Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1) Acetohexamide (synonym)
2) Carbutamide (synonym)
3) Chlorpropamide (synonym)
4) Glibenclamide (synonym)
5) Glibornuride (synonym)
6) Gliclazide (synonym)
7) Glimepiride (synonym)
8) Glipizide (synonym)
9) Glisolamide (synonym)
10) Glisoxipide (synonym)
11) Glyburide (synonym)
12) Glymidine (synonym)
13) Metahexamide (synonym)
14) Sulphonylurea
15) Tolazamide (synonym)
16) TOLAZamide (synonym)
17) Tolbutamide (synonym)

1.2.1) MOLECULAR FORMULA
1) CHLORPROPAMIDE: C10H13ClN2O3S
2) GLIMEPIRIDE: C24H34N4O5S
3) GlipiZIDE: C21H27N5O4S
4) GlyBURIDE: C23H28ClN3O5S
5) TOLAZamide: C14H21N3O3S
6) TOLBUTamide: C12H18N2O3S

Available Forms Sources

A)

1) FIRST GENERATION SULFONYLUREAS

a) ACETOHEXAMIDE: 250 and 500 mg tablets
b) CHLORPROPAMIDE: 100 and 250 mg tablets
c) TOLAZAMIDE: 100, 250, and 500 mg tablets
d) TOLBUTAMIDE: 250 and 500 mg tablets

2) SECOND GENERATION SULFONYLUREAS

a) GLIPIZIDE: 5 and 10 mg tablets
b) GLYBURIDE/GLIBENCLAMIDE: 1.25, 2.5, and 5 mg tablets
c) MICRONIZED GLYBURIDE: 1.5 and 3 mg tablets
d) GLIMEPIRIDE: 1, 2 and 4 mg tablets

B)

1) ADULTERATED PRODUCTS

a) In Singapore, severe hypoglycemia was reported in a cluster of nondiabetic individuals consuming an illegal health product sold as an herbal preparation for sexual enhancement called Power 1 Walnut. The herbal product was sold as a synthetic replacement to sildenafil, but was found to contain high concentrations of glibenclamide (it was not determined why this class of drug was used). Of 8 cases with known severe hypoglycemia, one patient died of complications after 28 days in a persistent vegetative state, 5 developed moderate to severe disability, one had slight disability and one recovered completely (Lim et al, 2009).
b) STREET VALIUM: GlyBURIDE poisoning occurred in 2 non-diabetic adults following the purchase of "street valium". Both patients developed symptomatic hypoglycemia and altered mental status with laboratory confirmation of glyBURIDE exposure (Lung et al, 2012).
c) HERBAL PREPARATION: A 56-year-old man developed hypoglycemia after taking a Malaysian herbal preparation, ZhenQi, which was contaminated with glibenclamide (Goudie & Kaye, 2001).

Overview

Laboratory Monitoring

A)

B)

C)

D)

E)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Asymptomatic patients need to be observed closely for signs or symptoms of hypoglycemia. Patients should be encouraged to eat, but should not be given prophylactic dextrose infusions. Beside glucose determinations should be made every 1 to 2 hours for the first 8 to 12 hours after the initial exposure. Asymptomatic children should be observed with serial blood glucose monitoring for 24 hours following ingestion.

B) MANAGEMENT OF SEVERE TOXICITY

1) The primary objective of sulfonylurea poisoning is correction of hypoglycemia. Patients with symptomatic hypoglycemia should be treated immediately with intravenous concentrated dextrose of 0.5 to 1 g/kg. Once the patient is normoglycemic, the patient should be allowed to eat, provided their mental status is appropriate. In patients who develop hypoglycemia, octreotide should be administered at a dose of 50 to 100 mcg subQ in adults, 1 mcg/kg in children (may be repeated every 6 hours if hypoglycemia recurs) once serum glucose has been corrected with intravenous dextrose. Repeat boluses and/or continuous dextrose infusions should be administered if recurrent hypoglycemia develops despite octreotide; however excessive dextrose infusions can cause hyperglycemia which serves as a stimulus for increased insulin secretion and may cause further hypoglycemia. Hypoglycemic seizures usually respond briskly to glucose replacement. Patients should be watched for at least 6 hours following discontinuation of any dextrose infusions and at least 12 hours after octreotide administration to monitor for recurrence of hypoglycemia.

C) DECONTAMINATION

1) PREHOSPITAL: Decontamination is not recommended because of the potential for somnolence and seizures.
2) HOSPITAL: Activated charcoal can be used if the patient presents early and is able to protect their airway. Activated charcoal may be useful even several hours after ingestion of a extended release product.

D) ANTIDOTE

1) Intravenous dextrose will initially reverse hypoglycemia (50 mL of 50% dextrose in adults; in children 0.5 to 1 g/kg of 25% dextrose in water (D25W 2 to 4 mL/kg/dose)). Octreotide is a somatostatin analogue that inhibits insulin secretion and can be used for patients who are refractory to standard therapy with dextrose boluses and infusions. Octreotide should only be used after euglycemia has been achieved with IV dextrose as it will only prevent further episodes of hypoglycemia. In adults, 50 to 100 mcg subQ can be used every 6 to 12 hours. Continuous infusions of 50 to 125 mcg/hr have also been used. Alternatively, 50 to 100 mcg can be given IV every 4 hours. In children, a dose of 1 mcg/kg subQ every 6 hours can be used. A continuous infusion of octreotide was administered in a toddler with prolonged, refractory hypoglycemia. Octreotide is generally considered to be well tolerated with local irritant effects predominating after subQ injection.

E) AIRWAY MANAGEMENT

1) The airway may need to be protected in patients with coma that persists after serum glucose correction.

F) ENHANCED ELIMINATION

1) Hemodialysis is unlikely to be of value because of the high degree of protein binding. Hemoperfusion and urinary alkalinization have been used with success in chlorpropamide ingestions, but they are unlikely to be of benefit with modern sulfonylurea medications.

G) PATIENT DISPOSITION

1) HOME CRITERIA: There is no role for home management of inadvertent or deliberate sulfonylurea overdose.
2) OBSERVATION CRITERIA: Intentional ingestions by adults and any ingestion by a child should be evaluated in a health care facility. Asymptomatic children should be observed with serial blood glucose monitoring for 24 hours following an ingestion. Adults with a suspected overdose should be admitted and observed for at least 12 hours following an immediate release agent. In adults, that may have ingested an extended release product (eg, glipiZIDE extended release tablets can reach maximal concentrations within 6 to 12 hours after dosing and may be maintained for 24 hours) monitoring for 24 hours may be indicated.
3) ADMISSION CRITERIA: Any adult who becomes hypoglycemic and all children should be admitted for observation and serial blood glucose monitoring. Onset of symptoms may be delayed. Hypoglycemia may persist for more than 72 hours. Most authors suggest that patients with a suspected overdose should be admitted and monitored for a minimum of 8 to 12 hours.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist in cases of severe poisonings.

H) PITFALLS

1) Recurrent and/or delayed hypoglycemia. Ingestion of an extended release product (eg, Glucotrol XL(R), glipiZIDE extended release tablet) may delay hypoglycemic effects.

I) PHARMACOKINETICS

1) IMMEDIATE RELEASE: Onset of action for the majority of these agents is 0.5 to 1 hour; peak effects usually occur at 2 to 4 hours (eg, glyBURIDE, chlorpropamide, glimepiride). Duration of effect is variable and can be up to 24 hours. Sulfonylureas have small volumes of distribution, but are highly protein bound. EXTENDED RELEASE products may have a delayed onset. GlipiZIDE (Glucotrol XL(R)) extended release tablets have a peak plasma concentration that gradually rises and reaches a maximum concentration within 6 to 12 hours after dosing. Plasma concentrations are maintained throughout the 24 hour dosing period.

J) TOXICOKINETICS

1) Variable; dependent on agent. In general, hypoglycemia occurs within 8 hours of ingestion, but has been reported to occur as late as 21 hours after ingestion in a child. Duration of hypoglycemic effect may be prolonged in overdose.

K) DIFFERENTIAL DIAGNOSIS

1) Exposure to other hypoglycemic agents such as insulin or a meglitinide. The differential diagnosis of hypoglycemia is otherwise very broad and includes sepsis, liver failure, malnutrition, neoplasm, adrenal insufficiency, insulinoma and others.

Range Of Toxicity

A)

B)

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Class of oral hypoglycemic agents used to treat type II diabetes.
B) PHARMACOLOGY: Antagonizes the potassium channel on beta islet cells of the pancreas resulting in increased release of insulin.
C) TOXICOLOGY: Hypoglycemic effects develop in overdose.
D) EPIDEMIOLOGY: Poisoning is not common, but often results in symptomatic hypoglycemia which can result in serious neurological injury. Sulfonylurea poisoning has been associated with Munchausen-by-proxy syndrome and homicide attempts. Children may be at greater risk to develop complications than adults and become profoundly hypoglycemic.
E) WITH THERAPEUTIC USE

1) COMMON: Hypoglycemia is the primary adverse effect associated with therapeutic use. Other common adverse effects include: nausea, vomiting and abdominal pain. Use of sulfonylurea with ethanol can result in a disulfiram-like reaction. Chlorpropamide and TOLBUTamide have been associated with the syndrome of inappropriate antidiuretic hormone.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Toxicity results almost exclusively from hypoglycemia. Tremor, diaphoresis, nausea, headache, and tachycardia may occur in mild hypoglycemia although these responses may not be seen in longstanding diabetics. Alternatively, patients with longstanding poor glycemic control may become symptomatic at more "normal" serum glucose concentrations.
2) SEVERE TOXICITY: Severe CNS symptoms resulting from hypoglycemia including seizures, altered mental status, delirium, focal neurologic effects, and coma may result. In addition, patients may have dysrhythmias (usually sinus tachycardia, atrial fibrillation, or premature ventricular contractions). Patients with underlying cardiac conditions are at risk for ischemic events secondary to the increased myocardial stress. Patients with prolonged severe hypoglycemia may sustain permanent neurologic injury.

0.2.7)

A) Hypoglycemia may cause dizziness, weakness, paresthesia, headache, lethargy, seizures, coma, alteration in consciousness or neuropsychiatric symptoms.

0.2.8)

A) Nausea, vomiting, and epigastric pain may occur with therapeutic use or overdose.

0.2.9)

A) Hepatitis has been reported with therapeutic use acetohexamide, glibenclamide and glyBURIDE.

0.2.12)

A) Hyponatremia, possibly due to excessive ADH activity, has been reported with therapeutic use.

