Professional Information

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 ^{07}

BAN:
Glyburide—Glibenclamide ^{07}

JAN:
Glyburide—Glibenclamide ^{07}

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. ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{52} ^{56} ^{57} ^{58} ^{60} ^{61} ^{67} ^{73} ^{77} ^{79} ^{80} ^{81} An attempt to control diabetes through changes in diet and level of physical activity is usually first-line management before beginning pharmacologic treatment. ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{52} ^{56} ^{57} ^{60} ^{61} ^{62} ^{78} ^{80} ^{81} ^{82} 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. ^{09} ^{23} ^{27} ^{44} ^{80} ^{81} ^{104} ^{120}

—Diabetes mellitus, other, associated with certain conditions or syndromes, such as: ^{61}    • 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 ^{61} ^{65}
   • 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. ^{61} ^{65}
   • 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. ^{61} ^{65}

—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. ^{03} ^{04} ^{05} ^{14} ^{16} ^{56} ^{57} ^{58} ^{60} ^{78} ^{81} ^{82} ^{120}

—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. ^{03} ^{06} ^{12} ^{15} ^{40} ^{52} ^{56} ^{61} ^{67} ^{79} ^{80} ^{81}

—The effectiveness of sulfonylureas in controlling blood glucose can decrease over time. ^{15} ^{73} ^{79} ^{81} 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.^{244} 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. ^{02} ^{04} ^{05} ^{11} ^{20} ^{21} ^{22} ^{23} ^{24} However, complications, such as weight gain, the effects of hyperinsulinemia, and an increased risk of hypoglycemia need to be considered. ^{02} ^{20} ^{21} ^{22} ^{23} ^{24} ^{190} ^{191} ^{192} Some patients with type 2 diabetes who are nonobese and who are experiencing secondary sulfonylurea failure may be best treated with insulin. ^{11} ^{24} 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. ^{15} ^{24} ^{80} ^{81} ^{192} ^{193}

[Diabetes insipidus, central, partial (treatment)]¹—Chlorpropamide is also indicated as secondary therapy ^{09} 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. ^{09}

Unaccepted
Sulfonylureas are not effective in the treatment of type 1 diabetes (previously known as insulin-dependent diabetes mellitus [IDDM]). ^{15} ^{120}

