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Anti- Diabetic Agents

Alpha-glucosidase Inhibitors Biguanides (Including combination products) - e.g. Metformin
Glitazones - Thiazolidinediones Meglitinides (e.g. Prandin)
Sulfonylureas Glucagon
exenatide (Byetta ®) pramlintide (Symlin ® )

Alpha-glucosidase Inhibitors    return to top of page

acarbose (Precose ®):

CLINICAL PHARMACOLOGY
Acarbose is a complex oligosaccharide that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, acarbose reduces levels of glycosylated hemoglobin in patients with type 2 diabetes mellitus. Systemic non-enzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.


Mechanism of Action: In contrast to sulfonylureas, acarbose does not enhance insulin secretion. The antihyperglycemic action of acarbose results from a competitive, reversible inhibition of pancreatic alpha-amylase and membrane-bound intestinal alpha-glucoside hydrolase enzymes. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, while the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in a delayed glucose absorption and a lowering of postprandial hyperglycemia.

Because its mechanism of action is different, the effect of acarbose to enhance glycemic control is additive to that of sulfonylureas, insulin or metformin when used in combination. In addition, acarbose diminishes the insulinotropic and weight-increasing effects of sulfonylureas.

Acarbose has no inhibitory activity against lactase and consequently would not be expected to induce lactose intolerance.

INDICATIONS AND USAGE
Acarbose tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.


CONTRAINDICATIONS
Acarbose is contraindicated in patients with known hypersensitivity to the drug and in patients with diabetic ketoacidosis or cirrhosis. acarbose is also contraindicated in patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or in patients predisposed to intestinal obstruction. In addition, acarbose is contraindicated in patients who have chronic intestinal diseases associated with marked disorders of digestion or absorption and in patients who have conditions that may deteriorate as a result of increased gas formation in the intestine.

Dosing:
Oral:  - Adults: Dosage must be individualized on the basis of effectiveness and tolerance while not exceeding the maximum recommended dose

Initial dose: 25 mg 3 times/day with the first bite of each main meal.

Maintenance dose: Should be adjusted at 4- to 8-week intervals based on 1-hour postprandial glucose levels and tolerance. Dosage may be increased from 25 mg 3 times/day to 50 mg 3 times/day. Some patients may benefit from increasing the dose to 100 mg 3 times/day.

Maintenance dose ranges: 50-100 mg 3 times/day.

Maximum dose:

</= 60 kg: 50 mg 3 times/day
>60 kg: 100 mg 3 times/day

Patients receiving sulfonylureas: Acarbose given in combination with a sulfonylurea will cause a further lowering of blood glucose and may increase the hypoglycemic potential of the sulfonylurea. If hypoglycemia occurs, appropriate adjustments in the dosage of these agents should be made.

Dosing adjustment in renal impairment: Clcr<25 mL/minute: Peak plasma concentrations were 5 times higher and AUCs were 6 times larger than in volunteers with normal renal function; however, long-term clinical trials in diabetic patients with significant renal dysfunction have not been conducted and treatment of these patients with acarbose is not recommended.

Supplied
Tablet: 25 mg, 50 mg, 100 mg

Miglitol (Glycet ®):

CLINICAL PHARMACOLOGY
Miglitol is a desoxynojirimycin derivative that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, GLYSET Tablets reduce levels of glycosylated hemoglobin in patients with Type II (non-insulin-dependent) diabetes mellitus. Systemic nonenzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.

Mechanism of Action
In contrast to sulfonylureas, GLYSET does not enhance insulin secretion. The antihyperglycemic action of miglitol results from a reversible inhibition of membrane-bound intestinal alpha-glucoside hydrolase enzymes. Membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia.

Because its mechanism of action is different, the effect of GLYSET to enhance glycemic control is additive to that of sulfonylureas when used in combination. In addition, GLYSET diminishes the insulinotropic and weight-increasing effects of sulfonylureas.

Miglitol has minor inhibitory activity against lactase and consequently, at the recommended doses, would not be expected to induce lactose intolerance.

INDICATIONS AND USAGE
GLYSET Tablets, as monotherapy, are indicated as an adjunct to diet to improve glycemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM) whose hyperglycemia cannot be managed with diet alone. GLYSET may also be used in combination with a sulfonylurea when diet plus either GLYSET or a sulfonylurea alone do not result in adequate glycemic control. The effect of GLYSET to enhance glycemic control is additive to that of sulfonylureas when used in combination, presumably because its mechanism of action is different.

In initiating treatment for NIDDM, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling blood glucose and symptoms of hyperglycemia. The importance of regular physical activity when appropriate should also be stressed. If this treatment program fails to result in adequate glycemic control, the use of GLYSET should be considered. The use of GLYSET must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint.

CONTRAINDICATIONS
GLYSET Tablets are contraindicated in patients with:

-Diabetic ketoacidosis
-Inflammatory bowel disease, colonic ulceration, or partial intestinal obstruction, and in patients predisposed to intestinal obstruction
-Chronic intestinal diseases associated with marked disorders of digestion or absorption, or with conditions that may deteriorate as a result of increased gas formation in the intestine
-Hypersensitivity to the drug or any of its components.

Dosing
Adults: Oral: 25 mg 3 times/day with the first bite of food at each meal; the dose may be increased to 50 mg 3 times/day after 4-8 weeks; maximum recommended dose: 100 mg 3 times/day
Dosing adjustment in renal impairment : Miglitol is primarily excreted by the kidneys; there is little information of miglitol in patients with a Clcr<25 mL/minute

Supplied
Tablet: 25 mg, 50 mg, 100 mg

Biguanides (Including combination products) return to top of page

metformin (Glucophage ®):

Mechanism of Action
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see package insert for PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease

INDICATIONS AND USAGE
GLUCOPHAGE (metformin hydrochloride) Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.

GLUCOPHAGE XR (metformin hydrochloride) Extended-Release Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.


CONTRAINDICATIONS
GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:

Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels geq1.5 mg/dL [males],
geq1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see package insert for WARNINGS and PRECAUTIONS).

Known hypersensitivity to metformin hydrochloride.

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

GLUCOPHAGE and GLUCOPHAGE XR should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function


Management of type 2 diabetes mellitus
: Standard release tablet or oral solution:
Dosing (Adults)
:  Start: 500 mg twice daily (give with the morning and evening meals) or 850 mg once daily; increase dosage incrementally. (A lower recommended starting dose and gradual increased dosage is recommended to minimize gastrointestinal symptoms).
Adjustment: Incremental dosing recommendations are based on dosage form:
500 mg tablet: One tablet/day at weekly intervals.
850 mg tablet: One tablet/day every other week.
Oral solution: 500 mg twice daily every other week.
Note: Doses of up to 2000 mg/day may be given in divided doses twice daily. If a dose >2000 mg/day is required, it may be better tolerated in three divided doses.
Maximum recommended dose: 2550 mg/day.

Extended release tablet: Initial: 500 mg once daily (with the evening meal). Dosage may be increased by 500 mg weekly. Maximum dose: 2000 mg once daily. If glycemic control is not achieved at maximum dose, may divide dose to 1000 mg twice daily. If doses >2000 mg/day are needed, switch to regular release tablets and titrate to maximum dose of 2550 mg/day.

Renal dosing: Metformin is contraindicated in the presence of renal dysfunction defined as a serum creatinine >1.5 mg/dL in males, or >1.4 mg/dL in females and in patients with abnormal clearance.
Hepatic impairment: Avoid metformin.

Supplied: Tablet: 500 mg, 850 mg, 1000 mg. Extended release tablet: 500 mg, 750 mg, 1000 mg. Oral solution: 100 mg/ml (118 ml, 473 ml).

Avandamet® (Rosiglitazone + Metformin)

Management of type 2 diabetes mellitus: initial (previously receiving rosiglitazone 4 mg/day): Avandamet® 2/500mg po bid. (previously receiving rosiglitazone 8 mg/day): 4/500mg po bid. (previously receiving metformin 1000 mg/day): 2/500mg po bid. (previously receiving metformin 2000 mg/day): 2/1000mg po bid.
Titrate in increments of rosiglitazone 4 mg and/or metformin 500 mg po daily. Maximum: 8 mg/2000 mg daily.

Other: take with meals. When switching from metformin and rosiglitazone therapy given as separate tablets, starting dose of Avandamet is the dose of each drug previously taken. Dose titration should occur at 1 to 2 week intervals. If the dose of metformin is increased, dose titration should occur at 8 to 12 week intervals. If the dose of rosiglitazone is increased therapeutic response evaluation should be based on fasting plasma glucose values. Monitoring: renal function, baseline and at least annually.
[Supplied: 1 mg/500 mg, 2 mg/500 mg, 4 mg/500 mg] .

