Tolazamide

311.4

311.40

214-588-3

9LT1BRO48Q

758149|70762

DTXSID3021358

C29502

Crystals|WHITE TO OFF-WHITE, CRYSTALLINE POWDER

A - Alimentary tract and metabolism

2935904000

86.9

1.5

Tolazamide appears as white to off-white crystalline powder. Odorless or with a slight odor. (NTP, 1992)

1.2228 (rough estimate)

170-173 °C

300°C (rough estimate)

100 °C

1.6740 (estimate)

3.08e-01 g/L

Refrigerator

LD50 in rats, mice (mg/kg): >5000 orally, 2239 i.p. (Dulin)

ODORLESS OR HAS SLIGHT ODOR

PKA @ 25 °C, 3.6; PKA @ 37.5 °C, 5.68

173.3 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

This chemical may be sensitive to prolonged exposure to air. Insoluble in water.

Amides and Imides

TOLAZAMIDE is an amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx). This chemical is incompatible with acids. (NTP, 1992).

NONH for all modes of transport

3

22

36

YT4400000

Xn

P260, P264, P270, P307+P311, P321, P405, P501

H370

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

DHEW/NCI; Bioassay of Tolazamide for Possible Carcinogenicity (1978) Technical Rpt Series No. 51 DHEW Pub No. (NIH) 78-1756

Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

|Danger|H370 (100%): Causes damage to organs [Danger Specific target organ toxicity, single exposure]|P260, P264, P270, P307+P311, P321, P405, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory.

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should keep this material in a tightly-closed container under an inert atmosphere, and store it at refrigerated temperatures. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Overdosage of sulfonylureas can produce hypoglycemia. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization.

DRUGS THAT MAY INCR RISK OF HYPOGLYCEMIA FROM SULFONYL UREAS INCL OTHER HYPOGLYCEMIC AGENTS, SULFONAMIDES, PROPRANOLOL, SALICYLATES, PHENYLBUTAZONE, PROBENECID, DICUMAROL, CHLORAMPHENICOL, MONOAMINE OXIDASE INHIBITORS, & ALCOHOL. /SULFONYLUREAS/|...TOLAZAMIDE...MAY INTERACT WITH GUANETHIDINE...|HYPOGLYCEMIC ACTIVITY OF CHLORPROPAMIDE MAY BE ENHANCED BY CONCURRENT ADMIN OF CLOFIBRATE. ... SULFONYLUREAS...TOLAZAMIDE...DEMONSTRATED SIMILAR INTERACTION WITH CLOFIBRATE. HALOFENATE...WAS REPORTED TO ENHANCE HYPOGLYCEMIC EFFECT OF SULFONYLUREAS TO GREATER DEGREE THAN CLOFIBRATE.|ISONIAZID MAY INCR BLOOD GLUCOSE LEVELS & IMPAIR GLUCOSE TOLERANCE. ... PRECAUTIONS ARE INDICATED WHEN ISONIAZID IS ADMIN TO DIABETIC PT TREATED BY...ORAL HYPOGLYCEMICS (EG, SULFONYLUREAS...).|For more Interactions (Complete) data for TOLAZAMIDE (25 total), please visit the HSDB record page.

A bioassay of ... tolazamide for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered /the test cmpd/ at one of two doses, either 5,000 or 10,000 ppm for 103 wk. Matched controls consisted of 15 rats and 15 mice of each sex. All surviving rats and mice were /sacrificed/ at 104 or 105 wk. Survival rates of the dosed rats of each sex were higher than those for the matched controls and were adequate for the development of late appearing tumors. Survival rates for the mice were lower than those for the rats, particularly for the dosed females (matched controls 67%, low dose 34%, high dose 32%). However, a large number of these deaths in the dosed females occurred after 90 wk on study, and survival of both males and females was adequate for the development of late appearing tumors. All observed tumors were of types commonly found in the strains of animals used, and there were no statistically significant incr in the incidence of tumors in dosed animals as compared with controls. It is concluded that under the conditions of this bioassay, tolazamide was not carcinogenic for Fischer 344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative.

For use as an adjunct to diet to lower the blood glucose in patients with non-insulin dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone.

Hypoglycemic Agents|...THIS POTENT AGENT LACKS ANTIDIURETIC ACTION & MAY BE ESPECIALLY USEFUL IN TREATMENT OF PT WHO HAVE TENDENCY TO RETAIN WATER.|SULFONYLUREAS SHOULD BE USED ONLY IN SUBJECTS WITH DIABETES OF MATURITY-ONSET TYPE WHO CANNOT BE TREATED WITH DIET ALONE OR WHO ARE UNWILLING OR UNABLE TO TAKE INSULIN IF WT REDN & DIETARY CONTROL FAIL. /SULFONYLUREAS/|ORAL HYPOGLYCEMIC|Sulfonylureas are indicated as adjunctive therapy to diet and exercise in the treatment and control of certain patients with NIDDM (Type II diabetes; previously known as 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. An attempt to control diabetes through changes; in diet and level of physical activity is usually first line management before beginning pharmacologic treatment. Those patients not responding adequately to diet alone or those patients requiring 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. /Included in US product labeling; Sulfonylurea antidiabetic agents/