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 (%)
Drug	V _D (L/kg)	Protein binding ^* (%)	Biotransformation (%)	Elimination half-life (hrs)	Time to peak (hrs)	Concentration per mL	Dose (mg)	Duration of action (hrs)	Elimination (%)
Acetohexamide Hydroxyhexamide ^‡ (metabolite)	0.21 ^{95}	Very high, 65–90; Ionic ^{87} ^{89}	Hepatic, mainly; ^{56} erythrocytes ^{03} ^{94}	1.3 ^† ^{03} ^{56} ^{93} 4.6–6 ^{03} ^{56} ^{93}	1.5–2 ^{03} ^{56} ^{86} 2–6 ^{56} ^{88}	47 mcg ^{88} 60 mcg ^{88}	1000 ^{88}	8–24 ^{03} ^{88}	Renal: 71 ^{03} ^{93} Fecal: 15 ^{93}
Chlorpropamide	0.09–0.27 ^{101}	Very high, >90; Ionic ^{101}	Hepatic ^{06} ^{95} ^{101}	36 ^§ (range, 24–48) ^{03} ^{95}	2–4 ^{06} ^{57} ^{95}	N/A	N/A	24–72 ^{03} ^{57} ^{95}	Renal: In 96 hours: Unchanged—6–20 Active and inactive metabolites
Gliclazide	0.2 ^{101}	Very high, 94; ^{79} Nonionic	Hepatic ^{79} ^{101}	10.4 ^{79}	4–6 ^{79}	5 mcg ^{79}	3 ^{79}	24 ^{101}	Renal: Unchanged—<1 Metabolites, conjugates—60–70 ^{79} Fecal: Metabolites, conjugates—10–20 ^{79}
Glimepiride	8.8 ^{44}	Very high, > 99.5 ^{44}	Hepatic ^{44}	5 ^{44} (following a single dose) ^{44} 9.2 ^{44} (following multiple doses) ^{44}	2–3 ^{44}	N/A	N/A	N/A	Renal: 60 ^{44} Fecal: 40 ^{44}
Glipizide	0.14–0.16 ^{14} ^{80} ^{101}	Very high, 99; ^{14} ^{52} ^{80} Nonionic ^{101}	Hepatic (no first-pass) ^{52} ^{80}	2–4 ^{14} ^{52} ^{80} ^{95}		N/A	N/A		Renal: Unchanged—<10 ^{14} ^{52} ^{80} Metabolites, inactive, and conjugates—80 ^{80} Fecal: 10 ^{80}
immediate release					1–3 ^{14} ^{52}			12–24 ^{14} ^{52} ^{101}
extended release					6–12 ^{80}			24 ^{80}
Glyburide	0.14–0.16 ^{105}	Very high, 99; ^{105} Nonionic ^{12} ^{40} ^{73} ^{81} ^{105}	Hepatic ^{67} ^{105}					24 ^{12} ^{14} ^{40} ^{73} ^{81}	Renal: 50 ^{12} ^{40} ^{73} ^{81} ^{105} Metabolites, active—2 weak, short-lived ^{12} ^{40} ^{73} ^{81} Biliary: 50 ^{12} ^{40} ^{73} ^{81} ^{105}
Nonmicronized				6–10 ^# ^{12} ^{40} ^{106}	3.4–4.5 ^{12} ^{40} ^{106}	87.5 nanograms ^{81} ^{106}	5
Micronized				4 ^# ^{81} ^{106}	2.3–3.5 ^{106}	97.2 nanograms ^{81} ^{106}	3
Tolazamide ^**	N/A	Very high, 94; ^{95} Ionic ^{101}	Hepatic ^{95}	7 ^{15} ^{95}	3–4 ^{15}	N/A		10–20 ^{15} ^{91} ^{95} ^{96}	Renal: 85 ^†† ^{15} Metabolites, major—5 metabolites (potency 0–70%) ^{15} ^{97} Fecal: 7 ^{15}
Tolbutamide ^**	0.10 ^{97} ^{101}	Very high, 96; Ionic ^{101}	Hepatic ^{97} ^{101}	4.5–6.5 ^{16} ^{60} ^{107}	3–4 ^{16}	N/A		6–12 ^{16} ^{60} ^{95} ^{101}	Renal: 100 Metabolites, inactive—75 ^{16} ^{95}

^* Primarily to albumin. ^{80} ^{101}
^† Renal impairment prolongs acetohexamide half-life to 30 hours. ^{36} ^{93}
^‡ A primary metabolite for acetohexamide, hydroxyhexamide, accounts for 47 to 60% of dose and is 2.5 times more potent than its parent. ^{03} ^{51} ^{93}
^§ 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). ^{102}
^# 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. ^{81} ^{106}
^** Tolazamide is approximately 5 to 6.7 times more potent than tolbutamide and equal in potency to chlorpropamide on a milligram-per-milligram basis. ^{15}
^†† The majority of a single dose of tolazamide is eliminated in urine within 24 hours and elimination is complete after 5 days. ^{15} Less active metabolites include carboxytolazamide, hydroxytolazamide, and p-toulene sulfonamide. ^{97}

Physicochemical characteristics:

