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Erectile dysfunction and Viagra (page6,7) - Wayne

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Erectile dysfunction and Viagra (page6,7) - Wayne

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https://science.howstuffworks.com/viagra5.htm

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Wayne

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Termination of pregnancy | Guidance and guidelines | NICE

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ROCKVILLE, Md., April 29-The FDA announced today it has approved a new injectable diabetes drug synthesized from gila monster saliva, but says the drug should only be used in combination with older oral medications.

Eli Lilly of Indianapolis and co-marketer Amylin Pharmaceuticals of San Diego say their new type 2 diabetes drug -- Byetta (exenatide) -- will be in drug stores by June.

The drug, which is an insulin sensitizer, was approved for treatment of type 2 diabetes in combination with older medications such as metformin. The drug is a hormone derived from the saliva of the gila monster.

Byetta is the first of new class of drugs called incretin mimetics, which mimic the action of GLP-1 (incretin), the peptide hormone that regulates post-prandial insulin production in the gut. In clinical studies submitted to the FDA, combining Byetta with metformin caused an average 1% drop in patients' HbA1C levels, a significant reduction.

The drug has multiple mechanisms of action:

It controls glucose concentrations in the blood by suppressing glucagon, which stimulates glucose release from the liver.

It stimulates satiety in the brain, which slows the absorption of nutrients into the blood, controlling postprandial glucose "spikes."

It stimulates the formation of pancreatic cells.

The drug, however, requires two injections daily, which may be a constraint for some patients who are used to oral medications.

In clinical studies the most common side effect was nausea. Although labeling details are not yet available, the manufacturers said patients using Byetta plus metformin may need to use lower doses of metformin in order to avoid hypoglycemia.

The drug makers are expected to submit additional studies to the FDA to support use of Byetta as stand alone therapy.

Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine

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FDA Approves 'Gila Monster' Diabetes Drug

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ROCKVILLE, Md.-The FDA announced today it has approved a new injectable diabetes drug synthesized from gila monster saliva, but says the drug should only be used in combination with older oral medicat

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Gary

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Diabetic Ketoacidosis (DKA) Explained Clearly - Diabetes Complications

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Gary

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Diabetes is a condition that's characterized by high blood sugar levels. This can be due to the body's inability to make any or enough insulin, use insulin effectively, or both.

Insulin is a hormone that helps the cells of your body absorb blood sugar to make energy. Insulin is produced by the pancreas in larger amounts after you eat food.

There are two major classifications of diabetes:

Type 1 diabetes occurs when the body's immune system attacks and destroys insulin-producing cells in the pancreas. This type is usually diagnosed in childhood and develops quickly.

Type 2 diabetes occurs when cells are no longer able to use insulin effectively. This state is called insulin resistance. Type 2 diabetes develops gradually and is associated with being overweight and having a sedentary lifestyle.

Diabetes causes blood glucose, or blood sugar, to rise to abnormally high levels. In type 1 diabetes, the body may also begin to burn fat for energy because the cells aren't getting the glucose they need. When this happens, the body produces chemicals called ketones.

When ketones build up in the blood, they make the blood more acidic. A buildup of ketones can poison the body and result in coma or even death.

Urine tests aren't ever used to diagnose diabetes. However, they may be used to monitor a person's levels of urine ketones and urine glucose. Sometimes they're used to ensure diabetes is being managed properly.

A urine test may be given as part of a routine checkup. A lab may test your urine for the presence of glucose and ketones. If either are present in the urine, it could mean that you're not producing enough insulin.

Some diabetes medications such as canagliflozin (Invokana) and empagliflozin (Jardiance) cause an increase of sugar to spill into urine. For people taking these medications, glucose levels shouldn't be tested by urine but testing ketones is still okay.

Glucose levels

In the past, urine tests for glucose were used to diagnose and monitor diabetes. Now, they aren't as commonly used anymore.

In order to diagnose diabetes more accurately, a doctor will typically rely on a blood glucose test. Blood tests are more accurate and can measure the exact amount of glucose in the blood.

Want to check your own at home? Shop for an at-home urine glucose or at-home blood glucose test.

Ketones

Urine ketone testing is most often necessary in people with type 1 diabetes who:

Ketone levels can be monitored with an at-home urine test kit. A urine test for ketones should be used if you match the descriptions above or have any of the following symptoms of DKA:

You may also need to take a urine ketone test if:

Shop for an at-home ketone test.

People with diabetes, especially type 1 diabetes, should get recommendations from their doctor as to when they should test for ketones. Typically, if your diabetes is well-managed, you may not be required to regularly check your ketone levels.

If you begin experiencing any symptoms as mentioned above, your sugar levels are above 250 mg/dL, or your body isn't responding to insulin injections, then you may need to begin monitoring your ketone levels.

Before your test, make sure to drink enough water so you can provide an adequate sample of urine. Be sure to tell your doctor about any medications or supplements you're taking, as these may affect the results.

Urine can easily be contaminated by bacteria and cells. You should cleanse your genital area with water before providing a sample of urine.

You may be asked to give a sample of urine while at the doctor's office. Urine test kits are also available for use at home. A urine test is fairly simple and carries no risk. You shouldn't feel any discomfort during this test.

At the doctor's office

Your doctor will provide instructions on how to give the sample and where to leave it when you're done. In general, this is what can be expected during an office urine test:

1. You'll be given a plastic cup labeled with your name and other medical information.

2. You'll take the cup into a private bathroom and urinate into the cup. Use the "clean catch" method to avoid contamination with bacteria or cells on your skin. With this method, you'll only collect your urine midstream. The rest of your urine flow can go into the toilet.

3. Place the lid on the cup and wash your hands.

4. Bring the cup to wherever your doctor told you to leave it when you're done. If you aren't sure, ask a nurse or other staff member.

5. The sample will then be analyzed for the presence of glucose and ketones. The results should be ready shortly after the sample is given.

At-home test strips

Ketone tests are available at the pharmacy without a prescription, or online. Be sure to read the directions on the package carefully or go over how to use the strips with your doctor prior to doing the test.

Before using the test strip, check to make sure it isn't outdated or expired.

In general, the at-home urine test involves the following steps:

1. Start by reading the manufacturer's instructions.

2. Urinate into a clean container.

3. Dip the strip in the urine. The strips are coated with chemicals that react with ketones. Shake the excess urine off the strip.

4. Wait for the strip pad to change color. The instructions that came with the strips should tell you how long to wait. You may want to have a watch or timer available.

5. Compare the strip color to the color chart on the packaging. This gives you a range for the amount of ketones found in your urine.

6. Immediately write down your results.

Healthy individuals generally shouldn't have glucose in their urine at all. If the test shows the presence of glucose in your urine, you should discuss the possible causes with your doctor.

Urine testing doesn't test your current blood levels of glucose. It can only provide insights into whether or not glucose is spilling into your urine. It also merely reflects the state of your blood sugar over the prior few hours.

Blood glucose testing is the primary test used to determine actual glucose levels.

Monitoring ketone levels in urine is important if you have type 1 diabetes. Ketones are more commonly seen in the urine of people with type 1 diabetes than in people with type 2 diabetes.

If you're told to monitor your ketones, ask your healthcare team to help you develop a plan for what to do if you do detect ketones in your urine.

Normal or trace levels of ketones in urine are less than 0.6 millimoles per liter (mmol/L), according to the National Health Service (NHS).

An abnormal result means you have ketones in your urine. The readings are usually classified as small, moderate, or large.

Small to moderate

A ketone level of 0.6 to 1.5 mmol/L (10 to 30 mg/dL) is considered small to moderate. This result may mean that ketone buildup is starting. You should test again in a few hours.

This time, drink plenty of water prior to the test. Don't exercise if your blood glucose levels are also high. Starvation may also cause a small amount of ketones in the urine, so avoid skipping meals.

Moderate to large

A ketone level of 1.6 to 3.0 mmol/L (30 to 50 mg/dL) is considered moderate to large. This result can signal that your diabetes isn't being managed well.

At this point, you should call your doctor or seek medical attention.

Very large

A ketone level greater than 3.0 mmol/L (50 mg/dL) can indicate that you have DKA. This is a life-threatening condition and requires immediate medical treatment. Go directly to the emergency room if your levels are this large.

Other than large ketone levels in the urine, the symptoms of ketoacidosis include:

vomiting

nausea

confusion

a breath odor described as "fruity"

Ketoacidosis can cause brain swelling, coma, and even death if left untreated.

If glucose or ketones are found in the urine during a routine exam, your doctor will do additional testing to determine why this is happening. This may include a blood glucose test.