HEMATOLOGICAL (LEUKOPENIA, AGRANULOCYTOSIS, THROMBOCYTOPENIA, PANCYTOPENIA, & HEMOLYTIC ANEMIA), CUTANEOUS (RASHES, PHOTOSENSITIVITY), GI (NAUSEA, VOMITING, RARELY HEMORRHAGE), & HEPATIC (INCR SERUM ALKALINE PHOSPHATASE, CHOLESTATIC JAUNDICE) REACTIONS HAVE BEEN REPORTED.|...CONTRAINDICATED IN DIABETES COMPLICATED BY ACIDOSIS, KETOSIS, SEVERE INFECTIONS, COMA, SEVERE TRAUMA, OR MAJOR SURGERY.|MOST REACTIONS ARE OBSERVED IN PT OVER 50 YR OF AGE, & THEY ARE MORE LIKELY TO OCCUR IN PT WITH IMPAIRED HEPATIC OR RENAL FUNCTION. OVERDOSAGE OR INADEQUATE OR IRREGULAR FOOD INTAKE MAY INITIATE HYPOGLYCEMIA.|SULFONYLUREAS SHOULD NOT BE USED IN PT WITH HEPATIC OR RENAL INSUFFICIENCY BECAUSE OF IMPORTANT ROLE OF LIVER IN THEIR METABOLISM & OF KIDNEY IN EXCRETION OF DRUGS & THEIR METABOLITES. /SULFONYLUREAS/|For more Drug Warnings (Complete) data for TOLAZAMIDE (17 total), please visit the HSDB record page.

Tolazamide is an oral blood glucose lowering drug of the sulfonylurea class. Tolazamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolazamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Some patients who are initially responsive to oral hypoglycemic drugs, including tolazamide, may become unresponsive or poorly responsive over time. Alternatively, tolazamide may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. In addition to its blood glucose lowering actions, tolazamide produces a mild diuresis by enhancement of renal free water clearance.

Substances which lower blood glucose levels. (See all compounds classified as Hypoglycemic Agents.)

Rapidly and well absorbed from the gastrointestinal tract.|Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0% to 70%. They are excreted principally in the urine.|AFTER ORAL ADMIN PEAK PLASMA LEVELS REACH PEAK IN 4-8 HR.|TOLAZAMIDE IS SLOWLY ABSORBED; ONSET OF HYPOGLYCEMIC ACTION OCCURS @ 4-6 HR & PERSISTS @ SIGNIFICANT LEVEL UP TO 15 HR AFTER SINGLE DOSE. TOLAZAMIDE IS METABOLIZED TO NUMBER OF HYPOGLYCEMIC SUBSTANCES THAT ARE LARGELY EXCRETED BY KIDNEY.|Some metabolites with moderate activity excreted via kidney. /from table/|Excreted (percentage)...85-95 /from table/|For more Absorption, Distribution and Excretion (Complete) data for TOLAZAMIDE (7 total), please visit the HSDB record page.

Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0 to 70%.|TOLAZAMIDE IS METABOLIZED TO A NUMBER OF HYPOGLYCEMIC SUBSTANCES...|Sulfonylureas are rapidly absorbed from the gastrointestinal tract, transported in the blood in highly protein-bound complexes, and subjected to extensive hepatic metabolism (except for chlorpropamide). Wide variation exists among the sulfonylureas in hepatic metabolism and remnal clearance, factors that tend to alter the steady-state serum levels. Metabolites may be active, so there may be a variation between the plasma half-life of the parent drug and the degree of hypoglycemia encountered. /Sulfonylurea/|Active metabolites may accumulate in renal failure. /from table/|Although the exact metabolic fate of tolazamide has not been clearly established, the drug is metabolized, probably in the liver, to two hydroxymetabolites, p-toluenesulfonamide, p-carboxytolazamide, and an unidentified metabolite; several of these metabolites are pharmacologically active. Tolazamide is excreted in urine principally as metabolites; small amounts are excreted in urine unchanged.

The average biological half-life of the drug is 7 hours.|PLASMA T/2 IS ABOUT 7 HR...|AVG BIOLOGICAL HALF LIFE...IS 7 HR.|Half-life...7 /hours/ /from table/

Sulfonylureas likely bind to ATP-sensitive potassium-channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin.|Sulfonylureas are now...thought to act by a number of different mechanisms. 1. ...produce a depolarization of the pancreatic islet beta cell membrane potassium ion permeability. This results in a release of preformed insulin into the circulation and occurs mostly in non-insulin dependent diabetics. 2. ...reduce basal glucose output from the liver... 3. increase insulin receptor binding... 4. ...increasing intracellular levels of AMP... 5. increase insulin secretion by suppressing the release of glucagon and somatostatin from alpha and delta pancreatic cells. /Sulfonylureas/|Sulfonylureas lower blood glucose in NIDDM 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. Therefore, sulfonylureas are effective only in patients whose pancreata are capable of producing insulin. /Sulfonylurea antidiabetic agents/

SYMPTOMS: Symptoms of exposure to this compound may include nausea, vomiting, epigastric pain, dizziness, weakness, paresthesia, sensitivity reactions such as fever, eosinophilia, jaundice and skin rashes, blood disorders such as leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis, and intolerance to alcohol (with facial flushing). Hypoglycemia can also occur. Hematological disorders include pancytopenia and hemolytic anemia. Photosensitivity, hemorrhage, increased serum alkaline phosphatase and cholestatic jaundice have been reported. Other symptoms may include heartburn, fatigue, malaise and allergic skin reactions which include pruritis, erythema, urticaria and morbilliform or maculopapular eruptions. ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound emits very toxic fumes of nitrogen oxides and sulfur oxides. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

HYPOGLYCEMIC REACTIONS, INCL COMA, MAY OCCUR. ...SEVERAL FATALITIES HAVE BEEN REPORTED.|Coma or altered mental status is generally the most important presenting sign in the majority (90%) of patients who have ingested excessive doses of the sulfonylureas ... /Sulfonylurea/

Tolazamide

... usually administered in a daily dose of 100 to 250 mg, while 750 to 1000 mg is maximal.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients