose at times may be reduced by 25 to 50%. {05} {19} {27} {192}

When adding a sulfonylurea to maximum doses of metformin or metformin to maximum doses of a sulfonylurea, even if primary or secondary failure of a sulfonylurea has occurred, the new medication should be added gradually and titrated to the lowest effective dose. {59} {239} {240} {241} Both agents should be discontinued and insulin should be initiated if the patient does not respond to maximum doses within 3 months (or less, depending on clinician's decision). {59} {239} No transition time is needed when transferring between sulfonylureas, metformin, or insulin, except with chlorpropamide, which may require a 2-week transition because of chlorpropamide's prolonged duration of action. {59}

Diet/Nutrition
Absorption of chlorpropamide or glipizide may be delayed if the medication is ingested with food; glipizide should be taken 30 minutes before a meal. {52} Gliclazide may be taken 30 minutes before a meal or with a meal but not after a meal. Glimepiride should be taken with breakfast or the first main meal. {44} Nonmicronized glyburide should not be taken with a diet high in fat; nonmicronized glyburide does not have any other dietary restrictions. {14} {29} {30} {31} {80} {104} {106}

For treatment of adverse effects and/or overdose
Recommended treatment consists of the following:
For mild to moderate hypoglycemia—

   • Treating with immediate ingestion of a source of sugar, such as glucose gel, glucose tablets, fruit juice, corn syrup, nondiet soft drinks, honey, sugar cubes, or table sugar dissolved in water. A frequently used source of sugar is a glassful of orange juice. {63}
   • Documenting blood glucose and rechecking in 15 minutes.
   • Counseling patient to seek medical assistance promptly.
   • Closely monitoring for at least 3 to 5 days patients who develop hypoglycemia during use of chlorpropamide. {06}

Note: Glucose administration is the basis for treatment of hypoglycemia; however, an exposure to sudden or excessive hyperglycemia caused by an injection of hypertonic glucose solution may further stimulate the sulfonylurea-primed pancreas to release more insulin, worsening the hypoglycemia. {63} {139}

For severe hypoglycemia or acute overdose, including coma—

   • Counseling patient to obtain emergency medical assistance immediately
   • Immediately treating with 50 mL of 50% dextrose injection given intravenously to stabilize the patient. Then, administering a continuous infusion of 5 to 10% dextrose injection to maintain slight hyperglycemia (approximately 100 mg/dL blood glucose concentration) for up to 12 days. The intravenous glucose therapy should not be terminated suddenly. A central venous line for long-term use (24 to 48 hours) in cases of chlorpropamide overdose may be required. (Oral glucose cannot be relied upon to maintain euglycemia because 60% of an oral glucose dose is stored as hepatic glycogen with only 15% left for brain utilization and 15% for insulin-dependent tissues even though 75% of oral glucose is absorbed after 150 to 180 minutes.) {95} {139}
   • Glucagon, 1 to 2 mg administered intramuscularly, is useful for fast onset of action to mobilize hepatic glucose stores but may be ineffective or variable in its effect if glycogen stores are depleted and must follow the use of glucose. {95}
   • Diazoxide therapy (200 mg orally every 4 hours or 300 mg intravenously over a 30-minute period every 4 hours) can be used for patients who do not respond to glucose therapy or for patients in a coma as an aid to glucose infusion to reduce hypoglycemia; the patient should be monitored for sodium concentration and for hypotension. {95} {139}
   • Emesis can be induced with ipecac syrup if sulfonylurea overdose is recent (within the past 30 minutes) and the patient is alert, has an intact gag reflex, and is not obtunded or convulsing. Otherwise, gastric lavage after endotracheal tube placement is required. {95} {139}
   • Gastric removal by administration of repeated doses of oral activated charcoal with appropriate cathartic, although the usefulness of this has not been established. {95}
   • Alkalinization of urine with sodium bicarbonate to pH of 8 can eliminate 80% of chlorpropamide over 24 hours, but is not useful with other sulfonylureas. Caution with concurrent use with diazoxide treatment because of possible significant sodium retention. {102}
   • Monitoring vital signs, arterial blood gases, blood glucose, and serum electrolytes (especially calcium, potassium, and sodium) as required. Initially, blood glucose concentrations should be monitored as frequently as every 1 to 3 hours. Blood urea nitrogen and serum creatinine concentrations should also be obtained. {95}
   • Cerebral edema—Managing with mannitol and dexamethasone. {95}
   • Hypokalemia—Managing with potassium supplements. {95}
   • Hospitalization for 6 to 91 hours (mean, 24 hours) because the hypoglycemia may be recurrent and prolonged; for chlorpropamide this period may be extended to 3 to 5 days or longer. {63} {95} {115} {139}
   • Other supportive measures should also be employed as needed.

ACETOHEXAMIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Protein binding—Very high, ionic. {03}

Serum half-life—Parent 1.3 hours; metabolite 6 hours. {03}

Duration of action—8 to 24 hours. {03}

Active metabolite. {03}



Precautions:
Laboratory value alterations—Reduces serum uric acid concentration. {03}

Medical considerations/contraindications—Not recommended for use in patients with renal function impairment. {03}



Additional Dosing Information
See also General Dosing Information .

When patients are transferred to acetohexamide from another sulfonylurea antidiabetic medication (with the exception of chlorpropamide), no transition period is required. {03} When transferring patients from chlorpropamide, caution should be exercised during the first 1 to 2 weeks {03} because of the prolonged retention of chlorpropamide in the body.

During conversion from insulin therapy to acetohexamide therapy, no gradual dosage adjustment usually is required for patients using less than 20 USP Units of insulin daily. {03} For patients using 20 or more USP Units daily, a 25 to 30% reduction in insulin every day or every second day with gradual dosage adjustment is advisable. {03} Hospitalization for some patients on a higher insulin dosage may be required for uneventful conversion. {03}


Oral Dosage Forms

ACETOHEXAMIDE TABLETS USP

Usual adult dose
Antidiabetic
Initial: Oral, 250 mg once a day, the dosage being increased by 250 or 500 mg every five to seven days as needed. {03} {32} {56}

Maintenance: Oral, 250 to 1000 mg once a day before breakfast or 1000 to 1500 mg divided into two doses taken before breakfast and evening meals. {03} {56}


Usual adult prescribing limits
1.5 grams daily. {03} {32} {56}

Usual pediatric dose
Safety and efficacy have not been established. {03} {32} {56}

Usual geriatric dose
See Usual adult dose . {03} {32} {56}

Note: If an elderly patient tends toward hypoglycemia during the first twenty-four hours after an initial dose of 250 mg at breakfast, the dose should be reduced or the medication discontinued. {56}


Strength(s) usually available
U.S.—


250 mg (Rx) [Dymelor (scored){03}][Generic]{32}


500 mg (Rx) [Dymelor (scored){03}][Generic]{32}

Canada—


500 mg (Rx) [Dimelor (scored){56}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. {03} {18} {32} Store in a well-closed container. {18} {32}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • Do not take other medicines without advice from your doctor.
   • Avoid too much sun.


CHLORPROPAMIDE

Summary of Differences


Indications:
Also indicated in the treatment of central diabetes insipidus.



Pharmacology/pharmacokinetics:
Other actions/effects—Antidiuretic effect.

Protein binding—Very high, ionic. {01}

Half-life, serum—36 hours.



Precautions:
Pregnancy—Crosses the placenta.

Breast-feeding—Distributed into breast milk.

Geriatrics—Use is generally avoided.

Drug interactions and/or related problems—Risk of disulfiram-like reaction with alcohol is higher with chlorpropamide than with other sulfonylureas.

Medical considerations/contraindications—Not recommended for use in patients with renal function impairment or congestive heart failure.



Side/adverse effects:
Potential for serious adverse effects (e.g., prolonged hypoglycemia and severe hyponatremia) because of prolonged action of chlorpropamide, especially with predisposed individuals.



Additional Dosing Information
See also General Dosing Information .