0.2.13)

A) Thrombocytopenia has been reported with therapeutic use of glyBURIDE.

0.2.16)

A) Hypoglycemia and resultant neurologic findings are most severe in patients with a restricted carbohydrate intake, hepatic and/or renal insufficiency, and in geriatric patients. Malnourished and alcoholic patients are also at increased risk. Hypoglycemia may persist for several days following overdosage.

0.2.19)

A) Hypersensitivity reactions such as fever, eosinophilia, jaundice, skin rashes, and blood dyscrasias (leukopenia, thrombocytopenia, aplastic anemia, agranulocytosis) have been reported with therapeutic use.

0.2.20)

A) Sulfonylurea agents are classified as FDA pregnancy category C. A retrospective study showed congenital anomalies with administration of oral glycemics to pregnant women with non-insulin-dependent diabetes mellitus. Severe, hypoglycemia has been reported in neonates following maternal use of sulfonylurea drugs, particularly those with long half-lives, at the time of delivery. In addition, there have been reports of congenital malformations in neonates of mothers with abnormal glucose control. One systematic review found that glyBURIDE use during pregnancy was not associated with increased perinatal adverse effects over insulin therapy. However, many experts recommend insulin for pre-gestational or gestational diabetes during pregnancy because of the need for precise control of maternal glucose levels and the limited information regarding fetal effects of some oral hypoglycemics.

0.2.22)

A) A disulfiram-like reaction characterized by facial flushing, nausea, vomiting and rarely hypotension has been reported following ethanol use.

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) COMMON: Hypoglycemia is the primary adverse effect associated with therapeutic use. Other common adverse effects include: nausea, vomiting and abdominal pain. Use of sulfonylurea with ethanol can result in a disulfiram-like reaction. Chlorpropamide and TOLBUTamide have been associated with the syndrome of inappropriate antidiuretic hormone.

F)

1) MILD TO MODERATE TOXICITY: Toxicity results almost exclusively from hypoglycemia. Tremor, diaphoresis, nausea, headache, and tachycardia may occur in mild hypoglycemia although these responses may not be seen in longstanding diabetics. Alternatively, patients with longstanding poor glycemic control may become symptomatic at more "normal" serum glucose concentrations.
2) SEVERE TOXICITY: Severe CNS symptoms resulting from hypoglycemia including seizures, altered mental status, delirium, focal neurologic effects, and coma may result. In addition, patients may have dysrhythmias (usually sinus tachycardia, atrial fibrillation, or premature ventricular contractions). Patients with underlying cardiac conditions are at risk for ischemic events secondary to the increased myocardial stress. Patients with prolonged severe hypoglycemia may sustain permanent neurologic injury.

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) ACCOMMODATION INSUFFICIENCY has been reported following a therapeutic dose.

a) CASE REPORT: A 35-year-old man developed difficulties with near vision secondary to an accommodation insufficiency 2 days after beginning therapy with glibenclamide 10 mg/day (Teller et al, 1989). Vision returned to normal after glibenclamide was discontinued.

B) WITH POISONING/EXPOSURE

1) OPTIC ATROPHY has been reported following overdose.

a) CASE REPORT: CHILDREN: Optic atrophy was reported as a sequelae to an unintentional ingestion of 15 mg of glyBURIDE in a 20-month-old child (Habel & Spranger, 1975; Simon, 1975).

Cardiovascular

3.5.2)

A) PALPITATIONS

1) WITH POISONING/EXPOSURE

a) Patients who become hypoglycemic may complain of palpitations (Sener et al, 1995).

B) MYOCARDIAL INFARCTION

1) WITH THERAPEUTIC USE

a) CASE SERIES: In a review of 19 cases of severe hypoglycemia associated with glipiZIDE use, one 90-year-old man received 10 mg for hyperglycemia after minor surgery (Asplund et al, 1991). The following day the patient developed profound hypoglycemia and a myocardial infarction.

2) WITH POISONING/EXPOSURE

a) GLIBENCLAMIDE: CASE REPORT: A 76-year-old woman without diabetes mellitus was inadvertently dispensed glibenclamide (Daonil (R)), in the place of danazol (Danol (R)), 3 weeks prior to presenting to the emergency department (ED) with a 30-minute episode of "crushing" chest pain, presyncope, weakness, and diaphoresis. She arrived at the ED 5 hours after the onset of symptoms with a blood glucose level of 2.5 mmol/L, which was confirmed on repeat testing. Upon examination, her heart rate was 94 beats/min, blood pressure 181/95 mmHg, and ECG showed left bundle branch block. Further laboratory analysis showed serum troponin, 0.14 nanograms (ng)/mL (reference; less than 0.06 ng/mL); creatine kinase, 220, international units/L (reference: less than 170 international units/L); potassium 3.1 mmol/L (reference; 3.5 to 5.3 mmol/L). She was treated with 5% IV dextrose. Twenty-four hours later, coronary angiography showed hypertensive cardiomyopathy but was otherwise normal. After 3 days of IV dextrose therapy, her glucose levels normalized and the weakness, residual chest pain, and other cardiac symptoms resolved immediately. She was discharged home without further sequelae (Corley et al, 2011).

C) MYOCARDIAL DYSFUNCTION

1) WITH POISONING/EXPOSURE

a) ELEVATED CARDIAC ENZYMES

1) MIXED INGESTION:GLIMEPIRIDE/ZOLPIDEM: A 40-year-old man with diabetes mellitus was admitted to the hospital due to poor glycemic control. During his hospitalization he intentionally ingested an estimated 42 mg (14 tablets of 3 mg each) of glimepiride and 50 mg of zolipdem (10 tablets of 5 mg each) and developed a loss of consciousness. When found, his glucose level was 40 mg/dL and he received immediate glucose. However, despite frequent intravenous glucose administration his altered mental status did not improve and tachycardia was present (142 beats/min). He was transferred to a higher level of care for frequent glucose and vital sign monitoring. A glimepiride concentration was 37.43 ng/mL immediately following overdose. A head CT scan was normal. The following day, an increase in creatine kinase-MB fraction (112 Unit/L) and troponin l levels (8.77 ng/mL), without ECG changes, were observed. Due to ongoing disturbances in consciousness, an acute myocardial infarction was suspected. The patient also had several severe episodes of hypoglycemia up to 60 hours after exposure despite glucose replacement; his glimepiride concentration was still elevated (13.61 ng/mL) at 48 hours. Serial cardiac ultrasounds remained normal. He gradually improved. By day 11, he was discharged to home without sequelae. Follow-up cardiac diagnostic studies were normal with no evidence of myocardial ischemia or an old infarction (Chou et al, 2015).

D) PERIPHERAL ISCHEMIA

1) WITH THERAPEUTIC USE

a) Therapeutic doses of glyBURIDE decrease blood flow to the lower legs and decrease the vasodilatory response to 10 minutes of complete ischemia (Kosmas et al, 1995).

Neurologic

3.7.1)

A) Hypoglycemia may cause dizziness, weakness, paresthesia, headache, lethargy, seizures, coma, alteration in consciousness or neuropsychiatric symptoms.

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH THERAPEUTIC USE

a) Altered mental status is common in patients who become hypoglycemic. Effects may include confusion, hallucinations, disorientation, lethargy, dizziness, slurred speech, and drowsiness (Sledge & Broadstone, 1993; Wou, 1994; Huminer et al, 1989; Catellier et al, 1992; Asplund et al, 1991; Chan et al, 1994).
b) Almost any alteration in consciousness or neuropsychiatric status may be noted. Initial symptoms may be transient.

2) WITH POISONING/EXPOSURE

a) INCIDENCE: CHILDREN: Altered mental status ranging from unusual behavior to coma was observed in 41 (14%) patients in a retrospective, cohort study of 300 pediatric patients less than 6 years of age who experienced sulfonylurea exposures resulting in hypoglycemia (glucose level less than 60 mg/dL) (Lung & Olson, 2011).

B) COMA

1) WITH POISONING/EXPOSURE

a) The major toxicity of these agents is prolonged hypoglycemia and coma.
b) Prolonged and relapsing coma, up to 36 hours, has been reported even with so-called short-acting derivatives such as glipiZIDE, despite continuous dextrose therapy (Goran et al, 1981).
c) INCIDENCE: CHILDREN: In a retrospective study of 93 pediatric sulfonylurea ingestions, loss of consciousness occurred in 2 cases (Quadrani-Kushner et al, 1996).
d) INCIDENCE: ADULTS: In a retrospective series of 19 adults with severe hypoglycemia from glipiZIDE overdose, 11 (58%) developed coma (Asplund et al, 1991).

C) SEIZURE

1) WITH THERAPEUTIC USE

a) Seizures may develop in patients who become hypoglycemic (Fanego et al, 1992).

2) WITH POISONING/EXPOSURE

a) INCIDENCE: CHILDREN: In a retrospective, cohort study, seizure was observed in 5 (1.7%) of 300 pediatric patients less than 6 years of age who experienced sulfonylurea exposures resulting in hypoglycemia (glucose level less than 60 mg/dL). One child required endotracheal intubation as a result of seizure (Lung & Olson, 2011).

D) HEMIPLEGIA

1) WITH POISONING/EXPOSURE

a) Focal neurologic deficits such as hemiparesis or paraparesis have been reported in patients who became hypoglycemic after overdose of sulfonylurea hypoglycemic agents (Kleinfeld et al, 1987; Bonnici, 1985; Sener et al, 1995)

E) SYNCOPE

1) WITH POISONING/EXPOSURE

a) Patients who develop hypoglycemia from sulfonylurea overdose may present with syncope or near syncope (Asplund et al, 1991; Sener et al, 1995).

F) SEQUELA

1) WITH POISONING/EXPOSURE

a) Patients with prolonged profound hypoglycemia from sulfonylurea overdose may develop long lasting or permanent neurologic sequelae or posthypoglycemic encephalopathy, including intellectual impairment, confusion, memory loss, and coma (Gasparetto et al, 2006; Scala-Barnett & Donoghue, 1986; Asplund et al, 1991; Kumar & Boulton, 1993).
b) Epilepsy, hemiparesis and mental retardation have been described following overdose (Pavone et al, 1980).
c) CASE REPORT: CHILDREN: A 9-year-old boy was inadvertently given sulfonylurea (thought to be an analgesic by his grandmother) for 2 days and was admitted with decreased consciousness and tonic-clonic seizures. Blood glucose was 21 mg/dL on admission. An initial head CT scan was normal; however, a repeat scan several days later showed multiple hypodense subcortical areas in the temporal, parietal and occipital lobes consistent with an acute ischemic event. Neurologically the child slowly improved and had mild cognitive and motor deficits at discharge. Four months later, the patient had hyporeflexia in the lower extremity, stereognosis, and mild motor incoordination (Gasparetto et al, 2006).