Glucovance (Glyburide + Metformin)

Management of type 2 diabetes mellitus:
Dosing
(initial): 1.25 mg/250 mg once or twice daily with meals. Dosage increases should be made in increments of 1.25 mg/250 mg per day every two weeks up to the minimum effective dose necessary to achieve adequate control of blood glucose. Glucovance 5 mg/500 mg should not be used as initial therapy due to an increased risk of hypoglycemia. Maximum recommended daily dose: 20 mg glyburide/2000 mg metformin.
Administration
: Glucovance should be given with meals and should be initiated at a low dose, with gradual dose escalation in order to avoid hypoglycemia (largely due to glyburide), to reduce GI side effects (largely due to metformin), and to permit determination of the minimum effective dose for adequate control of blood glucose for the individual patient.

Glucovance Use in Previously Treated Patients: Recommended starting dose: 2.5 mg/500 mg or 5 mg/500 mg twice daily with meals. In order to avoid hypoglycemia, the starting dose of Glucovance should not exceed the daily doses of glyburide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day.

[Supplied: 1.25 mg/250 mg, 2.5 mg/500 mg, 5 mg/500 mg tablet ]

Metaglip (Glipizide + Metformin)

Management of type 2 diabetes mellitus:
Dosing
(initial): 2.5 mg/250 mg qd with a meal. For patients whose FPG is 280 to 320 mg/dl a starting dose of Metaglip 2.5 mg/500 mg twice daily should be considered. The efficacy of Metaglip in patients whose FPG exceeds 320 mg/dl has not been established. Dosage increases to achieve adequate glycemic control should be made in increments of one tablet per day every two weeks up to maximum of 10 mg/1000 mg or 10 mg/2000 mg per day given in divided doses. Maximum recommended daily dose: 20 mg glipizide/2000 mg metformin.

Second-Line Therapy For patients not adequately controlled on either glipizide (or another sulfonylurea) or metformin alone: 2.5 mg/500 mg or 5mg/500mg bid with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of Metaglip should not exceed the daily doses of glipizide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day.

[Supplied: 2.5 mg/250 mg, 2.5 mg/500 mg, 5 mg/500 mg tablet ]

Glitazones - Thiazolidinediones  return to top of page

pioglitazone (Actos ®):

Mechanism of Action
ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARgamma nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin

INDICATIONS AND USAGE
ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.


CONTRAINDICATIONS
Initiation of ACTOS in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see package insert for BOXED WARNING).

ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components

Dosing (Adults)
Oral:
Monotherapy: Initial: 15-30 mg once daily; if response is inadequate, the dosage may be increased in increments up to 45 mg once daily; maximum recommended dose: 45 mg once daily

Combination therapy: Maximum recommended dose: 45 mg/day.
With sulfonylureas: Initial: 15-30 mg once daily; dose of sulfonylurea should be reduced if the patient reports hypoglycemia

With metformin: Initial: 15-30 mg once daily; it is unlikely that the dose of metformin will need to be reduced due to hypoglycemia

With insulin: Initial: 15-30 mg once daily; dose of insulin should be reduced by 10% to 25% if the patient reports hypoglycemia or if the plasma glucose falls to <100 mg/dL.

Dosage adjustment in patients with CHF (NYHA Class II) in mono- or combination therapy: Initial: 15 mg once daily; may be increased after several months of treatment, with close attention to heart failure symptoms

Elderly: No dosage adjustment is recommended in elderly patients.

Dosage adjustment in hepatic impairment: Clearance is significantly lower in hepatic impairment. Therapy should not be initiated if the patient exhibits active liver disease or increased transaminases (>2.5 times the upper limit of normal) at baseline.
Supplied
Tablet: 15 mg, 30 mg, 45 mg

rosiglitazone (Avandia ®):

Mechanism of Action
Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARgamma). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARgamma nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARgamma-responsive genes also participate in the regulation of fatty acid metabolism.

Insulin resistance is a common feature characterizing the pathogenesis of type 2 diabetes. The antidiabetic activity of rosiglitazone has been demonstrated in animal models of type 2 diabetes in which hyperglycemia and/or impaired glucose tolerance is a consequence of insulin resistance in target tissues. Rosiglitazone reduces blood glucose concentrations and reduces hyperinsulinemia in the ob/ob obese mouse, db/db diabetic mouse, and fa/fa fatty Zucker rat.

In animal models, the antidiabetic activity of rosiglitazone was shown to be mediated by increased sensitivity to insulin’s action in the liver, muscle, and adipose tissues. Pharmacological studies in animal models indicate that rosiglitazone inhibits hepatic gluconeogenesis. The expression of the insulin-regulated glucose transporter GLUT-4 was increased in adipose tissue. Rosiglitazone did not induce hypoglycemia in animal models of type 2 diabetes and/or impaired glucose tolerance


INDICATIONS AND USAGE
Monotherapy and Combination Therapy:
Rogislitazone tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use:
Due to its mechanism of action, Rosiglitazone maleate is active only in the presence of endogenous insulin. Therefore, Rosiglitazone maleate should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

The coadministration of Rosiglitazone maleate and insulin is not recommended.

The use of Rosiglitazone maleate with nitrates is not recommended


Dosing (Adults):
Oral:
Monotherapy: Initial: 4 mg daily as a single daily dose or in divided doses twice daily. If response is inadequate after 12 weeks of treatment, the dosage may be increased to 8 mg daily as a single daily dose or in divided doses twice daily. In clinical trials, the 4 mg twice-daily regimen resulted in the greatest reduction in fasting plasma glucose and Hb A1c.

Combination therapy:
With sulfonylureas: Initial: 4 mg daily as a single daily dose or in divided doses twice daily; dose of sulfonylurea should be reduced if the patient reports hypoglycemia. Doses of rosiglitazone >4 mg/day are not indicated in combination with sulfonylureas.

With metformin: Initial: 4 mg daily as a single daily dose or in divided doses twice daily. If response is inadequate after 12 weeks of treatment, the dosage may be increased to 8 mg daily as a single daily dose or in divided doses twice daily. It is unlikely that the dose of metformin will need to be reduced due to hypoglycemia

With insulin: Initial: 4 mg daily as a single daily dose or in divided doses twice daily. Dose of insulin should be reduced by 10% to 25% if the patient reports hypoglycemia or if the plasma glucose falls to <100 mg/dL. Doses of rosiglitazone >4 mg/day are not indicated in combination with insulin.

Elderly: No dosage adjustment is recommended

Monitoring: Hemoglobin A1c, serum glucose; signs and symptoms of heart failure; liver enzymes (prior to initiation of therapy, then periodically thereafter). Patients with an elevation in ALT >3 times the upper limit of normal should be rechecked as soon as possible. If the ALT levels remain >3 times the upper limit of normal, therapy with rosiglitazone should be discontinued.

Dosage comment in hepatic impairment: Clearance is significantly lower in hepatic impairment. Therapy should not be initiated if the patient exhibits active liver disease of increased transaminases (>2.5 times the upper limit of normal) at baseline.

Supplied
Tablet: 2 mg, 4 mg, 8 mg

Meglitinides  return to top of page

Nateglinide (Starlix ®)

CLINICAL PHARMACOLOGY
Mechanism of Action
Nateglinide is an amino-acid derivative that lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Nateglinide interacts with the ATP-sensitive potassium (K+ ATP) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide is highly tissue selective with low affinity for heart and skeletal muscle

INDICATIONS AND USAGE
Nateglinide Tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with Type 2 diabetes mellitus.


CONTRAINDICATIONS
Nateglinide Tablets are contraindicated in patients with:

1) Known hypersensitivity to the drug or its inactive ingredients.
2) Type 1 diabetes.
3) Diabetic ketoacidosis. This condition should be treated with insulin.

Dosing (Adults): Management of type 2 diabetes mellitus: Oral: Initial and maintenance dose: 120 mg 3 times/day, 1-30 minutes before meals; may be given alone or in combination with metformin or a thiazolidinedione; patients close to Hb A1c goal may be started at 60 mg 3 times/day. Patients who are anorexic or NPO will need to have their dose held to avoid hypoglycemia.

Elderly: No changes in safety and efficacy were seen in patients 65 years; however, some elderly patients may show increased sensitivity to dosing.

Dosage adjustment in hepatic impairment: Increased serum levels seen with mild hepatic insufficiency; no dosage adjustment is needed. Has not been studied in patients with moderate to severe liver disease; use with caution.

Supplied
Tablet: 60 mg, 120 mg

repaglinide (Prandin ®):

Mechanism of Action
Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (ß) cells in the pancreatic islets. Insulin release is glucose-dependent and diminishes at low glucose concentrations.

Repaglinide closes ATP-dependent potassium channels in the ß-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes the ß-cell, which leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion. The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle.

INDICATIONS AND USAGE
PRANDIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

CONTRAINDICATIONS
PRANDIN is contraindicated in patients with:

1) Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
2) Type 1 diabetes.
3) Co-administration of gemfibrozil.
4)Known hypersensitivity to the drug or its inactive ingredients

Dosing (Adults): Oral: Should be taken within 15 minutes of the meal, but time may vary from immediately preceding the meal to as long as 30 minutes before the meal
Initial: For patients not previously treated or whose Hb A1c is <8%, the starting dose is 0.5 mg. For patients previously treated with blood glucose-lowering agents whose Hb A1c is >/= 8%, the initial dose is 1 or 2 mg before each meal.

