Antidiabetic Drugs

Posts Tagged ‘Amaryl’

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

INNs in other languages (French, Latin, and Spanish):

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Glimepiride). A white to almost white powder. It exhibits polymorphism. Practically insoluble in water slightly soluble in dichloromethane soluble in dimethylformamide very slightly soluble in methyl alcohol.

The United States Pharmacopeia 31, 2008 (Glimepiride). A white to almost white powder. Practically insoluble in water sparingly soluble in dichloromethane soluble in dimethylformamide slightly soluble in methyl alcohol. It dissolves in dilute alkali hydroxides and in dilute acids. Store at a temperature not exceeding 25°.

Adverse Effects, Treatment, and Precautions

As for sulfonylureas in general. In some countries hepatic and haematological monitoring is recommended in patients receiving glimepiride in the UK the BNF considers the practical value of such monitoring unproven.

Fasting. Glimepiride, given in unchanged doses but with the time of the single daily dose switched from morning to just before breaking fast after sunset, was used in Muslim patients during Ramadan without causing an increased incidence of hypoglycaemic episodes.

For further advice on the management of diabetes mellitus in fasting Muslim patients during Ramadan see under Precautions of Insulin.

Interactions

As for sulfonylureas in general.

Pharmacokinetics

Glimepiride is completely absorbed from the gastrointestinal tract. Peak plasma concentrations occur in 2 to 3 hours, and it is highly protein bound. The drug is extensively metabolised to two main metabolites, a hydroxy derivative and a carboxy derivative. The half-life after multiple doses is about 9 hours. About 60% of a dose is eliminated in the urine and 40% in the faeces.

Uses and Administration

Glimepiride is a sulfonylurea antidiabetic. It is given orally for the treatment of type 2 diabetes mellitus. Initial doses of 1 to 2 mg daily may be increased if necessary to 4 mg daily for maintenance. The maximum recommended dose is 6 mg in the UK and 8 mg in the USA.

Preparations

The United States Pharmacopeia 31, 2008: Glimepiride Tablets.

Proprietary Preparations

Argentina: Adiuvan Amaryl Endial Glemaz Gluceride Glucopirida Islopir Lomet Next Step

Australia: Amaryl Aylide Diapride Dimirel

Austria: Amaryl

Belgium: Amarylle

Brazil: Amaryl Azulix Bioglic Diamellitis Glimepibal Glimepil Glimeprid † Glimeran Glimesec † Hipomeril

Canada: Amaryl

Chile: Amaryl Glemaz Glucomet

Czech Republic: Amarwin Amaryl Amyx Apo-Glimep Eglymad Glemid GlimTek Glymexan Melyd Metis Oltar

Denmark: Amaryl

Finland: Amaryl

France: Amarel

Germany: Amaryl Glimegamma Glimerid

Greece: Dialosa Glimepiron Glimespes Glimexin Gliperin Mepirid Penoza Pharlecon Saccharofar Solosa Sucryl Tipo II Toremol

Hong Kong: Amaryl Diapride

Hungary: Amaryl Dialosa Glempid GlimeWin Gl

India Gliprex Limeral Meglimid Melyd Sintecal

India: Amaryl Betaglim Diaglim Euglim Glimcip Glimiprex Glimitab Glimulin Glyree Glyree M Karmelitos

Indonesia: Amadiab Amaryl Anpiride Glamarol Glimexal Gluvas Mapryl Metrix Relide

Ireland: Amaryl

Israel: Amaryl

Italy: Amaryl Solosa

Malaysia: Amaryl Diapride Glimaryl Glimin Glimulin Miaryl

Mexico: Amaryl Glupropan Zukedib

The Netherlands: Amaryl

Norway: Amaryl

New Zealand: Amaryl

Philippines: Imerid Norizec Solosa

Poland: Amaryl Amyx Avaron Betaglid Diaril Glemid Glibetic Glibezid Glidiamid Glimehexal Glimesan Glipid Limeral Melyd Oltar Pemidal Symglic

Portugal: Amaryl Diapiride Glimial Gludon

Russia: Amaryl Glemaz

South Africa: Amaryl Glamaryl

Singapore: Amaryl Diapride

Spain: Amaryl Roname

Sweden: Amaryl

Switzerland: Amaryl

Thailand: Amaryl

Turkey: Amaryl Diameprid Glimax

UK: Amaryl Niddaryl

USA: Amaryl

Venezuela: Amaryl Dimavyl Glimerid.

Multi-ingredient

Czech Republic: Avaglim Tandemact

France: Avaglim Tandemact

Greece: Avaglim

Hungary: Avaglim

India: Betaglim Mf Exermet GM Glimiprex M † Glimulin-MF †

Indonesia: Avandaryl

Portugal: Avaglim Tandemact

USA: Avandaryl Duetact.