G) HEADACHE

1) WITH THERAPEUTIC USE

a) Headache may be noted.

H) PARESTHESIA

1) WITH THERAPEUTIC USE

a) Paresthesias may be noted.

I) DIZZINESS

1) WITH THERAPEUTIC USE

a) Patients may complain of dizziness and weakness (Huminer et al, 1989; Shumak et al, 1991; Sener et al, 1995; Wou, 1994).

J) DYSTONIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 41-year-old non-diabetic woman ingested an unknown amount of sulfonylurea in a suicide attempt and subsequently developed severe hypoglycemia and coma. Eight years postingestion, the patient's Glasgow Coma Score was 9 and she continued to experience persistent generalized dystonia of her face, neck, trunk, and limbs, and dysphasia. An MRI brain scan revealed frontal and temporal lobe atrophy with enlargement of the Sylvian fissures, but there was no evidence of damage to the basal ganglia. Tetrabenazine appeared to improve her hyperkinetic dystonic movements and her neck dystonia; however, the dystonic inversion of her feet and the marked dystonia of her hands continued to persist (Mahapatra et al, 2005).

Gastrointestinal

3.8.1)

A) Nausea, vomiting, and epigastric pain may occur with therapeutic use or overdose.

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Mild effects include nausea, vomiting, and epigastric pain.

2) WITH POISONING/EXPOSURE

a) Vomiting was observed in 5 (1.7%) children in a retrospective, cohort study of 300 pediatric patients less than 6 years of age who experienced sulfonylurea exposures resulting in hypoglycemia (glucose level less than 60 mg/dL) (Lung & Olson, 2011).

B) COPROPORPHYRIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 49-year-old man developed a syndrome consistent with coproporphyria (episodic abdominal pain, elevated urinary and fecal coproporphyrins) 1 month after beginning glipiZIDE therapy (Moder & Schwenk, 1991). Symptoms resolved and coproporphyrins returned to normal after glipiZIDE was discontinued.

C) DISORDER OF PANCREAS

1) CASE REPORT: Hyperplasia of the pancreatic islet cells was reported in a 25-year-old woman who was suspected of having recurrent hypoglycemia induced by surreptitious use of chlorpropamide (Grayman et al, 1984).

Hepatic

3.9.1)

A) Hepatitis has been reported with therapeutic use acetohexamide, glibenclamide and glyBURIDE.

3.9.2)

A) CHOLESTATIC HEPATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 63-year-old man developed cholestatic hepatitis associated with glibenclamide therapy of 5 years duration (Del-Val et al, 1991).
b) CASE REPORT: Cholestatic hepatitis was reported in one case after approximately 1-1/2 years of acetohexamide therapy; symptoms resolved promptly upon discontinuation of the drug (Rank & Olson, 1989).

B) TOXIC HEPATITIS

1) WITH THERAPEUTIC USE

a) CASE SERIES: Hepatitis was temporally associated with initiating or increasing the dose of glyBURIDE in 3 patients (Meadow & Tulio, 1989; Goodman et al, 1987). All 3 improved when glyBURIDE was discontinued.

Hematologic

3.13.1)

A) Thrombocytopenia has been reported with therapeutic use of glyBURIDE.

3.13.2)

A) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) CASE SERIES: Thrombocytopenia was reported in two patients taking oral glyBURIDE. In both cases, platelet count normalized upon cessation of the drug (Israeli et al, 1988).
b) CASE REPORT: A 68-year-old man developed a petechial rash, multiple hematomas, hemorrhagic bullae in the mouth, gingival bleeding and severe thrombocytopenia (platelet count 1 x 10(9)/L) 3 days after restarting therapy with glimepiride (he had taken glimepiride for several weeks uneventfully 3 months earlier). Glimepiride was withdrawn and he was treated with prednisone. Platelet count returned to normal after 4 weeks (Cartron et al, 2000).

B) HEMOLYTIC ANEMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Autoimmune hemolytic anemia developed in a 48-year-old man taking glibenclamide and resolved when the drug was discontinued (Nataas & Nesthus, 1987).

Dermatologic

3.14.2)

A) EXCESSIVE SWEATING

1) WITH THERAPEUTIC USE

a) Diaphoresis is common in patients with hypoglycemia (Asplund et al, 1991; Catellier et al, 1992; Huminer et al, 1989; Sener et al, 1995; Shumak et al, 1991).

2) WITH POISONING/EXPOSURE

a) INCIDENCE: CHILDREN: In a retrospective, cohort study, diaphoresis was observed in 10 (3.3%) of 300 pediatric patients less than 6 years of age who experienced sulfonylurea exposures resulting in hypoglycemia (glucose level less than 60 mg/dL) (Lung & Olson, 2011).

B) BULLOUS ERUPTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: One case of pemphigus vulgaris has been associated with glibenclamide therapy (Paterson et al, 1992).

C) LICHENOID DERMATITIS

1) WITH THERAPEUTIC USE

a) Lichen planus has been associated with sulfonylurea therapy (Thompson & Skaehill, 1994).

Endocrine

3.16.1)

A) Hypoglycemia and resultant neurologic findings are most severe in patients with a restricted carbohydrate intake, hepatic and/or renal insufficiency, and in geriatric patients. Malnourished and alcoholic patients are also at increased risk. Hypoglycemia may persist for several days following overdosage.

3.16.2)

A) HYPOGLYCEMIA

1) WITH THERAPEUTIC USE

a) Hypoglycemic reactions have been reported after a single dose, and after several days or months of treatment (Gilman et al, 1985).

2) WITH POISONING/EXPOSURE

a) Hypoglycemia and hyperinsulinemia are consistent findings with sulfonylurea toxicity (Klonoff, 1988). The major toxicity of these agents is prolonged hypoglycemia and coma.

1) The predisposing factors to hypoglycemic coma include decreased food or carbohydrate intake, increased age, hepatic and/or renal insufficiency, and infection (Krepinsky et al, 2000; Ben-Ami et al, 1999; Sills et al, 1997).

b) PREDICTIVE OUTCOME: CHILDREN: Many attempts have been made to determine which children are at risk for hypoglycemia after potential sulfonylurea exposure:

1) Spiller et al (1997) suggested that the following may be predictive of a benign outcome in pediatric sulfonylurea ingestions (Spiller et al, 1997):

a) Lack of onset of clinical or numeric hypoglycemia (blood glucose less than 60 mg/dL) in the first 8 hours after ingestion
b) Time of day of ingestion did NOT predict the risk of developing hypoglycemia
c) While children who ingest more than 0.3 mg/kg of glyBURIDE or glipiZIDE appear to be at somewhat greater risk of hypoglycemia, the ingested dose does not appear to have adequate sensitivity or specificity to determine patients who will become hypoglycemic
d) Observing children for onset of hypoglycemia while receiving only oral foods appears safe. Some children, however, will require intravenous dextrose infusions.
e) This study has been criticized because it did not confirm the ingestion of sulfonylurea with urinary assays and thus may underestimate the risk of delayed hypoglycemia more than 8 hours after ingestion. Some authors recommend a minimum of 24 hours of observation after unintentional ingestion of sulfonylureas in children, with hourly blood glucose monitoring during this period (Bosse, 2002).

c) INCIDENCE OF HYPOGLYCEMIA

1) CHILDREN: In an observational prospective 1-year study of 185 cases of pediatric (less than 12 years old) sulfonylurea ingestions, hypoglycemia occurred in 30% of the cases (Spiller et al, 1997).
2) CHILDREN: In a retrospective study of 93 cases of pediatric sulfonylurea ingestion, hypoglycemia occurred in 27% of cases (Quadrani-Kushner et al, 1996).
3) CHILDREN: In a prospective series of 137 children with sulfonylurea ingestion, 42 (31%) developed a blood glucose less than 60 milligrams/deciliter (Spiller et al, 1995).
4) ADULTS and CHILDREN: In a retrospective series of 40 patients admitted for sulfonylurea overdose (including 3 children), 31 (78%) developed hypoglycemia (Palatnick et al, 1991).

d) SEVERITY

1) In a retrospective cohort study of 300 pediatric patients less than 6 years of age who developed hypoglycemia of less than 60 mg/dL after sulfonylurea exposure, the following was observed: Intravenous glucose was administered in 260 cases (87%); 71 (24%) children were treated with activated charcoal; 36 (12%) children were treated with food only; octreotide was administered as first-line therapy in 31 (10%) cases and as second-line therapy in 23 (8%) cases; emesis was induced in 7 (2.3%) cases; gastric lavage was performed in 2 (0.67%) cases. One episode of hypoglycemia was reported in 194 (65%) children, 61 (20%) children had 2 episodes of hypoglycemia, 30 (10%) children had 3 episodes, and 13 (4.3%) had 4 or more episodes of hypoglycemia. Admission to a noncritical care unit was required for 196 (65%) children, 87 (29%) were admitted to an ICU, and 14 (5%) were observed in the emergency department for 12 hours or less (Lung & Olson, 2011).
2) CHILDREN: In a retrospective study of 93 cases of pediatric sulfonylurea overdose; the average minimum blood glucose was 46.5 mg/dL. The lowest blood sugar measured was 20 mg/dL. Hypoglycemia was persistent in 9 patients, in spite of administration of intravenous dextrose (Quadrani-Kushner et al, 1996).
3) CHILDREN: In a prospective study of 185 pediatric sulfonylurea exposures, 54 patients developed hypoglycemia, of which 40 patients (74%) had a blood glucose concentration less than 60 mg/dL within 4 hours of ingestion; 53 patients (93%) had blood glucose less than 60 mg/dL within 8 hours of ingestion. Eighty-seven children were treated with oral supplementation only; 13 cases required advancement of treatment to intravenous glucose or glucagon with the onset of hypoglycemia. The lowest reported blood glucose was 38 mg/dl which was 14 hours (time of initial evaluation) after ingestion (Spiller et al, 1997; Spiller et al, 1997).
4) CHILDREN: In a prospective series of 137 children with sulfonylurea ingestion, 42 (31%) developed a blood glucose less than 60 mg/dL and 5 (7%) developed a blood glucose less than 40 mg/dL (Spiller et al, 1995).

