1.AMARYL HISTORY
(How was Amaryl discovered?)

Amaryl is a product of Sanofi-Aventis.

The FDA approved Amaryl in December 1995.

The Sanofi-Aventis Group is the world's 3rd largest pharmaceutical company, ranking number 1 in Europe. Backed by a world-class R&D organization, Sanofi-Aventis is developing leading positions in seven major therapeutic areas:

• cardiovascular disease,
• thrombosis,
• oncology,
• diabetes,
• central nervous system,
• internal medicine, and
• vaccines.

2.AMARYL FACTS

Amaryl (glimepiride) is an antidiabetic medication, which is used in those patients with adult maturity onset or non-insulin dependent diabetes (NIDDM).

Amaryl works by lowering blood sugar levels by stimulating the production and release of insulin from the pancreas. It also promotes the movement of sugar from the blood into the cells in the body, which need it.

These two mechanisms in conjunction with a diet low in sugar and fat allows diabetics to control their blood sugar levels more effectively. 

3.ABOUT AMARYL MEDICATION

What is Diabetes and what are its causes

Diabetes (diabetes mellitus): a condition characterized by hyperglycemia resulting from the body's inability to use blood glucose for energy. In type 1 diabetes, the pancreas no longer makes insulin and therefore blood glucose cannot enter the cells to be used for energy. In type 2 diabetes, either the pancreas does not make enough insulin or the body is unable to use insulin correctly.

Pre-diabetes : a condition in which blood glucose levels are higher than normal but are not high enough for a diagnosis of Diabetes. People with pre-diabetes are at increased risk for developing type 2 diabetes and for heart disease and stroke. Other names for pre-diabetes are impaired glucose tolerance and impaired fasting glucose.

Type 1 diabetes : a condition characterized by high blood glucose levels caused by a total lack of insulin. Occurs when the body's immune system attacks the insulin-producing beta cells in the pancreas and destroys them. The pancreas then produces little or no insulin. Type 1 diabetes develops most often in young people but can appear in adults.

Type 2 diabetes : a condition characterized by high blood glucose levels caused by either a lack of insulin or the body's inability to use insulin efficiently. Type 2 diabetes develops most often in middle-aged and older adults but can appear in young people.

 

 

 

 

 

 

Other causes of diabetes

There are some other causes of diabetes, including certain diseases of the pancreas, but they are all very rare. Sometimes an accident or an illness may reveal diabetes if it is already there, but they do not cause it.

What are the symptoms of Diabetes?

The main symptoms of diabetes are:

• increased thirst
• going to the loo all the time – especially at night
• extreme tiredness
• weight loss
• genital itching or regular episodes of thrush
• blurred vision.

Type 2 diabetes develops slowly and the symptoms are usually less severe. Some people may not notice any symptoms at all and their diabetes is only picked up in a routine medical check up. Some people may put the symptoms down to 'getting older' or 'overwork'.

Type 1 diabetes develops much more quickly, usually over a few weeks, and symptoms are normally very obvious.

In both types of diabetes, the symptoms are quickly relieved once the diabetes is treated. Early treatment will also reduce the chances of developing serious health problems.

What are the risk factors for Diabetes?

Age :

All people are vulnerable to the disease throughout their lives. However, the risk is higheras you grow older. There is a gradual increase in susceptibility, with slight peaks at puberty and during pregnancy, until we reach the age of 40. Then there is a rapid jump.

Heredity

If you have a family history of diabetes, especially parents or siblings with diabetes, then you're near the top of the list in terms of risk. Heredity is the most important predisposing factor for diabetes, especially for type-I diabetes.

Type II diabetes also tends to run in families, but since 80 to 85 percent of all cases occur among people who are over 40 and overweight, obesity is considered more important in the development of this form of the disease.

Obesity

80 to 85 percent of people with type II diabetes are overweight. It is true that not all overweight people have diabetes. But if you are obese, you may be setting yourself up for this disease 10 or 20 years from now. (You are considered obese, if you are more than 20 percent over ideal body weight.)

Race

In the United States the disease is more common among African-Americans, Hispanics and American Indians. More than 40% of Pima Indians in the United States have type 2 diabetes. However, that race alone does not predict diabetes; it must be combined with another factor, such as obesity.

Poverty

Researchers have uncovered a link between poverty and diabetes. In a survey in the USA, households with the lowest income-under $15,000- was found to have the highest incidence of diabetes.

Having impaired glucose tolerance

Having high blood pressure or high cholesterol levels (240 mg/dl or more)

In women, having a history of gestational diabetes or delivery of babies weighing more than 9 pounds

Complications of Diabetes

When you are not properly managing your type 2 diabetes, you greatly increase your risk of diabetes-related complications. Every one percent increase in your A1C level above 6 percent elevates the risk of diabetes-related complications, including stroke, heart attack, blindness and loss of limbs. Here are some of the more common risks associated with type 2 diabetes:

Heart Disease and Stroke

• Diabetes carries an increased risk for heart attack and stroke related to poor circulation.
• People with diabetes are two to four times more likely to suffer strokes.
• Two-thirds of the people with diabetes die of heart disease or stroke.

Kidney Disease

• The kidneys filter the waste products from the body.
• Diabetes can damage the kidneys, leading to failure.

Eye Complications

• Diabetes can cause eye problems and may lead to blindness.
• Every year up to 24,000 people lose their sight to diabetes.

Nerve Damage

• Diabetes can cause nerve damage (neuropathy), which can affect feelings in arms, hands, legs or feet, and cause you to lose sensitivity to pain.
• Severe nerve damage can lead to limb amputation.

Foot Complications

• Diabetes can cause foot ulcers, nerve damage to the feet, infections and loss of blood flow resulting in possible amputation.

Skin Complications

• Diabetes can cause a range of skin disorders, such as itching, diabetic blisters, bacterial and fungus infections.
• Although these conditions are serious, you can lower your risk of Diabetes-related complications by managing your Diabetes every day.

Treatment of Diabetes

An antidiabetic drug or oral hypoglycemic agent is used to treat diabetes mellitus. They usually work by lowering the glucose levels in the blood. There are different types of anti-diabetic drugs, and their use depends on the nature of the diabetes, age and situation of the person, as well as other factors.

Insulin is the only non-oral antidiabetic drug. It is the mainstay of treatment in type I diabetes, in which insulin production is impaired. In Type II diabetes, it is used when oral medication has become ineffective.

Antidiabetics

Sulfonylureas

Sulfonylureas were the first widely used oral hypoglycemic medications. They are insulin secretagogues, triggering insulin release by direct action on the KATP channel of the pancreatic beta cells. Seven types of these pills have been marketed in North America. Four, known as "first-generation" drugs, have been in use for some time, but not all remain available. Three "second-generation" drugs, are now more commonly used. They are stronger than first-generation drugs and have fewer side effects.

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 biguanides and glitazones. The toxicity of these drugs on the whole is relatively low.

First-generation agents

• Tolbutamide (Orinase)
• Acetohexamide (Dymelor)
• Tolazamide (Tolinase)
• Chlorpropamide (Diabinese)

Second-generation agents

• Glipizide
• Glyburide (Diabeta, Micronase, Glynase)
• Glimepiride (Amaryl)

Meglitinides

Meglitinides are related to sulfonylureas. The amplification of insulin release is shorter and more intense, and they are taken with meals to boost the insulin response to each meal.

• Repaglinide (Prandin)
• Nateglinide (Starlix)

Biguanides

Biguanides reduce hepatic glucose output. Although it must be used with caution in patients with impaired liver or kidney function, metformin has become the most commonly used agent for type 2 diabetes in children and teenagers.

• Metformin (Glucophage)
• Phenformin (DBI): used in 1960-1980s, withdrawn due to lactic acidosis risk.  

Thiazolidinediones

Thiazolidinediones, also known as "glitazones," bind to PPAR?, a type of nuclear regulatory protein involved in transcription of numerous genes regulating glucose and fat metabolism. They act as "insulin sensitizers" without increasing insulin secretion.

• Rosiglitazone (Avandia)
• Pioglitazone (Actos)
• Troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.

Alpha glucosidase inhibitors

Alpha glucosidase inhibitors are "diabetes pills" but not technically hypoglycemic agents because they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small intestine, so that glucose from the starch of a meal enters the bloodstream more slowly, and can be matched more effectively by an impaired insulin response or sensitivity. These agents are effective by themselves only in the earliest stages of impaired glucose tolerance, but can be helpful in combination with other agents in type 2 diabetes.

• Miglitol (Glyset)
• Acarbose (Precose)

Experimental agents

Many other potential drugs are currently in investigation by pharmaceutical companies. Some of these are simply newer members of one of the above classes, but some work by novel mechanisms. For example, at least one compound that enhances the sensitivity of glucokinase to rising glucose is in the stage of animal research.

Insulin by mouth

The basic appeal of oral hypoglycemic agents is that most people would prefer a pill to an injection. Unlike all the oral drugs described in this article, insulin is a protein. Protein hormones, like meat proteins, are digested in the stomach and gut.

However, the potential market for an oral form of insulin is enormous and many laboratories have attempted to devise ways of moving enough intact insulin from the gut to the portal vein to have a measurable effect on blood sugar. One can find several research reports over the years describing promising approaches or limited success in animals, and limited human testing, but as of 2004, no products appear to be successful enough to bring to market. 

4.AMARYL EFFECTIVENESS
(When is Amaryl best taken?)

