Antidiabetic Drugs

Posts Tagged ‘Precose’

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Acarbosa; Acarbosum; Akarboosi; Akarbos; Akarbosa; Akarboz; Akarboze; Bay-g-5421.

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Acarbose). A white or yellowish, amorphous, hygroscopic powder. Very soluble in water practically insoluble in dichloromethane soluble in methyl alcohol. A 5% solution in water has a pH of 5.5 to 7.5. Store in airtight containers.

The United States Pharmacopeia 31, 2008 (Acarbose). Produced by certain strains of Actinoplanes utahensis. Store in airtight containers.

Adverse Effects

Acarbose often causes gastrointestinal disturbances, particularly flatulence due to bacterial action on non-absorbed carbohydrate in the colon. Abdominal distension, diarrhoea, and pain may occur. Ileus has been rarely reported. A decrease in dosage and improved dietary habits may reduce these adverse effects. Hepatotoxicity may occur and may necessitate a reduction in dosage or withdrawal of the drug. Skin reactions have occurred rarely. Very rarely oedema has been reported.

Incidence of adverse effects. The manufacturers reported that adverse effects of acarbose were rarer in a postmarketing surveillance study than in previous clinical trials this was held to represent better tailoring of individual doses to patient tolerability.

Effects on the liver. Hepatocellular liver damage, with jaundice and elevated serum aminotransferases, have been reported in patients receiving acarbose. Symptoms resolved on stopping the drug.

Effects on the skin. Generalised erythema multiforme and eosinophilia occurred in a male diabetic patient 13 days after starting acarbose. The hypersensitivity reaction was confirmed by rechallenge.

Precautions

Acarbose is contra-indicated in inflammatory bowel disease, particularly where there is associated ulceration, and in gastrointestinal obstruction or patients predisposed to it. It should be avoided in patients with chronic intestinal diseases that significantly affect digestion or absorption, and in conditions which may deteriorate as a result of increased gas formation, such as hernia.

Acarbose is also contra-indicated in patients with hepatic impairment and liver enzyme values should be monitored, particularly at high doses. If hypoglycaemia should develop in a patient receiving acarbose it needs to be treated with glucose, since the action of acarbose inhibits the hydrolysis of disaccharides.

Breast feeding. In the absence of evidence, licensed product information recommends that acarbose should be avoided during breastfeeding.

Interactions

Acarbose may enhance the effects of other antidiabetics, including insulin, and a reduction in their dosage may be needed. Use with gastrointestinal adsorbents and digestive enzyme preparations can diminish the effects of acarbose and should be avoided. Neomycin and colestyramine may enhance the effects of acarbose and a reduction in its dosage may be required. Acarbose may inhibit the absorption of digoxin.

Pharmacokinetics

After ingestion of acarbose, the majority of active unchanged drug remains in the lumen of the gastrointestinal tract to exert its pharmacological activity and is metabolised by intestinal enzymes and by the microbial flora. Ultimately about 35% of a dose is absorbed in the form of metabolites. Acarbose is excreted in the urine and faeces.

Uses and Administration

Acarbose is an inhibitor of alpha glucosidases, especially sucrase. This slows the digestion and absorption of carbohydrates in the small intestine and hence reduces the increase in blood-glucose concentrations after a carbohydrate load. It is given in the treatment of type 2 diabetes mellitus either alone or with a sulfonylurea, biguanide, or insulin. Acarbose treatment may be started with a low oral dose of 25 or 50 mg daily to minimise gastrointestinal disturbance. It is then gradually increased to a usual dose of 25 or 50 mg three times daily, immediately before food. Doses up to 100 to 200 mg three times daily may be given if necessary. Some benefit has also been found when acarbose is used to supplement insulin therapy in type 1 diabetes mellitus.

Acarbose has also been studied for the treatment of reactive hypoglycaemia, the dumping syndrome, and certain types of hyperlipoproteinaemia.

Impaired glucose tolerance. A prospective study of patients with impaired glucose tolerance concluded that acarbose significantly reduced the incidence of cardiovascular disease and hypertension.