e) ONSET

1) CHILDREN: A retrospective cohort study was conducted of 300 pediatric patients less than 6 years of age who developed hypoglycemia of less than 60 mg/dL after sulfonylurea exposure to evaluate the onset of hypoglycemia and the effect of different therapies on that onset. Among children who did not receive prophylactic food or IV glucose, the mean time to onset of hypoglycemia was 2 hours (range: 0.5 to 7 hours). Hypoglycemia occurred within 1 to 18 hours among those receiving prophylactic food, within 1.5 to 9 hours with prophylactic IV glucose, and with both food and IV glucose within 2.5 to 15 hours. Seven patients treated with prophylactic food developed hypoglycemia more than 8 hours after exposure (blood glucose nadir 38 to 59 mg/dL onset 9.5 to 18 hours after ingestion). This study suggests that either free access to food or intravenous dextrose can delay the onset of hypoglycemia to more than 8 hours after ingestion (Lung & Olson, 2011).
2) CHILDREN: In a prospective 1-year study of 185 pediatric exposures, 56 patients developed hypoglycemia. Fifty-four (96%) developed hypoglycemia within 8 hours of ingestion. A 2-year-old girl, who had ingested 1.1 mg/kg of glyBURIDE, was the only case to develop a blood glucose (BG) concentration less than 60 mg/dL 16 hours after ingestion despite an intravenous infusion of D5W at 3 mg/kg and monitoring BG every 2 hours (Spiller et al, 1997).
3) CHILDREN: In a prospective series of 137 children with sulfonylurea ingestion, 36 of the 42 patients (86%) who developed a blood glucose less than 60 mg/dL did so within 6 hours of ingestion. Of the remaining 6 children, 3 developed blood glucose of 60 to 62 milligrams/deciliter within 8 hours of ingestion while IV dextrose was infusing, 2 presented more than 12 hours after ingestion, and one had a single blood glucose less than 60 mg/dL 18 hours after ingestion which did not require therapy.(Spiller et al, 1995).

f) DURATION

1) Duration of hypoglycemia may be particularly prolonged in patients with end stage renal failure (Krepinsky et al, 2000).
2) Duration of hypoglycemia may also be particularly prolonged after ingestion of chlorpropamide, due to its long duration of action and half-life (Ciechanowski et al, 1999).
3) CHILDREN: In a retrospective, cohort study of 300 pediatric patients less than 6 years of age who experienced sulfonylurea exposures resulting in hypoglycemia (glucose level less than 60 mg/dL), hypoglycemia persisted for greater than or equal to 12 hours in 31 (10%) patients despite treatment (Lung & Olson, 2011).
4) CASE SERIES: In a series of 40 cases of sulfonylurea overdose recurrent hypoglycemia was a problem in 21 (53%). The required duration of treatment was 8 to 62 hours in the 6 patients treated with diazoxide and 6 to 91 hours in the 15 patients treated with dextrose infusions. (Palatnick et al, 1991).
5) GLIBENCLAMIDE: CASE SERIES: In a series of 13 patients with hypoglycemia from glibenclamide overdose, recurrent hypoglycemia persisted for more than 24 hours in 8 (62%) and in 2 patients (15%) it persisted for more than 60 hours (Sonnenblick & Shilo, 1986).
6) GLYBURIDE: CASE SERIES: Protracted hypoglycemia of 12 to 72 hours duration occurred in 24 of 57 episodes of glyBURIDE-induced hypoglycemia; 10 had a fatal outcome (Asplund et al, 1983).

g) CASE REPORTS

1) CHILDREN: A 3-year-old child ingested chlorpropamide, appeared well for 24 hours, later became symptomatic and was admitted with a blood glucose of 28 mg/dL 36 hours after ingestion (Greenberg et al, 1968). It is unclear when hypoglycemia developed in this child.
2) CHILDREN: A two-year-old child developed delayed hypoglycemia 11 hours after ingesting 1 glipiZIDE 5 mg tablet and 1 hydrochlorothiazide 25 mg tablet. The patient had received activated charcoal, intravenous dextrose solutions (5% dextrose at 20 ml/hr), and a full diet prior to the onset of hypoglycemia (Szlatenyi et al, 1998).
3) MIXED INGESTION:GLIMEPIRIDE/ZOLPIDEM: A 40-year-old man with diabetes mellitus was admitted to the hospital due to poor glycemic control. During his hospitalization he intentionally ingested an estimated 42 mg (14 tablets of 3 mg each) of glimepiride and 50 mg of zolipdem (10 tablets of 5 mg each) and developed a loss of consciousness. When found, his glucose level was 40 mg/dL and he received immediate glucose. However, despite frequent intravenous glucose administration his altered mental status did not improve and tachycardia was present (142 beats/min). He was transferred to a higher level of care for frequent glucose and vital sign monitoring. A glimepiride concentration was 37.43 ng/mL immediately following overdose. A head CT scan was normal. The following day, an increase in creatine kinase-MB fraction (112 Unit/L) and troponin l levels (8.77 ng/mL), without ECG changes, were observed. Due to ongoing disturbances in consciousness, an acute myocardial infarction was suspected. The patient also had several severe episodes of hypoglycemia up to 60 hours after exposure despite glucose replacement; his glimepiride concentration was still elevated (13.61 ng/mL) at 48 hours. Serial cardiac ultrasounds remained normal. He gradually improved. By day 11, he was discharged to home without sequelae. Follow-up cardiac diagnostic studies were normal with no evidence of myocardial ischemia or an old infarction (Chou et al, 2015).
4) GLIBENCLAMIDE: ADULTS: Severe hypoglycemia of 2.5 mmol/L blood glucose was detected in a 76-year-old woman without diabetes mellitus when she presented to the emergency department with symptoms of myocardial infarction. Three weeks prior to presentation, she had been inadvertently dispensed glibenclamide (Daonil (R)), in the place of danazol (Danol (R)). After 3 days of IV dextrose therapy, her glucose levels normalized and cardiac symptoms resolved. She was discharged home without further sequelae an (Corley et al, 2011).
5) GLIMEPIRIDE: ADULTS: Ingestion of 90 glimepiride tablets caused recurrent hypoglycemia lasting 8 days in a 22-year-old man (Rambo & Queralt, 1998).

Immunologic

3.19.1)

A) Hypersensitivity reactions such as fever, eosinophilia, jaundice, skin rashes, and blood dyscrasias (leukopenia, thrombocytopenia, aplastic anemia, agranulocytosis) have been reported with therapeutic use.

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) Hypersensitivity reactions, manifested by fever, eosinophilia, jaundice, skin rashes, and blood dyscrasias including leukopenia, thrombocytopenia, aplastic anemia, and agranulocytosis have been reported.

Reproductive

3.20.1)

A) Sulfonylurea agents are classified as FDA pregnancy category C. A retrospective study showed congenital anomalies with administration of oral glycemics to pregnant women with non-insulin-dependent diabetes mellitus. Severe, hypoglycemia has been reported in neonates following maternal use of sulfonylurea drugs, particularly those with long half-lives, at the time of delivery. In addition, there have been reports of congenital malformations in neonates of mothers with abnormal glucose control. One systematic review found that glyBURIDE use during pregnancy was not associated with increased perinatal adverse effects over insulin therapy. However, many experts recommend insulin for pre-gestational or gestational diabetes during pregnancy because of the need for precise control of maternal glucose levels and the limited information regarding fetal effects of some oral hypoglycemics.

3.20.2)

A) LACK OF INFORMATION

1) GLYBURIDE

a) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans (Prod Info DiaBeta(R) oral tablets, 2009).

B) CONGENITAL ANOMALY

1) GLIPIZIDE: A retrospective study compared 20 women with non-insulin-dependent diabetes mellitus (NIDDM) who became pregnant while using oral hypoglycemic agents with 40 matched controls (NIDDM patients who did not use oral hypoglycemics during early pregnancy). Overall, ten (50%) of the infants exposed to oral hypoglycemic agents had congenital malformations, which was significantly higher than the rate in controls (15%). Five (25%) of the chlorpropamide-exposed infants had an ear malformation (Piacquadio et al, 1991); however, the same type of ear malformation was reported in an infant of an insulin-dependent mother (Tolmie, 1991). Although this retrospective study suggests that oral hypoglycemics are associated with an increase in congenital malformations above the expected rate in NIDDM patients, the issue of glucose control over the first 8 weeks of gestation was not effectively addressed (Steel & Johnstone, 1991).

C) ANIMAL STUDIES

1) GLYBURIDE

a) RATS: Shortening of the long bone structures, particularly the humerus and femur, was observed during the period of lactation in rat pups when glyBURIDE was administered at doses 6250 times the maximum recommended human dose. These effects were not observed during the period of organogenesis (Prod Info DiaBeta(R) oral tablets, 2009).

2) TOLAZAMIDE

a) RATS: There was no evidence of teratogenicity when pregnant rats were given TOLAZamide at doses that were 10 times the human dose. There was no evidence of reproductive aberrations or drug-related fetal anomalies when rats were given TOLAZamide at doses of 14 mg/kg (Prod Info Tolazamide oral tablets, 2009).

3.20.3)

A) PREGNANCY CATEGORY

1) Manufacturers have classified the following hypoglycemic agents as FDA category C:

1) ACETOHEXAMIDE
2) CHLORPROPAMIDE
3) GLIMEPIRIDE (Prod Info AMARYL(R) oral tablets, 2012)
4) GLIPIZIDE (Prod Info GLUCOTROL XL(R) extended release oral tablets, 2009)
5) GLYBURIDE (Prod Info DiaBeta(R) oral tablets, 2009)
6) TOLAZamide (Prod Info Tolazamide oral tablets, 2009)
7) TOLBUTAMIDE

B) HYPOGLYCEMIA

1) Prolonged severe hypoglycemia has been reported during the first few days (4 to 10 days) following delivery in neonates whose mothers were treated with sulfonylurea agents during pregnancy (Prod Info DiaBeta(R) oral tablets, 2009; Prod Info GLUCOTROL XL(R) extended release oral tablets, 2009; Prod Info Tolazamide oral tablets, 2009; Paice et al, 1985).
2) Several cases of drug-induced hypoglycemia have been reported to have occurred in newborns of mothers taking acetohexamide, TOLAZamide, or chlorpropamide (Seltzer, 1972).
3) GLIMEPIRIDE: There are no adequate or well controlled studies of glimepiride use during human pregnancy. Prolonged severe hypoglycemia lasting between 4 and 10 days has been reported in infants whose mothers were receiving a sulfonylurea at the time of delivery (Prod Info AMARYL(R) oral tablets, 2012).

