Insulin and Hypoglycemic Drugs A

Insulin and Hypoglycemic Drugs

I. OVERVIEW:

The pancreas is both an endocrine gland that produces the peptide hormones insulin and glucagon and an exocrine gland that produces digestive enzymes. Insulin and glucagon play an important role in regulating the metabolic activities of the body, and in doing so, help maintain the homeostasis of bold glucose levels.

II. METABOLIC ROLE OF INSULIN AND GLUCAGON

High serum glucose stimulates an increase in insulin release from ß cells of the pancreas. Increased serum insulin serves to lower blood glucose levels driving the carbohydrate into cells unable to take up glucose in the absence of insulin.

III. DIABETES MELLITUS

Diabetes is not a single disease, instead it is a heterogenous group of syndromes all characterized by an elevation of blood glucose caused by a relative or absolute deficiency of insulin.

A. Type I Diabetes(Insulin-dependent diabetes mellitus)1. Cause of the disease: Insulin-dependent diabete is characterized by an absolute deficiency

of insulin caused by massive ß cell lesions or necrosis.2. Occurrence of the disease: Insulin-dependent diabetics constitute 10-20% of the 6 million

diabetics in the United States. The disease occurs most commonly among juveniles, but it can occur among adults.

3. Treatment of type I diabetes: Normally, after ingestion of a meal, a burst of insulin secretion occurs in response to transient increases in the levels of circulating glucose and amino acids. In the postabsorptive period, ß-cell secretion maintains low, basal levels of circulating insulin. However, the Type I diabetic has virtually no functional ß cells and can neither respond to variations in circulating fuels nor maintain even a basal secretion of insulin (Figure 26.2). The diabetic must rely on exogenous (injected) insulin in order to control the hyperglycemia and ketoacidosis. The goal in administering insulin to Type I diabetics is to maintain blood glucose concentrations as close to normal as possible and to avoid wide swings in blood glucose levels that may contribute to the long-term complications of the diseases.

B. Type II diabetes(non-insulin-dependent diabetes mellitus)1. Cause of the disease: in non-insulin-dependent diabetes, the pancreas retains some ß-

cells capacity, resulting in insulin levels that vary from below normal to above normal, but in all cases, insulin levels are less than that required to maintain glucose homeostasis (Figure26.2). Patients with Type II diabetes are often obese. Type II diabetes is frequently accompanied by target organ insulin resistance that results in a decreased responsiveness to both endogenous and exogenous insulin. In some cases,

insulin resistance can be due to a decreased number of insulin receptors. Other patients show an as yet undefined defect in the events that occur after insulin binds to its receptor on the cell membrane.

2. Occurrence of the diseases: Patients with Type II disease constitute 80-90% of the diabetics in the United States. It is almost completely determined by genetic factors. No involvement of viruses or autoimmune anti bodies is apparent. The metabolic alterations observed are milder than those described for the insulin dependent form of the disease.

3. Treatment of type II diabetes: The goal in treating type II diabetes is to maintain blood glucose concentration within normal limits and to prevent the development of long-term complications of Diabetes Mellitus.

COMPARISON OF INSULIN-DEPENDENT AND NON_INSULIN DEPENDENT

Insulin-dependent Diabetes Non- insulin-dependent diabetes

Age of onset Usually during childhood or puberty

Frequently Over age 35

Nutritional status at time of onset of disease

Frequently undernourished Obesity usually present

Prevalence 10-20% of diagnosed diabetics

80-90% of diagnosed diabetics

Genetic predisposition Moderate Very strongDefect or deficiency ßcells destroyed eliminating

production of insulinInability of ß cells to produce appropriate quantities of insulin; insulin resistance; other unknown defects

INSULIN PREPARATIONS:A. Rapid action Insulin preparations

1. Crystalline zinc insulin- is purified insulin extracted from pork or beef pancreas or synthetically prepared human insulin that is crystallized as a zinc salt.

2. Semilente insulin- is a suspension of amorphous insulin derived from pork or beef. It is used most commonly as a supplement for intermediate or prolonged action from of insulin

B. Intermediate action insulin preparations1. Isophane insulin suspension: is a suspension of crystalline zinc insulin with the

positively charged peptide mixture called protamine at neutral pH.2. Insulin zinc suspension: is a mixture of 30% semilente insulin and 70% ultralente

insulin. It is given only subcutaneously and is used for previously untreated diabetics who require insulin.

C. Prolonged action insulin preparations

1. Protamine zinc insulin: is prepared by treating CZI with protamine at neutral pH, resulting in a fine precipitate. Injected subcutaneously.

2. Extended insulin zinc suspension: is a crystalline zinc insulin that is poorly soluble. It therefore has a delayed onset and prolonged duration of action.

ORAL HYPOGLYCEMIC AGENTS: SULFONYLUREAS

These agents are useful in the treatment of patients who have non-insulin-dependent diabetes but cannot be managed by diet alone. Their mechanisms of actions include:1) stimulation of insulin release from the ß cells of the pancreas. 2) reduction of serum glucagon levels

acarbose (Precose ®): 

CLINICAL PHARMACOLOGYAcarbose 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 USAGEAcarbose 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:  Plasma concentrations of acarbose in renally impaired volunteers were proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine > 2 mg/dL) have not been conducted. Therefore, treatment of these patients with acarbose is not recommended.

SuppliedTablet: 25 mg, 50 mg, 100 mg

Miglitol (Glycet ®):  

CLINICAL PHARMACOLOGYMiglitol 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 ActionIn contrast to sulfonylureas, GLYSET does not enhance insulin secretion. The antihyperglycemic action of miglitol results from a reversible inhibition of membrane-bound intestinal -glucoside hydrolase enzymes. Membrane-bound intestinal -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 USAGEGLYSET 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.

CONTRAINDICATIONSGLYSET 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.

DosingAdults: 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 : Clcr<25 mL/minute:  Plasma concentrations of GLYSET in renally impaired volunteers were 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 GLYSET is not recommended.

SuppliedTablet: 25 mg, 50 mg, 100 mg

Background  

Alpha-glucosidase inhibitors are oral anti-diabetic drugs used for diabetes mellitus type 2 that work by preventing the digestion of carbohydrates (such as starch and table sugar). Carbohydrates are normally converted into simple sugars (monosaccharides), which can be absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce the impact of carbohydrates on blood sugar.

Examples of alpha-glucosidase inhibitors include:1. Acarbose- Precose2. Miglitol - Glyset

Even though the drugs have a similar mechanism of action, there are subtle differences between acarbose and miglitol. Acarbose is an oligosaccharide, whereas miglitol resembles a monosaccharide. Miglitol is fairly well absorbed by the body, as opposed to acarbose. Moreover, acarbose inhibits pancreatic alpha-amylase in addition to alpha-glucosidase.

Role in clinical use  [source] Alpha-glucosidase inhibitors are used to establish greater glycemic control over hyperglycemia in diabetes mellitus type 2, particularly with regard to postprandial hyperglycemia. They may be used as monotherapy in conjunction with an appropriate diabetic diet and exercise, or they may be used in conjunction with other anti-diabetic drugs.

Alpha-glucosidase inhibitors may also be useful in patients with diabetes mellitus type 1; however, this use has not been officially approved by the Food and Drug Administration.

These medications are rarely used in the United States because of the severity of their side effects (flatulence and bloating). They are more commonly prescribed in Europe. They do have the potential to cause weight loss by lowering the amount of sugar metabolized.

Mechanism of actionAlpha-glucosidase inhibitors are saccharides that act as competitive inhibitors of enzymes needed to digest carbohydrates: specifically alpha-glucosidase enzymes in the brush border of the small intestines. The membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine.