These agents are derivatives of sulfonic acid and urea, and produce their effects by binding to receptors on the surface of pancreatic beta cells. The binding of sulfonylureas results in depolarization of the cell membrane, the influx of calcium ions, and subsequent release of insulin. The sulfonylureas were developed in 1954 and continue to be the most widely prescribed oral agents for the treatment of type 2 diabetes. Early evidence of associated increased cardiovascular morbidity has not been reproduced, and today sulfonylureas are considered relatively safe agents that have proven effective over long-term use.

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.

Patient-Specific Considerations

New antidiabetic agents were approved for the U.S. market. They are metformin, acarbose and glimepiride. Precautions associated with their use in the patient with renal insufficiency will now be described.

Metformin (Glucophage): The biguanide hypoglycemic agent metformin (Glucophage) is approved for use in the treatment of diabetes mellitus. Metformin is indicated for use as an adjunct to diet and/or a sulfonylurea agent when either of these treatment regimens does not control hyperglycemia. The mechanism of action for metformin differs from the sulfonylureas. Metformin decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and use and by decreasing hepatic glucose production. The primary concern with metformin is the development of lactic acidosis, especially in patients with renal insufficiency.

Metformin is a congener of phenformin, also a biguanide hypoglycemic agent, which was pulled off the market in the U.S. in 1977 due to concerns with phenformin causing lactic acidosis. Metformin has also been associated with causing lactic acidosis; however, the rate of metformin-associated lactic acidosis is one-tenth that of phenformin (one in 4,000 vs. one in 40,000 – 80,000). Cases of metformin-induced lactic acidosis have occurred primarily in patients with renal insufficiency and increased age.

The biguanides can induce lactic acidosis through an increase in cellular lactate production and a decrease in the hepatic metabolism of lactate. Diabetic patients are particularly at high risk for metformin-induced lactic acidosis due to their predisposition to renal dysfunction and impaired clearance of the drug, as well as their abnormal lactate metabolism. Due to the high risk of lactic acidosis in patients with renal dysfunction, metformin is contraindicated in patients with serum creatinine levels >1.5 mg/dL for males and >1.4 mg/dL for females.

The signs and symptoms of biguanide-induced lactic acidosis are nonspecific and include (in decreasing order of frequency) vomiting, somnolence, nausea, epigastric pain, anorexia, hyperpnea, lethargy, diarrhea and thirst. The hallmark of biguanide-associated lactic acidosis is severe lactic acidosis without evidence of hypoperfusion or hypoxia. The treatment of biguanide-induced lactic acidosis is support of the circulation and removal of the drug from the body.

Acarbose (Precose): Acarbose is a complex oligosaccharide that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. In patients with renal impairment, plasma concentrations of acarbose have been shown to be proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine >2.0 mg/dL) have not been conducted. Therefore, treatment of these patients with acarbose is not recommended.

Glimepiride (Amaryl): Glimepiride is a new sulfonylurea blood glucose-lowering agent. Patients with renal impairment may be more sensitive to the glucose-lowering effect of glimepiride. Thus, in patients who have renal dysfunction, a starting dose of 1 mg once daily followed by appropriate dose titration is recommended. Pharmacist’s Involvement

With the provision of pharmaceutical care, the pharmacist should be closely involved with the diabetic patient in renal failure and can offer the patient assistance in several health-care areas, including the management of his/her diabetes. The pharmacist can educate the patient about diabetes, its complications and the importance of controlling blood glucose levels through proper diet, exercise and use of medications. The proper use of a blood glucose machine to monitor home blood glucose levels can also be taught by the pharmacist, as well as frequently measuring and monitoring the patient’s blood glucose. Since hypertension can worsen renal function, the pharmacist should also periodically monitor the patient’s blood pressure and teach the patient how to measure his or her blood pressure at home. In monitoring blood glucose and blood pressure, the pharmacist also needs to assess the patient’s diet, activity level and health status.

In addition, the pharmacist should evaluate the patient’s drug therapy — assessing not only the medication’s efficacy, but also the medication’s effect on blood glucose, blood pressure, electrolytes, lipids and renal function. The patient’s optimal drug therapy, lifestyle, blood glucose, blood pressure and renal function must be monitored to prevent further complications.Summary

Renal failure seriously impacts the quality of life and management of the diabetic patient. There are numerous patient considerations that the pharmacist must evaluate. Additionally, an understanding of the effect renal failure has on insulin greatly assists the pharmacist who is providing pharmaceutical care to the diabetic patient with renal insufficiency.

The U.S. Food and Drug Administration has expanded the indications of Hoechst Marion Roussel’s diabetes medication Amaryl® (glimepiride tablets). Amaryl was previously approved as a first-line medication for Type II diabetes in combination with diet and exercise and as a component in second-line therapy in combination with insulin. The new FDA ruling approves Amaryl for the second-line treatment of Type II diabetes in combination with the drug metformin. Developers note that the Amaryl/metformin combination has been shown to achieve adequate blood glucose control, while neither of the drugs showed a similar level of effectiveness when used alone.