C) FETAL/NEONATAL ADVERSE EFFECTS

1) GLYBURIDE: During a retrospective population-based cohort study, an increased risk of admission to the neonatal intensive care unit, respiratory distress, hypoglycemia, birth injury, and large for gestational age were reported with glyBURIDE use compared with insulin use during pregnancy. There was no increased risk of obstetric trauma, preterm birth, or jaundice with glyBURIDE use compared with insulin. The risk of cesarean section delivery was 3% lower in the glyBURIDE group compared with the insulin group. For both treatment groups, patients had a minimum of 1 day of treatment and a maximum of 150 days of treatment with either glyBURIDE or insulin. The mean treatment duration with glyBURIDE was 50.4 days compared with 54.1 for insulin (Camelo Castillo et al, 2015).

D) POOR GLYCEMIC CONTROL

1) There have been reports of congenital malformations in neonates of mothers with abnormal glucose control (Prod Info GLUCOTROL XL(R) extended release oral tablets, 2009). Diabetes mellitus in pregnant women is associated with a 3-fold increase in congenital anomalies that include cardiac malformations, lumbosacral agenesis, hyperbilirubinemia, polycythemia, and renal vein thrombosis. Offspring of diabetic mothers have a mortality rate that is 5 times greater than that of nondiabetic mothers; the mortality rate is higher at all gestational ages (Behrman et al, 1992). Therefore, many experts recommend insulin for pre-gestational or gestational diabetes during pregnancy because of the need for precise control of maternal glucose levels and the limited information regarding fetal effects of some oral hypoglycemics (Prod Info GLUCOTROL XL(R) extended release oral tablets, 2009; Buchanan & Coustan, 1995; Cunningham et al, 1993).

E) LACK OF EFFECT

1) GLICLAZIDE

a) In one case report, gliclazide and ramipril use during the first 16 weeks of gestation did not lead to maternal or fetal complications. A 42-year-old female with type 2 diabetes and hypertension was admitted to an endocrinology unit during week 16 of gestation. One month prior to her last menstrual period, her fasting blood glucose level was 88 mg/dL and hemoglobin A1C level was 5.1%. History included treatment with gliclazide 30 mg/day and ramipril 10 mg/day for 2 years prior to admission. Gliclazide and ramipril were stopped and intensive insulin therapy was started in an outpatient clinic during week 17. Methyldopa 500 mg 4 times per day was started to control the patient’s high blood pressure. The patient gave birth to a 3200 g female infant by caesarean section following a normal gestation period, no abnormalities were observed. The infant’s Apgar scores were 8 at 1 minute and 10 at 5 minutes; blood glucose, C-peptide, and insulin levels were all within normal limits. Abdominal ultrasonography and echocardiography were normal. The child was considered to be healthy at 1.5 years of age (Kolagasi et al, 2009).

2) GLYBURIDE

a) A systematic review and meta-analysis of 9 randomized and cohort studies found that glyBURIDE use during pregnancy was not associated with increased perinatal adverse effects over insulin therapy. Among glyBURIDE-exposed pregnancies (n=745) and insulin-exposed pregnancies (n=637), there were no significant differences in birth weight (weighted mean difference (WMD) odds ratio (OR), 20.46 g; 95% CI, -34.9 to 75.82 g), gestational age at birth (WMD, 0.02 wk; 95% CI, -0.23 to 0.26), ICU admission (OR, 0.95; 95% CI, 0.43 to 2.09), rate of large for gestational age (OR, 1.04; 95% CI, 0.75 to 1.43), risk of neonatal hypoglycemia (OR, 1.24; 95% CI, 0.91 to 1.69), or risk of macrosomia (OR, 1.07; 95% CI, 0.78 to 1.47). The incidence of neonatal hypoglycemia was slightly higher with maternal insulin use, although systematic blood sugar evaluation was only performed in 3 of the studies (Moretti et al, 2008).
b) In a randomized controlled trial comparing glyBURIDE with insulin therapy in 404 women with gestational diabetes, there were no differences between the groups in respect to cord-serum insulin concentrations, incidence of macrosomia, cesarean delivery or neonatal hypoglycemia. GlyBURIDE was not detected in the cord serum of any infant, and there was no evidence of hyperinsulinemia caused by transplacental passage of glyBURIDE (Langer et al, 2000).

F) ANIMAL STUDIES

1) TOLAZAMIDE

a) RATS: There were decreased litter sizes when pregnant rats were given TOLAZamide at doses that were 10 times the human dose. There was also a decreased number of pups born and increased perinatal mortality when rats were given an elevated TOLAZamide dose of 100 mg/kg/day (Prod Info Tolazamide oral tablets, 2009).

3.20.4)

A) BREAST MILK

1) Some sulfonylurea agents have been shown to be excreted in human milk (Prod Info Tolazamide oral tablets, 2009).
2) GLIPIZIDE, GLYBURIDE: Data regarding the use of glipiZIDE during human lactation or measurement of the amount, if any, of the drug excreted into breast milk are limited. In a daily-dose study conducted with glyBURIDE and glipiZIDE, neither drug was detected in breast milk. Starting on the first postpartum day, 5 women were given a daily dose of 5 mg/day of either glyBURIDE or glipiZIDE. Drug concentrations in maternal blood and milk and infant blood glucose were measured for 5 to 16 days after delivery. Neither drug was detected in the breast milk and 3 of the infants who were wholly breastfed had normal blood glucose concentrations. The maximum theoretical infant dose (MTID; mg/kg/day), based on a detection limit of 0.08 mcg/mL and a milk intake of 150 mL/kg/day, was expressed as a percentage of the weight adjusted maternal dose. The MTID was less than 28% for glyBURIDE and less than 27% for glipiZIDE, which was attributed to the insensitivity of the assays (Feig et al, 2005).
3) GLIMEPIRIDE: Lactation studies with glimepiride have not been conducted in humans. Pre- and postnatal animal studies have revealed that significant concentrations of glimepiride were present in the milk of lactating rats and the serum of nursing pups. Pups exposed to high levels of glimepiride during pregnancy as well as lactation developed skeletal deformities including bending, thickening, and/or shortening of the humerus (Prod Info AMARYL(R) oral tablets, 2012).

3.20.5)

A) LACK OF INFORMATION

1) GLIPIZIDE

a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to glipiZIDE (Prod Info GLUCOTROL XL(R) extended release oral tablets, 2009).

2) GLYBURIDE

a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to glyBURIDE (Prod Info DiaBeta(R) oral tablets, 2009).

B) ANIMAL STUDIES

1) GLIPIZIDE

a) GLIPIZIDE: There were no adverse effects on fertility in male or female rats that were exposed to glipiZIDE at doses up to 75 times the human dose (Prod Info GLUCOTROL XL(R) extended release oral tablets, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Immediate bedside glucose level.
B) Serum glucose, electrolytes, including magnesium should be obtained.
C) Serum drug concentrations are not readily available and thus not immediately helpful, urinary sulfonylurea may be used to confirm diagnosis in the rare case where this is desirable.
D) Obtain an ECG and cardiac enzymes in susceptible patients with chest pain.
E) CT brain for patients who remain comatose despite normalization of serum glucose.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor blood glucose levels hourly. Monitor for clinical evidence of hypoglycemia, signs and symptoms of hypoglycemia may develop in patients, with a rapid decrease in blood glucose, even in the absence of numeric hypoglycemia (Boyle et al, 1988).
2) Chlorpropamide may cause hyponatremia; monitor electrolytes (Slade & Iosefa, 1967; Weissman et al, 1971).
3) Proinsulin levels, c-peptide and insulin levels and blood or urine sulfonylurea levels obtained while the patient is hypoglycemic can help distinguish patients with surreptitious sulfonylurea or insulin use from those with insulinoma or decreased glucose production (Bosse, 2002).
4) SULFONYLUREA INGESTION - High plasma insulin and c-peptide, proinsulin present and sulfonylureas may be detected in blood or urine.

a) EXOGENOUS INSULIN USE - High plasma insulin, low C-peptide and absent proinsulin.
b) INSULINOMA - High plasma insulin and c-peptide, proinsulin present and sulfonylureas not present in blood or urine
c) DECREASED GLUCOSE PRODUCTION - Low plasma insulin and c-peptide, proinsulin present.

4.1.4)

A) OTHER

1) ECG and cardiac enzymes should be obtained in susceptible patients with chest pain.

Radiographic Studies

A)

1) CT of the brain should be obtained in patients who remain comatose despite normalization of serum glucose.

B)

1) In a small study of 8 patients with severe hypoglycemia (less than 4 mmol/L or 75 mg/dL) following inadvertent glibenclamide exposure, typical lesions involved the hippocampus and cerebral cortex with no evidence of injury to the cerebellum or the subcortical white matter. Lesions in the caudate nucleus and basal ganglia were only observed in severely affected patients. All but one of these patients sustained permanent neurologic injury secondary to severe hypoglycemia. The utility of neuroimaging for prognosis may be limited, but it may have a role in distinguishing effects due to acute ischemic injury (Lim et al, 2009).

Methods

A)

1) HPLC methods for detecting glipiZIDE and gliclazide in plasma have been described (Sener et al, 1995).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) SUMMARY

1) Any adult who becomes hypoglycemic and all children should be admitted for observation and serial blood glucose monitoring.
2) Onset of symptoms may be delayed. Hypoglycemia may persist for more than 72 hours. Most authors suggest that patients with suspected overdose should be admitted and monitored for a minimum of 8 to 12 hours (Kokan, 2000; Burkhart, 1998). Some authors advocate a minimum of 24 hours of observation with hourly blood glucose determination in all patients (Lung & Olson, 2011; Bosse, 2002). It has been suggested that most children developing hypoglycemia will do so within 8 hours of ingestion (Calello et al, 2006), however, there is evidence that administration of food or dextrose can delay the onset of hypoglycemia to more than 8 hours in children with sulfonylurea exposure (Lung & Olson, 2011).