Acarbose also blocks pancreatic alpha-amylase in addition to inhibiting membrane-bound alpha-glucosidases. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine.

Inhibition of these enzyme systems reduces the rate of digestion of carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules. In diabetic patients, the short-term effect of these drugs therapies is to decrease current blood glucose levels: the long term effect is a small reduction in hemoglobin A1c level. 

Source: http://www.globalrph.com/alpha-glucosidase-inhibitors.htm

Sulfonylureas

Drug Monographs  

First-generation agents

Chlorpropamide (Diabinese ®) Tolazamide (Tolinase ®)

Tolbutamide (Orinase ®) acetohexamide (Dymelor)

Second-generation agents

glimepiride (Amaryl ®) glyburide (Micronase ®, Diabeta ®)

glipizide (Glucotrol ®) -----------------------

Typical reductions in A1C values - 2nd gen sulfonylureas:

1.0 - 2.0%.Background

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.

SuppliedTablet: 100 mg, 250 mg

glimepiride (Amaryl ®): 

Mechanism of ActionThe 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 USAGEAMARYL 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.

CONTRAINDICATIONSAMARYL 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.

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

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

SuppliedTablet: 1 mg, 2 mg, 4 mg

glyburide (Micronase ®, Diabeta ®): 

CLINICAL PHARMACOLOGYDia eta 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 Dia eta 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, Dia eta 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 Dia eta

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

CONTRAINDICATIONSDia eta 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 to 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 to 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 to 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

SuppliedTablet (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 ActionThe 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 EffectsIt 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.

CONTRAINDICATIONSGlipizide 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 to 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.

Administration: 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 to 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 to 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/dL: 250 mg/day

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

Adjust dose in increments of 100 to 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 to 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]

Background 

Sulfonylureas were the first widely used oral anti-hyperglycemic medications. They are insulin secretagogues, triggering insulin release by direct action on the KATP channel of the pancreatic beta cells. The primary mechanism of action of sulfonylureas 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. This is supported by both preclinical and clinical studies demonstrating that the administration of a sulfonylurea 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 sulfonylurea therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, the mechanism by which sulfonylureas lower blood glucose during long-term administration has not been clearly established.

All may cause weight gain.

Sulfonylureas bind strongly to plasma proteins.

Sulfonylureas are only useful in Type II diabetes, as they work by stimulating endogenous release of

insulin.

They work best with patients over 40 years old, who have had diabetes mellitus for under ten years.

They cannot be used with type I diabetes, or diabetes of pregnancy. They can be safely used with metformin or -glitazones.

The primary side effect is hypoglycemia.

Megalitinides

Drug Monographs  

Products

Nateglinide (Starlix ®) repaglinide (Prandin ®)

Typical reductions in A1C values - Meglitinides:

0.5 - 1.0%. Background

Nateglinide (Starlix ®)  

CLINICAL PHARMACOLOGYMechanism of ActionNateglinide 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.

CONTRAINDICATIONSNateglinide 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 HbA1c 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.

SuppliedTablet: 60 mg, 120 mg

repaglinide (Prandin ®):  

Mechanism of ActionRepaglinide 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.

CONTRAINDICATIONSPRANDIN 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.

<20 ml/min or Hemodialysis:Studies were not conducted in patients with creatinine clearances below 20 mL/min or patients with renal failure requiring hemodialysis.

SuppliedTablet: 0.5 mg, 1 mg, 2 mg

Background - Meglitinides [Non-sulfonylurea secretagogues]  

Meglitinides lower 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. Meglitinides interact 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.

They are taken with or shortly before meals to boost the insulin response to each meal. If a meal is skipped, the medication is also skipped. Adverse reactions include weight gain and hypoglycemia.

Biguanides

Drug Monographs  

Products

metformin (Glucophage ®) Avandamet® (Rosiglitazone + Metformin)

Glucovance (Glyburide + Metformin) Metaglip (Glipizide + Metformin)

Typical reductions in A1C values - Biguanides:

1.5 - 2.0%.Background

WARNINGS:

WARNINGLactic Acidosis:

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with GLUCOPHAGE or GLUCOPHAGE XR; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking GLUCOPHAGE or GLUCOPHAGE XR and by use of the minimum effective dose of GLUCOPHAGE or GLUCOPHAGE XR. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUCOPHAGE or GLUCOPHAGE XR treatment should not be initiated in patients 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, GLUCOPHAGE and GLUCOPHAGE XR should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, GLUCOPHAGE and GLUCOPHAGE XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking GLUCOPHAGE

or GLUCOPHAGE XR, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, GLUCOPHAGE and GLUCOPHAGE XR should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS - PACKAGE INSERT).

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS - PACKAGE INSERT). GLUCOPHAGE and GLUCOPHAGE XR should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of GLUCOPHAGE or GLUCOPHAGE XR, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking GLUCOPHAGE or GLUCOPHAGE XR do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS - PACKAGE INSERT)

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking GLUCOPHAGE or GLUCOPHAGE XR, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS - PACKAGE INSERT)

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 USAGEGLUCOPHAGE (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.

CONTRAINDICATIONSGLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:

Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels 1.5 mg/dL [males], 1.4 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 - Riomet®: 100 mg/ml (118 ml, 473 ml).

Extended release brand names and strengths:Fortamet®: 500 mg, 1000 mgGlucophage® XR: 500 mg, 750 mgGlumetza®: 500 mg, 1000 mg

Avandamet® (Rosiglitazone + Metformin)  

These highlights do not include all the information needed to use this medication safely and effectively. See full prescribing information for ADDITONAL INFORMATION.

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) 

These highlights do not include all the information needed to use this medication safely and effectively. See full prescribing information for ADDITONAL INFORMATION.

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) 

These highlights do not include all the information needed to use this medication safely and effectively. See full prescribing information for ADDITONAL INFORMATION.

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 ]

Background  

Insulin sensitizers address the core problem in Type II diabetes—insulin resistance.

Biguanides reduce hepatic glucose output and increase uptake of glucose by the periphery, including skeletal muscle. Amongst common diabetic drugs, metformin is the only widely used oral drug that does not cause weight gain.

• Metformin (Glucophage) may be the best choice for patients who also have heart failure, but it should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast, as patients are at an increased risk of lactic acidosis.

• Phenformin (DBI) was used from 1960s through 1980s, but was withdrawn due to lactic acidosis risk.• Buformin also was withdrawn due to lactic acidosis risk.

Metformin is usually the first-line medication used for treatment of type 2 diabetes. It is generally prescribed at initial diagnosis in conjunction with exercise and weight loss as opposed to in the past, where it was prescribed after diet and exercise had failed. Initial dosing is 500 mg once daily, then if need be increased to 500 mg twice daily up to 1000 mg twice daily. It is also available in combination with other oral diabetic medications. There is an extended release formulation available, but it is typically reserved for patients experiencing GI side effects.

Glitazones

Drug Monographs  

Products

pioglitazone (Actos ®) rosiglitazone (Avandia ®)

Combination Products

Avandamet® (Rosiglitazone + Metformin)

Typical reductions in A1C values - Thiazolidinediones:

1.5 - 2.0%.Background

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 (PPAR ). PPAR receptors are found in tissues

important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR 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 to 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 to 30 mg once daily; it is unlikely that the dose of metformin will need to be reduced due to hypoglycemia.

With insulin: Initial: 15 to 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.

SuppliedTablet: 15 mg, 30 mg, 45 mg

rosiglitazone (Avandia ®): 

Mechanism of ActionRosiglitazone, 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 (PPAR ). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPAR -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:[1] 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.

[2] The coadministration of Rosiglitazone maleate and insulin is not recommended.

[3] 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.

SuppliedTablet: 2 mg, 4 mg, 8 mg

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] .

Background  

Insulin sensitizers address the core problem in Type II diabetes—insulin resistance.

Thiazolidinediones (TZDs), also known as "glitazones," bind to PPAR , a type of nuclear regulatory protein involved in transcription of genes regulating glucose and fat metabolism. These PPARs act on peroxysome proliferator responsive elements (PPRE). The PPREs influence insulin sensitive genes, which enhance production of mRNAs of insulin-dependent enzymes. The final result is better use of glucose by the cells.

Mode of actionThiazolidinediones or TZDs act by binding to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus, specifically PPAR (gamma). The ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes.

By activating PPAR :1. Insulin resistance is decreased2. Adipocyte differentiation is modified [1]3. VEGF-induced angiogenesis is inhibited[2]4. Leptin levels increase (leading to a decreased appetite)5. Levels of certain interleukins (e.g. IL-6) fall6. Adiponectin levels rise

TZDs also increase the synthesis of certain proteins involved in fat and glucose metabolism, which reduces levels of certain types of lipids, and circulating free fatty acids. TZDs generally decrease triglycerides and increase high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Although the increase in LDL-C may be more focused on the larger LDL particles, which may be less atherogenic, the clinical significance of this is currently unknown. Nonetheless, rosiglitazone, a certain glitazone, was suspended from allowed use by medical authorities in Europe, as it has been linked to an increased risk of heart attack and stroke.

Some examples are:• rosiglitazone (Avandia)• pioglitazone (Actos)• troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.

Multiple retrospective studies have resulted in a concern about rosiglitazone's safety, although it is established that the group, as a whole, has beneficial effects on diabetes. The greatest concern is an increase in the number of severe cardiac events in patients taking it. The ADOPT study showed initial therapy with drugs of this type may prevent the progression of disease, as did the DREAM trial.

Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine. There have been a significant number of publications since then,

and a Food and Drug Administration panel voted, with some controversy, 20:3 that available studies "supported a signal of harm," but voted 22:1 to keep the drug on the market. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate the issue, and several other reports have failed to conclude the controversy. This weak evidence for adverse effects has reduced the use of rosiglitazone, despite its important and sustained effects on glycemic control. Safety studies are continuing.

In contrast, at least one large prospective study, PROactive 05, has shown that pioglitazone may decrease the overall incidence of cardiac events in people with type 2 diabetes who have already had a heart attack.

Amylin agonist

pramlintide  (Symlin ® ) 

WARNINGS:

WARNINGSYMLIN is used with insulin and has been associated with an increased risk of insulin-induced severe hypoglycemia, particularly in patients with type 1 diabetes. When severe hypoglycemia associated with SYMLIN use occurs, it is seen within 3 hours following a SYMLIN injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries may occur. Appropriate patient selection, careful patient instruction, and insulin dose adjustments are critical elements for reducing this risk.

Mechanism of ActionSYMLIN, 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 USAGESYMLIN 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.

CONTRAINDICATIONSSYMLIN 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.

WARNINGS:Patient Selection:Proper patient selection is critical to safe and effective use of SYMLIN.

Before initiation of therapy, the patient's HbA1c, recent blood glucose monitoring data, history of insulin-induced hypoglycemia, current insulin regimen, and body weight should be reviewed. SYMLIN therapy should only be considered in patients with insulin-using type 2 or type 1 diabetes who fulfill the following criteria:

have failed to achieve adequate glycemic control despite individualized insulin management;are receiving ongoing care under the guidance of a healthcare professional skilled in the use of insulin and supported by the services of diabetes educator(s).

Patients meeting any of the following criteria should NOT be considered for SYMLIN therapy:

-poor compliance with current insulin regimen; -poor compliance with prescribed self-blood glucose monitoring;

-have an HbA1c > 9%; -recurrent severe hypoglycemia requiring assistance during the past 6 months; -presence of hypoglycemia unawareness; -confirmed diagnosis of gastroparesis; -require the use of drugs that stimulate gastrointestinal motility; -pediatric patients.

Hypoglycemia:SYMLIN alone does not cause hypoglycemia. However, SYMLIN is indicated to be co-administered with insulin therapy and in this setting SYMLIN increases the risk of insulin-induced severe hypoglycemia, particularly in patients with type 1 diabetes. Severe hypoglycemia associated with SYMLIN occurs within the first 3 hours following a SYMLIN injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries may occur. Therefore, when introducing SYMLIN therapy, appropriate precautions need to be taken to avoid increasing the risk for insulin-induced severe hypoglycemia. These precautions include frequent pre- and post-meal glucose monitoring combined with an initial 50% reduction in pre-meal doses of short-acting insulin (see DOSAGE and ADMINISTRATION).

Symptoms of hypoglycemia may include hunger, headache, sweating, tremor, irritability, or difficulty concentrating. Rapid reductions in blood glucose concentrations may induce such symptoms regardless of glucose values. More severe symptoms of hypoglycemia include loss of consciousness, coma, or seizure.

Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes; diabetic nerve disease; use of medications such as beta-blockers, clonidine, guanethidine, or reserpine; or intensified diabetes control.

The addition of any antihyperglycemic agent such as SYMLIN to an existing regimen of one or more antihyperglycemic agents (e.g., insulin, sulfonylurea), or other agents that can increase the risk of hypoglycemia may necessitate further insulin dose adjustments and particularly close monitoring of blood glucose.

The following are examples of substances that may increase the blood glucose-lowering effect and susceptibility to hypoglycemia: oral anti-diabetic products, ACE inhibitors, diisopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates, and sulfonamide antibiotics.

Clinical studies employing a controlled hypoglycemic challenge have demonstrated that SYMLIN does not alter the counter-regulatory hormonal response to insulin-induced hypoglycemia. Likewise, in SYMLIN-treated patients, the perception of hypoglycemic symptoms was not altered with plasma glucose concentrations as low as 45 mg/dL.

DOSAGE AND ADMINISTRATION:

SYMLIN dosage differs depending on whether the patient has type 2 or type 1 diabetes (see below). When initiating therapy with SYMLIN, initial insulin dose reduction is required in all patients (both type 2 and type 1) to reduce the risk of insulin-induced hypoglycemia. As this reduction in insulin can lead to glucose elevations, patients should be monitored at regular intervals to assess SYMLIN tolerability and the effect on blood glucose, so that individualized insulin adjustments can be initiated. If SYMLIN therapy is discontinued for any reason (e.g., surgery or illnesses), the same initiation protocol should be followed when SYMLIN therapy is re-instituted (see below). Initiation of SYMLIN therapy:

Patients With Insulin-Using Type 2 Diabetes

In patients with insulin-using type 2 diabetes, SYMLIN should be initiated at a dose of 60 mcg and increased to a dose of 120 mcg as tolerated.

Patients should be instructed to:

Initiate SYMLIN at 60 mcg subcutaneously, immediately prior to major meals; Reduce preprandial, rapid-acting or short-acting insulin dosages, including fixed-mix insulins

(70/30) by 50%; Monitor blood glucose frequently, including pre- and post-meals and at bedtime; Increase the SYMLIN dose to 120 mcg when no clinically significant nausea has occurred for 3-7

days. SYMLIN dose adjustments should be made only as directed by the healthcare professional. If significant nausea persists at the 120 mcg dose, the SYMLIN dose should be decreased to 60 mcg;

Adjust insulin doses to optimize glycemic control once the target dose of SYMLIN is achieved and nausea (if experienced) has subsided. Insulin dose adjustments should be made only as directed by the healthcare professional;

Contact a healthcare professional skilled in the use of insulin to review SYMLIN and insulin dose adjustments at least once a week until a target dose of SYMLIN is achieved, SYMLIN is well-tolerated, and blood glucose concentrations are stable.

Patients With Type 1 Diabetes

In patients with type 1 diabetes, SYMLIN should be initiated at a dose of 15 mcg and titrated at 15-mcg increments to a maintenance dose of 30 mcg or 60 mcg as tolerated.

Patients should be instructed to:

Initiate SYMLIN at a starting dose of 15 mcg subcutaneously, immediately prior to major meals; Reduce preprandial, rapid-acting or short-acting insulin dosages, including fixed-mix insulins

(e.g., 70/30) by 50%; Monitor blood glucose frequently, including pre- and post-meals and at bedtime; Increase the SYMLIN dose to the next increment (30 mcg, 45 mcg, or 60 mcg) when no clinically

significant nausea has occurred for at least 3 days. SYMLIN dose adjustments should be made only as directed by the healthcare professional. If significant nausea persists at the 45 or 60 mcg dose level, the SYMLIN dose should be decreased to 30 mcg. If the 30 mcg dose is not tolerated, discontinuation of SYMLIN therapy should be considered;

Adjust insulin doses to optimize glycemic control once the target dose of SYMLIN is achieved and nausea (if experienced) has subsided. Insulin dose adjustments should be made only as directed by the healthcare professional;

Contact a healthcare professional skilled in the use of insulin to review SYMLIN and insulin dose adjustments at least once a week until a target dose of SYMLIN is achieved, SYMLIN is well-tolerated, and blood glucose concentrations are stable.

Once Target Dose of SYMLIN is Achieved in Type 2 or Type 1 Patient:

After a maintenance dose of SYMLIN is achieved, both insulin-using patients with type 2 diabetes and patients with type 1 diabetes should be instructed to:

Adjust insulin doses to optimize glycemic control once the target dose of SYMLIN is achieved and nausea (if experienced) has subsided. Insulin dose adjustments should be made only as directed by a healthcare professional;

Contact a healthcare professional in the event of recurrent nausea or hypoglycemia. An increased frequency of mild to moderate hypoglycemia should be viewed as a warning sign of increased risk for severe hypoglycemia.

Administration:SYMLIN should be administered subcutaneously immediately prior to each major meal ( 250 kcal or containing 30 g of carbohydrate).

SYMLIN should be at room temperature before injecting to reduce potential injection site reactions. Each SYMLIN dose should be administered subcutaneously into the abdomen or thigh (administration into the arm is not recommended because of variable absorption). Injection sites should be rotated so that the same site is not used repeatedly. The injection site selected should also be distinct from the site chosen for any concomitant insulin injection.

SYMLIN and insulin should always be administered as separate injections.

SYMLIN should not be mixed with any type of insulin. If a SYMLIN dose is missed, wait until the next scheduled dose and administer the usual amount.

SymlinPen® pen-injector

The SymlinPen® pen-injector is available in two presentations:

SymlinPen® 60 pen-injector for doses of 15 mcg, 30 mcg, 45 mcg, 60 mcg. SymlinPen® 120 pen-injector for doses of 60 mcg and 120 mcg.

See the accompanying Patient Instructions for Use for instructions for using the SymlinPen® pen-injector.

The patient should be advised:

to confirm they are using the correct pen-injector that will deliver their prescribed dose; on proper use of the pen-injector, emphasizing how and when to set up a new pen-injector; not to transfer SYMLIN from the pen-injector to a syringe. Doing so could result in a higher dose

than intended, because SYMLIN in the pen-injector is a higher concentration than SYMLIN in the SYMLIN vial;

not to share the pen-injector and needles with others; that needles are not included with the pen-injector and must be purchased separately; which needle length and gauge should be used; to use a new needle for each injection.

SYMLIN vials

To administer SYMLIN from vials, use a U-100 insulin syringe (preferably a 0.3 mL [0.3 cc] size) for optimal accuracy. If using a syringe calibrated for use with U-100 insulin, use the chart below (Table 8) to measure the microgram dosage in unit increments.

Table 8: Conversion of SYMLIN Dose to Insulin Unit Equivalents

Dosage Prescribed (mcg) Increment Using a U-100 Syringe (Units) Volume (cc or mL)

15 2½ 0.025

30 5 0.05

45 7½ 0.075

Table 8: Conversion of SYMLIN Dose to Insulin Unit Equivalents

Dosage Prescribed (mcg) Increment Using a U-100 Syringe (Units) Volume (cc or mL)

60 10 0.1

120 20 0.2

Always use separate, new syringes and needles to give SYMLIN and insulin injections.

Discontinuation of Therapy:SYMLIN therapy should be discontinued if any of the following occur:

Recurrent unexplained hypoglycemia that requires medical assistance; Persistent clinically significant nausea; Noncompliance with self-monitoring of blood glucose concentrations; Noncompliance with insulin dose adjustments; Noncompliance with scheduled healthcare professional contacts or recommended clinic visits.

Preparation and HandlingSYMLIN should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and the container permit.

HOW SUPPLIED:

SYMLIN is supplied as a sterile injection in the following dosage forms:

1.5 mL disposable multidose SymlinPen® 60 pen-injector containing 1000 mcg/mL pramlintide (as acetate).

2.7 mL disposable multidose SymlinPen® 120 pen-injector containing 1000 mcg/mL pramlintide (as acetate).

5 mL vial, containing 600 mcg/mL pramlintide (as acetate), for use with an insulin syringe.

To administer SYMLIN from vials, use a U-100 insulin syringe (preferably a 0.3 mL [0.3 cc] size). If using a syringe calibrated for use with U-100 insulin, use the chart (Table 8) in the DOSAGE AND ADMINISTRATION section to measure the microgram dosage in unit increments.

Do not mix SYMLIN with insulin.

SYSYMLIN Injection is available in the following package sizes:

SymlinPen® 60 pen-injector, containing 1000 mcg/mL pramlintide (as acetate)2 X 1.5 mL disposable multidose pen-injector(NDC 66780-115-02)

SymlinPen® 120 pen-injector, containing 1000 mcg/mL pramlintide (as acetate)2 X 2.7 mL disposable multidose pen-injector(NDC 66780-121-02)

5 mL vial, containing 600 mcg/mL pramlintide (as acetate), for use with an insulin syringe(NDC 66780-110-01)

STORAGE:SYMLIN pen-injectors and vials not in use: Refrigerate (36°F to 46°F; 2°C to 8°C), and protect from light. Do not freeze. Do not use if product has been frozen. Unused SYMLIN (opened or unopened) should not be used after the expiration (EXP) date printed on the carton and the label.

SYMLIN pen-injectors and vials in use: After first use, refrigerate or keep at a temperature not greater than 86°F (30°C) for 30 days. Use within 30 days, whether or not refrigerated.

Storage conditions are summarized in Table 9. Table 9: Storage Conditions

Dosage FormUnopened (not in use)

Refrigerated

Open (in use)Refrigerated or Temperature

Up To 86°F (30°C)

1.5 mL pen-injector2.7 mL pen-injector

5 mL vialUntil Expiration Date Use Within 30 days

The SymlinPen® pen-injectors and SYMLIN vials are manufactured for:Amylin Pharmaceuticals, Inc.San Diego, CA 92121 USA1-800-349-8919http://www.SYMLIN.com

Rx only

The SYMLIN mark, SYMLIN design mark, and SymlinPen are registered trademarks of Amylin Pharmaceuticals, Inc. Copyright © 2005-2008, Amylin Pharmaceuticals, Inc. All rights reserved. Literature Revised July 2008

Background 

Amylin analoguesAmylin agonist analogues slow gastric emptying and suppress glucagon. They have all the incretins actions except stimulation of insulin secretion. As of 2007, pramlintide is the only clinically available amylin analogue. Like insulin, it is administered by subcutaneous injection. The most frequent and severe adverse effect of pramlintide is nausea, which occurs mostly at the beginning of treatment and gradually reduces.

Drug Monographs  

Products

Linagliptin - Tradjenta™ Saxagliptin - Onglyza™

Sitagliptin - Januvia® -----------------

Combination Products

KOMBIGLYZE XR (saxagliptin and metformin HCl ER)

JANUMET® (sitagliptin and metformin HCl) tablets

Typical reductions in A1C values - DPP-4 INHIBITORS:

~ 0.74% (0.73 - 1.2)Background

Overview

Linagliptin - Tradjenta™ 

INDICATIONS AND USAGE:TRADJENTA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important limitations of use: -Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. -Has not been studied in combination with insulin.

DOSAGE AND ADMINISTRATION:The recommended dose of TRADJENTA is 5 mg once daily. TRADJENTA can be taken with or without food.

DOSAGE FORMS AND STRENGTHS:Tablets: 5 mg

CONTRAINDICATIONS:History of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS: When used with an insulin secretagogue (e.g., sulfonylurea), consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

ADVERSE REACTIONS: -Adverse reactions reported in 5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis. -Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. -Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person years versus zero in 433 person years for comparator).

To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or 1-800-459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS:P-glycoprotein/CYP 3A4 inducer: The efficacy of TRADJENTA may be reduced when administered in combination (e.g., with rifampin). Use of alternative treatments is strongly recommended.

USE IN SPECIFIC POPULATIONS:1] Pregnancy: There are no adequate and well-controlled studies in pregnant women. TRADJENTA tablets should be used during pregnancy only if clearly needed.2] Nursing mothers: Caution should be exercised when TRADJENTA is administered to a nursing woman.3] Pediatric patients: Safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.4] Renal or hepatic impairment: No dose adjustment recommended.

CLINICAL PHARMACOLOGYMechanism of Action:Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting

in a reduction in hepatic glucose output.

Pharmacodynamics: Linagliptin binds to DPP-4 in a reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion thus resulting in a better regulation of the glucose homeostasis. Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.

Cardiac Electrophysiology: In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of 5 mg or the 100 mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5 mg dose.

Pharmacokinetics: The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a single 5-mg dose to healthy subjects, peak plasma concentrations of linagliptin occurred at approximately 1.5 hours post dose (Tmax); the mean plasma area under the curve (AUC) was 139 nmol*h/L and maximum concentration (Cmax) was 8.9 nmol/L. Plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4. The prolonged elimination phase does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin 5 mg are reached by the third dose, and Cmax and AUC increased by a factor of 1.3 at steady state compared with the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Plasma AUC of linagliptin increased in a less than dose proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type 2 diabetes.

Absorption: The absolute bioavailability of linagliptin is approximately 30%. High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. TRADJENTA may be administered with or without food.

Distribution: The mean apparent volume of distribution at steady state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75%-89% at 30 nmol/L, reflecting saturation of binding to DPP-4 with

increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.

Metabolism: Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin. Excretion Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 mL/min.

Saxagliptin - Onglyza™ 

INDICATIONS AND USAGE:ONGLYZA is a dipeptidyl peptidase-4 inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. (Monotherapy and Combination Therapy)

Important limitations of use:Should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

DOSAGE AND ADMINISTRATION:The recommended dose is 2.5 mg or 5 mg once daily taken regardless of meals.

Other: -----------------------------------------[1 ] Patients with Renal Impairment:No dosage adjustment for ONGLYZA is recommended for patients with mild renal impairment (creatinine clearance [CrCl] >50 mL/min).

The dose of ONGLYZA is 2.5 mg once daily for patients with moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] 50 mL/min). ONGLYZA should be administered following hemodialysis. ONGLYZA has not been studied in patients undergoing peritoneal dialysis. Assess renal function prior to initiation of ONGLYZA and periodically thereafter.

Creatinine clearance was estimated from serum creatinine based on the Cockcroft-Gault formula:Cockcroft-Gault formula:CrCl = [140 - age (years)] x weight (kg) / [72 x serum creatinine (mg/dL)] {x 0.85 for female patients}

[ 2 ] Strong CYP3A4/5 Inhibitors:The dose of ONGLYZA is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).

DOSAGE FORMS AND STRENGTHS:Tablets: 5 mg and 2.5 mg

Combination product: Saxagliptin and Metformin (Kombiglyze™ XR)Tablet, variable release, oral:Kombiglyze™ XR 2.5/1000: Saxagliptin 2.5 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]Kombiglyze™ XR 5/500: Saxagliptin 5 mg [immediate release] and metformin hydrochloride 500 mg [extended release] Kombiglyze™ XR 5/1000: Saxagliptin 5 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]

CONTRAINDICATIONS:None.

WARNINGS AND PRECAUTIONS:When used with an insulin secretagogue (e.g., sulfonylurea), a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA or any other antidiabetic drug.

ADVERSE REACTIONS:1] Adverse reactions reported in 5% of patients treated with ONGLYZA and more commonly than in patients treated with placebo are: upper respiratory tract infection, urinary tract infection, and headache.

2] Peripheral edema was reported more commonly in patients treated with the combination of ONGLYZA and a thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD.

3] Hypoglycemia was reported more commonly in patients treated with the combination of ONGLYZA

and sulfonylurea than in patients treated with the combination of placebo and sulfonylurea.

4] Hypersensitivity-related events (e.g., urticaria, facial edema) were reported more commonly in patients treated with ONGLYZA than in patients treated with placebo.

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS:Coadministration with strong CYP3A4/5 inhibitors (e.g., ketoconazole) significantly increases saxagliptin concentrations. Recommend limiting ONGLYZA dose to 2.5 mg once daily.

USE IN SPECIFIC POPULATIONS:1] There are no adequate and well-controlled studies in pregnant women.

2] Safety and effectiveness of ONGLYZA in pediatric patients below the age of 18 have not been established.

CLINICAL PHARMACOLOGY:Mechanism of Action:Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the dipeptidyl peptidase-4 (DPP4) enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus.

Pharmacodynamics:In patients with type 2 diabetes mellitus, administration of ONGLYZA inhibits DPP4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

Cardiac Electrophysiology:In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, ONGLYZA was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the MRHD).

Pharmacokinetics:The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type 2 diabetes mellitus. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite was less than 25%.

No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.

Absorption:The median time to maximum concentration (Tmax) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite. Administration with a high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. ONGLYZA may be administered with or without food.

Distribution:The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.

Metabolism:The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite. [See Drug Interactions (7).]

Excretion:Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230

mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following a single oral dose of ONGLYZA 5 mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.Because the dose of ONGLYZA should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of ONGLYZA and periodically thereafter. Renal function can be estimated from serum creatinine using the Cockcroft-Gault formula or Modification of Diet in Renal Disease formula.

Sitagliptin - Januvia® 

These highlights do not include all the information needed to use JANUVIA safely and effectively. See full prescribing information for JANUVIA.

INDICATIONS AND USAGE:JANUVIA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use:JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. JANUVIA has not been studied in patients with a history of pancreatitis.

DOSAGE AND ADMINISTRATION:The recommended dose of JANUVIA is 100 mg once daily. JANUVIA can be taken with or without food.

Patients with Renal Insufficiency:Dosage adjustment is recommended for patients with moderate or severe renal insufficiency or end-stage renal disease.

For patients with mild renal insufficiency: (creatinine clearance [CrCl] 50 mL/min, approximately corresponding to serum creatinine levels of 1.7 mg/dL in men and 1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

For patients with moderate renal insufficiency: (CrCl 30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to 3.0 mg/dL in men and >1.5 to 2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. There have been postmarketing reports of worsening renal function in patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin.

Cockcroft-Gault formula:CrCl = [140 - age (years)] x weight (kg) / [72 x serum creatinine (mg/dL)] {x 0.85 for female patients}

Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin:When JANUVIA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.

DOSAGE FORMS AND STRENGTHS:Tablets: 100 mg, 50 mg, and 25 mg.

CONTRAINDICATIONS:History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

WARNINGS AND PRECAUTIONS:There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue JANUVIA.

There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD. Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter.

There is an increased risk of hypoglycemia when JANUVIA is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy. Consider lowering the dose of the sulfonylurea or insulin to reduce the

risk of hypoglycemia.

There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with JANUVIA such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop JANUVIA, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug.

ADVERSE REACTIONS:Adverse reactions reported in 5% of patients treated with JANUVIA and more commonly than in patients treated with placebo are: upper respiratory tract infection, nasopharyngitis and headache. In the add-on to sulfonylurea and add-on to insulin studies, hypoglycemia was also more commonly reported in patients treated with JANUVIA compared to placebo.

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Safety and effectiveness of JANUVIA in children under 18 years have not been established. (8.4)There are no adequate and well-controlled studies in pregnant women. To report drug exposure during pregnancy call 1-800-986-8999. (8.1)

CLINICAL PHARMACOLOGY:Mechanism of Action:Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, JANUVIA increases insulin release and decreases glucagon levels in the

circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

Pharmacodynamics:General:In patients with type 2 diabetes, administration of JANUVIA led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes.

In studies with healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemia.

Cardiac Electrophysiology:In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of JANUVIA 100 mg, JANUVIA 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline was observed at 3 hours postdose and was 8.0 msec. This increase is not considered to be clinically significant. At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100 mg dose.

In patients with type 2 diabetes administered JANUVIA 100 mg (N=81) or JANUVIA 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.

Pharmacokinetics:The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 µM•hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients

of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

Absorption: The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food.

Distribution: The mean volume of distribution at steady state following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).

Metabolism: Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

Excretion: Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

Combination Products  

  KOMBIGLYZE XR (saxagliptin and metformin HCl ER)  

These highlights do not include all the information needed to use KOMBIGLYZE XR safely and effectively. See full prescribing information for KOMBIGLYZE XR.

KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets

DOSAGE AND ADMINISTRATION:Administer once daily with the evening meal. -Individualize the starting dose based on the patient’s current regimen then adjust the dose based on effectiveness and tolerability. -Do not exceed a daily dose of 5 mg saxagliptin/2000 mg metformin HCl extended-release. -Swallow whole. Never crush, cut, or chew. -Limit the saxagliptin dose to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole).

Strong CYP3A4/5 Inhibitors:The maximum recommended dose of saxagliptin is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). For these patients, limit the KOMBIGLYZE XR dose to 2.5 mg/1000 mg once daily.

No studies have been performed specifically examining the safety and efficacy of KOMBIGLYZE XR in patients previously treated with other antihyperglycemic medications and switched to KOMBIGLYZE XR. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Inform patients that KOMBIGLYZE XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of KOMBIGLYZE XR will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet.

DOSAGE FORMS AND STRENGTHS:Tablets:5 mg saxagliptin/500 mg metformin HCl extended-release5 mg saxagliptin/1000 mg metformin HCl extended-release2.5 mg saxagliptin/1000 mg metformin HCl extended-release

CONTRAINDICATIONS:[1] Renal impairment.[2] Hypersensitivity to metformin hydrochloride. [3] Metabolic acidosis, including diabetic ketoacidosis.[4] Temporarily discontinue in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials.

WARNINGS AND PRECAUTIONS:Lactic acidosis: Warn patients against excessive alcohol intake. KOMBIGLYZE XR not recommended in hepatic impairment and contraindicated in renal impairment. Ensure normal renal function before initiating and at least annually thereafter. Temporarily discontinue KOMBIGLYZE XR for surgical procedures necessitating restricted intake of food and fluids.

Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually.

Hypoglycemia: When used with an insulin secretagogue (e.g., sulfonylurea), a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia.

Macrovascular outcomes: No conclusive evidence of macrovascular risk reduction with KOMBIGLYZE XR or any other antidiabetic drug.

ADVERSE REACTIONS:Adverse reactions reported in >5% of patients treated with metformin extended-release and more commonly than in patients treated with placebo are: diarrhea and nausea/vomiting.

Adverse reactions reported in 55% of patients treated with saxagliptin and more commonly than in patients treated with placebo are: upper respiratory tract infection, urinary tract infection, and headache.

Adverse reactions reported in 55% of treatment-naive patients treated with coadministered saxagliptin and metformin and more commonly than in patients treated with metformin alone are: headache and nasopharyngitis.

Hypersensitivity-related events (e.g., urticaria, facial edema) were reported more commonly in patients treated with saxagliptin than in patients treated with placebo.

   JANUMET® (sitagliptin/metformin HCl) tablets 

These highlights do not include all the information needed to use JANUMET safely and effectively. See full prescribing information for JANUMET.

Initial U.S. Approval: 2007

WARNING: LACTIC ACIDOSISSee full prescribing information for complete boxed warning.Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate. If acidosis is suspected, discontinue JANUMET and hospitalize the patient immediately.

INDICATIONS AND USAGE:JANUMET is a dipeptidyl peptidase-4 (DPP-4) inhibitor and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate.

Important Limitations of Use:JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.JANUMET has not been studied in patients with a history of pancreatitis.

DOSAGE AND ADMINISTRATION:Individualize the starting dose of JANUMET based on the patient’s current regimen.

May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin.

JANUMET should be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects due to metformin.

DOSAGE FORMS AND STRENGTHS:Tablets: 50 mg sitagliptin/500 mg metformin HCl and 50 mg sitagliptin/1000 mg metformin HCl

CONTRAINDICATIONS:Renal dysfunction, e.g., serum creatinine 1.5 mg/dL [males], 1.4 mg/dL [females] or abnormal creatinine clearance.

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

History of a serious hypersensitivity reaction to JANUMET or sitagliptin (one of the components of

JANUMET), such as anaphylaxis or angioedema.

Temporarily discontinue JANUMET in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials.

WARNINGS AND PRECAUTIONS:Do not use JANUMET in patients with hepatic disease.

There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Before initiating JANUMET and at least annually thereafter, assess renal function and verify as normal.

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue JANUMET.

Measure hematologic parameters annually.

Warn patients against excessive alcohol intake.

May need to discontinue JANUMET and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.

Promptly evaluate patients previously controlled on JANUMET who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.

When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.

There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of JANUMET), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop JANUMET, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET or any other anti-diabetic drug.

ADVERSE REACTIONS:The most common adverse reactions reported in 5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported in 5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.

Hypoglycemia was the only adverse reaction reported in 5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin.

Nasopharyngitis was the only adverse reaction reported in 5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.

The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS:Cationic drugs eliminated by renal tubular secretion: Use with caution.

USE IN SPECIFIC POPULATIONS:Safety and effectiveness of JANUMET in children under 18 years have not been established.

There are no adequate and well-controlled studies in pregnant women. To report drug exposure during pregnancy call 1-800-986-8999.

Background  

Dipeptidyl peptidase-4 (DPP-4) inhibitors:Their mechanism of action is thought to result from increased incretin levels (GLP-1 and GIP) by inhibiting its degradation by dipeptidyl peptidase-4. Increased incretin levels inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.

GLP-1: glucagon-like peptide-1. GIP: gastric inhibitory peptide (glucose-dependent insulinotropic peptide).

Glucagon-like peptide (GLP) agonists bind to a membrane GLP

receptor. As a consequence, insulin release from the pancreatic beta cells is increased. Endogenous GLP has a half life of only a few minutes, thus an analogue of GLP would not be practical.

GLP-1 analogs resulted in weight loss and had more gastrointestinal side effects, while DPP-4 inhibitors were generally weight neutral and increased risk for infection and headache, but both classes appear to present an alternative to other antidiabetic drugs.

Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).

[source]

"In one RCT comprising 206 patients aged 65 or older (mean baseline HgbA1c of 7.8%) receiving either 50 or 100 mg/d of Sitagliptin was shown to reduce HbA1c by 0.7% (combined result of both doses). A combined result of 5 RCTs enlisting a total of 279 patients aged 65 or older (mean baseline HbA1c of 8%) receiving 5 mg/d of Saxagliptin was shown to reduce HbA1c by 0.73%. A combined result of 5 RCTs enlisting a total of 238 patients aged 65 or older (mean baseline HbA1c of 8.6%) receiving 100 mg/d of Vildagliptin was shown to reduce HbA1c by 1.2%. Another set of 6 combined RCTs involving Alogliptin (not yet approved, might be released in 2012) was shown to reduce HbA1c by 0.73% in 455 patients aged 65 or older who received 12.5 or 25 mg/d of the medication." [source]

DPP-4 inhibitors lowered hemoglobin A1C values by 0.74%, comparable to other anti-diabetic drugs.

The first agent of the class - sitagliptin - was approved by the FDA in 2006.

Examples - Drugs belonging to this class are :

1. sitagliptin (FDA approved 2006, marketed by Merck & Co. as Januvia),2. vildagliptin (marketed in the EU by Novartis as Galvus),3. saxagliptin (FDA approved in 2009, marketed as Onglyza),4. linagliptin (FDA approved in 2011, marketed as Tradjenta by Eli Lilly Co and Boehringer Ingelheim),5. dutogliptin (being developed by Phenomix Corporation), Phase III6. gemigliptin (being developed by LG Life Sciences,Korea)7. alogliptin (developed by Takeda Pharmaceutical Company, whose FDA application for the product is currently suspended as of June 2009)

Berberine, the common herbal dietary supplement, too inhibits dipeptidyl peptidase-4, which at least partly explains its antihyperglycemic activity.

Risks and side effects:Long-term effects of DPP-4 inhibitors on mortality and morbidity are so far inconclusive, although adverse effects, including nasopharyngitis (the common cold), headache, nausea, hypersensitivity and skin reactions, have been observed in clinical studies. Other possible adverse effects, including hypersensitivity reactions and pancreatitis, have been reported.

Although extensive long-term, preclinical studies of the major DPP-4 inhibitors have failed to show any evidence of potential to cause tumors in laboratory animals, one in vitro study has raised some questions.

Drug Monographs  

Products

exenatide (Byetta ®) Liraglutide (Victoza®)

Typical reductions in A1C values - Incretin Mimetics:

0.5 - 1.0%.

Background

Overview

exenatide (Byetta ®): 

These highlights do not include all the information needed to use BYETTA safely and effectively. See full prescribing information for BYETTA.

CLINICAL PHARMACOLOGY: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.

First-phase insulin response: In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of BYETTA at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with BYETTA compared with saline (p <0.001 for both).

Pharmacokinetics:Absorption:Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC 0-inf) was 1036 pg·h/mL following SC administration of a 10-mcg dose of BYETTA. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 mcg to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of BYETTA in the abdomen, thigh, or upper arm.

Distribution:The mean apparent volume of distribution of exenatide following SC administration of a single dose of BYETTA is 28.3 L.

Metabolism and Elimination:Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 h post-dose.

INDICATIONS AND USAGE:Type 2 Diabetes Mellitus:BYETTA is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of UseBYETTA 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

DOSAGE AND ADMINISTRATION:Recommended Dosing:BYETTA should be initiated at 5 mcg administered twice daily at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). BYETTA should not be administered after a meal. Based on clinical response, the dose of BYETTA can be increased to 10 mcg twice daily after 1 month of therapy. Initiation with 5 mcg reduces the incidence and severity of gastrointestinal side effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh, abdomen, or upper arm. No data are available on the safety or efficacy of intravenous or intramuscular injection of BYETTA.

Use BYETTA only if it is clear, colorless and contains no particles.

Renal Impairment:BYETTA is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 mL/min) and should be used with caution in patients with renal transplantation. No dosage adjustment of BYETTA is required in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min). Caution should be applied when initiating or escalating doses of BYETTA from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min)

DOSAGE FORMS AND STRENGTHS:BYETTA is supplied as 250 mcg/mL exenatide in:5 mcg per dose, 60 doses, 1.2 mL prefilled pen10 mcg per dose, 60 doses, 2.4 mL prefilled pen

CONTRAINDICATIONS:History of severe hypersensitivity to exenatide or any product components .

WARNINGS AND PRECAUTIONS:Pancreatitis: Postmarketing reports, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Discontinue BYETTA promptly. BYETTA should not be restarted. Consider other antidiabetic therapies in patients with a history of pancreatitis.Hypoglycemia: Increased risk when BYETTA is used in combination with a sulfonylurea. Consider reducing the sulfonylurea dose.Renal Impairment: Postmarketing reports, sometimes requiring hemodialysis and kidney transplantation. BYETTA should not be used in patients with severe renal impairment or end-stage renal disease and should be used with caution in patients with renal transplantation. Caution should be applied when initiating BYETTA or escalating the dose of BYETTA in patients with moderate renal failure.Severe Gastrointestinal Disease: Use of BYETTA is not recommended in patients with severe gastrointestinal disease (e.g., gastroparesis).Hypersensitivity: Postmarketing reports of hypersensitivity reactions (e.g. anaphylaxis and angioedema). The patient should discontinue BYETTA and other suspect medications and promptly seek medical advice.There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYETTA or any other antidiabetic drug.

ADVERSE REACTIONS:Most common ( 5%) and occurring more frequently than placebo in clinical trials: nausea, hypoglycemia, vomiting, diarrhea, feeling jittery, dizziness, headache, dyspepsia. Nausea usually decreases over time.

Postmarketing reports of increased international normalized ratio (INR) with concomitant use of warfarin, sometimes with bleeding.

To report SUSPECTED ADVERSE REACTIONS contact Amylin Pharmaceuticals, Inc. and Eli Lilly and Company at 1-800-868-1190 and www.byetta.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS:Warfarin: Postmarketing reports of increased INR sometimes associated with bleeding. Monitor INR frequently until stable upon initiation or alteration of BYETTA therapy.

USE IN SPECIFIC POPULATIONS:Pregnancy: Based on animal data, BYETTA may cause fetal harm. BYETTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To report drug exposure during pregnancy call 1-800-633-9081.Nursing Mothers: Caution should be exercised when BYETTA is administered to a nursing woman (8.3).

Liraglutide (Victoza®) 

These highlights do not include all the information needed to use Victoza safely and effectively. See full prescribing information for Victoza.

Victoza® (liraglutide (rDNA origin) injection), solution for subcutaneous use - Initial U.S. Approval: 2010

WARNING: RISK OF THYROID C-CELL TUMORS

See full prescribing information for complete boxed warning.

Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in rodents. It is unknown whether Victoza causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be determined by clinical or nonclinical studies.Victoza is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

INDICATIONS AND USAGE:Victoza is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use:[1] Not recommended as first-line therapy for patients inadequately controlled on diet and exercise.[2] Has not been studied sufficiently in patients with a history of pancreatitis. Use caution.[3] Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.[4] Has not been studied in combination with insulin.

DOSAGE AND ADMINISTRATION:

Administer once daily at any time of day, independently of meals.

Inject subcutaneously in the abdomen, thigh or upper arm.

The injection site and timing can be changed without dose adjustment.

Initiate at 0.6 mg per day for one week. This dose is intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control. After one week, increase the dose to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg.

When initiating Victoza, consider reducing the dose of concomitantly-administered insulin secretagogues to reduce the risk of hypoglycemia.

Victoza solution should be inspected prior to each injection, and the solution should be used only if it is clear, colorless, and contains no particles.

DOSAGE FORMS AND STRENGTHS:

Solution for subcutaneous injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL)

CONTRAINDICATIONS:Do not use in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.

WARNINGS AND PRECAUTIONS:Thyroid C-cell tumors in animals: Human relevance unknown. Counsel patients regarding the risk of medullary thyroid carcinoma and the symptoms of thyroid tumors.

Pancreatitis: In clinical trials, there were more cases of pancreatitis among Victoza-treated patients than among comparator-treated patients. If pancreatitis is suspected, Victoza and other potentially suspect drugs should be discontinued. Victoza should not be restarted if pancreatitis is confirmed. Use with

caution in patients with a history of pancreatitis.

Serious hypoglycemia: Can occur when Victoza is used with an insulin secretagogue (e.g. a sulfonylurea). Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia.

Macrovascular outcomes: There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza or any other antidiabetic drug.

ADVERSE REACTIONS:The most common adverse reactions, reported in 5% of patients treated with Victoza and more commonly than in patients treated with placebo, are: headache, nausea, diarrhea and anti-liraglutide antibody formation.Immunogenicity-related events, including urticaria, were more common among Victoza-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials.

To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-877-484-2869 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS:Victoza delays gastric emptying. May impact absorption of concomitantly administered oral medications. Use caution.

USE IN SPECIFIC POPULATIONS:There are no data in patients below 18 years of age.Use with caution in patients with renal or hepatic impairment.

CLINICAL PHARMACOLOGY:Mechanism of Action:Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). GLP-1(7-37) represents <20% of total circulating endogenous GLP-1. Like GLP-1(7-37), liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. Liraglutide increases intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Liraglutide also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay in gastric emptying.

GLP-1(7-37) has a half-life of 1.5-2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is

stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once daily administration, is a result of self-association that delays absorption, plasma protein binding and stability against metabolic degradation by DPP-IV and NEP.

Pharmacodynamics:Victoza’s pharmacodynamic profile is consistent with its pharmacokinetic profile observed after single subcutaneous administration as Victoza lowered fasting, premeal and postprandial glucose throughout the day.

Fasting and postprandial glucose was measured before and up to 5 hours after a standardized meal after treatment to steady state with 0.6, 1.2 and 1.8 mg Victoza or placebo. Compared to placebo, the postprandial plasma glucose AUC 0-300min was 35% lower after Victoza 1.2 mg and 38% lower after Victoza 1.8 mg.

Glucose-dependent insulin secretionThe effect of a single dose of 7.5 mcg/kg (~ 0.7 mg) Victoza on insulin secretion rates (ISR) was investigated in 10 patients with type 2 diabetes during graded glucose infusion. In these patients, on average, the ISR response was increased in a glucose-dependent manner (Figure 2).

Figure 2: Mean Insulin Secretion Rate (ISR) versus Glucose Concentration Following Single-Dose Victoza 7.5 mcg/kg (~ 0.7 mg) or Placebo in Patients with Type 2 Diabetes (N=10) During Graded Glucose Infusion

Glucagon secretion:Victoza lowered blood glucose by stimulating insulin secretion and lowering glucagon secretion. A single dose of Victoza 7.5 mcg/kg (~ 0.7 mg) did not impair glucagon response to low glucose concentrations.

Gastric emptying:

Victoza causes a delay of gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.

Cardiac Electrophysiology (QTc):The effect of Victoza on cardiac repolarization was tested in a QTc study. Victoza at steady state concentrations with daily doses up to 1.8 mg did not produce QTc prolongation.

Pharmacokinetics:Absorption - Following subcutaneous administration, maximum concentrations of liraglutide are achieved at 8-12 hours post dosing. The mean peak (Cmax) and total (AUC) exposures of liraglutide were 35 ng/mL and 960 ng·h/mL, respectively, for a subcutaneous single dose of 0.6 mg. After subcutaneous single dose administrations, Cmax and AUC of liraglutide increased proportionally over the therapeutic dose range of 0.6 mg to 1.8 mg. At 1.8 mg Victoza, the average steady state concentration of liraglutide over 24 hours was approximately 128 ng/mL. AUC0- was equivalent between upper arm and abdomen, and between upper arm and thigh. AUC0- from thigh was 22% lower than that from abdomen. However, liraglutide exposures were considered comparable among these three subcutaneous injection sites. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%.

Distribution - The mean apparent volume of distribution after subcutaneous administration of Victoza 0.6 mg is approximately 13 L. The mean volume of distribution after intravenous administration of Victoza is 0.07 L/kg. Liraglutide is extensively bound to plasma protein (>98%).

Metabolism - During the initial 24 hours following administration of a single [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination.

Elimination - Following a [3H]-liraglutide dose, intact liraglutide was not detected in urine or feces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or feces (6% and 5%, respectively). The majority of urine and feces radioactivity was excreted during the first 6-8 days. The mean apparent clearance following subcutaneous administration of a single dose of liraglutide is approximately 1.2 L/h with an elimination half-life of approximately 13 hours, making Victoza suitable for once daily administration.

Recommended Storage:Prior to first use, Victoza should be stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze Victoza and do not use Victoza if it has been frozen.

After initial use of the Victoza pen, the pen can be stored for 30 days at controlled room temperature

(59°F to 86°F; 15°C to 30°C) or in a refrigerator (36°F to 46°F; 2°C to 8°C). Keep the pen cap on when not in use. Victoza should be protected from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the Victoza pen without an injection needle attached. This will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy.

Background  

Incretins are insulin secretagogues. The two main candidate molecules that fulfill criteria for being an incretin are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic peptide, GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).

Glucagon-like peptide analogs and agonists"Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor. As a consequence, insulin release from the pancreatic beta cells is increased. Endogenous GLP has a half life of only a few minutes, thus an analogue of GLP would not be practical.

Exenatide (also Exendin-4, marketed as Byetta) is the first GLP-1 agonist approved for the treatment of type 2 diabetes. Exenatide is not an analogue of GLP, but rather a GLP agonist. Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life. Typical reductions in A1C values are 0.5-1.0%.

Liraglutide, a once daily human analogue (97% homology), has been developed by Novo Nordisk under the brand name Victoza.

Taspoglutide is presently in Phase III clinical trials with Hoffman-La Roche.

These agents may also cause a decrease in gastric motility, responsible for the common side effect of nausea, and is probably the mechanism by which weight loss occurs."

Diabetes:  Drug Class Navigation 

Secretagogues Insulin sensitizers Alpha-glucosidase inh

Sulfonylureas Biguanides e.g. Metformin Alpha-glucosidase Inhibitors

Meglitinides (e.g. Prandin) Glitazones - Thiazolidinediones

Peptide analogs

AMYLIN AGONISTS - Anti- hyperglycemic Synthetic Analogs

DPP-4 INHIBITORS - Dipeptidyl peptidase-4 inhibitor – Gliptins

Glucagon-like peptide-1 (GLP-1) AGONIST - Incretin Mimetics