When patients are transferred to chlorpropamide from another sulfonylurea, no transition period is required. {06} When transferring patients from chlorpropamide, caution should be exercised during the first 1 to 2 weeks because of the prolonged retention of chlorpropamide in the body. {33}

During conversion from insulin therapy to chlorpropamide therapy, no gradual dosage adjustment usually is required for patients using less than 40 USP Units of insulin daily. {33} For patients using 40 USP Units or more daily, a 50% reduction in insulin the first few days is advisable. {06} {33} Hospitalization for some patients on a higher insulin dosage may be required for uneventful conversion.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CHLORPROPAMIDE TABLETS USP

Usual adult dose
Antidiabetic
Initial: Oral, 250 mg once a day, the dosage being changed by 50 to 125 mg every three to five days if needed. {06}

Maintenance: Oral, 100 to 500 mg a day as a single dose. {06}

[Antidiuretic ]1
Oral, 100 to 250 mg as a single dose daily, the dosage being adjusted at two- or three-day intervals as needed and tolerated.


Note: Occasionally, divided doses are administered, usually twice a day before the morning and evening meals, to improve gastrointestinal tolerance. {06}


Usual adult prescribing limits
Antidiabetic
750 mg per day. {06}

[Antidiuretic ]1
500 mg per day.


Usual pediatric dose
Safety and efficacy have not been established. {06}

Usual geriatric dose
Antidiabetic
Oral, initially 100 to 125 mg once a day, the dosage being increased by 50 to 125 mg at three- to five-day intervals as needed. {06} {57}


Strength(s) usually available
U.S.—


100 mg (Rx) [Diabinese (scored){06}][Generic] ( may be scored){33}{34}{35}


250 mg (Rx) [Diabinese (scored){06}][Generic] ( may be scored){33}{34}{35}

Canada—


100 mg (Rx) [Apo-Chlorpropamide (scored){74}] [Diabinese (scored){57}][Generic]


250 mg (Rx) [Apo-Chlorpropamide (scored){74}] [Diabinese (scored){57}] [Novo-Propamide (scored){71}][Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), {06} {33} {34} {35} unless otherwise specified by manufacturer. Store in a well-closed container. {18} {33} {34} {35}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • Do not take other medicines without advice from your doctor.
   • Avoid too much sun.


GLICLAZIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Other actions/effects—Protective activity for some cardiac arrhythmias; also, reduces platelet adhesiveness and aggregation and has fibrinolytic activity.

Protein binding—Very high, {79} nonionic.

Serum half-life—Approximately 10.4 hours.

Duration of action—Approximately 24 hours.



Precautions:
Drug interactions and/or related problems—Displacement from plasma proteins by other medications is less likely.

Medical considerations/contraindications—May be preferred for those patients with moderate renal function impairment; should not be used with severe renal failure. {79}



Side/adverse effects:
Less weight gain when compared to other sulfonylureas.



Additional Dosing Information
See also General Dosing Information .

When patients are transferred to gliclazide from another sulfonylurea antidiabetic medication (with the exception of chlorpropamide), no transition period is required. When transferring patients from chlorpropamide, caution should be exercised during the first 1 to 2 weeks because of the prolonged retention of chlorpropamide in the body.

During conversion from insulin therapy to gliclazide therapy, no gradual dosage adjustment usually is required for patients using less than 20 USP Units of insulin daily. For patients using 20 or more USP Units daily, a 25 to 30% reduction in insulin every day or every second day with gradual dosage adjustment is advisable. Hospitalization for some patients on a higher insulin dosage may be required for uneventful conversion.


Oral Dosage Forms

GLICLAZIDE TABLETS

Usual adult dose
Antidiabetic
Initial: Oral, 160 mg two times a day with meals. {79}

Maintenance: Oral, 80 to 320 mg a day with meals. {79}


Usual adult prescribing limits
320 mg daily. {79}

Usual pediatric dose
Safety and efficacy have not been established. {79}

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


80 mg (Rx) [Diamicron (quad-scored){79}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages. {79}
   • Do not take other medicines without advice from your doctor.
   • Avoid too much sun.


GLIMEPIRIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Protein binding—Very high. {44}

Serum half-life—5 and 9.2 hours following single and multiple doses, respectively. {44}



Precautions:
Breast-feeding—Distributed into the milk of rats in significant concentrations. Offspring of rats exposed to high concentrations during pregnancy developed skeletal abnormalities after nursing. Not recommended for use by nursing mothers. {44}



Additional Dosing Information
See also General Dosing Information .

Secondary failure may be treated by using insulin in combination with glimepiride. {44} The fasting glucose concentration for instituting combination therapy is > 150 mg per dL in plasma or serum. {44} Periodic adjustments in insulin dosage may be necessary as guided by glucose and glycosylated hemoglobin concentrations. {44} Combination insulin-glimepiride therapy may increase the potential for development of hypoglycemia. {44}

When patients are transferred to glimepiride from another sulfonylurea antidiabetic medication (with the exception of chlorpropamide), no transition period is required. {44} When transferring patients from chlorpropamide, caution should be exercised during the first 1 to 2 weeks because of the prolonged retention of chlorpropamide in the body. {44}


Oral Dosage Forms

GLIMEPIRIDE TABLETS

Usual adult dose
Antidiabetic


Monotherapy:
Initial: Oral, 1 to 2 mg once a day with breakfast or the first main meal. {44}
Note: Patients with renal function impairment should receive an initial dose of 1 mg once a day. {44}



Maintenance: Oral, 1 to 4 mg once a day. {44} After reaching a dose of 2 mg, increases in dosage should be made in increments of up to 2 mg every one to two weeks based on blood glucose response. {44}



Combination therapy with insulin:
Oral, 8 mg once a day with breakfast or the first main meal. {44}



Combination therapy with metformin:
Oral, 8 mg once a day with breakfast or the first main meal.{244}

Note: Attempts should be made to identify the minimum effective dose of each drug.{244}




Usual adult prescribing limits
8 mg once a day. {44}

Usual pediatric dose
Safety and efficacy have not been established. {44}

Usual geriatric dose
See Usual adult dose .

Note: Geriatric patients should receive an initial dose of 1 mg once a day. {44}


Strength(s) usually available
U.S.—


1 mg (Rx) [Amaryl (scored){44}]


2 mg (Rx) [Amaryl (scored){44}]


4 mg (Rx) [Amaryl (scored){44}]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F) in a well-closed container, {44} unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages. {79}
   • Do not take other medicines without advice from your doctor. {79}


GLIPIZIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Other actions/effects—Has mild diuretic effect.

Protein binding—Very high, {14} {80} {101} nonionic. {101}

Serum half-life—2 to 4 hours.

Duration of action—12 to 24 hours.



Precautions:


Drug interactions and/or related problems—
Displacement from plasma proteins by other medications is less likely than with ionic sulfonylureas. {14} {101}




Additional Dosing Information
See also General Dosing Information .

When patients are transferred to glipizide from another sulfonylurea antidiabetic medication (with the exception of chlorpropamide), no transition period is required. {14} {52} {80} When transferring patients from chlorpropamide, caution should be exercised during the first 1 to 2 {12} {14} {16} {52} weeks because of the prolonged retention of chlorpropamide in the body. {14} {80}

During conversion from insulin therapy to glipizide therapy, no gradual dosage adjustment usually is required for patients using less than 20 USP Units of insulin daily. {14} {52} {80} For patients using 20 or more USP Units daily, a 50% reduction of insulin the first day, with gradual dosage adjustments of glipizide as needed, is desirable. {14} {52} {80} Hospitalization for some patients on a higher insulin dosage may be required for uneventful conversion. {14} {52} {80}


Oral Dosage Forms

GLIPIZIDE TABLETS USP

Usual adult dose
Antidiabetic
Initial: Oral, 5 mg once a day thirty minutes before breakfast, with dosage being changed by 2.5 to 5 mg every several days as needed. {14} {52}

Maintenance: Oral, up to 40 mg a day thirty minutes before meals. Single daily doses are adequate with 15 mg or less but may be divided when necessary, while larger doses should be divided into two doses a day and taken thirty minutes before meals. {14} {52}