B) PEDIATRIC EXPOSURE

1) In a retrospective, cohort study of 300 pediatric (children less than 6 years old) with sulfonylurea exposures that developed hypoglycemia (glucose concentration less than 60 mg/dL), the onset of hypoglycemia can be delayed by greater than 8 hours by the free access to food or administration of IV glucose requiring a longer observation period. Among children who did not receive free access to food or IV glucose, the mean time to onset of hypoglycemia was 2 hours (range: 0.5 to 7 hours). Hypoglycemia occurred within 1 to 18 hours among those receiving free access to food, within 1.5 to 9 hours with prophylactic IV glucose, and with both food and IV glucose within 2.5 to 15 hours. Hypoglycemia persisted for greater than or equal to 12 hours in 31 (10%) patients despite treatment. Seven children (12 months to greater than 24 months) receiving free access to food developed hypoglycemia greater than 8 (range: 9.5 to 18 hours) hours after ingestion had nadir blood glucose (mg/dL) concentrations of 38 to 59. The authors found that the 8-hour observation period allowing free access to food may be too unreliable and recommend a 24-hour observation or overnight hospital admission for pediatric sulfonylurea exposures (Lung & Olson, 2011).
2) In a prospective observational 1-year study of 185 pediatric sulfonylurea ingestions, 54 (96%) patients developed hypoglycemia within 8 hours of ingestion. 87 patients were managed with oral supplementation only; 13 went onto require intravenous glucose or glucagon. No statistical difference in outcome was observed with either treatment {oral vs. intravenous} (Spiller et al, 1997).

a) Based on these findings the authors offer the following algorithm to manage a suspected accidental pediatric sulfonylurea ingestion (Spiller et al, 1997):

1) MONITORING: Direct clinical observation of the child for 8 hours with repeated blood glucose measurement. Free access to oral foods.
2) BLOOD GLUCOSE at 8 hours:

a) BLOOD GLUCOSE less than 60 mg/dL or Clinical Symptoms: Admit child. Continue blood glucose monitoring. Supplement with food or intravenous dextrose as indicated.
b) BLOOD GLUCOSE greater than 60 mg/dL and Asymptomatic: Discharge child. Instruct parents to allow child free access to foods. Return to health care facility if the following symptoms present: excessive drowsiness, diaphoresis or unexplained agitation.

3) This study has been criticized because it did not confirm the ingestion of sulfonylurea with urinary assays and thus may underestimate the risk of delayed hypoglycemia more than 8 hours after ingestion. Some authors recommend a minimum of 24 hours of observation after unintentional ingestion of sulfonylureas in children, with hourly blood glucose monitoring during this period (Bosse, 2002).

6.3.1.2) HOME CRITERIA/ORAL

A) There is no role for home management of inadvertent or deliberate sulfonylurea overdose.
B) ADULTS: In a retrospective review of poison center records over a 3 year period, 85 cases of diabetic adults inadvertently ingesting supratherapeutic doses (ingesting more than their usual single or usual daily dose) of sulfonylureas were safely monitored at home. All preparations were immediate release and 45% of the cases involved glyBURIDE. Fifty-two patients also ingested supratherapeutic doses of other medications concomitantly, which included beta-blockers in 13 patients. Sixty-one cases (72%) had at least one documented glucose determination after ingestion, with no glucose concentration below 60 mg/dL. A total of 68 cases (43%) took oral glucose or carbohydrate supplementation. Eight individuals complained of shakiness or dizziness following doses of 2 to 4 times their usual single dose and up to double their usual daily dose. No patient developed symptoms that were not controlled by oral glucose/carbohydrate supplementation. Intravenous dextrose was not required (Cantrell & Clark, 2007). The authors concluded that adults inadvertently ingesting more than their usual daily dose who are comfortable monitoring for signs/symptoms of hypoglycemia can be safely monitored at home; however, further prospective studies are suggested.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist in cases of severe poisonings.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Adults with suspected overdose should be observed for at least 12 hours with serial blood glucose monitoring. Patients who ingest extended release product should be monitored for 24 hours.
B) Most authors suggest that patients with suspected overdose should be monitored for a minimum of 8 to 12 hours (Kokan, 2000; Burkhart, 1998). Some authors advocate a minimum of 24 hours of observation with hourly blood glucose determination in all patients (Lung & Olson, 2011; Bosse, 2002)

Monitoring

A)

B)

C)

D)

E)

Oral Exposure

6.5.1)

A) Prehospital gastrointestinal decontamination is not recommended because of the potential for somnolence and seizures.

6.5.2)

A) Activated charcoal can be used if the patient presents early and is able to protect their airway. Activated charcoal may be useful even several hours after ingestion of a extended release product.
B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

3) EFFICACY

a) The absorption of TOLBUTAMIDE, 500 mg, was reduced by 90% by the administration of 50 g activated charcoal five minutes following ingestion (Neuvonen & Karkkainen, 1983).
b) At a pH 7.5 in vitro, activated charcoal 1 g was reported to adsorb about 500 mg of TOLBUTamide (Neuvonen & Karkkainen, 1983).
c) When repeated doses of charcoal were taken starting six hours after chlorpropamide, the half-life was NOT reduced and the excretion of CHLORPROPAMIDE into the urine was REDUCED by 40% (Neuvonen & Karkkainen, 1983).
d) The second generation sulfonylureas GLIPIZIDE and GLYBURIDE have a greater affinity for activated charcoal (Kannisto & Neuvonen, 1984; Kivisto & Neuvonen, 1990).

6.5.3)

A) HYPOGLYCEMIA

1) DEXTROSE

a) Treat patients who develop laboratory evidence of hypoglycemia (blood glucose less than 60 milligrams/deciliter) or clinical signs of hypoglycemia with food and IV dextrose.
b) DOSE

1) ADULT

a) BOLUS: The administration of 25 g dextrose solution will correct the majority of acute hypoglycemic states. This dose may need to be repeated in patients with profound hypoglycemia.
b) INFUSION: Initiation of a continuous 10% to 20% dextrose intravenous infusion is recommended in any patient who becomes hypoglycemic, as recurrent prolonged episodes of hypoglycemia are common after overdose (Sonnenblick & Shilo, 1986; Palatnick et al, 1991).

1) Infusion was recommended to treat glyBURIDE overdose, since intermittent boluses may have an additive effect on insulin secretion and produce a rapid decrease in blood sugar (Zilker et al, 1977).
2) Do not stop the IV dextrose infusion abruptly. Intravenous dextrose may need to be prolonged or repeated, depending upon the duration of action and amount of the sulfonylurea ingested.
3) Slowly decrease the rate of dextrose infusion with hourly monitoring of blood glucose after blood glucose levels have been stable for 6 to 8 hours.
4) Prophylactic dextrose administration is not recommended in patients who are not hypoglycemic, as it may make it difficult to distinguish patients who become hypoglycemic and require prolonged hospitalization from those who remain asymptomatic and may be discharged sooner (Spiller et al, 1995; Kokan & Dart, 1996).

2) PEDIATRIC

a) BOLUS: 0.5 to 1 g/kg intravenously, usually administered as D25W (2 to 4 mL/kg/dose) given over 1 to 2 minutes

1) D50W (1 to 2 mL/kg/dose) may be used for children greater than 5 years and D10W for preterm infants.

b) INFUSION: Initiation of a continuous 10% to 20% dextrose in 0.2% normal saline intravenous infusion is recommended in any patient who becomes hypoglycemic, as recurrent prolonged episodes of hypoglycemia are common after overdose (Sonnenblick & Shilo, 1986; Palatnick et al, 1991). Titrate to maintain blood glucose above 100 mg/dL.

1) Do not stop the IV dextrose infusion abruptly. Intravenous dextrose may need to be prolonged or repeated, depending upon the duration of action and amount of the sulfonylurea ingested.
2) Slowly decrease the rate of dextrose infusion with hourly monitoring of blood glucose after blood glucose levels have been stable for 6 to 8 hours.
3) Prophylactic dextrose administration is not recommended in children who do not become hypoglycemic, as it may make it difficult to distinguish patients who become hypoglycemic and require prolonged hospitalization from those who remain asymptomatic and may be discharged sooner (Calello et al, 2006; Spiller et al, 1995; Kokan & Dart, 1996).

c) PRECAUTIONS

1) Avoid subcutaneous administration.
2) Avoid fluid overload with intravenous infusion.
3) Be cautious in using intravenous infusion with congestive heart failure.
4) Hyperosmolar coma may occur in diabetics receiving intravenous infusion.
5) Do not stop the intravenous glucose abruptly.

2) OCTREOTIDE

a) SUMMARY

1) This is a long acting analogue of somatostatin which antagonizes insulin release. It should be used in any patient who requires more than one dextrose bolus or a dextrose infusion to maintain normal blood glucose.
2) Intravenous octreotide, given with intravenous 50% dextrose, has effectively reversed hypoglycemia caused by sulfonylurea in healthy volunteers (Justice et al, 1991; Boyle et al, 1993).

b) DOSING

1) SUMMARY

a) Subcutaneous administration or continuous infusion reduced the need for dextrose administration and the risk of recurrent hypoglycemia in a retrospective series of 9 patients with sulfonylurea overdose (McLaughlin et al, 2000). ADULT DOSE: 50 to 100 mcg subQ, repeated every 6 to 12 hours as needed (McLaughlin et al, 2000).
b) Subcutaneous administration or continuous infusion reduced the need for dextrose administration and the risk of recurrent hypoglycemia in a retrospective series of 9 patients with sulfonylurea overdose (McLaughlin et al, 2000). ADULT DOSE: 50 to 100 mcg subQ, repeated every 6 to 12 hours as needed (McLaughlin et al, 2000).