Your doctor will go over your treatment plan with you if you have diabetes. You can manage your blood sugar levels with the help of:

If you have type 1 diabetes, you may have to regularly monitor ketone levels in your urine using a home test strip. If ketone levels get too large, you can develop DKA.

If the test shows that you have small or moderate ketones, follow the plan that you've set up with your healthcare team. If you have large levels of ketones in your urine, contact your healthcare provider right away or go to the emergency room.

DKA will be treated with intravenous (IV) fluids and insulin.

Speak with your doctor about what can be done to prevent future episodes. Keeping track of your results and the conditions that triggered an episode of large ketones can help you and your doctor adjust your diabetes treatment plan.

Healthline and our partners may receive a portion of revenues if you make a purchase using a link above.

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Urine Tests for Diabetes: Purpose, Procedure, and Results

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Urine tests for diabetes aren't used in diagnosis, but they can be used to help manage the condition. Learn about the 2 different types: the glucose level test and the ketone test. Find out what the symptoms of diabetic ketoacidosis are, how to interpret your results, what steps to take after your test, and more.

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Muntasha

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Chronic Microvascular Complications of Diabetes Mellitus

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Microvascular complications of diabetes mellitus can have a devastating effect on quality of life and can decrease survival. Do you know what the symptoms are?

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Hemoglobin A1c, often abbreviated HbA1c, is a form of hemoglobin (a blood pigment that carries oxygen) that is bound to glucose.

The blood test for HbA1c level is routinely performed in people with type 1 and type 2 diabetes mellitus.

Blood HbA1c levels are reflective of how well diabetes is controlled.

The normal range for level for hemoglobin A1c is less than 6%.

HbA1c also is known as glycosylated, or glycated hemoglobin.

HbA1c levels are reflective of blood glucose levels over the past six to eight weeks and do not reflect daily ups and downs of blood glucose.

High HbA1c levels indicate poorer control of diabetes than levels in the normal range.

HbA1c is typically measured to determine how well a type 1 or type 2 diabetes treatment plan (including medications, exercise, or dietary changes) is working.

Hemoglobin is the oxygen-carrying pigment that gives blood its red color and is also the predominant protein in red blood cells. About 90% of hemoglobin is hemoglobin A (the "A" stands for adult type). Although one chemical component accounts for 92% of hemoglobin A, approximately 8% of hemoglobin A is made up of minor components that are chemically slightly different. These minor components include hemoglobin A1c, A1b, A1a1, and A1a2. Hemoglobin A1c (HbA1c) is a minor component of hemoglobin to which glucose is bound. HbA1c also is sometimes referred to as glycated, glycosylated hemoglobin, or glycohemoglobin.

The test for hemoglobin A1c depends on the chemical (electrical) charge on the molecule of HbA1c, which differs from the charges on the other components of hemoglobin. The molecule of HbA1c also differs in size from the other components. HbA1c may be separated by charge and size from the other hemoglobin A components in blood by a procedure called high pressure (or performance) liquid chromatography (HPLC). HPLC separates mixtures (for example, blood) into its various components by adding the mixtures to special liquids and passing them under pressure through columns filled with a material that separates the mixture into its different component molecules.

HbA1c testing is done on a blood sample. Because HbA1c is not affected by short-term fluctuations in blood glucose concentrations, for example, due to meals, blood can be drawn for HbA1c testing without regard to when food was eaten. Fasting for the blood test is not necessary.

In healthy people, the HbA1c level is less than 6% of total hemoglobin. A level of 6.5% signals that diabetes is present. Studies have demonstrated that the complications of diabetes can be delayed or prevented if the HbA1c level can be kept below 7%. It is recommended that treatment of diabetes be directed at keeping an individual's HbA1c level as close to normal as possible (<6%) without episodes of hypoglycemia ( low blood glucose levels).

*Any test for diagnosis of diabetes requires confirmation with a second measurement unless there are clear symptoms of diabetes.

SOURCE: Centers for Disease Control and Prevention

As mentioned previously, normal levels of HbA1c are less than 6%, so a measurement over 6% is considered high. For many people with type 1 and type 2 diabetes, the goal is to keep the HbA1c levels under 7%, since keeping levels below 7% has been shown to delay the complications of diabetes.

Many laboratories report a calculated eAG (estimated average glucose) along with every HbA1c results. This is a correlation of the HbA1c levels with the average blood sugar level. For example, a HbA1c measurement of 7% corresponds to an eAG measurement of 154 mg/dl.

The American Diabetes Association has a calculator to help you convert your A1c level to the average blood glucose level (http://www.diabetes.org/living-with-diabetes/treatment-and-care/blood-glucose-control/a1c/).

In addition to random fasting blood glucose levels, HbA1c levels are routinely measured (tested) in the monitoring of people with type 1 and type 2 diabetes. HbA1c levels depend on the blood glucose concentration. That is, the higher the glucose concentration in blood, the higher the level of HbA1c. Levels of HbA1c are not influenced by daily fluctuations in the blood glucose concentration but reflect the average glucose levels over the prior six to eight weeks. Therefore, HbA1c is a useful indicator of how well the blood glucose level has been controlled in the recent past (over two to three months) and may be used to monitor the effects of diet, exercise, and drug therapy on blood glucose in people with diabetes.

Following your type 1 or type 2 diabetes management plan can help lower your HbA1c level. This may consist of

dietary modifications,

physical activity,

medications,

a combination of these.

A normal or only slightly elevated HbA1c level is an indication that your diabetes is under good control. If your HbA1c level remains high despite following your treatment plan, your doctor may suggest changing your treatment plan.

Since HbA1c is not influenced by daily fluctuations in blood glucose concentration, it cannot be used to monitor day-to-day blood glucose concentrations and is inappropriate to be used for adjusting insulin doses; nor can it detect the day-to-day presence or absence of hyperglycemia or hypoglycemia. HbA1c may be increased falsely in certain medical conditions. These conditions include

Medical conditions that may falsely decrease HbA1c include

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Hemoglobin A1c Test Normal & High Ranges (HbA1c Levels & Chart)

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Hemoglobin A1c (HbA1c) is a form of hemoglobin. The HbA1c test is a routine test for people with diabetes. The normal range of HbA1c is less than 6%, and measures blood glucose levels over a period of time. It cannot be used for daily blood glucose testing.

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The C-peptide test is a tool your doctor uses to monitor and treat diabetes. It shows how well your body makes insulin, which moves sugar (or "glucose") from your blood into your cells.

The test can help your doctor decide whether you need to take insulin to control your condition or to check your dosage if you already take it.

Doctors can use the test whether you have type 1 diabetes, when the immune system attacks and destroys cells in the pancreas, or type 2, when your body doesn't use insulin as well it should.

Where Does C-Peptide Come In?

Beta cells in your pancreas make insulin. During that process, these cells also release C-peptide.

This substance doesn't actually affect your blood sugar. But your doctor can measure the level of it to help her figure out how much insulin you're making.

Why Would I Get This Test?

Doctors don't use it to actually diagnose diabetes, but it can give them a reading to help treat it.

It can tell the difference between insulin your body has made and insulin that you took.

You might get the C-peptide test:

To find out whether you have type 1 or type 2 diabetes

When you have type 1 and your doctor needs to know how much insulin your pancreas still makes

When you have type 2 diabetes and she needs to measure how much insulin you make on you own -- or whether you need to begin taking it yet

To find out why you have low blood sugar (hypoglycemia)

To diagnose a tumor of the pancreas that releases insulin, called an insulinoma

If you've had your pancreas removed

How to Prepare

You might need to stop eating 8 to 10 hours before the test. Sometimes, it's done after you eat.

Let your doctor know about any medicines you are on. Include medicine you take by prescription and those you buy over the counter, such as herbal supplements or vitamins.

How Is It Done?

The C-peptide test uses a sample of your blood or urine.

To take a blood test, someone in your doctor's office or a lab places a needle into a vein, usually in your forearm. You may feel a slight prick. The blood will collect into a vial or syringe.

For a urine test, you will pee into a cup as instructed. For a 24-hour sample, you'll need to collect all that you produce in a day.

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Find out when your doctor might recommend the C-peptide test and what your results mean for your diabetes.

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compare and contrast type 1 and type 2 diabetes

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compare and contrast type 1 and type 2 diabetes

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There are two main types of diabetes: type 1 and type 2. Both types of diabetes are chronic diseases that affect the way your body regulates blood sugar, or glucose. Glucose is the fuel that feeds your body's cells, but to enter your cells it needs a key. Insulin is that key.

People with type 1 diabetes don't produce insulin. You can think of it as not having a key.

People with type 2 diabetes don't respond to insulin as well as they should and later in the disease often don't make enough insulin. You can think of this as having a broken key.

Both types of diabetes can lead to chronically high blood sugar levels. That increases the risk of diabetes complications.

Both types of diabetes, if not controlled, share many similar symptoms, including:

frequent urination

feeling very thirsty and drinking a lot

feeling very hungry

feeling very fatigued

blurry vision

cuts or sores that don't heal properly

People with type 1 diabetes may also experience irritability and mood changes, and unintentionally lose weight. People with type 2 diabetes may also have numbness and tingling in their hands or feet.

Although many of the symptoms of type 1 and type 2 diabetes are similar, they present in very different ways. Many people with type 2 diabetes won't have symptoms for many years. Then often the symptoms of type 2 diabetes develop slowly over the course of time. Some people with type 2 diabetes have no symptoms at all and don't discover their condition until complications develop.

The symptoms of type 1 diabetes develop fast, typically over the course of several weeks. Type 1 diabetes, which was once known as juvenile diabetes, usually develops in childhood or adolescence. But it's possible to get type 1 diabetes later in life.

Type 1 and type 2 diabetes may have similar names, but they are different diseases with unique causes.

Causes of type 1 diabetes

The body's immune system is responsible for fighting off foreign invaders, like harmful viruses and bacteria. In people with type 1 diabetes, the immune system mistakes the body's own healthy cells for foreign invaders. The immune system attacks and destroys the insulin-producing beta cells in the pancreas. After these beta cells are destroyed, the body is unable to produce insulin.

Researchers don't know why the immune system attacks the body's own cells. It may have something to do with genetic and environmental factors, like exposure to viruses. Research is ongoing.

Causes of type 2 diabetes

People with type 2 diabetes have insulin resistance. The body still produces insulin, but it's unable to use it effectively. Researchers aren't sure why some people become insulin resistant and others don't, but several lifestyle factors may contribute, including excess weight and inactivity.

Other genetic and environmental factors may also contribute. When you develop type 2 diabetes, your pancreas will try to compensate by producing more insulin. Because your body is unable to effectively use insulin, glucose will accumulate in your bloodstream.

Type 2 diabetes is much more common that type 1. According to the 2017 National Diabetes Statistics Report, there are 30.3 million people in the United States with diabetes. That's close to 1 in 10 people. Among all these people living with diabetes, 90 to 95 percent have type 2 diabetes.

The percentage of people with diabetes increases with age. Less than of the general population has diabetes, but among those 65 and older, the incidence rate reaches a high of 25.2 percent. Only about 0.18 percent of children under the age of 18 had diabetes in 2015.

Men and women get diabetes at roughly the same rate, but incidence rates are higher among certain races and ethnicities. American Indians and Alaskan Natives have the highest prevalence of diabetes among both men and women. The black and Hispanic populations have higher rates of diabetes than non-Hispanic whites.

Risk factors for type 1 diabetes include:

Family history: People with a parent or sibling with type 1 diabetes have a higher risk of developing it themselves.

Age: Type 1 diabetes can appear at any age, but it's most common among children and adolescents.

Geography: The prevalence of type 1 diabetes increases the farther away you are from the equator.

Genetics: The presence of some genes point to an increased risk of developing type 1 diabetes.

Type 1 diabetes can't be prevented.

You are at risk of developing type 2 diabetes if you:

have prediabetes (slightly elevated blood sugar levels)

are overweight or obese

have an immediate family member with type 2 diabetes

are over age 45

are physically inactive

have ever had gestational diabetes, which is diabetes during pregnancy

have given birth to a baby weighing more than 9 pounds

are African-American, Hispanic or Latino American, American Indian, or Alaska Native

have polycystic ovarian syndrome

have a lot of belly fat

It may be possible to lower your risk of developing type 2 diabetes through lifestyle changes:

Maintain a healthy weight.

If you're overweight, work with your doctor to develop a healthy weight-loss plan.

Increase your activity levels.

Eat a balanced diet, and reduce your intake of sugary or overly processed foods.

The primary test for both type 1 and type 2 diabetes is known as the glycated hemoglobin (A1C) test. An A1C test is a blood test that determines your average blood sugar level for the past two to three months. Your doctor may draw your blood or give you a small finger prick.

The higher your blood sugar levels have been over the past few months, the higher your A1C level will be. An A1C level of 6.5 or higher indicates diabetes.

There's no cure for type 1 diabetes. People with type 1 diabetes don't produce insulin, so it must be regularly injected into your body. Some people take injections into the soft tissue, such as the stomach, arm, or buttocks, several times per day. Other people use insulin pumps. Insulin pumps supply a steady amount of insulin into the body through a small tube.

Blood sugar testing is an essential part of managing type 1 diabetes, because levels can go up and down quickly.

Type 2 diabetes can be controlled and even reversed with diet and exercise alone, but many people need extra support. If lifestyle changes aren't enough, your doctor may prescribe medications that help your body use insulin more effectively.

Monitoring your blood sugar is an essential part of diabetes management because it's the only way to know if you're meeting your target levels. Your doctor may recommend testing your blood sugar occasionally or more frequently. If your blood sugars are high, your doctor may recommend insulin injections.

With careful monitoring, you can get your blood sugar levels back to normal and prevent the development of serious complications.

Nutritional management is an important part of life for people living with diabetes.

If you have type 1 diabetes, work with your doctor to identify how much insulin you may need to inject after eating certain types of food. For example, carbohydrates can cause blood sugar levels to quickly increase in people with type 1 diabetes. You'll need to counteract this by taking insulin, but you'll need to know how much insulin to take.

People with type 2 diabetes need to focus on healthy eating. Weight loss is often a part of type 2 diabetes treatment plans, so your doctor may recommend a low-calorie meal plan. This could mean reducing your consumption of animal fats and junk food.

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difference between type 1 and type 2 diabetes

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What's the Difference Between Type 1 and Type 2 Diabetes?

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There are two main types of diabetes: type 1 and type 2. Both types of diabetes are chronic diseases that affect the way your body regulates blood sugar, or glucose. Glucose is the fuel that feeds your body's cells, but to enter your cells it needs a key. Insulin is that key.

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Julia
https://bnf.nice.org.uk/treatment-summary/diabetic-ketoacidosis.html

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The NICE British National Formulary (BNF) site is only available to users in the UK, Crown Dependencies and British Overseas Territories.

If you believe you are seeing this page in error please contact us.

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The NICE British National Formulary (BNF) site is only available to users in the UK, Crown Dependencies and British Overseas Territories. If you believe you are seeing this page in error please contact us.

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Julia
search type one as well on the same website

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Diagnosis

Type 2 diabetes is usually diagnosed using the glycated hemoglobin (A1C) test. This blood test indicates your average blood sugar level for the past two to three months. Results are interpreted as follows:

Below 5.7% is normal.

5.7% to 6.4% is diagnosed as prediabetes.

6.5% or higher on two separate tests indicates diabetes.

If the A1C test isn't available, or if you have certain conditions that interfere with an A1C test, your health care provider may use the following tests to diagnose diabetes:

Random blood sugar test. Blood sugar values are expressed in milligrams of sugar per deciliter ( mg/dL) or millimoles of sugar per liter ( mmol/L) of blood. Regardless of when you last ate, a level of 200 mg/dL (11.1 mmol/L) or higher suggests diabetes, especially if you also have symptoms of diabetes, such as frequent urination and extreme thirst.

Fasting blood sugar test. A blood sample is taken after you haven't eaten overnight. Results are interpreted as follows:

Less than 100 mg/dL (5.6 mmol/L) is considered healthy.

100 to 125 mg/dL (5.6 to 6.9 mmol/L) is diagnosed as prediabetes.

126 mg/dL (7 mmol/L) or higher on two separate tests is diagnosed as diabetes.

Oral glucose tolerance test. This test is less commonly used than the others, except during pregnancy. You'll need to not eat for a certain amount of time and then drink a sugary liquid at your health care provider's office. Blood sugar levels then are tested periodically for two hours. Results are interpreted as follows:

Less than 140 mg/dL (7.8 mmol/L) after two hours is considered healthy.

140 to 199 mg/dL (7.8 mmol/L and 11.0 mmol/L) is diagnosed as prediabetes.

200 mg/dL (11.1 mmol/L) or higher after two hours suggests diabetes.

Screening. The American Diabetes Association recommends routine screening with diagnostic tests for type 2 diabetes in all adults age 35 or older and in the following groups:

After a diagnosis

If you're diagnosed with diabetes, your health care provider may do other tests to distinguish between type 1 and type 2 diabetes because the two conditions often require different treatments.