Preparations

Proprietary Preparations

Argentina: Glucobay

Australia: Glucobay

Austria: Glucobay

Belgium: Glucobay

Brazil: Aglucose Glucobay

Canada: Prandase

Chile: Glucobay

Czech Republic: Glucobay

Denmark: Glucobay

France: Glucor

Germany: Glucobay

Greece: Glucobay

Hong Kong: Glucobay

Hungary: Glucobay

India: Acarbay Asucrose Glubose Glucar Glucobay

Indonesia: Glucobay

Ireland: Glucobay

Israel: Prandase

Italy: Glicobase Glucobay

Malaysia: Dibose Glucar Glucobay Precose

Mexico: Glucobay Incardel Sincrosa

The Netherlands: Glucobay

Norway: Glucobay

New Zealand: Glucobay

Philippines: Glucobay Gluconase

Poland: Glucobay

Portugal: Glucobay

Russia: Glucobay (Глюкобай)

South Africa: Glucobay

Singapore: Glucobay

Spain: Glucobay Glumida

Sweden: Glucobay

Switzerland: Glucobay

Thailand: Glucobay

Turkey: Glucobay Glynose

UK: Glucobay

USA: Precose

Venezuela: Glucobay

Alpha-glucosidase inhibitors also were popular in Europe prior to their introduction into the American market. At this time, they remain one of the most frequendy prescribed antidiabetic agents in Europe. Acarbose was the first agent in this class widely available in the United States. Alpha-glucosidase inhibitors act by blocking the absorption of carbohydrate from the gastrointestinal tract and are most effective in decreasing postprandial glucose elevation. The main advantage of these agents is that they act locally in the gut and are not systemic in their activity. Due to their nonsystemic activity, hypoglycemia is not associated with alpha-glucosidase inhibitors. The disadvantages, however, are greater in number.

Acarbose

Brand Name Drug: in Europe under the brand name Glucobay, in North America as Precose, and in Canada as Prandase

Acarbose and the other agents of this class have relatively weak antidiabetic activity, only reducing HgbA₁C by .5%-1% in most patients. Diarrhea and flatulence are the most common side effects, occurring in up to 40% of patients in most trials. Secondary to the high incidence of gastrointestinal distress, acarbose should be initiated slowly. It comes in 50-mg and 100-mg tablets, and it is currendy recommended that patients begin with 25 mg daily taken with a meal. Afterward, it can be advanced to 25 mg with two meals and slowly increased to a maximum of 300 mg/day. Acarbose should be taken with the first bite of the meal and the most benefit is achieved with doses > 150 mg/day. It is at these higher dosages that a recent study has shown reduction of HgbA₁C of 1%-2%. Unfortunately, the incidence of gastrointestinal side effects often precludes reaching these doses.

Miglitol

Brand Name Drug: Glyset

Recendy, miglitol, a new alpha-glucosidase inhibitor, was approved by the Food and Drug Administration. It reportedly has many of the gastrointestinal side effects that limit acarbose use. However, in preliminary studies, miglitol effectively lowered postprandial blood glucose and glycosylated hemoglobin levels.

Approximately 40% of all type 2 diabetics take a drug from the sulfonylurea class (see TABLE 2) — usually glyburide, glipizide, or chlorpropamide. The sulfonylureas cause the beta-cells of the pancreas to increase insulin secretion. Weight gain is common with sulfonylurea use and ranges from 1.8 to 2.8 kg.

Metformin (Glucophage) is a biguanide antidiabetic agent that reduces basal hepatic glucose production by altering gluconeogenesis and/or glycogenolysis. Additionally, metformin decreases insulin resistance by promoting insulin-sensitive glucose uptake by muscle cells. Metformin can also reduce triglycerides and low-density lipoprotein (LDL) cholesterol, and increase high-density lipoprotein (HDL) cholesterol. Weight reductions of 0.6 to 0.8 kg have been noted in study subjects taking metformin.When metformin is combined with the sulfonylurea glyburide, however, average weight gains of 0.7 kg have been reported.