2) PEDIATRIC

a) In a review of 5 pediatric sulfonylurea-poisoned patients, 4 of the 5 children had a recurrence of hypoglycemia between 6 and 17 hours after being administered the first dose of octreotide (Calello et al, 2006). Based on these cases the suggested pediatric starting dose is as follows:

1) INITIAL DOSE: 1 mcg/kg administered IV or subQ which may need to be titrated upwards or repeated after 6 hours if hypoglycemia is present or if the effects of sulfonylurea is anticipated to be prolonged. For SEVERELY poisoned patients: A continuous intravenous infusion of octreotide may be considered: Start at 15 ng/kg/min and titrate upwards as indicated. MONITORING: Ongoing monitoring is suggested after intravenous dextrose has been stopped and should be continued for 8 hours after receiving the last dose of octreotide, and then have the child be allowed to be fasted through a regular sleep cycle before discharge (Calello et al, 2006).

b) SEVERE PEDIATRIC POISONING

1) CONTINUOUS INFUSION: A 17 month-old boy was admitted unarousable and hypothermic (93.7 degrees F) approximately 24 hours after ingesting an unknown quantity of standard-release glipiZIDE (10 mg tablets). He presented with severe hypoglycemia (blood glucose 18 mg/dL), diffuse cerebral edema without herniation or hemorrhage and persistent seizures. Four dextrose boluses (0.5 g/kg) were given immediately with temporary improvement in blood glucose. Other therapies included intubation and mechanical ventilation and IV boluses of benzodiazepines to treat his seizures. Thirty hours after exposure, he was transferred to the PICU with a continuous infusion of D12 0.9% sodium chloride. Despite an ongoing dextrose infusion, the toddler continued of have episodes of hypoglycemia. At 31 hours post ingestion, octreotide 1 mcg/kg subcutaneously was started. However, during the next 12 hours, multiple episodes of hypoglycemia occurred and the patient was started on a continuous infusion of octreotide at 1 mcg/kg/h along with an increase in dextrose (D50) to maintain a glucose infusion rate at a smaller volume and a 6% hypertonic saline drip. Blood glucose levels quickly normalized and no further dextrose boluses were needed. The octreotide infusion was continued for a total of 67 hours. During this time enteral feeds were gradually increased with a decrease in parenteral dextrose. Blood glucose remained stable 6 hours after discontinuing octreotide and IV fluids. By 36 hours, the toddler developed agitation without purposeful movement and at 71 hours sedation was discontinued and intermittent purposeful movement were noted. At 85 hours, cerebral edema had resolved and the patient was successfully extubated the following day. Initially, he had poor tone and his developmental skills were slow. By the time of discharge, he was able to walk and able to perform normal developmental tasks (Llamado et al, 2013).

c) CASE REPORTS

1) CASE REPORTS: Two young children (33 month-old girl and a 12 month-old boy) developed significant hypoglycemia following inadvertent ingestion of sulfonylureas, and were initially treated with intravenous dextrose and glucagon with only temporary improvement. The 33 month-old had an initial blood sugar of 1.1 mmol/L (conversion 19.8 mg/dL) with slight improvement (1.6 mmol/L {conversion 28.8 mg/dL}) following dextrose administration. However, blood sugar stabilized after receiving an initial 2 mcg/kg dose of octreotide followed by a 2 mcg/kg/hour infusion which resulted in a normal blood sugar within 2 hours with no further symptoms. The second child was asymptomatic but had an initial blood sugar of 2.4 mmol/L (conversion 43.2 mg/dL). Despite dextrose administration, blood sugar remained below 3 mmol/L (conversion 54 mg/dL). A single dose of 2.5 mcg/kg of octreotide increased blood sugar within 30 minutes with no further treatment needed (Rath et al, 2008).
2) CASE REPORT: A 5-year-old boy with ADHD presented in status epilepticus with a blood glucose of 12 mg/dl after mistakenly receiving glipiZIDE 7.5 mg twice daily for 3 days instead of his prescribed Adderall(R). He developed recurrent hypoglycemia that resolved after 25 mcg of IV octreotide. Serum insulin and simultaneous glucose were 53 microIU/ml and 45 mg/dL respectively before octreotide and 16 microIU/ml and 183 mg/dL 3 hours after octreotide administration (Mordel et al, 1998).
3) CASE REPORT/SUSTAINED RELEASE GLIPIZIDE: Subcutaneous doses of octreotide (4 25-mcg doses over 24 hours) along with a dextrose infusion were used to treat persistent hypoglycemia in a 6-year-old child following the unintentional ingestion of an extended release tablet of glipiZIDE. Her intravenous glucose requirements decreased after the first dose, but she continued to have some degree of blood glucose fluctuation up to 70 hours after exposure. The octreotide dose per day was 3.5 mcg/kg/day which is similar to the range (2 to 10 mcg/kg/day) reported for children being treated with congenital hyperinsulinemic hypoglycemia. No adverse events to the therapy were reported and the child made a complete recovery (Pelavin et al, 2009).

3) DIAZOXIDE

a) SUMMARY: Diazoxide has been used successfully in the treatment of sulfonylurea-induced hypoglycemia that does not respond to dextrose, or glucagon (Jacobs et al, 1978; Palatnick et al, 1991). It is rarely used and octreotide is generally preferred.
b) DOSE

1) 3 to 8 mg/kg/24 hours

a) 300 milligrams slowly via intravenous piggyback given over one hour.

2) MECHANISM: Diazoxide directly inhibits insulin secretion from the pancreas as evidenced by a decrease in plasma insulin concentrations following an intravenous infusion of diazoxide. Slow intravenous infusion should cause no decrease in blood pressure (Johnson et al, 1977).
3) CASE SERIES

a) Palatnick et al (1991) reported 6 patients who were treated with diazoxide when they failed to respond to glucose(6) and steroids(2).

1) A single bolus produced a response in 2 patients. Multiple boluses were required in 2 patients. A constant infusion was necessary in the remaining 2 patients.

4) GLUCAGON

a) SUMMARY: Glucagon is of limited value in the treatment of hypoglycemia caused by sulfonylureas, except when treatment with glucose is not available or possible.
b) Because of the short half-life of glucagon, repeated hypoglycemia may occur. Oral carbohydrate or IV dextrose should be given as soon as possible. May not be effective in children, alcoholics, or malnourished patients due to decreased glycogen stores.
c) CHLORPROPAMIDE-INDUCED HYPOGLYCEMIA

1) May be difficult to correct with glucose alone necessitating the concurrent use of glucagon to maintain normal blood sugar levels.

d) MECHANISM: Glucagon stimulates gluconeogenesis and glycogenolysis by stimulation of cyclic AMP synthesis, especially in hepatic and adipose tissue.
e) Circulatory epinephrine (already present from the reactive sympathetic discharge) has the same effect, and the addition of glucagon may not have noticeable additional benefit (Larner, 1980).
f) GLYCOGEN STORES: For glucagon to be effective, the patient needs adequate liver glycogen stores.

1) Glycogen stores are usually adequate in infants of diabetic mothers (as opposed to other infants, whose stores are depleted).

g) DOSE

1) ADULTS: 1 to 5 mg intravenously, intramuscularly, or subcutaneously; a therapeutic response may be expected within 20 minutes of a subcutaneous dose; repeat doses may be necessary.
2) CHILDREN: If glucose is unavailable, 0.03 to 0.1 mg/kg/dose intramuscularly or intravenously (1 mg may be given at any age).
3) This will provide transient elevation of glucose level if there are adequate liver stores; dose may be repeated in 20 minutes.
4) AVAILABLE FORMS: Glucagon for Injection(R) (1 and 10 mg dosage forms)

h) PRECAUTIONS: Caution in patients with history of insulinoma or pheochromocytoma; of little benefit in presence of starvation, adrenal insufficiency, liver disease, alcoholism or chronic hypoglycemia.
i) ADVERSE EFFECTS: Nausea and vomiting and stimulation of hepatic ketogenesis (Johnson et al, 1977).
j) MONITORING PARAMETERS: Monitor blood glucose.

B) DIETARY FINDING

1) Any patient with suspected sulfonylurea overdose should be fed.

C) FLUID/ELECTROLYTE BALANCE REGULATION

1) MONITOR FLUID and ELECTROLYTE BALANCE: Potassium supplementation may be needed.

Enhanced Elimination

A)

1) Hemodialysis is unlikely to be of value due to the high degree of protein binding of sulfonylureas (Seger, 1988).

B)

1) Charcoal hemoperfusion was used successfully to treat a chlorpropamide-intoxicated patient with chronic renal failure. Over 80% of the total body burden of chlorpropamide was removed, and plasma half-life was reduced from 93.6 hours to 3.4 hours during treatment (Ludwig et al, 1987).

C)

1) CHLORPROPAMIDE

a) Alkalinization of the urine appears to significantly enhance the elimination of chlorpropamide (Neuvonen & Karkkainen, 1983) (Karkkainen et al, 1983), and may be useful following overdosage with other sulfonylureas.
b) The half-life of chlorpropamide following a therapeutic dose was shortened from 49.7 hours to 12.8 hours with alkalinization of the urine (Neuvonen & Karkkainen, 1983).
c) A pH of 8 and an adequate urine flow can shorten chlorpropamide half-life and result in the elimination of 80 percent of the drug within 24 hours (Neuvonen & Karkkainen, 1983).

2) SODIUM BICARBONATE/INITIAL DOSE

a) Administer 1 to 2 milliequivalents/kilogram of sodium bicarbonate as an intravenous bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. In patients with underlying dehydration additional administration of 0.9% saline may be needed to maintain adequate urine output (1 to 2 milliliters/kilogram/hour). Manipulate bicarbonate infusion to maintain a urine pH of at least 7.5.

3) SODIUM BICARBONATE/REPEAT DOSES

a) Additional sodium bicarbonate (1 to 2 milliequivalents per kilogram) and potassium chloride (20 to 40 milliequivalents per liter) may be needed to achieve an alkaline urine.

4) CAUTION

a) Obtain hourly intake/output and urine pH. Assure adequate hydration and renal function prior to alkalinization. Do not administer potassium to an oliguric or anuric patient. Monitor fluid and electrolyte balance carefully. Monitor blood pH, especially in intubated patients, to avoid severe alkalemia.

Abstracts

Case Reports

A)

1) GLYBURIDE: An 11-month-old infant was given an unknown amount of glyBURIDE. Serum glucose 12 hours postingestion was 4.7 mg/dL. She was comatose, with seizures. EEG revealed patchy CNS involvement. After 1 year, the girl was retarded, suffered hemiparesis, and infrequent seizures (Pavone et al, 1980).
2) GLYBURIDE: A 20-month-old child ingested 15 mg glyBURIDE. He was admitted 21 hours postingestion with somnolence, seizures, and a blood glucose of 52 mg/dL. A protracted course ensued, with coma lasting 4 days. Residual effects included optic nerve atrophy, seizures, and developmental retardation (Habel & Spranger, 1975).
3) GLYBURIDE: An observed ingestion of glyBURIDE 5 mg in a 22-month-old boy resulted in a blood glucose of 64 mg/dL 2.5 hours postingestion. The child remained asymptomatic (Habel & Spranger, 1975).

B)

1) INHALATION

a) GLYBURIDE: Profound hypoglycemia was reported in a 33-year-old man after inhaling glyBURIDE Micronized dust at a pharmaceutical manufacturing facility (Albert et al, 1993).