Your health care provider will test A1C levels at least two times a year and when there are any changes in treatment. Target A1C goals vary depending on age and other factors. For most people, the American Diabetes Association recommends an A1C level below 7%.

You also receive tests to screen for complications of diabetes and other medical conditions.

Treatment

Management of type 2 diabetes includes:

Healthy eating.

Regular exercise.

Weight loss.

Possibly, diabetes medication or insulin therapy.

Blood sugar monitoring.

These steps make it more likely that blood sugar will stay in a healthy range. And they may help to delay or prevent complications.

Healthy eating

There's no specific diabetes diet. However, it's important to center your diet around:

A regular schedule for meals and healthy snacks.

Smaller portion sizes.

More high-fiber foods, such as fruits, nonstarchy vegetables and whole grains.

Fewer refined grains, starchy vegetables and sweets.

Modest servings of low-fat dairy, low-fat meats and fish.

Healthy cooking oils, such as olive oil or canola oil.

Fewer calories.

Your health care provider may recommend seeing a registered dietitian, who can help you:

Physical activity

Exercise is important for losing weight or maintaining a healthy weight. It also helps with managing blood sugar. Talk to your health care provider before starting or changing your exercise program to ensure that activities are safe for you.

Aerobic exercise. Choose an aerobic exercise that you enjoy, such as walking, swimming, biking or running. Adults should aim for 30 minutes or more of moderate aerobic exercise on most days of the week, or at least 150 minutes a week.

Resistance exercise. Resistance exercise increases your strength, balance and ability to perform activities of daily living more easily. Resistance training includes weightlifting, yoga and calisthenics. Adults living with type 2 diabetes should aim for 2 to 3 sessions of resistance exercise each week.

Limit inactivity. Breaking up long periods of inactivity, such as sitting at the computer, can help control blood sugar levels. Take a few minutes to stand, walk around or do some light activity every 30 minutes.

Weight loss

Weight loss results in better control of blood sugar levels, cholesterol, triglycerides and blood pressure. If you're overweight, you may begin to see improvements in these factors after losing as little as 5% of your body weight. However, the more weight you lose, the greater the benefit to your health. In some cases, losing up to 15% of body weight may be recommended.

Your health care provider or dietitian can help you set appropriate weight-loss goals and encourage lifestyle changes to help you achieve them.

Monitoring your blood sugar

Your health care provider will advise you on how often to check your blood sugar level to make sure you remain within your target range. You may, for example, need to check it once a day and before or after exercise. If you take insulin, you may need to check your blood sugar multiple times a day.

Monitoring is usually done with a small, at-home device called a blood glucose meter, which measures the amount of sugar in a drop of blood. Keep a record of your measurements to share with your health care team.

Continuous glucose monitoring is an electronic system that records glucose levels every few minutes from a sensor placed under the skin. Information can be transmitted to a mobile device such as a phone, and the system can send alerts when levels are too high or too low.

Diabetes medications

If you can't maintain your target blood sugar level with diet and exercise, your health care provider may prescribe diabetes medications that help lower glucose levels, or your provider may suggest insulin therapy. Medicines for type 2 diabetes include the following.

Metformin (Fortamet, Glumetza, others) is generally the first medicine prescribed for type 2 diabetes. It works mainly by lowering glucose production in the liver and improving the body's sensitivity to insulin so it uses insulin more effectively.

Some people experience B-12 deficiency and may need to take supplements. Other possible side effects, which may improve over time, include:

Sulfonylureas help the body secrete more insulin. Examples include glyburide (DiaBeta, Glynase), glipizide (Glucotrol XL) and glimepiride (Amaryl). Possible side effects include:

Glinides stimulate the pancreas to secrete more insulin. They're faster acting than sulfonylureas. But their effect in the body is shorter. Examples include repaglinide and nateglinide. Possible side effects include:

Thiazolidinediones make the body's tissues more sensitive to insulin. An example of this medicine is pioglitazone (Actos). Possible side effects include:

DPP-4 inhibitors help reduce blood sugar levels but tend to have a very modest effect. Examples include sitagliptin (Januvia), saxagliptin (Onglyza) and linagliptin (Tradjenta). Possible side effects include:

GLP-1 receptor agonists are injectable medications that slow digestion and help lower blood sugar levels. Their use is often associated with weight loss, and some may reduce the risk of heart attack and stroke. Examples include exenatide (Byetta, Bydureon Bcise), liraglutide (Saxenda, Victoza) and semaglutide (Rybelsus, Ozempic, Wegovy). Possible side effects include:

SGLT2 inhibitors affect the blood-filtering functions in the kidneys by blocking the return of glucose to the bloodstream. As a result, glucose is removed in the urine. These medicines may reduce the risk of heart attack and stroke in people with a high risk of those conditions. Examples include canagliflozin (Invokana), dapagliflozin (Farxiga) and empagliflozin (Jardiance). Possible side effects include:

Vaginal yeast infections.

Urinary tract infections.

Low blood pressure.

High cholesterol.

Risk of gangrene.

Risk of bone fractures (canagliflozin).

Risk of amputation (canagliflozin).

Other medicines your health care provider might prescribe in addition to diabetes medications include blood pressure and cholesterol-lowering medicines, as well as low-dose aspirin, to help prevent heart and blood vessel disease.

Insulin therapy

Some people who have type 2 diabetes need insulin therapy. In the past, insulin therapy was used as a last resort, but today it may be prescribed sooner if blood sugar targets aren't met with lifestyle changes and other medicines.

Different types of insulin vary on how quickly they begin to work and how long they have an effect. Long-acting insulin, for example, is designed to work overnight or throughout the day to keep blood sugar levels stable. Short-acting insulin generally is used at mealtime.

Your health care provider will determine what type of insulin is right for you and when you should take it. Your insulin type, dosage and schedule may change depending on how stable your blood sugar levels are. Most types of insulin are taken by injection.

Side effects of insulin include the risk of low blood sugar - a condition called hypoglycemia - diabetic ketoacidosis and high triglycerides.

Weight-loss surgery

Weight-loss surgery changes the shape and function of the digestive system. This surgery may help you lose weight and manage type 2 diabetes and other conditions related to obesity. There are several surgical procedures. All of them help people lose weight by limiting how much food they can eat. Some procedures also limit the amount of nutrients the body can absorb.

Weight-loss surgery is only one part of an overall treatment plan. Treatment also includes diet and nutritional supplement guidelines, exercise and mental health care.

Generally, weight-loss surgery may be an option for adults living with type 2 diabetes who have a body mass index (BMI) of 35 or higher. BMI is a formula that uses weight and height to estimate body fat. Depending on the severity of diabetes or the presence of other medical conditions, surgery may be an option for someone with a BMI lower than 35.

Weight-loss surgery requires a lifelong commitment to lifestyle changes. Long-term side effects may include nutritional deficiencies and osteoporosis.

Pregnancy

People living with type 2 diabetes often need to change their treatment plan during pregnancy and follow a diet that controls carbohydrates. Many people need insulin therapy during pregnancy. They also may need to stop other treatments, such as blood pressure medicines.

There is an increased risk during pregnancy of developing a condition that affects the eyes called diabetic retinopathy. In some cases, this condition may get worse during pregnancy. If you are pregnant, visit an ophthalmologist during each trimester of your pregnancy and one year after you give birth. Or as often as your health care provider suggests.

Signs of trouble

Regularly monitoring your blood sugar levels is important to avoid severe complications. Also, be aware of symptoms that may suggest irregular blood sugar levels and the need for immediate care:

High blood sugar. This condition also is called hyperglycemia. Eating certain foods or too much food, being sick, or not taking medications at the right time can cause high blood sugar. Symptoms include:

Hyperglycemic hyperosmolar nonketotic syndrome (HHNS). This life-threatening condition includes a blood sugar reading higher than 600 mg/dL (33.3 mmol/L). HHNS may be more likely if you have an infection, are not taking medicines as prescribed, or take certain steroids or drugs that cause frequent urination. Symptoms include:

Diabetic ketoacidosis. Diabetic ketoacidosis occurs when a lack of insulin results in the body breaking down fat for fuel rather than sugar. This results in a buildup of acids called ketones in the bloodstream. Triggers of diabetic ketoacidosis include certain illnesses, pregnancy, trauma and medicines - including the diabetes medicines called SGLT2 inhibitors.

The toxicity of the acids made by diabetic ketoacidosis can be life-threatening. In addition to the symptoms of hyperglycemia, such as frequent urination and increased thirst, ketoacidosis may cause:

Nausea.

Vomiting.

Abdominal pain.

Shortness of breath.

Fruity-smelling breath.

Low blood sugar. If your blood sugar level drops below your target range, it's known as low blood sugar. This condition also is called hypoglycemia. Your blood sugar level can drop for many reasons, including skipping a meal, unintentionally taking more medication than usual or being more physically active than usual. Symptoms include:

If you have symptoms of low blood sugar, drink or eat something that will quickly raise your blood sugar level. Examples include fruit juice, glucose tablets, hard candy or another source of sugar. Retest your blood in 15 minutes. If levels are not at your target, eat or drink another source of sugar. Eat a meal after your blood sugar level returns to normal.

If you lose consciousness, you need to be given an emergency injection of glucagon, a hormone that stimulates the release of sugar into the blood.

More Information

Show more related information

Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

Careful management of type 2 diabetes can reduce the risk of serious - even life-threatening - complications. Consider these tips:

Commit to managing your diabetes. Learn all you can about type 2 diabetes. Make healthy eating and physical activity part of your daily routine.

Work with your team. Establish a relationship with a certified diabetes education specialist, and ask your diabetes treatment team for help when you need it.

Identify yourself. Wear a necklace or bracelet that says you are living with diabetes, especially if you take insulin or other blood sugar-lowering medicine.

Schedule a yearly physical exam and regular eye exams. Your diabetes checkups aren't meant to replace regular physicals or routine eye exams.

Keep your vaccinations up to date. High blood sugar can weaken your immune system. Get a flu shot every year. Your health care provider also may recommend the pneumonia vaccine. The Centers for Disease Control and Prevention (CDC) also recommends the hepatitis B vaccination if you haven't previously received this vaccine and you're 19 to 59 years old. Talk to your health care provider about other vaccinations you may need.

Take care of your teeth. Diabetes may leave you prone to more-serious gum infections. Brush and floss your teeth regularly and schedule recommended dental exams. Contact your dentist right away if your gums bleed or look red or swollen.

Pay attention to your feet. Wash your feet daily in lukewarm water, dry them gently, especially between the toes, and moisturize them with lotion. Check your feet every day for blisters, cuts, sores, redness and swelling. Contact your health care provider if you have a sore or other foot problem that isn't healing.

Keep your blood pressure and cholesterol under control. Eating healthy foods and exercising regularly can go a long way toward controlling high blood pressure and cholesterol. Take medication as prescribed.

If you smoke or use other types of tobacco, ask your health care provider to help you quit. Smoking increases your risk of diabetes complications. Talk to your health care provider about ways to stop using tobacco.

Use alcohol sparingly. Depending on the type of drink, alcohol may lower or raise blood sugar levels. If you choose to drink alcohol, only do so with a meal. The recommendation is no more than one drink daily for women and no more than two drinks daily for men. Check your blood sugar frequently after drinking alcohol.

Make healthy sleep a priority. Many people with type 2 diabetes have sleep problems. And not getting enough sleep may make it harder to keep blood sugar levels in a healthy range. If you have trouble sleeping, talk to your health care provider about treatment options.

Alternative medicine

Many alternative medicine treatments claim to help people living with diabetes. According to the National Center for Complementary and Integrative Health, studies haven't provided enough evidence to recommend any alternative therapies for blood sugar management. Research has shown the following results about popular supplements for type 2 diabetes:

Chromium supplements have been shown to have few or no benefits. Large doses can result in kidney damage, muscle problems and skin reactions.

Magnesium supplements have shown benefits for blood sugar control in some but not all studies. Side effects include diarrhea and cramping. Very large doses - more than 5,000 mg a day - can be fatal.

Cinnamon, in some studies, has lowered fasting glucose levels but not A1C levels. Therefore, there's no evidence of overall improved glucose management.

Talk to your health care provider before starting a dietary supplement or natural remedy. Do not replace your prescribed diabetes medicines with alternative medicines.

Coping and support

Type 2 diabetes is a serious disease, and following your diabetes treatment plan takes commitment. To effectively manage diabetes, you may need a good support network.

Anxiety and depression are common in people living with diabetes. Talking to a counselor or therapist may help you cope with the lifestyle changes and stress that come with a type 2 diabetes diagnosis.

Support groups can be good sources of diabetes education, emotional support and helpful information, such as how to find local resources or where to find carbohydrate counts for a favorite restaurant. If you're interested, your health care provider may be able to recommend a group in your area.

You can visit the American Diabetes Association website to check out local activities and support groups for people living with type 2 diabetes. The American Diabetes Association also offers online information and online forums where you can chat with others who are living with diabetes. You also can call the organization at 800-DIABETES (800-342-2383).

Preparing for your appointment

At your annual wellness visit, your health care provider can screen for diabetes and monitor and treat conditions that increase your risk of diabetes, such as high blood pressure, high cholesterol or a high BMI.

If you are seeing your health care provider because of symptoms that may be related to diabetes, you can prepare for your appointment by being ready to answer the following questions:

When did your symptoms begin?

Does anything improve the symptoms or worsen the symptoms?

What medicines do you take regularly, including dietary supplements and herbal remedies?

What are your typical daily meals? Do you eat between meals or before bedtime?

How much alcohol do you drink?

How much daily exercise do you get?

Is there a history of diabetes in your family?

If you are diagnosed with diabetes, your health care provider may begin a treatment plan. Or you may be referred to a doctor who specializes in hormonal disorders, called an endocrinologist. Your care team also may include the following specialists:

Talk to your health care provider about referrals to other specialists who may be providing care.

Questions for ongoing appointments

Before any appointment with a member of your treatment team, make sure you know whether there are any restrictions, such as not eating or drinking before taking a test. Questions that you should regularly talk about with your health care provider or other members of the team include:

How often do I need to monitor my blood sugar, and what is my target range?

What changes in my diet would help me better manage my blood sugar?

What is the right dosage for prescribed medications?

When do I take the medications? Do I take them with food?

How does management of diabetes affect treatment for other conditions? How can I better coordinate treatments or care?

When do I need to make a follow-up appointment?

Under what conditions should I call you or seek emergency care?

Are there brochures or online sources you recommend?

Are there resources available if I'm having trouble paying for diabetes supplies?

What to expect from your doctor

Your health care provider is likely to ask you questions at your appointments. Those questions may include:

Do you understand your treatment plan and feel confident you can follow it?

How are you coping with diabetes?

Have you had any low blood sugar?

Do you know what to do if your blood sugar is too low or too high?

What's a typical day's diet like?

Are you exercising? If so, what type of exercise? How often?

Do you sit for long periods of time?

What challenges are you experiencing in managing your diabetes?

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High blood sugar levels are the main problem in diabetes. Learn about lifestyle changes to lower the risk and treatments to manage type 2 diabetes.

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Julia
https://www.youtube.com/watch?v=XAnMhq_dX0k

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An abortion is a procedure to end a pregnancy.
It's also sometimes known as a termination of pregnancy.

The pregnancy is ended either by taking medicines or having a surgical procedure.

How to get an abortion

Abortions can only be carried out under the care of an NHS hospital or a licensed clinic, and are usually available free of charge on the NHS.

If you're less than 10 weeks pregnant you may be able to have a medical abortion at home after an initial appointment with the hospital or clinic.

There are 3 main ways to get an abortion on the NHS:

Waiting times can vary, but you should not have to wait more than 2 weeks from when you (or a doctor) first contact an abortion provider to having an abortion.

You can also pay for an abortion privately (not on the NHS) if you prefer. Costs for private abortions vary depending on the stage of pregnancy and the method used to carry out the procedure.

When an abortion can be carried out

Most abortions in England, Wales and Scotland are carried out before 24 weeks of pregnancy.

They can be carried out after 24 weeks in very limited circumstances - for example, if the mother's life is at risk or the child would be born with a severe disability.

Most abortion services will ask to perform an ultrasound scan to work out how many weeks pregnant you are. The length of pregnancy is calculated from the first day of your last period.

Abortions are safer the earlier they're carried out. Getting advice early on will give you more time to make a decision if you're unsure.

Deciding to have an abortion

The decision to have an abortion is yours alone.

Some women may be certain they want to have an abortion, while others may find it more difficult to make a decision.

All women requesting an abortion can discuss their options with, and receive support from, a trained pregnancy counsellor if they wish.

Impartial information and support are available from:

You may also want to speak to your partner, friends or family, but you do not have to. They do not have a say in your decision.

If you do not want to tell anyone, your details will be kept confidential.

If you're under 16, your parents do not usually need to be told. The doctor or nurse may encourage you to tell a parent, carer or other adult you trust, but they will not make you.

There are organisations, usually known as crisis pregnancy centres, that offer counselling around pregnancy. They do not refer people for abortion, and may not offer balanced or accurate advice.