Dose adjustment: Determine dosing adjustments by blood glucose response, usually fasting blood glucose. Double the preprandial dose up to 4 mg until satisfactory blood glucose response is achieved. At least 1 week should elapse to assess response after each dose adjustment.

Dose range: 0.5-4 mg taken with meals. Repaglinide may be dosed preprandial 2, 3 or 4 times/day in response to changes in the patient's meal pattern. Maximum recommended daily dose: 16 mg.

Patients receiving other oral hypoglycemic agents: When repaglinide is used to replace therapy with other oral hypoglycemic agents, it may be started the day after the final dose is given. Observe patients carefully for hypoglycemia because of potential overlapping of drug effects. When transferred from longer half-life sulfonylureas (eg, chlorpropamide), close monitoring may be indicated for up to >/= 1 week.

Combination therapy: If repaglinide monotherapy does not result in adequate glycemic control, metformin or a thiazolidinedione may be added. Or, if metformin or thiazolidinedione therapy does not provide adequate control, repaglinide may be added. The starting dose and dose adjustments for combination therapy are the same as repaglinide monotherapy. Carefully adjust the dose of each drug to determine the minimal dose required to achieve the desired pharmacologic effect. Failure to do so could result in an increase in the incidence of hypoglycemic episodes. Use appropriate monitoring of FPG and Hb A1c measurements to ensure that the patient is not subjected to excessive drug exposure or increased probability of secondary drug failure. If glucose is not achieved after a suitable trial of combination therapy, consider discontinuing these drugs and using insulin.

Dosing adjustment in renal impairment:
Clcr 40-80 mL/minute (mild to moderate renal dysfunction): Initial dosage adjustment does not appear to be necessary.
Clcr 20-40 mL/minute: Initiate 0.5 mg with meals; titrate carefully.

Supplied
Tablet: 0.5 mg, 1 mg, 2 mg

Sulfonylureas  return to top of page

Chlorpropamide (Diabinese ®):

Dosing (Adults):
Oral: The dosage of chlorpropamide is variable and should be individualized based upon the patient's response
Initial dose:

Adults: 250 mg/day in mild to moderate diabetes in middle-aged, stable diabetic

Elderly: 100-125 mg/day in older patients

Subsequent dosages may be increased or decreased by 50-125 mg/day at 3- to 5-day intervals
Maintenance dose: 100-250 mg/day; severe diabetics may require 500 mg/day; avoid doses >750 mg/day

Dosing adjustment/comments in renal impairment: Clcr<50 mL/minute: Avoid use
Hemodialysis: Removed with hemoperfusion
Peritoneal dialysis: Supplemental dose is not necessary

Dosing adjustment in hepatic impairment: Dosage reduction is recommended. Conservative initial and maintenance doses are recommended in patients with liver impairment because chlorpropamide undergoes extensive hepatic metabolism.

Supplied
Tablet: 100 mg, 250 mg

glimepiride (Amaryl ®):

Mechanism of Action
The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which AMARYL therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.

AMARYL is effective as initial drug therapy. In patients where monotherapy with AMARYL or metformin has not produced adequate glycemic control, the combination of AMARYL and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different primary mechanisms of action. This complementary effect has been observed with metformin and other sulfonylureas, in multiple studies

INDICATIONS AND USAGE
AMARYL is indicated as an adjunct to diet and exercise to lower the blood glucose in patients with noninsulin-dependent (Type 2) diabetes mellitus (NIDDM) whose hyperglycemia cannot be controlled by diet and exercise alone. AMARYL may be used concomitantly with metformin when diet, exercise, and AMARYL or metformin alone do not result in adequate glycemic control.

AMARYL is also indicated for use in combination with insulin to lower blood glucose in patients whose hyperglycemia cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic agent. Combined use of glimepiride and insulin may increase the potential for hypoglycemia.

In initiating treatment for noninsulin-dependent diabetes, diet and exercise should be emphasized as the primary form of treatment. Caloric restriction, weight loss, and exercise are essential in the obese diabetic patient. Proper dietary management and exercise alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. In addition to regular physical activity, cardiovascular risk factors should be identified and corrective measures taken where possible.

If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of AMARYL must be viewed by both the physician and patient as a treatment in addition to diet and exercise and not as a substitute for diet and exercise or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet and exercise alone may be transient, thus requiring only short-term administration of AMARYL.

During maintenance programs, AMARYL monotherapy should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations. Secondary failures to AMARYL monotherapy can be treated with AMARYL-insulin combination therapy.