C)

1) ACETOHEXAMIDE: A 16-year-old adolescent ingested fifty 250 mg tablets of acetohexamide. She was opisthotonic and unresponsive to stimuli, and exhibited tonic-clonic seizures, hypotension, and bradycardia. Serum glucose was less than 20 mg/dL, but was corrected with IV dextrose and supportive therapy. Seven days after admission she had recovered (Cowen et al, 1967).
2) CHLORPROPAMIDE: A 13-year-old girl presented with drowsiness and a serum glucose of 35 mg/dL 18 hours after ingesting 3 grams of chlorpropamide. Loss of consciousness and seizures soon followed. Coma was prolonged, lasting 78 hours postingestion, but appropriate dextrose/glucagon treatment and supportive therapy resulted in full recovery (Dowell & Imrie, 1972).
3) GLYBURIDE: A 25-year-old nondiabetic man ingested fifty 10 mg glyBURIDE tablets. Two hours postingestion, blood sugar was 28 mg/dL. Fourteen hours postingestion, it was 40 mg/dL after 50 grams of IV glucose. Glucose infusions were required for 5 days (Zilker et al, 1977).
4) GLYBURIDE: Hypoglycemic coma occurred in a 79-year-old nondiabetic woman unintentionally given 5 mg glyBURIDE. Three hours postingestion, serum glucose was 2.6 mmol/L (46.8 mg/dL); 10-1/2 hours postingestion, hypoglycemic coma ensued. The authors suggest 24-hour monitoring in patients with inadvertent glyBURIDE ingestion (Sketris et al, 1984).

D)

1) CHLORPROPAMIDE : A 9-year-old boy ingested 5 g chlorpropamide. He was comatose 24 hours postingestion, and had seizures despite intensive dextrose treatment. Ten hours after admission, diazoxide 5 mg/kg/day was started, resulting in a substantial reduction of the patient's dextrose requirements. He was discharged 8 days later with no sequelae (Jacobs et al, 1978).
2) GLIPIZIDE: A 2-year-old child developed delayed hypoglycemia 11 hours after ingesting 1 glipiZIDE 5 mg tablet and 1 hydrochlorothiazide 25 mg tablet (Frederick & Wang, 1994). The patient had a history of asthma which was being treated with albuterol and cromolyn.

a) Within 40 minutes of ingestion, the child was treated at an emergency department with activated charcoal, and intravenous fluids (5% dextrose in 0.2% NaCl). A full diet was also consumed. Baseline serum glucose levels were 106 mg/dL. Serum glucose levels were monitored hourly.
b) Eleven hours post drug ingestion, serum glucose levels dropped to 49 mg/dL. Orange juice and increased intravenous dextrose (10% in 0.45% NaCl) were administered. Fluctuations in glucose levels continued to occur. The patient was discharged after glucose levels stabilized.

3) GLYBURIDE: A 30-month-old child ingested an unknown amount of 5 mg glyBURIDE tablets. Blood glucose was initially nondetectable, and seizures occurred. Prolonged hypoglycemia ensued, lasting 48 to 72 hours despite a bolus of 50% dextrose and infusion of 10% dextrose. Twelve months later, the child exhibited serious sequelae including epilepsy, third nerve palsy, and retardation (Sillence & Court, 1975).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) FIRST GENERATION SULFONYLUREAS

1) CHLORPROPAMIDE

a) INITIAL: Mild to moderate, stable type 2 diabetes: 250 mg daily. Elderly should start at 100 to 125 mg daily. MAINTENANCE: Most moderately severe, stable type 2 diabetes: 250 mg daily; milder diabetics may be able to take 100 mg or less. Severely diabetic patients may require 500 mg daily (Prod Info DIABENESE(R) oral tablets, 2006).

2) TOLBUTAMIDE

a) INITIAL: 1 to 2 gram(s) daily. MAINTENANCE: 0.25 to 3 grams daily; maintenance doses above 2 grams are seldom required. Maximum dose should not exceed 3 grams daily (Prod Info tolbutamide oral tablets, 2002).

B) SECOND GENERATION SULFONYLUREAS

1) GLIPIZIDE

a) INITIAL: 5 mg daily; elderly may be started at 2.5 mg. MAINTENANCE: Total daily doses above 30 mg have been safely given on twice daily basis to long term patients. Maximum dose should not exceed 40 mg daily (Prod Info GLUCOTROL(R) oral tablets, 2008).

2) GLYBURIDE

a) INITIAL: 2.5 to 5 mg daily. MAINTENANCE: Usual maintenance dose is 1.25 to 20 mg daily. Maximum dose should not exceed 20 mg daily (Prod Info Micronase(R) oral tablets, 2008).

7.2.2)

A) These agents are not typically recommended for use in pediatric patients. Safety and efficacy have not been established (Prod Info GLUCOTROL(R) oral tablets, 2008; Prod Info Micronase(R) oral tablets, 2008; Prod Info DIABENESE(R) oral tablets, 2006; Prod Info tolbutamide oral tablets, 2002).

Maximum Tolerated Exposure

A)

1) Many of the reports involve amounts of hypoglycemic agents given in the usual therapeutic doses. Hypoglycemia is more common in patients with inadequate carbohydrate stores, and in patients with renal or liver insufficiency.
2) There are cases of hypoglycemic coma induced by TOLBUTamide with as little as 500 milligrams per day given for 5 days. Coma was prolonged up to 96 hours.
3) Hypoglycemic episodes lasting several days required repeated dextrose administration. Reactions have been reported after a single dose, and after several days or months of treatment (Gilman et al, 1985).

B)

1) ACETOHEXAMIDE

a) ACETOHEXAMIDE: Cases have been reported with acetohexamide given as low as 500 milligrams. Most of the cases also involved renal failure patients.

2) CHLORPROPAMIDE

a) CHLORPROPAMIDE: More hypoglycemic deaths have been associated with chlorpropamide than other sulfonylureas. Forty-three individuals took 500 milligrams/day and 12 others 750 milligrams/day for more than 2 weeks before onset of hypoglycemia was documented.

3) GLIBENCLAMIDE

a) ADULTERATED PRODUCT: In Singapore, severe hypoglycemia was reported in a cluster of nondiabetic individuals consuming an illegal health product sold as an herbal preparation for sexual enhancement called Power 1 Walnut. The herbal product was sold as a synthetic replacement to sildenafil, but was found to contain high concentrations of glibenclamide (it was not determined why this class of drug was used). Of 8 cases with known severe hypoglycemia, one patient died of complications after 28 days in a persistent vegetative state, 5 developed moderate to severe disability, one had slight disability and one recovered completely (Lim et al, 2009).

4) GLIMEPIRIDE

a) MIXED INGESTION:GLIMEPIRIDE/ZOLPIDEM: A 40-year-old man with diabetes mellitus was admitted to the hospital due to poor glycemic control. During his hospitalization he intentionally ingested an estimated 42 mg (14 tablets of 3 mg each) of glimepiride and 50 mg of zolipdem (10 tablets of 5 mg each) and developed a loss of consciousness. When found, his glucose level was 40 mg/dL and he received immediate glucose. However, despite frequent intravenous glucose administration his altered mental status did not improve and tachycardia was present (142 beats/min). He was transferred to a higher level of care for frequent glucose and vital sign monitoring. A glimepiride concentration was 37.43 ng/mL immediately following overdose. A head CT scan was normal. The following day, an increase in creatine kinase-MB fraction (112 Unit/L) and troponin l levels (8.77 ng/mL), without ECG changes, were observed. Due to ongoing disturbances in consciousness, an acute myocardial infarction was suspected. The patient also had several severe episodes of hypoglycemia up to 60 hours after exposure despite glucose replacement; his glimepiride concentration was still elevated (13.61 ng/mL) at 48 hours. Serial cardiac ultrasounds remained normal. He gradually improved. By day 11, he was discharged to home without sequelae. Follow-up cardiac diagnostic studies were normal with no evidence of myocardial ischemia or an old infarction (Chou et al, 2015).

5) GLIPIZIDE

a) EXTENDED RELEASE: A 6-year-old girl with a laboratory confirmed ingestion of a 10 mg extended-release glipiZIDE tablet presented with severe hypoglycemia (20 mg/dL), 45 hours after unintentional exposure. The child had persistent hypoglycemia which lasted up to 70 hours after exposure, despite multiple boluses of dextrose and subcutaneous octreotide. The patient gradually improved with no permanent sequelae (Pelavin et al, 2009). The authors did suggest that because of the elevated serum glipiZIDE concentration (1000 ng/mL approximately 57 hours after ingestion) and persistent symptoms, the child may have ingested more than one tablet which was prescribed for a family member.

6) GLYBURIDE

a) ADULT

1) A 49-year-old man ingested 100 milligrams of glyBURIDE, and did not develop hypoglycemia despite a serum glyBURIDE level of 191 micrograms/liter 14 hours postingestion. The patient had non-insulin-dependent diabetes and alcoholic pancreatitis and had received glyBURIDE therapeutically for 6 years (Ferner et al, 1986).
2) A dose of 2.5 milligrams in an elderly patient decreased serum glucose for 36 hours (Edwards et al, 1985).

b) CHILD

1) Witnessed ingestion of 5 milligrams in a 22-month-old child resulted in asymptomatic hypoglycemia (blood glucose 64 milligrams/deciliter) (Habel & Spranger, 1975).
2) Witnessed ingestion of 10 to 15 milligrams (most of one tablet was recovered in emesis) in a 20-month-old child resulted in hypoglycemic coma, seizures, and permanent sequelae; however, treatment was delayed for 21 hours (Habel & Spranger, 1975).
3) Administration of 2.5 milligrams to 23 healthy fasted children, aged 5 to 15 years, resulted in a maximal decrease in blood glucose of 23% of control at 120 minutes.

a) After a dose of 5 milligrams in the same children, the maximal decrease was 21.1% which occurred 90 minutes after ingestion. None of the children developed clinical symptoms of hypoglycemia.
b) After 6 hours, the blood glucose levels were still low, but no further levels were obtained (Weber & Hahn, 1970).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) GlyBURIDE: Therapeutic concentration: 40 to 50 nanograms/milliliter.

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) GlipiZIDE: EXTENDED RELEASE: A 6-year-old girl with a laboratory confirmed ingestion of a 10 mg extended-release glipiZIDE tablet presented with hypoglycemia (20 mg/dL), 45 hours after unintentional exposure. Approximately 57 hours after ingestion, her glipiZIDE concentration was 1000 ng/mL (in an adult with type 2 diabetes mellitus a mean plasma glipiZIDE concentration 24 hours after 10 mg is estimated to be 158 +/- 20 ng/mL) (Pelavin et al, 2009). The authors suggest that the child may have ingested more than one tablet that was prescribed for a family member.
b) CHLORPROPAMIDE: Serum chlorpropamide levels above 400 mcg/mL are considered potentially lethal in the non-diabetic subject (Forrest, 1974).

Pharmacology Toxicology

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Physical Characteristics

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Animal Toxicology

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SULFONYLUREA AND RELATED DRUGS

Classification | Detailed evidence-based information

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