Absorption:
After oral administration, Amaryl is completely (100%) absorbed from the GI tract. Studies with single oral doses of Amaryl in normal subjects and with multiple oral doses of Amaryl in patients with NIDDM have shown significant absorption of Amaryl within 1 hour after administration and peak drug levels (Cmax) at 2 to 3 hours. When Amaryl dose was given with meals, the mean Tmax (time to reach Cmax) was slightly increased (12%) and the mean Cmax and AUC (area under the curve) were slightly decreased (8% and 9%, respectively).

Distribution:
After intravenous (IV) dosing in normal subjects, the volume of distribution (Vd) was 8.8 L (113 ml/kg), and the total body clearance (CL) was 47.8 ml/min. Protein binding was greater than 99.5%.

Metabolism:
Amaryl is completely metabolized by oxidative biotransformation after either an IV or oral dose of Amaryl. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 II C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear.

Excretion:
When 14C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80% to 90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in the feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. No parent drug was recovered from urine or feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed. 

5.AMARYL EFFECTS ON SPECIAL POPULATION
(How do different people react to Amaryl?)

Geriatric:
Comparison of Amaryl pharmacokinetics in NIDDM patients £65 years and those >65 years was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in Amaryl pharmacokinetics between the two age groups. The mean AUC at steady state for the older patients was about 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was about 11% higher than that for the younger patients.

Pediatric:
No studies were performed in pediatric patients.

Gender:
There were no differences between males and females in the pharmacokinetics of Amaryl when adjustment was made for differences in body weight.

Race:
No pharmacokinetic studies to assess the effects of race have been performed, but in placebo-controlled studies of Amaryl tablets in patients with NIDDM, the antihyperglycemic effect was comparable in whites (n=536), blacks (n=63), and Hispanics (n=63).

6.AMARYL EFFECTS ON MEDICAL CONDITIONS
(How does Amaryl affect your existing condition/ailment?)

Renal Insufficiency:

A single-dose, open-label study was conducted in 15 patients with renal impairment. Amaryl(3 mg) was administered to 3 groups of patients with different levels of mean creatinine clearance (CLcr); (Group I, CLcr=77.7 ml/min, n=5), (Group II, CLcr=27.7 ml/min, n=3), and (Group III, CLcr=9.4 ml/min, n=7). Amaryl was found to be well tolerated in all 3 groups. The results showed that glimepiride serum levels decreased as renal function decreased. However, M1 and M2 serum levels (mean AUC values) increased 2.3 and 8.6 times from Group I to Group III. The apparent terminal half-life (T½) for Amaryl did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as percent of dose, however, decreased (44.4%, 21.9%, and 9.3% for Groups I to III).

A multiple-dose titration study was also conducted in 16 NIDDM patients with renal impairment using doses ranging from 1 to 8 mg daily for 3 months. The results were consistent with those observed after single doses. All patients with a CLcr less than 22 ml/min had adequate control of their glucose levels with a dosage regimen of only 1 mg daily. The results from this study suggested that a starting dose of 1 mg Amaryl may be given to NIDDM patients with kidney disease, and the dose may be titrated based on fasting blood glucose levels.

Hepatic Insufficiency:

No studies were performed in patients with hepatic insufficiency. 

7.OTHER/ALTERNATE USES OF AMARYL
(What else does Amaryl treat?)

Amaryl may be used as prescribed by your physician.

8.ADVERSE/SIDE EFFECTS of AMARYL
(What are the side effects of Amaryl?)

The incidence of hypoglycemia with Amaryl, as documented by blood glucose values <60 mg/dl, ranged from 0.9% to 1.7% in two large, well-controlled, 1-year studies.

Amaryl has been evaluated for safety in 2013 patients in US controlled trials, and in 1551 patients in foreign controlled trials. More than 1650 of these patients were treated for at least 1 year.

Adverse events, other than hypoglycemia, considered to be possibly or probably related to study drug that occurred in US placebo-controlled trials in more than 1% of patients treated with glimepiride are shown in table below.

Adverse Events Occurring in ³ 1% Amaryl Patients
	Amaryl		Placebo
	No.	%	No.	%
Total Treated	746	100	294	100
Dizziness	13	1.7	1	0.3
Asthenia	12	1.6	3	1.0
Headache	11	1.5	4	1.4
Nausea	8	1.1		0.0

Gastrointestinal Reactions : Vomiting, gastrointestinal pain, and diarrhea have been reported, but the incidence in placebo-controlled trials was less than 1%. In rare cases, there may be an elevation of liver enzyme levels. In isolated instances, impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may also lead to liver failure have been reported with sulfonylureas, including Amaryl.

Dermatologic Reactions : Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in less than 1% of treated patients. These may be transient and may disappear despite continued use of glimepiride; if skin reactions persist, the drug should be discontinued. Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Metabolic Reactions : Hepatic porphyria reactions and disulfiram-like reactions have been reported with sulfonylureas; however, no cases have yet been reported with glimepiride tablets. Cases of hyponatremia have been reported with Amaryl and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.