If you go to a place that offers pregnancy counselling and you're not sure if they will refer you for an abortion, ask if they refer people for an abortion.

What happens during an abortion

Before having an abortion, you'll have an appointment to talk about your decision and what happens next.

Whenever possible, you should be given a choice of how you would like the abortion to be carried out.

There are 2 options:

medical abortion ("abortion pill") - you take 2 medicines, usually 24 to 48 hours apart, to induce an abortion

surgical abortion - you have a procedure to remove the pregnancy and normally go home soon afterwards

After an abortion, you'll probably need to take things easy for a few days. It's likely you'll have some discomfort and vaginal bleeding for up to 2 weeks.

Read more about how an abortion is carried out.

Risks of an abortion

Abortion is a safe procedure. Abortions are safest, and happen with less pain and bleeding, when carried out as early as possible in pregnancy.

Most women will not experience any problems, but there is a small risk of complications, such as:

infection of the womb (uterus)

some of the pregnancy remaining in the womb

excessive bleeding

damage to the womb or entrance of the womb (cervix)

If complications do occur, you may need further treatment, including surgery.

Having an abortion will not affect your chances of becoming pregnant again and having normal pregnancies in the future.

You may be able to get pregnant immediately after an abortion. You should use contraception if you do not want to get pregnant.

Read more about the risks of abortion.

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Find out what an abortion involves, how you can get one on the NHS, and what support is available to help you make a decision.

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NICE guidelines for diabetes in pregnancy-riccardo

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NICE guidelines for diabetes in pregnancy-riccardo

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Diabetes in pregnancy: management from preconception to the postnatal period | Guidance and guidelines | NICE

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Evidence-based recommendations on managing diabetes in pregnancy and its complications from pre-conception until after the birth

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Diabetes checks are extremely important

Diabetes check ups are an extremely important part of diabetes care.

There are some diabetes checks that you can carry out at home with others offered by the NHS.

These checks are a vital part of weekly, monthly and annual diabetes care. There are some types of diabetes checks that you can carry out at home, and others are offered by the NHS.

This includes glucose control, foot care, weight, and keeping a diary.

Checks for diabetes is where the individual can really make a difference to their own diabetes management, above and beyond the check ups offered by healthcare professionals.

Diabetes check ups for newly diagnosed people with diabetes

Diabetes check ups for children are a specialist subject, and parents and children will be taught how to check up on their diabetes by specialist diabetes healthcare professionals.

For adults, there are a range of educational courses to help people with diabetes understand their condition.

These courses include DAFNE and Bertie for type 1 diabetes, and DESMOND and XPERT for type 2 diabetes.

These courses help show adults the type of diabetes check ups needed to ensure good diabetes care.

Education should include weight guidance, testing blood sugar, and how to look after your feet and eyes.

Daily diabetes check ups

Daily diabetes check ups should include feet and blood sugar.

Daily foot check ups are essential for people with diabetes.

Especially for those with a history of diabetes neuropathy, foot infections can spread very quickly.

Checking feet daily is a way to identify problems early. Daily blood glucose testing is not recommended for all diabetics, but Diabetes UK advises that all diabetics should test their blood sugar.

Testing and understanding what your blood sugar results mean is an essential way to manage diabetes. Understanding what to do if blood glucose is low or high is the key.

Diabetes check ups help you to stay on top of your diabetes. Check ups are the best place to discuss medication regimes, lifestyle and any factors that can impact upon your diabetes control.

Children will have their diabetes care managed by a paediatric team that will be used to dealing with children with type 1 diabetes.

Clinics may be run once every 6 months, depending on your child's needs. Clinics give children and parents a chance to discuss diabetes management and regimes with a consultant.

Adults with diabetes should receive a diabetes review at least once each year. People newly diagnosed with diabetes, or with conditions that need closer monitoring, should receive more regular reviews.

Reviews may be with a consultant, GP or a practice nurse depending on your area and your needs. A number of health checks may be run as part of your diabetes care. The following should take place once a year for all people with diabetes except under 12s:

HbA1c test - a test for long term blood sugar control

A cholesterol (or blood lipids) test

A kidney function test

Blood pressure measurement

Foot checks

Body weight measurement

Diabetes reviews are a useful way to learn about diabetes. Bring along any questions you have for your doctor to answer. Diabetes can be a lot to take and you may wish to request to join a diabetes education course in your area.

Education courses are available for type 1 and type 2 diabetes.

Your diabetes nurse will give you the training necessary to test and understand blood glucose levels.

1 week-3 monthly check ups

A variety of weekly and monthly check ups can help you to look after your diabetes. HbA1c tests provide a three monthly guide to your average blood glucose levels. You should also check blood pressure monthly and review medication monthly.

If you are trying to lose weight, check your weight every week and visit your clinic if you need further help.

Professional check ups for diabetes

Whether you are trying to gain between control of weight, blood pressure or blood glucose professional help from your diabetes specialist nurse can help you to understand more about what your check ups mean. This type of monthly check is essential for those who are striving for good control. Regular patient-nurse contact for check ups is the key to excellent diabetes control.

Annual check ups for diabetes

Your diabetes doctor or nurse should conduct annual tests for a variety of different diabetes complications. Many people with diabetes simply don't get the check ups they need, and even if they do the results are often not acted upon.

Remember to share personal information with your doctor, including how you are feeling. Annual check ups should include eyes, feet, circulation, diet, weight, neuropathy, heart, blood pressure, thyroid, electrolytes, cholesterol, blood and more.

Annual educational check up

Diabetes check ups should include education.

Annual educational check up should include:

Diet

Lifestyle

Insulin (if type 1 diabetic)

Testing blood glucose

Blood pressure

Cardiovascular risk

Relevant educational programs

Keep a diary to support your diabetes check ups

Check ups with healthcare professionals can be made much easier by keeping a diary. Diabetes specialist nurses should check your diary and inform you about your progress.

Write down your day to day problems, sugar levels and the results of your check ups. This could help you to fight diabetes complications.

Use the Internet to support your diabetes check ups

Diabetes check ups can be made much easier by using the Internet for support. The internet helps to improve contact between patients and fellow patients, and patients and professionals.

Join the Diabetes Newsletter

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Diabetes check ups are an extremely important part of diabetes care. There are some diabetes checks that you can carry out at home with others offered by the NHS.

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VIAGRA®
(sildenafil citrate) Tablets

DESCRIPTION

VIAGRA (sildenafil citrate), an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula:

Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7.

VIAGRA is formulated as blue, film-coated rounded-diamond-shaped tablets equivalent to 25 mg, 50 mg and 100 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake.

INDICATIONS

VIAGRA is indicated for the treatment of erectile dysfunction.

DOSAGE AND ADMINISTRATION

Dosage Information

For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, VIAGRA may be taken anywhere from 30 minutes to 4 hours before sexual activity. The maximum recommended dosing frequency is once per day.

Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg.

Use With Food

VIAGRA may be taken with or without food.

Dosage Adjustments In Specific Situations

VIAGRA was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors such as organic nitrates or organic nitrites in any form is therefore contraindicated [seeCONTRAINDICATIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

When VIAGRA is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at 25 mg [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

Dosage Adjustments Due To Drug Interactions

Ritonavir

The recommended dose for ritonavir-treated patients is 25 mg prior to sexual activity and the recommended maximum dose is 25 mg within a 48 hour period because concomitant administration increased the blood levels of sildenafil by 11-fold [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

CYP3A4 Inhibitors

Consider a starting dose of 25 mg in patients treated with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or saquinavir) or erythromycin. Clinical data have shown that co-administration with saquinavir or erythromycin increased plasma levels of sildenafil by about 3 fold [seeDRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Dosage Adjustments In Special Populations

Consider a starting dose of 25 mg in patients > 65 years, patients with hepatic impairment (e.g., cirrhosis), and patients with severe renal impairment (creatinine clearance < 30 mL/minute) because administration of VIAGRA in these patients resulted in higher plasma levels of sildenafil [see Use in Specific Populations and CLINICAL PHARMACOLOGY].

HOW SUPPLIED

Dosage Forms And Strengths

VIAGRA is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to 25 mg, 50 mg, or 100 mg of sildenafil. Tablets are debossed with PFIZER on one side and VGR25, VGR50 or VGR100 on the other to indicate the dosage strengths.

Storage And Handling

VIAGRA (sildenafil citrate) is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil and debossed on the obverse and reverse sides as follows:

Recommended Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Distributed by: Pfizer Labs, Division of Pfizer Inc., NY, NY 10017. Revised: Sep 2015

SIDE EFFECTS

The following are discussed in more detail in other sections of the labeling:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

VIAGRA was administered to over 3700 patients (aged 19-87 years) during pre-marketing clinical trials worldwide. Over 550 patients were treated for longer than one year.