Usual adult prescribing limits
40 mg daily. {14} {52}

Usual pediatric dose
Safety and efficacy have not been established. {14} {52}

Usual geriatric dose
Antidiabetic
Initial: Oral, 2.5 mg per day thirty minutes before breakfast, with dosage being changed by 2.5 to 5 mg every several days as needed. {14} {52}

Maintenance: See Usual adult dose . {14}


Strength(s) usually available
U.S.—


5 mg (Rx) [Glucotrol (scored){14}][Generic] (may be scored){52}{242}


10 mg (Rx) [Glucotrol (scored){14}][Generic] (may be scored){52}{242}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. {14} {52} {98}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • Do not take other medicines without advice from your doctor.
   • Avoid too much sun.
   • Take this medication on an empty stomach, 30 minutes before meals. {14}


GLIPIZIDE EXTENDED-RELEASE TABLETS

Usual adult dose
Antidiabetic
Initial: Oral, 5 mg once daily with breakfast; dosage is increased by 5 mg based on resulting hemoglobin A 1c measurements taken three months later or, less commonly, based on two or more consecutive fasting blood glucose measurements taken seven days apart. {80}

Maintenance: Oral, 5 to 10 mg once a day with breakfast. {80}


Note: In most cases, if no improvement of hemoglobin A 1c is noted after three months of use of a higher dose, the previous dose should be resumed. {80}


Usual adult prescribing limits
20 mg once a day. {80}

Usual pediatric dose
Safety and efficacy have not been established. {80}

Usual geriatric dose
See Usual adult dose . {80}

Note: When adjusting the dose in the elderly, consider that steady-state concentrations for glipizide extended-release tablets may be delayed by approximately one or two days as compared to other age groups. {80}


Strength(s) usually available
U.S.—


5 mg (Rx) [Glucotrol XL{80}]


10 mg (Rx) [Glucotrol XL{80}]

Note: Although similar in appearance to a conventional tablet, Glucotrol XL actually is a specially formulated gastrointestinal system (GITS) consisting of a semipermeable membrane surrounding an osmotically active drug core, which is designed to release glipizide at a constant rate over twenty-four hours; {80} following drug release, the system is eliminated in the feces as an insoluble shell. {80}


Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Swallow tablet whole. Do not break, crush, or chew. {80}
   • Avoid alcoholic beverages.
   • Do not take other medicines without advice from your doctor.
   • Avoid too much sun.


GLYBURIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Other actions/effects—Protective activity for some cardiac arrhythmias; also, has mild diuretic activity.

Protein binding—Very high, nonionic. {12} {105}

Half-life—10 hours.

Duration of action—24 hours.


Elimination—
Biliary: 50%.

Renal: 50%.




Precautions:


Geriatrics—
Use is generally avoided.



Drug interactions and/or related problems—
Disulfiram-type reaction with concurrent alcohol use less likely with glyburide than with other antidiabetics. {12} {81} Also, displacement from plasma proteins by other medications is less likely. {12} {81}




Side/adverse effects:
Fatal hypoglycemia occurs more often with glyburide than with chlorpropamide; potential for serious adverse effect because of prolonged action of glyburide, especially with predisposed individuals.



Additional Dosing Information
See also General Dosing Information .

When patients are transferred to glyburide from another sulfonylurea antidiabetic medication (with the exception of chlorpropamide), no transition period is required. {12} {40} {73} {81} When transferring patients from chlorpropamide, caution should be exercised during the first 1 to 2 weeks because of the prolonged retention of chlorpropamide in the body and subsequent overlapping of drug effects that could cause hypoglycemia. {12} {40} {73} {81}

During conversion from insulin therapy to glyburide therapy, no gradual dosage adjustment usually is required for patients using less than 40 USP Units of insulin daily. {12} {40} {73} {81} Patients requiring more than 40 USP Units should receive a 50% reduction of insulin the first day with initiation of 3 mg of micronized glyburide or 5 mg of nonmicronized glyburide as a single dose and gradual dosage adjustments of glyburide as needed. {12} {40} {73} {81} Hospitalization for some patients on a higher insulin dosage may be required for uneventful conversion.