In considering the use of AMARYL in asymptomatic patients, it should be recognized that blood glucose control in Type 2 diabetes has not definitely been established to be effective in preventing the long-term cardiovascular and neural complications of diabetes. However, the Diabetes Control and Complications Trial (DCCT) demonstrated that control of HbA1c and glucose was associated with a decrease in retinopathy, neuropathy, and nephropathy for insulin-dependent diabetic (IDDM) patients.


CONTRAINDICATIONS
AMARYL is contraindicated in patients with

1) Known hypersensitivity to the drug.
2) Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin

Dosing (Adults): Oral (allow several days between dose titrations):
Adults: Initial: 1-2 mg once daily, administered with breakfast or the first main meal; usual maintenance dose: 1-4 mg once daily; after a dose of 2 mg once daily, increase in increments of 2 mg at 1- to 2-week intervals based upon the patient's blood glucose response to a maximum of 8 mg once daily

Combination with insulin therapy (fasting glucose level for instituting combination therapy is in the range of >150 mg/dL in plasma or serum depending on the patient): initial recommended dose: 8 mg once daily with the first main meal

After starting with low-dose insulin, upward adjustments of insulin can be done approximately weekly as guided by frequent measurements of fasting blood glucose. Once stable, combination-therapy patients should monitor their capillary blood glucose on an ongoing basis, preferably daily.

Dosing adjustment/comments in renal impairment: Clcr<22 mL/minute: Initial starting dose should be 1 mg and dosage increments should be based on fasting blood glucose levels

Elderly: Initial: 1 mg/day; dose titration and maintenance dosing should be conservative to avoid hypoglycemia

Supplied
Tablet: 1 mg, 2 mg, 4 mg

glyburide (Micronase ®, Diabeta ®):

CLINICAL PHARMACOLOGY
Diabetaeta 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 Diabetaeta 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 play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

In addition to its blood glucose lowering actions, Diabetaeta produces a mild diuresis by enhancement of renal free water clearance. Clinical experience to date indicates an extremely low incidence of disulfiram-like reactions in patients while taking Diabetaeta

INDICATIONS AND USAGE
Diabetaeta is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

CONTRAINDICATIONS
Diabetaeta is contraindicated in patients:

-With known hypersensitivity to the drug or any of its excipients.
-With type I diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
-Treated with bosentan.
-With severely impaired renal and/or hepatic function: The metabolism and excretion may be slowed in patients with severely impaired renal and/or hepatic function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted

Dosing (Adults) Oral:
Initial: 2.5-5 mg/day, administered with breakfast or the first main meal of the day. In patients who are more sensitive to hypoglycemic drugs, start at 1.25 mg/day.

Increase in increments of no more than 2.5 mg/day at weekly intervals based on the patient's blood glucose response

Maintenance: 1.25-20 mg/day given as single or divided doses; maximum: 20 mg/day.

Administer with meals at the same time each day. Patients who are anorexic or NPO may need to have their dose held to avoid hypoglycemia.

Elderly: Initial: 1.25-2.5 mg/day, increase by 1.25-2.5 mg/day every 1-3 weeks

Micronized tablets (Glynase™ PresTab™): Adults:
Initial: 1.5-3 mg/day, administered with breakfast or the first main meal of the day in patients who are more sensitive to hypoglycemic drugs, start at 0.75 mg/day. Increase in increments of no more than 1.5 mg/day in weekly intervals based on the patient's blood glucose response.

Maintenance: 0.75-12 mg/day given as a single dose or in divided doses. Some patients (especially those receiving >6 mg/day) may have a more satisfactory response with twice-daily dosing.

Dosing adjustment/comments in renal impairment: Clcr<50 mL/minute: Not recommended

Dosing adjustment in hepatic impairment: Use conservative initial and maintenance doses and avoid use in severe disease

Supplied
Tablet (Diabeta®, Micronase®): 1.25 mg, 2.5 mg, 5 mg
Tablet, micronized (Glynase® PresTab®): 1.5 mg, 3 mg, 6 mg

glipizide (Glucotrol ®):

Sulfonylurea.
Mechanism of Action
The primary mode of action of glipizide in experimental animals appears to be the stimulation of insulin secretion from the beta cells of pancreatic islet tissue and is thus dependent on functioning beta cells in the pancreatic islets. In humans glipizide 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 glipizide lowers blood glucose during long-term administration has not been clearly established. In man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment. The insulinotropic response to a meal occurs within 30 minutes after an oral dose of glipizide in diabetic patients, but elevated insulin levels do not persist beyond the time of the meal challenge. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

Blood sugar control persists in some patients for up to 24 hours after a single dose of glipizide, even though plasma levels have declined to a small fraction of peak levels by that time.

Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs, including glipizide. Alternatively, glipizide maybe effective in some patients who have not responded or have ceased to respond to other sulfonylureas.

Other Effects
It has been shown that glipizide therapy was effective in controlling blood sugar without deleterious changes in the plasma lipoprotein profiles of patients treated for NIDDM.

In a placebo-controlled, crossover study in normal volunteers, glipizide had no anti-diuretic activity, and, in fact, led to a slight increase in free water clearance

INDICATIONS AND USAGE
Glipizide tablets are indicated as an adjunct to diet for the control of hyperglycemia and its associated symptomatology in patients with non-insulin-dependent diabetes mellitus (NIDDM; type II), formerly known as maturity-onset diabetes, after an adequate trial of dietary therapy has proved unsatisfactory.

In initiating treatment for non-insulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified, and corrective measures taken where possible.

If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of glipizide must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone also may be transient, thus requiring only short-term administration of glipizide.

During maintenance programs, glipizide should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations.

In considering the use of glipizide in asymptomatic patients, it should be recognized that controlling blood glucose in non-insulin-dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.


CONTRAINDICATIONS
Glipizide is contraindicated in patients with:

-Known hypersensitivity to the drug.
-Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

Dosing (Adults)
Oral (allow several days between dose titrations): Adults: Initial: 5 mg/day; adjust dosage at 2.5-5 mg daily increments as determined by blood glucose response at intervals of several days.
Immediate release tablet: Maximum recommended once-daily dose: 15 mg; maximum recommended total daily dose: 40 mg

Extended release tablet (Glucotrol® XL): Maximum recommended dose: 20 mg

When transferring from insulin to glipizide:

Current insulin requirement </= 20 units: Discontinue insulin and initiate glipizide at usual dose

Current insulin requirement >20 units: Decrease insulin by 50% and initiate glipizide at usual dose; gradually decrease insulin dose based on patient response. Several days should elapse between dosage changes.


Administer immediate release tablets 30 minutes before a meal to achieve greatest reduction in postprandial hyperglycemia. Extended release tablets should be given with breakfast. Patients who are NPO may need to have their dose held to avoid hypoglycemia.

Elderly: Initial: 2.5 mg/day; increase by 2.5-5 mg/day at 1- to 2-week intervals

Dosing adjustment/comments in renal impairment: Clcr<10 mL/minute: Some investigators recommend not using
Dosing adjustment in hepatic impairment: Initial dosage should be 2.5 mg/day

Supplied 
Tablet (Glucotrol®): 5 mg, 10 mg
Tablet, extended release: 5 mg, 10 mg
(Glucotrol® XL): 2.5 mg, 5 mg, 10 mg

Tolazamide (Tolinase ®):

Adult (usual):
Oral (doses >1000 mg/day normally do not improve diabetic control):

Initial: 100-250 mg/day with breakfast or the first main meal of the day
Fasting blood sugar <200 mg/dL: 100 mg/day
Fasting blood sugar >200 mg/: 250 mg/day

Patient is malnourished, underweight, elderly, or not eating properly: 100 mg/day

AdAdjust dose in increments of 100-250 mg/day at weekly intervals to response. If >500 mg/day is required, give in divided doses twice daily; maximum daily dose: 1 g (doses >1 g/day are not likely to improve control)
[Supplied  100 mg , 250 mg , 500 mg tablet]

Tolbutamide (Orinase ®):

Divided doses may improve gastrointestinal tolerance
Adults: Oral: Initial: 1-2 g/day as a single dose in the morning or in divided doses throughout the day. Total doses may be taken in the morning; however, divided doses may allow increased gastrointestinal tolerance. Maintenance dose: 0.25-3 g/day; however, a maintenance dose >2 g/day is seldom required.

Elderly: Oral: Initial: 250 mg 1-3 times/day; usual: 500-2000 mg; maximum: 3 g/day

[Supplied 500 mg tablet]

Other 

Glucagon:   return to top of page

Hypoglycemia: 1 mg IV/IM/SC. Onset 5-20min. May repeat in 20 minutes as needed. Note: If patient fails to respond to glucagon, I.V. dextrose must be given.

Beta-blocker overdose: Separate glucagon receptors stimulate adenylcyclase improving heart rate, blood pressure and conduction defects. Adults: 3 - 5 mg (up to 10 mg) IV push (over 1 minute) followed by an IV drip - usually 1 to 5 mg/hour. Note: bolus dose may be repeated in 10 minutes. Usually causes nausea and vomiting. May give Reglan IV, Compazine or Tigan.