In placebo-controlled clinical studies, the discontinuation rate due to adverse reactions for VIAGRA (2.5%) was not significantly different from placebo (2.3%).

In fixed-dose studies, the incidence of some adverse reactions increased with dose. The type of adverse reactions in flexible-dose studies, which reflect the recommended dosage regimen, was similar to that for fixed-dose studies. At doses above the recommended dose range, adverse reactions were similar to those detailed in Table 1 below but generally were reported more frequently.

Table 1: Adverse Reactions Reported by ≥ 2% of Patients Treated with VIAGRA and More Frequent than Placebo in Fixed-Dose Phase II/III Studies

†Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision.

When VIAGRA was taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials of two to twenty-six weeks duration, patients took VIAGRA at least once weekly, and the following adverse reactions were reported:

Table 2: Adverse Reactions Reported by ≥ 2% of Patients Treated with VIAGRA and More Frequent than Placebo in Flexible-Dose Phase II/III Studies

†Abnormal Vision: Mild and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision.

The following events occurred in < 2% of patients in controlled clinical trials; a causal relationship to VIAGRA is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful:

Body as a Whole: face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury.

Cardiovascular: angina pectoris, AV block, migraine, syncope, tachycardia, palpitation, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy.

Digestive: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, liver function tests abnormal, rectal hemorrhage, gingivitis.

Hemic and Lymphatic: anemia and leukopenia.

Metabolic and Nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia.

Musculoskeletal: arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

Nervous: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, reflexes decreased, hypesthesia.

Respiratory: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, cough increased.

Skin and Appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis.

Special Senses: sudden decrease or loss of hearing, mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, ear pain, eye hemorrhage, cataract, dry eyes.

Urogenital: cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence, abnormal ejaculation, genital edema and anorgasmia.

Analysis of the safety database from controlled clinical trials showed no apparent difference in adverse reactions in patients taking VIAGRA with and without anti-hypertensive medication. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of VIAGRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors.

Cardiovascular and Cerebrovascular

Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of VIAGRA. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of VIAGRA without sexual activity. Others were reported to have occurred hours to days after the use of VIAGRA and sexual activity. It is not possible to determine whether these events are related directly to VIAGRA, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors [see WARNINGS AND PRECAUTIONS and PATIENT INFORMATION].

Hemic and Lymphatic: vaso-occlusive crisis: In a small, prematurely terminated study of REVATIO (sildenafil) in patients with pulmonary arterial hypertension (PAH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported in patients who received sildenafil than in those randomized to placebo. The clinical relevance of this finding to men treated with VIAGRA for ED is not known.

Nervous: seizure, seizure recurrence, anxiety, and transient global amnesia.

Special senses

Hearing: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including VIAGRA. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of VIAGRA, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors [see WARNINGS AND PRECAUTIONS andPATIENT INFORMATION].

Ocular: diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal edema, retinal vascular disease or bleeding, and vitreous traction/detachment.

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including VIAGRA. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors [see WARNINGS AND PRECAUTIONS and PATIENT INFORMATION].

Urogenital: prolonged erection, priapism [see WARNINGS AND PRECAUTIONS and PATIENT INFORMATION], and hematuria.

DRUG INTERACTIONS

Nitrates

Administration of VIAGRA with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Consistent with its known effects on the nitric oxide/cGMP pathway, VIAGRA was shown to potentiate the hypotensive effects of nitrates [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, CLINICAL PHARMACOLOGY].

Alpha-blockers

Use caution when co-administering alpha-blockers with VIAGRA because of potential additive blood pressure-lowering effects. When VIAGRA is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Amlodipine

When VIAGRA 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Ritonavir And Other CYP3A4 Inhibitors

Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC). It is therefore recommended not to exceed a maximum single dose of 25 mg of VIAGRA in a 48 hour period [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in a 160% and 182% increases in sildenafil Cmax and AUC, respectively. Co-administration of saquinavir, a strong CYP3A4 inhibitor, resulted in 140% and 210% increases in sildenafil Cmax and AUC, respectively. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir. A starting dose of 25 mg of VIAGRA should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itraconazole) [seeDOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Alcohol

In a drug-drug interaction study sildenafil 50 mg given with alcohol 0.5 g/kg in which mean maximum blood alcohol levels of 0.08% was achieved, sildenafil did not potentiate the hypotensive effect of alcohol in healthy volunteers [see CLINICAL PHARMACOLOGY].

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiovascular

There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including VIAGRA, should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment.

VIAGRA has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg), [see CLINICAL PHARMACOLOGY]. While this normally would be expected to be of little consequence in most patients, prior to prescribing VIAGRA, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.

Use with caution in patients with the following underlying conditions which can be particularly sensitive to the actions of vasodilators including VIAGRA - those with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure.

There are no controlled clinical data on the safety or efficacy of VIAGRA in the following groups; if prescribed, this should be done with caution.

Prolonged Erection And Priapism

Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

Effects On The Eye

Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including VIAGRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥ 50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2 fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [seeADVERSE REACTIONS].

Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including VIAGRA, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including VIAGRA, for this uncommon condition.

There are no controlled clinical data on the safety or efficacy of VIAGRA in patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); if prescribed, this should be done with caution.

Hearing Loss

Physicians should advise patients to stop taking PDE5 inhibitors, including VIAGRA, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including VIAGRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [seeADVERSE REACTIONS].

Hypotension When Co-administered With Alpha-blockers Or Anti-hypertensives

Alpha-blockers

Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including VIAGRA, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may occur. In some patients, concomitant use of these two drug classes can lower blood pressure significantly [see DRUG INTERACTIONS andCLINICAL PHARMACOLOGY] leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting).

Consideration should be given to the following:

Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor.

In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose [see DOSAGE AND ADMINISTRATION].

In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.

Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

Anti-hypertensives

VIAGRA has systemic vasodilatory properties and may further lower blood pressure in patients taking antihypertensive medications.

In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and VIAGRA, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Adverse Reactions With The Concomitant Use Of Ritonavir

The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of sildenafil (11-fold increase in AUC). If VIAGRA is prescribed to patients taking ritonavir, caution should be used. Data from subjects exposed to high systemic levels of sildenafil are limited. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of sildenafil (200-800 mg). To decrease the chance of adverse reactions in patients taking ritonavir, a decrease in sildenafil dosage is recommended [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

Combination With Other PDE5 Inhibitors Or Other Erectile Dysfunction Therapies

The safety and efficacy of combinations of VIAGRA with other PDE5 Inhibitors, including REVATIO or other pulmonary arterial hypertension ( PAH) treatments containing sildenafil, or other treatments for erectile dysfunction have not been studied. Such combinations may further lower blood pressure. Therefore, the use of such combinations is not recommended.

Effects On Bleeding

There have been postmarketing reports of bleeding events in patients who have taken VIAGRA. A causal relationship between VIAGRA and these events has not been established. In humans, VIAGRA has no effect on bleeding time when taken alone or with aspirin. However, in vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). In addition, the combination of heparin and VIAGRA had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans.

The safety of VIAGRA is unknown in patients with bleeding disorders and patients with active peptic ulceration.

Counseling Patients About Sexually Transmitted Diseases

The use of VIAGRA offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus ( HIV), may be considered.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION)

Nitrates

Physicians should discuss with patients the contraindication of VIAGRA with regular and/or intermittent use of nitric oxide donors, such as organic nitrates or organic nitrites in any form [seeCONTRAINDICATIONS].

Guanylate Cyclase (GC) Stimulators

Physicians should discuss with patients the contraindication of VIAGRA with use of guanylate cyclase stimulators such as riociguat [see CONTRAINDICATIONS].

Concomitant Use with Drugs Which Lower Blood Pressure

Physicians should advise patients of the potential for VIAGRA to augment the blood pressure lowering effect of alpha-blockers and anti-hypertensive medications. Concomitant administration of VIAGRA and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, when VIAGRA is co-administered with alpha-blockers, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose [see WARNINGS AND PRECAUTIONS].

Cardiovascular Considerations

Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms (e.g., angina pectoris, dizziness, nausea) upon initiation of sexual activity should be advised to refrain from further activity and should discuss the episode with their physician [see WARNINGS AND PRECAUTIONS].

Sudden Loss of Vision

Physicians should advise patients to stop use of all PDE5 inhibitors, including VIAGRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including possible permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a "crowded" optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including VIAGRA, for this uncommon condition [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Sudden Hearing Loss

Physicians should advise patients to stop taking PDE5 inhibitors, including VIAGRA, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including VIAGRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Priapism

Physicians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result [see WARNINGS AND PRECAUTIONS].