Bioequivalence information
Micronized glyburide cannot be substituted for nonmicronized glyburide. Bioavailability studies have demonstrated that micronized glyburide is not bioequivalent to glyburide (nonmicronized); retitration is necessary if patients are transferred. {12} {73} {81}

Micronized glyburide has an AB rating {90} but may not be deemed bioequivalent according to some state formularies when the scored tablet is divided.

Glyburide (nonmicronized) has a BX rating and is not substitutable. {90} However, some specific products are manufactured under the same new drug application (NDA) and may be deemed bioequivalent by some state formularies:    • Pharmacia & Upjohn's product, Micronase , and Greenstone's generic glyburide (nonmicronized) are manufactured at Pharmacia & Upjohn under the same NDA; Greenstone's generic product is distributed by Geneva and Greenstone.
   • Hoescht Marion Roussel produces DiaBeta and its own generic, which is distributed by Copley, under the same NDA.The products manufactured under one NDA cannot be substituted for those products produced under the other NDA; the products are not bioequivalent nor substitutable. The FDA Orange Book will list an NDA only once with the original manufacturer that applied for the product; hence, the Orange Book does not address multiple manufacturers under one NDA. Pharmacists should verify the regulations and formularies of their state or verify with the physician before substituting a BX-rated product under one NDA for a similar product under another. {238}



Oral Dosage Forms

GLYBURIDE TABLETS USP

Note: Glyburide (nonmicronized) has an FDA BX rating denoting that data are insufficient to determine therapeutic equivalence. {90} However, glyburide produced and distributed by the U.S. manufacturer Hoescht Marion Roussel and also distributed by Copley may be substitutable by some state pharmacy formularies because they use the same NDA. Similarly, glyburide distributed by the U.S. manufacturers Greenstone and Pharmacia & Upjohn share the same NDA. As long as glyburide holds a BX rating, substitution of products of different NDAs is not permissible without the physician's permission. {239}
In contrast, glyburide (micronized) has an AB rating, {90} denoting that bioequivalence for many state formularies has been resolved; however, some state formularies have deemed the AB-rated generic nonsubstitutable if a scored tablet is divided. State formularies should be checked before substitution is made with this type of product.


Usual adult dose
Antidiabetic
Initial: Oral, 2.5 to 5 mg once a day with breakfast or the first main meal, with dosage changes being made by no more than 2.5 mg at weekly intervals if needed. Patients more sensitive to hypoglycemia may need 1.25 mg a day. {12} {40}

Maintenance: Oral, 1.25 to 20 mg a day, of which doses up to 10 mg are usually taken as a single dose with breakfast or the first main meal, while doses over 10 mg are usually divided into two daily doses with meals. {12} {40}


Usual adult prescribing limits
20 mg daily. {12} {40} {58} {67} {73}

Usual pediatric dose
Safety and efficacy have not been established. {12} {40}

Usual geriatric dose
Antidiabetic
Initial: Oral, 1.25 to 2.5 mg a day with breakfast, with dosage changes being made by no more than 2.5 mg at weekly intervals if needed. {40}

Maintenance: See Usual adult dose .

Note: This dose should also be used in patients with medical problems that make them more sensitive to the effects of glyburide. {40}



Strength(s) usually available
U.S.—


1.25 mg (Rx) [DiaBeta (scored){12}] [Micronase (scored){40}][Generic] ( may be scored)


2.5 mg (Rx) [DiaBeta (scored){12}] [Micronase (scored){40}][Generic] ( may be scored){85}


5 mg (Rx) [DiaBeta (scored){12}] [Micronase (scored){40}][Generic] ( may be scored){85}

Canada—


2.5 mg (Rx) [Albert Glyburide (scored){67}] [Apo-Glyburide (scored){68}{76}] [DiaBeta (scored){58}] [Euglucon (scored){76}{77}] [Gen-Glybe ( scored){69}] [Medi-Glybe{92}] [Novo-Glyburide (scored){70}{76}{78}] [Nu-Glyburide (scored){84}]


5 mg (Rx) [Albert Glyburide (scored){67}] [Apo-Glyburide (scored){68}{76}] [DiaBeta (scored){58}] [Euglucon (scored){76}{77}] [Gen-Glybe ( scored){69}{76}{78}] [Medi-Glybe{92}] [Novo-Glyburide ( scored){70}] [Nu-Glyburide ( scored){84}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container. {12} {40} {68} {69} {70} {81} {84} {85} {86} {103}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • Do not take other medicines without advice from your doctor.
   • Avoid too much sun.