Diagnostic aid: I.M., I.V.: 0.25-2 mg 10 minutes prior to procedure

Monitor blood glucose levels in hypoglycemic patients until they are asymptomatic; effective in treating hypoglycemia only if sufficient liver glycogen is present; since liver glycogen availability is necessary to treat hypoglycemic patients, glucagon has virtually no effects on patients in states of starvation, adrenal insufficiency, or chronic hypoglycemia.
(Recommended routes): IM, IV, or SC. Half-life: 8 to 18 minutes.

exenatide (Byetta ®) return to top of page

Mechanism of Action
Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. BYETTA is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.

The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide promotes insulin release from pancreatic beta cells in the presence of elevated glucose concentrations.

BYETTA improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.

Glucose-dependent insulin secretion: BYETTA has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, BYETTA does not impair the normal glucagon response to hypoglycemia


INDICATIONS AND USAGE
Type 2 Diabetes Mellitus
BYETTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use
BYETTA is not a substitute for insulin. BYETTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

The concurrent use of BYETTA with insulin has not been studied and cannot be recommended.

Based on postmarketing data BYETTA has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. BYETTA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using BYETTA. Other antidiabetic therapies should be considered in patients with a history of pancreatitis

Dosing (Adjunctive therapy of type 2 diabetes): Initial: 5 mcg SQ bid within 60 min prior to a meal (morning and evening). After 1 month, may be increased to 10 mcg SQ twice daily (based on response).

Renal
Not recommended in patients CRCL < 30 ml/min.
 
Supplied: Injection: [prefilled pen]: 250 mcg/ml (1.2 ml) [provides 5 mcg/dose]. 2.4 ml - [provides 10 mcg/dose]

pramlintide  (Symlin ® )  return to top of page

Mechanism of Action
SYMLIN, by acting as an amylinomimetic agent, has the following effects: 1) modulation of gastric emptying; 2) prevention of the postprandial rise in plasma glucagon; and 3) satiety leading to decreased caloric intake and potential weight loss.

Gastric Emptying
The gastric-emptying rate is an important determinant of the postprandial rise in plasma glucose. SYMLIN slows the rate at which food is released from the stomach to the small intestine following a meal and, thus, it reduces the initial postprandial increase in plasma glucose. This effect lasts for approximately 3 hours following SYMLIN administration. SYMLIN does not alter the net absorption of ingested carbohydrate or other nutrients.

Postprandial Glucagon Secretion
In patients with diabetes, glucagon concentrations are abnormally elevated during the postprandial period, contributing to hyperglycemia. SYMLIN has been shown to decrease postprandial glucagon concentrations in insulin-using patients with diabetes.

Satiety
SYMLIN administered prior to a meal has been shown to reduce total caloric intake. This effect appears to be independent of the nausea that can accompany SYMLIN treatment

INDICATIONS AND USAGE
SYMLIN is given at mealtimes and is indicated for:

Type 1 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy.
Type 2 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or metformin.

CONTRAINDICATIONS
SYMLIN is contraindicated in patients with any of the following:
-a known hypersensitivity to SYMLIN or any of its components, including metacresol;
-a confirmed diagnosis of gastroparesis;
-hypoglycemia unawareness.

Dosage: Adult (usual):
Type 1 diabetes mellitus (insulin dependent) Initial: 15 mcg SQ immediately prior to meals. Titrate in 15 mcg increments every 3 days (if no significant nausea occurs) to target dose of 30-60 mcg (consider discontinuation if intolerant of 30 mcg dose). Note: When initiating pramlintide, reduce current insulin dose (including rapidly and mixed-acting preparations) by 50% to avoid hypoglycemia.

Type 2 diabetes mellitus: Initial: 60 mcg SQ immediately prior to meals. After 3-7 days, increase to 120 mcg prior to meals if no significant nausea occurs (if nausea occurs at 120 mcg dose, reduce to 60 mcg).

If pramlintide is discontinued for any reason, restart therapy with same initial titration protocol.

Do not mix with other insulins. Administer SQ into abdominal or thigh areas at sites distinct from concomitant insulin injections (do not administer into arm due to variable absorption). Rotate injection sites frequently. For oral medications in which a rapid onset of action is desired, administer 1 hr before, or 2 hrs after pramlintide, if possible.

Supplied: Injection: Pramlintide acetate 0.6 mg/ml (5 ml).

Disclaimer

Listed dosages are for - Adult patients ONLY. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER. GlobalRPH does not directly or indirectly practice medicine or provide medical services and therefore assumes no liability whatsoever of any kind for the information and data accessed through the Service or for any diagnosis or treatment made in reliance thereon.

David F. McAuley, Pharm.D., R.Ph.  GlobalRPh Inc.
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