Chemical group—
    Sulfonylurea. ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{56} ^{57} ^{58} ^{60} ^{61} ^{73} ^{79} ^{80} ^{81} ^{82}
    First generation: Acetohexamide, chlorpropamide, tolazamide, tolbutamide. ^{03} ^{16}
    Second generation: Gliclazide, glimepiride, glipizide, glyburide. ^{14} ^{40} ^{58}
Molecular weight—
    Acetohexamide: 324.4 ^{07}
    Chlorpropamide: 276.75 ^{07}
    Gliclazide: 323.42 ^{07}
    Glimepiride: 490.63 ^{07}
    Glipizide: 445.55 ^{07} ^{80}
    Glyburide: 494.01 ^{07}
    Tolazamide: 311.41 ^{07}
    Tolbutamide: 270.35 ^{07}

pKa—
    Chlorpropamide: 4.8 ^{108}
    Gliclazide: 5.98 ^{08} ^{108} ^{109}
    Glipizide: 5.9 ^{52} ^{80}
    Glyburide: 5.3 ^{105}
    Tolazamide: 3.5, 5.7 ^{108}
    Tolbutamide: 5.3 ^{105} ^{108}

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. ^{09} ^{10} ^{11} ^{12} Sulfonylureas are effective only in patients whose pancreata are capable of producing insulin. ^{06} ^{09} ^{10} ^{11} ^{12} ^{15} ^{40} ^{52} ^{73} ^{79} ^{81}

With chronic sulfonylurea treatment, insulin production is not increased and may return to pretreatment values, ^{27} 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. ^{09} ^{10} ^{11} ^{12} ^{25} 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. ^{09} ^{10} ^{11} ^{25} 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. ^{09} ^{10} ^{11} ^{25} ^{62} ^{91} ^{109}

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. ^{93} 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. ^{79} ^{109} 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. ^{109} ^{172} ^{216} ^{217} ^{218} ^{219} ^{220} ^{221} Tolbutamide and chlorpropamide decrease free water clearance ^{222} while glyburide, glipizide, and tolazamide produce a mild diuresis effect by enhancement of renal free water clearance. ^{12} ^{15} ^{40} ^{52} ^{73} ^{80} ^{81} ^{220} In contrast to glyburide, tolazamide and tolbutamide increase hexose uptake in adipocytes and myocytes. ^{25} Sulfonylureas directly increase the secretion of pancreatic and gastric somatostatin and do not seem to have a direct effect on glucagon. ^{02} ^{09} ^{25} ^{28}

Absorption:

Rapidly and well absorbed but may have wide inter- and intra-individual variability. ^{03} ^{06} ^{08} ^{14} ^{15} ^{16} ^{31} ^{52} ^{58} ^{60} ^{67} ^{79} ^{80} ^{91} 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). ^{26}

Chlorpropamide—Food delays absorption of chlorpropamide. ^{91}

Gliclazide—Food delays absorption of gliclazide up to 187 minutes; may be best taken 30 minutes before or with a meal. ^{29} ^{30} ^{109}

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. ^{44} It is recommended that glimepiride be taken with breakfast or the first main meal. ^{44}

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. ^{14} ^{31} ^{80} ^{104}

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. ^{27} ^{106} Also, micronized glyburide is better absorbed and is effective at a lower dose than is nonmicronized glyburide. ^{91}

Tolbutamide—Absorption is unaltered if taken with food but is increased with high pH. ^{16} ^{91}

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. ^{11}

Carcinogenicity

Acetohexamide—Long-term studies in rats and mice showed no evidence of carcinogenicity. ^{03}

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. ^{06}

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. ^{44}

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. ^{14} ^{52} ^{80}

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. ^{12} ^{40} ^{73} ^{81}

Tolazamide—A 103-week study in rats and mice at both low and high doses showed no evidence of carcinogenicity. ^{15}

Tolbutamide—A 78-week study in male and female rats and mice showed no evidence of carcinogenicity. ^{16}

Mutagenicity

Acetohexamide—Sister chromatid exchange testing showed no evidence of mutagenicity. ^{03}

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. ^{36} 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. ^{36} ^{37}

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. ^{44}

Glipizide—Bacterial and in vivo mutagenicity testing showed no evidence of mutagenicity. ^{14} ^{52} ^{80}

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. ^{12} ^{37} ^{38} ^{40} ^{73} ^{81}

Tolbutamide—The Ames test ^{16} and the micronucleus test in mice (at doses of 500 mg/kg) showed no evidence of mutagenicity. ^{38}

Pregnancy/Reproduction
Fertility—

Acetohexamide, tolazamide, tolbutamide

Studies in humans have not been done.

Studies in animals have not been done. ^{03} ^{16}

Chlorpropamide

Studies in humans have not been done. ^{06}

Studies in rats treated with high doses of chlorpropamide (125 mg/kg) for 6 to 12 months showed varying degrees of spermatogenesis suppression. ^{06}

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. ^{44}

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. ^{44}

Glipizide

Studies in humans have not been done. ^{14}

Studies in male and female rats given 75 times the maximum human dose showed no evidence of impaired fertility. ^{14} ^{80}

Glyburide

Studies in humans have not been done. ^{12} ^{73} ^{81}

Studies in rats and rabbits given 500 times the human dose have not shown evidence of impaired fertility. ^{73} ^{81}

Pregnancy—
Chlorpropamide crosses the placenta; glyburide does not significantly cross the placenta, and it is not known whether other sulfonylureas cross the placenta. ^{39} ^{41} ^{50} ^{51} 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 ^{06} ^{15} ^{40} ^{44} ^{52} ^{73} ^{80} ^{81} during early pregnancy, and with increased perinatal morbidity and mortality later in pregnancy. ^{45} ^{49} ^{50} 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. ^{39} ^{41} ^{45} ^{50} Generally, sulfonylureas are not recommended during pregnancy. ^{53} ^{57} ^{79} 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. ^{06} ^{41} ^{49} ^{53} ^{111}

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. ^{03} ^{53}

FDA Pregnancy Category C. ^{03}

Chlorpropamide

Chlorpropamide crosses the placenta. ^{39} 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. ^{39} ^{41} The manufacturer recommends discontinuing chlorpropamide at least 1 month before the expected delivery date. ^{06}

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. ^{39}

FDA Pregnancy Category C. ^{06}

Gliclazide

Studies in humans have not been done. Gliclazide is not recommended for use during pregnancy. ^{79}

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. ^{30}

Glimepiride

Studies in humans have not been done. ^{44}

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. ^{44} 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. ^{44} 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. ^{44}

FDA Pregnancy Category C. ^{44}

Glipizide

Studies in humans have not been done. Glipizide should be discontinued at least 1 month before the expected delivery date. ^{14} ^{52} ^{80}

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. ^{14} ^{52} ^{80} No teratogenic effects were found in studies in rats and rabbits. ^{14} ^{52} ^{80}

FDA Pregnancy Category C. ^{14} ^{52} ^{80}

Glyburide

Glyburide does not significantly cross the placenta according to an in vitro study using human placentas. ^{51} Studies in humans have not been done. Use should be discontinued at least 2 weeks before the expected delivery date. ^{12} ^{40} ^{73} ^{81}

Studies in rats and rabbits given up to 500 times the human dose have produced no evidence of teratogenicity. ^{40} ^{81}

FDA Pregnancy Category B (Micronase, Glynase PresTab). ^{40} ^{73} ^{81}

FDA Pregnancy Category C (DiaBeta). ^{12}

Tolazamide

Studies in humans have not been done. Use should be discontinued at least 2 weeks before the expected delivery date. ^{15}

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. ^{15}

FDA Pregnancy Category C. ^{15}

Tolbutamide

Studies in humans have not been done. Use should be discontinued at least 2 weeks before the expected delivery date. ^{16}

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. ^{16} ^{27} ^{49} Repeat studies in rabbits showed no teratogenic effects. ^{16} ^{45} ^{49}

FDA Pregnancy Category C. ^{16}

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. ^{03} ^{06} ^{14} ^{15} ^{16} ^{44} ^{49} ^{55} ^{65} ^{80} 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. ^{44} It is not known whether acetohexamide, gliclazide, glipizide, glyburide, or tolazamide is distributed into breast milk. ^{03} ^{12} ^{14} ^{15} ^{16} ^{40} ^{52} ^{53} ^{65} ^{73} ^{79} ^{80} ^{81}