GLYBURIDE TABLETS (MICRONIZED)

Note: Micronized glyburide has an AB rating. {90} However, some state formularies may not consider certain generic products bioequivalent when scored tablets are divided; state formularies should be checked before substituting one product for another.
Micronized glyburide cannot be substituted for nonmicronized glyburide. Bioavailability studies have demonstrated that micronized glyburide is not bioequivalent to glyburide (nonmicronized); retitration is necessary if patients are transferred. {81}


Usual adult dose
Antidiabetic
Initial: Oral, 1.5 to 3 mg once a day with breakfast or the first main meal. Some patients sensitive to glyburide's effects may need to be started on 0.75 mg a day. Dose titration should be made with changes of no more than 1.5 mg at weekly increments. {81}

Maintenance: Oral, 0.75 to 12 mg a day; doses up to 6 mg are usually taken as a single dose with breakfast or the first main meal, while doses over 6 mg are usually taken as divided doses with meals. {81}


Usual adult prescribing limits
12 mg daily. {81}

Usual pediatric dose
Safety and efficacy have not been established. {81}

Usual geriatric dose
Antidiabetic
Initial: Oral, 0.75 to 3 mg per day with breakfast or the first main meal, with dosage being changed by no more than 1.5 mg at weekly increments. {81}

Maintenance: See Usual adult dose . {03}


Strength(s) usually available
U.S.—


1.5 mg (Rx) [Glynase PresTab (scored){81}][Generic] (may be scored ){66}{110}{243}


3 mg (Rx) [Glynase PresTab (scored){81}][Generic] (may be scored ){66}{110}{243}


4.5 mg (Rx)[Generic] (may be scored){66}


6 mg (Rx) [Glynase PresTab (scored){81}][Generic]{66}

Note: Glynase PresTab is formulated to divide easily in even halves by pressing gently on the scored area of the tablet. {81}


Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, {81} unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • Do not take other medicines without advice from your doctor.
   • Avoid too much sun.


TOLAZAMIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Other actions/effects—Has mild diuretic activity.

Protein binding—Very high, ionic. {101}

Serum half-life—7 hours.

Duration of action—10 or 20 hours.



Precautions:
Drug interactions and/or related problems—Displacement from plasma proteins by other medications is more likely than with nonionic sulfonylureas.

Medical considerations/contraindications—Tolazamide may accumulate in patients with creatinine clearance less than 30 mL per minute (0.5 mL/second).



Additional Dosing Information
See also General Dosing Information .

When patients are transferred to tolazamide from another sulfonylurea antidiabetic medication (with the exception of chlorpropamide), no transition period is required. {15} When transferring patients from chlorpropamide, caution should be exercised during the first 1 to 2 weeks because of the prolonged retention of chlorpropamide in the body. {15}

During conversion from insulin therapy to tolazamide therapy, no gradual dosage adjustment usually is required for patients using less than 40 USP Units of insulin daily. {15} Patients requiring 40 or more USP Units daily should receive a 50% reduction of insulin during the first few days, with gradual dosage adjustment of tolazamide as needed. {15} Hospitalization for some patients on a higher insulin dosage may be required for uneventful conversion.


Oral Dosage Forms

TOLAZAMIDE TABLETS USP

Usual adult dose
Antidiabetic
Initial: Oral, 100 to 250 mg once a day with breakfast or the first main meal, with dosage being changed by 100 to 250 mg at weekly intervals as needed. {15}

Maintenance: Oral, 250 to 500 mg a day with breakfast or the first main meal; some patients may need less (100 mg a day) or more (up to 1000 mg a day). Doses greater than 500 mg should be divided and given two times a day with meals. {15}


Usual adult prescribing limits
1 gram daily. {15}

Usual pediatric dose
Safety and efficacy have not been established. {15}

Usual geriatric dose
Antidiabetic
Initial: Oral, 100 mg once a day in the morning with breakfast or the first main meal, with the dose being changed by 100 to 250 mg at weekly intervals as needed. {15}

Note: Lower initial doses may be required in patients with medical problems that make them more sensitive to the effects of tolazamide. {15}


Maintenance: See Usual adult dose .


Strength(s) usually available
U.S.—


100 mg (Rx) [Tolinase (scored){15}][Generic] ( may be scored){43}


250 mg (Rx) [Tolinase (scored){15}][Generic] ( may be scored){42}


500 mg (Rx) [Tolinase (scored){15}][Generic] ( may be scored)

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. {18}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • Do not take other medicines without advice from your doctor.
   • Avoid too much sun.


TOLBUTAMIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Other actions/effects—Has mild antidiuretic activity.

Protein binding—Very high, {16} ionic.

Serum half-life—4.5 to 6.5 hours. {16}

Duration of action—6 to 12 hours.



Precautions:


Drug interactions and/or related problems—
Disulfiram-type reaction with concurrent alcohol use less likely with tolbutamide than with other antidiabetics. {16} Also, displacement from plasma proteins by other medications is more likely than with nonionic sulfonylureas. {16}

Metabolism of tolbutamide inhibited by sulfinpyrazone and phenylbutazone.



Laboratory value alterations—
Tolbutamide interferes with thyroidal uptake of I 123 and I 131.



Medical considerations/contraindications—
May be preferred for those patients with moderate renal function impairment but should be discontinued with renal failure.




Additional Dosing Information
See also General Dosing Information .

When patients are transferred to tolbutamide from another sulfonylurea antidiabetic medication (with the exception of chlorpropamide), no transition period is required. {45} When transferring patients from chlorpropamide, caution should be exercised during the first 1 to 2 {12} {14} {16} weeks because of the prolonged retention of chlorpropamide in the body. {45}

During conversion from insulin therapy to tolbutamide therapy, no gradual dosage adjustment usually is required for patients using less than 20 USP Units of insulin daily. {45} Patients using 20 to 40 USP Units require a 30 to 50% reduction in insulin the first day with gradual dosage adjustment as needed. {45} Patients requiring more than 40 USP Units should receive a 20% reduction of insulin the first day with gradual dosage adjustment of tolbutamide as needed. {45} Hospitalization for some patients on a higher insulin dosage may be required for uneventful conversion. {45}


Oral Dosage Forms

TOLBUTAMIDE TABLETS USP

Usual adult dose
Antidiabetic
Initial: Oral, 1000 to 2000 mg a day as single morning or divided doses. {16} {60}
Note: Lower initial doses may be required in patients with medical problems that make them more sensitive to the effects of tolbutamide.



Maintenance: Oral, 250 to 2000 mg a day as single morning or divided doses. {16}


Usual adult prescribing limits
3000 mg a day. {16}

Usual pediatric dose
Safety and efficacy have not been established. {16}

Usual geriatric dose
Lower initial dose may be required. See Usual adult dose . {16}

Strength(s) usually available
U.S.—


500 mg (Rx) [Orinase (scored){15}{16}{60}{83}][Generic] ( may be scored){46}{47}{48}

Canada—


500 mg (Rx) [Apo-Tolbutamide (scored){75}{83}] [Novo-Butamide (scored){71}] [Orinase (scored){16}{60}{83}][Generic]


1000 mg (Rx) [Orinase (scored){16}{60}{83}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container. {18}

Preparation of dosage form:
For patients who cannot take oral solids—Tolbutamide tablets may be dissolved in a glass of water and drunk. Additional water should then be added to the glass, stirred, and drunk to make sure all the medication is taken. {60}

Auxiliary labeling:
   • Avoid alcoholic beverages. {16}
   • Do not take other medicines without advice from your doctor. {16}
   • Avoid too much sun. {16}



Revised: 12/29/99



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