Acarbose (Precose) is an alpha-glucosidase inhibitor as well as an inhibitor of pancreatic alpha-amylase. These enzymes are responsible for the hydrolysis of oligosaccharides and related saccharides in the small intestine. Inhibition of these enzymes results in reductions in the rate and extent of carbohydrate digestion and absorption of glucose in the body. Patients treated with acarbose tend to experience no changes in weight or serum lipids.

Troglitazone (Rezulin) belongs to a new class of drugs called thiazolidinediones. It works by decreasing insulin resistance. Its primary actions involve increasing glucose disposal from the blood stream into muscle tissue and decreasing glucose production in the liver. No or very small weight changes in patients taking troglitazone are seen. Decreases in plasma triglyceride and free fatty acid levels have also been reported.

Approximately three-quarters of all the insulin used in the U.S. is taken by people with type 2 diabetes. Exogenous insulin reduces hepatic glucose production in type 2 diabetics. It also increases insulin-stimulated glucose utilization and endogenous insulin secretion. Weight gain is common in patients using insulin and may include gains up to 6.0 kg in a 12-month period.

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 FDA’s Endocrinologic and Metabolic Advisory Committee has recommended that acarbose (Precose/Bayer) be approved for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). The drug would be the first of a new class of antidiabetic drugs, the oral alpha-glucosidase inhibitors. These drugs act by impeding the digestion and absorption of carbohydrates and their subsequent conversion into glucose. The result should be improved control of blood glucose, the focus of diabetes therapy. Effective control of blood glucose may retard the development of complications such as blindness, renal failure, and neuropathy that are common in diabetes.

Acarbose has 100,000 times the binding affinity of glucose for alpha-glucosidase. It binds to the enzyme competitively in the brush border within the small intestine. By slowing the conversion and absorption of glucose, the drug reduces blood concentrations of glycosylated hemoglobin (HbA1c) by 0.5% to 1.0%. (Although glycosylated hemoglobin concentrations of 10% to 11% are associated with rapid progression of retinopathy, reducing the concentrations to 7% to 9% slows this progression significantly.) Acarbose improves postprandial hyperglycemia and maintains or lowers secretion of insulin (which is stimulated by hyperglycemia). As monotherapy, acarbose causes no hypoglycemia.

The mechanism of action of acarbose differs from that of other oral drugs such as sulfonylureas and metformin, which appear to control hyperglycemia by stimulating surviving beta cells in the pancreas to produce more insulin. These drugs can cause hypoglycemia. Acarbose, which shows little or no systemic absorption, has not been linked to serious adverse events. The main complaints are gastrointestinal symptoms (eg, flatulence, diarrhea) resulting from carbohydrate malabsorption. These can be minimized by using a low starting dose. In early studies, increases in serum hepatic transaminases were a concern, but these increases have been dramatically reduced with the lower dosages currently recommended by the sponsor (150 to 300 mg a day).

The advisory committee’s recommendation was based, at least in part, on a National Institutes of Health Diabetes Control and Complications Trial that demonstrated improved control of blood glucose with acarbose. Although that trial involved patients with type I (insulin-dependent) diabetes, panel members believe the findings will also apply to patients with NIDDM. In support of this hypothesis, a recently reported study indeed demonstrated the safety and efficacy of acarbose in a non-insulin-dependent diabetes mellitus (NIDDM) patient population. In a multicenter, double-blind, randomized trial conducted by Coniff et al., 290 NIDDM patients were randomly assigned to receive 200 mg acarbose, 250 to 1000 mg tolbutamide, acarbose plus tolbutamide, or placebo three times a day for 24 weeks. All active treatments were superior to placebo in controlling postprandial hyperglycemia and HbA1c. The two-drug combination was most effective, followed by tolbutamide and acarbose.

Tolbutamide increased body weight and postprandial insulin levels, but these effects were ameliorated when acarbose was given with tolbutamide. Elevated hepatic enzymes were observed in three patients receiving acarbose alone and two receiving acarbose plus tolbutamide; transaminase levels returned to normal when treatment was discontinued. The researchers concluded that acarbose was effective and well-tolerated and produced significantly better results than dietary restriction.