(British Approved Name, rINN)

Pharmacopoeias. In China, Europe, International, Japan, and US.

European Pharmacopoeia, 6th ed. (Tolbutamide). A white or almost white, crystalline powder. Practically insoluble in water soluble in alcohol and in acetone. It dissolves in dilute solutions of alkali hydroxides.

The United States Pharmacopeia 31, 2008 (Tolbutamide). A white or practically white, practically odourless, crystalline powder. Practically insoluble in water soluble in alcohol and in chloroform.

Adverse Effects, Treatment, and Precautions

As for sulfonylureas in general. Tolbutamide was implicated in the controversial reports of excess cardiovascular mortality associated with oral hypoglycaemic therapy (see under Sulfonylureas, Effects on the Cardiovascular System).

Thrombophlebitis with thrombosis has occurred after the intravenous injection of tolbutamide sodium, but this is usually painless and the vein gradually recovers. Rapid injection may cause a transient mild pain or sensation of heat in the vein.

The BNFhas suggested that tolbutamide may be suitable for use in patients with renal impairment, but that careful monitoring of blood-glucose concentration is essential. UK licensed product information recommends that it should not be used in patients with severe renal impairment.

Breast feeding. Tolbutamide is distributed into breast milk in relatively low quantities. The American Academy of Pediatricsstates that, although usually compatible with breast feeding, use of tolbutamide by breast-feeding mothers may possibly result in jaundice in the infant.

Porphyria. Tolbutamide has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Interactions

As for sulfonylureas in general.

Pharmacokinetics

Tolbutamide is readily absorbed from the gastrointestinal tract and is extensively bound to plasma proteins the half-life is generally within the range of 4 to 7 hours but may be considerably longer. Tolbutamide is metabolised in the liver by liydroxylation mediated by the cytochrome P450 isoenzyme CYP2C9. It is excreted in the urine chiefly as metabolites with little hypoglycaemic activity. Tolbutamide has been detected in breast milk.

Uses and Administration

Tolbutamide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus and has a duration of action of about 10 hours.

The usual initial dose in type 2 diabetes mellitus may range from 1 to 2 g daily, given either as a single dose with breakfast or, more usually, in divided doses. Maintenance doses usually range from 0.25 to 2 g daily. Although it is unlikely that the response will be improved by increasing the dose further, daily doses of 3 g have been given.

Tolbutamide sodium (C₁₂H₁₇N₂Na0₃S = 292.3) has sometimes been used in the diagnosis of insulinoma as well as other pancreatic disorders including diabetes mellitus. The equivalent of 1 g of tolbutamide is given by intravenous injection as a 5% solution usually over 2 to 3 minutes. Tolbutamide sodium 1.08 g is equivalent to about 1 g of tolbutamide.

Preparations

British Pharmacopoeia 2008: Tolbutamide Tablets

The United States Pharmacopeia 31, 2008: Tolbutamide for Injection Tolbutamide Tablets.

Proprietary Preparations

Australia: Rastinon

Czech Republic: Dirastan

Denmark: Arcosal

Germany: Orabet Hong Kong Diatol

Israel: Orsinon

Mexico: Artosin Bioglusil Dabetil Diatelan Diaval Flusan Ifumelus Rastinon

New Zealand: Diatol

Poland: Diabetol

South Africa: Tydadex

Singapore: Tolmide

USA: Orinase; Orinase Diagnostic

Sulfonylureas: First-Generation

Sulfonylureas consists of two groups or generations of agents. The first-generation agents are now less commonly used because second-generation agents are as effective and have fewer side effects. Two first-generation agents, chlorpropamide and tolbutamide are still popular with some physicians. This group also contains tolazamide and acetohexa-mide; both are rarely used today.

Chlorpropamide. Brand Name Drug: Diabinese. Chlorpropamide is administered once daily in a 100 mg or 250 mg tablet. Its half-life is extremely long, with effects lasting up to >48 hours. The principal disadvantage of this agent is that it is excreted almost entirely renally. Therefore, the risk of hypoglycemia makes this drug relatively contraindicated in the elderly and absolutely contraindicated in those with renal insufficiency. Chlorpropamide also enhances the effects of vasopressin, at times resulting in the syndrome of inappropriate antidiuretic hormone (SIADH). With the introduction of more potent agents that have a much shorter half-life and fewer side effects, today there is little reason to use chlorpropamide.

Tolbutamide. Brand Name Drug: Orinase. Tolbutamide has a much shorter duration of action (6-10 hours) and is metabolized primarily by the liver. It is a safer agent than chlorpropamide; however, it is relatively weak in its antidiabetic activity.

Sulfonylureas: Second-Generation

Second-generation sulfonylureas are the most commonly prescribed agents for treating type 2 diabetes. As a group, they are at least 100 times more potent than tolbutamide. They include glyburide, glipizide, and the newest agent, glimepiride. Glyburide and glipizide, when used as monotherapy, have proven effective in lowering HgbA₁C 1% to 2% in most studies.

Glyburide. Brand Names: Diabeta, Glycron, Glynase, Micronase. Glyburide is metabolized in the liver to metabolites with reduced hypoglycemic activity. These metabolites are then excreted renally. Therefore, in the elderly and patients with compromised renal function, glyburide is relatively contraindicated because of the risk of hypoglycemia. Even in normal subjects it is not unusual to see persistence of glyburide’s effects for up to 24 hours. In the United Kingdom Prospective Diabetes Study (UKPDS), a multicenter trial of >5000 patients with type 2 diabetes mellitus, the incidence of hypoglycemia with glyburide was similar to that seen with chlorpropamide. Patients usually are started on a 2.5-mg or 5-mg tablet in the morning before the first meal of the day. The dose can be escalated gradually to a maximum of 20 mg/day. However, it is rare to see further improvement in efficacy with doses > 10 mg/day. Again, this agent should be used with caution in the elderly population and in those with renal insufficiency.

There also is a micronized form of glyburide. However, it has been difficult to find exactly equivalent dosages between the two forms, which can lead to confusion for the patient and physician. The micronized agents have not been shown to have a higher bio availability or greater efficacy than regular glyburide.

Glipizide. Brand Name Drug: Glucotrol. Glipizide is completely metabolized in the liver and excreted primarily by the kidneys. However, it is not as potent as glyburide at raising basal insulin levels and therefore is the preferred sulfonylurea in elderly patients or those with renal insufficiency. It usually is started with 5 mg orally 30 minutes prior to breakfast. If the dose exceeds 15 mg/day, then it is best to divide the doses by giving it before breakfast and before dinner. The maximum recommended dose is 40 mg/day, although it is rare to see additional efficacy with doses >20 mg/day. There is also an extended release form of glipizide, which allows for once a day dosing.

Glimepiride. Brand Name Drug: Amaryl. In 1996, a new sulfonylurea, glimepiride, was approved for use in the treatment of type 2 diabetes. It is the most potent of the sulfonylureas to date, requiring a 1-, 2-, or 4-mg dose once daily. It is completely metabolized in the liver, making it safe in the elderly and in those with renal insufficiency. The maximal recommended dose is 6 mg/day, and this agent is of equal efficacy whether given once or twice daily. Like the other sulfonylureas, glimepiride acts as an insulin secretagogue, but in comparative trials, it caused fewer episodes of hypoglycemia. Other data from comparative trials show that glimepiride provides greater postprandial insulin secretion, but fasting glucose control and HgbA₁C lowering is similar to that of glyburide. Glimepiride has been shown to have extrapancreat-ic in vitro effects on glucose uptake, but the clinical significance of these effects is still to be determined.