Chlorpropamide: ^{33} 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. ^{06} Its effect on the nursing infant is not known. ^{53}

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. ^{44}

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. ^{53} ^{64}

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. ^{03} ^{06} ^{12} ^{14} ^{16} ^{40} ^{44} ^{52} ^{65} ^{73} ^{79} ^{80} ^{81}

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. ^{44} ^{80} 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. ^{31} ^{80} ^{96} 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; ^{55} 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. ^{30} ^{31} ^{78} ^{96}

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. ^{99} ^{100}

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. ^{12} ^{16} ^{58} ^{52} ^{60} ^{80} ^{81} 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. ^{97}

» Alcohol ^{06} ^{09} ^{12} ^{17} ^{30} ^{40} ^{56} ^{57} ^{58} ^{60} ^{65} ^{67} ^{73} ^{77} ^{79} ^{81} ^{99} ^{101} ^{118} ^{123}    (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 ^{17} ^{56} ^{57} ^{58} ^{118} ^{119} ^{123})

    (the risk of hypoglycemia may be increased or prolonged when moderate or large amounts of alcohol have been consumed concurrently with sulfonylurea antidiabetic agents; ^{121} ^{122} small amounts of alcohol taken with meals do not usually result in hypoglycemia ^{17} ^{62} ^{101} ^{124})

Allopurinol    (increased risk of hypoglycemia due to inhibition of renal tubular secretion of chlorpropamide; closer monitoring required ^{125})

Angiotensin-converting enzyme inhibitors, ^{09} ^{79} such as:
Captopril ^{112} or
Enalapril ^{113}    (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 ^{112} ^{113} ^{114} ^{116} ^{117})

» Anticoagulants, coumarin- or indandione-derivative ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{52} ^{56} ^{57} ^{58} ^{60} ^{67} ^{73} ^{77} ^{79} ^{80} ^{81} ^{87} ^{96} ^{97} ^{101} ^{125} ^{128}    (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 ^{87} ^{97} ^{125} ^{127} ^{128} ^{129})

    (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 ^{11} ^{14} ^{101})

» Antifungals, azole, systemic, ^{03} ^{12} ^{14} ^{16} ^{17} ^{40} ^{52} ^{80} ^{81} such as:
Miconazole ^{06} ^{12} ^{15} ^{30} ^{40} ^{44} ^{52} ^{58} ^{67} ^{73} ^{79} ^{80} ^{81} ^{169}
Fluconazole ^{17} ^{168}    (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 ^{30})

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 ^{61} ^{156} ^{157} or
» Corticosteroids ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{52} ^{56} ^{57} ^{58} ^{60} ^{61} ^{67} ^{73} ^{77} ^{79} ^{80} ^{81} ^{101} ^{155} or
» Diuretics, thiazide ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{52} ^{56} ^{57} ^{58} ^{60} ^{61} ^{67} ^{73} ^{77} ^{79} ^{80} ^{81} ^{101} ^{184} ^{185} ^{186} or
» Lithium ^{61} ^{166} ^{167}    (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 ^{101} ^{155} ^{185} ^{186} ^{204} ^{205})

    (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 ^{99} ^{100})

Barbiturates ^{06} ^{56} ^{57} ^{58} ^{60} ^{67} ^{77} ^{79}    (chlorpropamide may prolong the effect of barbiturates ^{06} 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 ^{57})

» Beta-adrenergic blocking agents, including ophthalmics, if significant absorption occurs ^{06} ^{09} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{52} ^{56} ^{57} ^{58} ^{59} ^{60} ^{67} ^{73} ^{77} ^{79} ^{80} ^{81} ^{97} ^{101} ^{130} ^{131} ^{184}    (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 ^{80} ^{97} ^{101} ^{130} ^{131} ^{132} ^{133} ^{134} ^{135})

» Cimetidine ^{27} ^{30} ^{58} ^{67} ^{79} ^{96} ^{109} ^{142} ^{143} or
» Ranitidine ^{27} ^{58} ^{67} ^{96} ^{144} ^{146}    (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 ^{145} and increased absorption of tolbutamide and glyburide; ranitidine did not affect glyburide's AUC; ^{109} ^{141} ^{142} ^{143} ^{144} ^{146} close monitoring for dose adjustments of sulfonylureas may be needed when these agents are added or withdrawn ^{27} ^{30} ^{109} ^{138} ^{139} ^{140} ^{141} ^{142} ^{143} ^{144} ^{145} ^{146} ^{186})

» Cyclosporine ^{194} ^{197}    (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, ^{12} ^{40} ^{58} ^{73} ^{81} such as ciprofloxacin ^{40} ^{73} ^{81}    (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 ^{12} ^{40} ^{81} ^{168} ^{169})

» Guanethidine ^{58} ^{67} ^{162} or
» Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{52} ^{56} ^{57} ^{58} ^{60} ^{67} ^{73} ^{77} ^{79} ^{80} ^{81} ^{101} ^{187} ^{188} ^{189} or
» Quinidine ^{174} or
» Quinine ^{174} or
» Salicylates, in large doses ^{06} ^{09} ^{12} ^{14} ^{15} ^{16} ^{40} ^{52} ^{56} ^{57} ^{58} ^{60} ^{65} ^{73} ^{77} ^{79} ^{80} ^{81} ^{96} ^{101} ^{177} ^{178}    (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 ^{101} ^{174} ^{177} ^{178})

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 ^{19})

Hepatic enzyme inducers, such as:
Rifabutin ^{13}
Rifampin ^{56} ^{58} ^{67} ^{97} ^{101} ^{176}    (metabolism of sulfonylureas may be increased due to stimulation of hepatic microsomal enzymes; dosage adjustments may be necessary during and after concurrent treatment ^{13} ^{56} ^{57} ^{58} ^{97} ^{176})

    (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 ^{13} ^{57} ^{58} ^{59} ^{60})

Hepatic enzyme inhibitors, such as:
» Chloramphenicol ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{52} ^{56} ^{58} ^{60} ^{67} ^{73} ^{80} ^{81} ^{96} ^{97} ^{101} ^{136} ^{137}    (metabolism of sulfonylureas may be decreased due to inhibition of hepatic microsomal enzymes; dosage adjustments may be necessary during and after concurrent use ^{97} ^{125} ^{136} ^{137})

    (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 ^{97} ^{125} ^{136} ^{137})

Highly protein-bound medications ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{52} ^{73} ^{80} ^{81} such as:
Anti-inflammatory drugs, nonsteroidal (NSAIDs), ^{03} ^{06} ^{09} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{52} ^{73} ^{80} ^{81} ^{101} such as phenylbutazone ^{57} ^{58} ^{60} ^{62} ^{67} ^{77} ^{79} ^{96} ^{101} ^{107} ^{170} ^{171} ^{172} ^{173} ^{180}
Clofibrate ^{03} ^{09} ^{56} ^{58} ^{60} ^{67} ^{77} ^{79} ^{96} ^{97} ^{101} ^{125} ^{147} ^{148} ^{149} ^{150} ^{209}
Probenecid ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{52} ^{56} ^{57} ^{58} ^{60} ^{73} ^{77} ^{79} ^{80} ^{81} ^{101} ^{125}
Sulfinpyrazone ^{58} ^{67} ^{101} ^{180}
Sulfonamides ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{52} ^{56} ^{57} ^{58} ^{60} ^{67} ^{73} ^{77} ^{79} ^{80} ^{81} ^{96} ^{101} ^{181} ^{182} ^{183}    (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 ^{96} ^{97} ^{101} ^{147} ^{148} ^{149} ^{150} ^{170} ^{171} ^{172} ^{173})

    (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 ^{96} ^{147} ^{148} ^{149} ^{150} ^{151})

    (sulfinpyrazone and phenylbutazone have been shown to inhibit the hepatic metabolism of tolbutamide; ^{97} 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 ^{101} ^{107} ^{180})

    (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 ^{147} ^{148} ^{149} ^{150} ^{151})

    (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 ^{11} ^{97} ^{101})

Hyperglycemia-causing agents, such as:
Anticonvulsants, hydantoin ^{03} ^{06} ^{09} ^{12} ^{14} ^{15} ^{16} ^{40} ^{56} ^{58} ^{60} ^{67} ^{73} ^{80} ^{81}
Calcium channel blocking agents ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{73} ^{77} ^{80} ^{81} ^{101}
Clonidine ^{09} ^{61}
Danazol ^{207}
Dextrothyroxine ^{96}
Diazoxide, parenteral ^{09} ^{58} ^{67} ^{205}
Estrogens ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{61} ^{73} ^{80} ^{81} ^{101}
Estrogen–progestin-containing oral contraceptives ^{03} ^{06} ^{09} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{56} ^{57} ^{58} ^{60} ^{61} ^{67} ^{73} ^{77} ^{79} ^{80} ^{81} ^{101}
Furosemide ^{58} ^{60} ^{61} ^{67} ^{77} ^{79} ^{158}
Glucagon ^{61} ^{67} ^{202}
Growth hormone ^{61} ^{202}
Isoniazid ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{56} ^{61} ^{73} ^{80} ^{81} ^{163}
Morphine ^{09} ^{61}
Niacin ^{03} ^{06} ^{09} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{56} ^{57} ^{58} ^{60} ^{61} ^{67} ^{73} ^{77} ^{79} ^{80} ^{81} ^{101}
Phenothiazines, such as chlorpromazine ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{52} ^{58} ^{61} ^{67} ^{73} ^{80} ^{81} ^{205}
Sympathomimetic agents, ^{06} ^{09} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{58} ^{67} ^{73} ^{77} ^{80} ^{81} such as beta-adrenergic agonists ^{03} ^{09} ^{55} ^{201} ^{202} ^{203} ^{204} ^{205}
Thyroid hormones ^{03} ^{06} ^{12} ^{14} ^{15} ^{16} ^{40} ^{44} ^{55} ^{58} ^{61} ^{67} ^{73} ^{80} ^{81}    (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 ^{55} ^{163})

    (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 ^{138} ^{140})

    (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 ^{163} ^{164})

    (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 ^{201} ^{202} ^{203})

Hypoglycemia-causing agents, such as:
Anabolic steroids ^{58} ^{62} ^{67}
Androgens ^{58} ^{62} ^{67}
Bromocriptine ^{09}
Disopyramide ^{67} ^{206}
Pyridoxine ^{09}
Tetracycline ^{09} ^{58} ^{67} ^{198}
Theophylline ^{09}    (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 ^{204} ^{205}    (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 ^{62} ^{204} ^{205})

» Octreotide ^{179} ^{199}    (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 ^{179} ^{199} ^{200})

» Pentamidine ^{09} ^{62} ^{214}    (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 ^{09} ^{62} ^{214})

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) ^{231} ^{232}    (acetohexamide produces a reaction with diacetyl and falsely elevates results of this test ^{231} ^{232})

Creatinine, serum ^{14} ^{54} ^{79} ^{80} ^{231} ^{232}    (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 ^{54} ^{231} ^{232})

Protein, total, serum    (tolbutamide interferes with sulfosalicylic acid test by causing turbidity ^{16} ^{60})

» Sodium iodide I 123 ^{60} ^{233} or
» Sodium iodide I 131 ^{60} ^{233}    (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 ^{60} ^{233})

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) ^{44} ^{54} or
Alkaline phosphatase ^{14} ^{54} ^{80} or
Aspartate aminotransferase (AST [SGOT]) ^{14} ^{44} ^{54} ^{79} ^{80} or
Lactate dehydrogenase (LDH) ^{14} ^{54} ^{79}    (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 ^{14} ^{54} ^{79} ^{80})

Bile, urine or
Bilirubin, urine    (concentrations may be mildly increased and usually do not present with cl

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