Avoid Use with other PDE5 Inhibitors

Physicians should inform patients not to take VIAGRA with other PDE5 inhibitors including REVATIO or other pulmonary arterial hypertension (PAH) treatments containing sildenafil. Sildenafil is also marketed as REVATIO for the treatment of PAH. The safety and efficacy of VIAGRA with other PDE5 inhibitors, including REVATIO, have not been studied [see WARNINGS AND PRECAUTIONS].

Sexually Transmitted Disease

The use of VIAGRA offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29-and 42-times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m² basis.

Mutagenesis

Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity.

Impairment of Fertility

There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC.

Use In Specific Populations

Pregnancy

Pregnancy Category B.

VIAGRA is not indicated for use in women. There are no adequate and well-controlled studies of sildenafil in pregnant women.

Risk Summary

Based on animal data, VIAGRA is not predicted to increase the risk of adverse developmental outcomes in humans.

Animal Data

No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 20 and 40 times the Maximum Recommended Human Dose (MRHD) on a mg/m² basis in a 50 kg subject. In the rat pre-and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days. In the nonpregnant rat the AUC at this dose was about 20 times human AUC.

Pediatric Use

VIAGRA is not indicated for use in pediatric patients. Safety and effectiveness have not been established in pediatric patients.

Geriatric Use

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18-45 years) [see CLINICAL PHARMACOLOGY]. Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [see CLINICAL PHARMACOLOGY].

Of the total number of subjects in clinical studies of Viagra, 18% were 65 years and older, while 2% were 75 years and older. No overall differences in safety or efficacy were observed between older ( > 65 years of age) and younger ( < 65 years of age) subjects.

However, since higher plasma levels may increase the incidence of adverse reactions, a starting dose of 25 mg should be considered in older subjects due to the higher systemic exposure [see DOSAGE AND ADMINISTRATION].

Renal Impairment

No dose adjustment is required for mild (CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment. In volunteers with severe renal impairment (Clcr < 30 mL/min), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (~2 fold), approximately doubling of Cmax and AUC. A starting dose of 25 mg should be considered in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION andCLINICAL PHARMACOLOGY].

Hepatic Impairment

In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for C max and 85% for AUC). The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied. A starting dose of 25 mg should be considered in patients with any degree of hepatic impairment [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

OVERDOSE

In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence rates and severities were increased.

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

CONTRAINDICATIONS

Nitrates

Consistent with its known effects on the nitric oxide/cGMP pathway [see CLINICAL PHARMACOLOGY], VIAGRA was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using nitric oxide donors such as organic nitrates or organic nitrites in any form either regularly and/or intermittently is therefore contraindicated.

After patients have taken VIAGRA, it is unknown when nitrates, if necessary, can be safely administered. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

Hypersensitivity Reactions

VIAGRA is contraindicated in patients with a known hypersensitivity to sildenafil, as contained in VIAGRA and REVATIO, or any component of the tablet. Hypersensitivity reactions have been reported, including rash and urticaria [see ADVERSE REACTIONS].

Concomitant Guanylate Cyclase (GC) Stimulators

Do not use VIAGRA in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including VIAGRA, may potentiate the hypotensive effects of GC stimulators.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.

Binding Characteristics

Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, > 80-fold for PDE1, > 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [see Pharmacodynamics].

In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.

Pharmacodynamics

Effects of VIAGRA on Erectile Response

In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan®), after VIAGRA administration compared with placebo. Most studies assessed the efficacy of VIAGRA approximately 60 minutes post dose. The erectile response, as assessed by RigiScan®, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours.

Effects of VIAGRA on Blood Pressure

Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/ diastolic blood pressure of 8.3/5.3 mmHg). The decrease in sitting blood pressure was most notable approximately 1-2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of VIAGRA, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [seeCONTRAINDICATIONS].

Figure 1: Mean Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers

Effects of VIAGRA on Blood Pressure When Nitroglycerin is Subsequently Administered

Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). In the following patients: age > 65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance < 30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [seeCONTRAINDICATIONS].

Effects of VIAGRA on Blood Pressure When Co-administered with Alpha-Blockers

Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of VIAGRA with doxazosin, an alpha-adrenergic blocking agent.

Study 1: VIAGRA with Doxazosin

In the first study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14 consecutive daily doses of doxazosin, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the VIAGRA dose was reduced to 25 mg. Thereafter, 17 subjects were treated with VIAGRA 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects). The mean subject age was 66.5 years.

For the 17 subjects who received VIAGRA 25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:

The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg VIAGRA or matching placebo are shown in Figure 2.

Figure 2: Mean Standing Systolic Blood Pressure Change from Baseline

Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after VIAGRA or matching placebo. Outliers were defined as subjects with a standing systolic blood pressure of < 85 mmHg or a decrease from baseline in standing systolic blood pressure of > 30 mmHg at one or more timepoints. There were no subjects treated with VIAGRA 25 mg who had a standing SBP < 85mmHg. There were three subjects with a decrease from baseline in standing systolic BP > 30mmHg following VIAGRA 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group.

Study 2: VIAGRA with Doxazosin

In the second study, a single oral dose of VIAGRA 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, VIAGRA 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). The mean subject age in this study was 63.9 years.

Twenty subjects received VIAGRA 50 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with VIAGRA 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study.

For the 19 subjects who received both VIAGRA and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:

Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)

VIAGRA 50 mg (95% CI)

The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg VIAGRA or matching placebo are shown in Figure 3.

Figure 3: Mean Standing Systolic Blood Pressure Change from Baseline

Blood pressure was measured after administration of VIAGRA at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of < 85 mmHg. In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of VIAGRA 50 mg and resolving after approximately 7.5 hours. There was one subject with a decrease from baseline in standing systolic BP > 30mmHg following VIAGRA 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study.

Study 3: VIAGRA with Doxazosin

In the third study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-label doxazosin and a single dose of VIAGRA 50 mg simultaneously, after at least 14 consecutive days of doxazosin. If a subject did not successfully complete this first dosing period, he was discontinued from the study. Subjects who had successfully completed the previous doxazosin interaction study (using VIAGRA 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. The mean subject age in this study was 66.4 years.

Twenty-five subjects were screened. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label VIAGRA 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using VIAGRA 50 mg).

For the 20 subjects who received VIAGRA 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:

The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg VIAGRA or matching placebo are shown in Figure 4.

Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline

Blood pressure was measured after administration of VIAGRA at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of < 85 mmHg. All three were taking VIAGRA 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following VIAGRA 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both VIAGRA 50 mg and 100 mg. There were no episodes of syncope reported in this study.

Effect of VIAGRA on Blood Pressure When Co-administered with Anti-hypertensives

When VIAGRA 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.

Effect of VIAGRA on Blood Pressure When Co-administered with Alcohol

VIAGRA (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%. The maximum observed decrease in systolic blood pressure was -18.5 mmHg when sildenafil was co-administered with alcohol versus -17.4 mmHg when alcohol was administered alone. The maximum observed decrease in diastolic blood pressure was -17.2 mmHg when sildenafil was co-administered with alcohol versus -11.1 mmHg when alcohol was administered alone. There were no reports of postural dizziness or orthostatic hypotension. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [see DRUG INTERACTIONS].

Effects of VIAGRA on Cardiac Parameters

Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers.

Studies have produced relevant data on the effects of VIAGRA on cardiac output. In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Ganz catheterization. A total dose of 40 mg sildenafil was administered by four intravenous infusions.

The results from this pilot study are shown in Table 3; the mean resting systolic and diastolic blood pressures decreased by 7% and 10% compared to baseline in these patients. Mean resting values for right atrial pressure, pulmonary artery pressure, pulmonary artery occluded pressure and cardiac output decreased by 28%, 28%, 20% and 7% respectively. Even though this total dosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients.

Table 3: Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil

In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or VIAGRA 100 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort. The mean times (adjusted for baseline) to onset of limiting angina were 423.6 and 403.7 seconds for sildenafil (N=70) and placebo, respectively. These results demonstrated that the effect of VIAGRA on the primary endpoint was statistically non-inferior to placebo.

Effects of VIAGRA on Vision

At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. Subjects in the study reported this finding as difficulties in discriminating blue/green. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of VIAGRA on visual acuity, intraocular pressure, or pupillometry.

Effects of VIAGRA on Sperm

There was no effect on sperm motility or morphology after single 100 mg oral doses of VIAGRA in healthy volunteers.

Pharmacokinetics

VIAGRA is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 2563%). The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil. Both sildenafil and the metabolite have terminal half lives of about 4 hours.

Mean sildenafil plasma concentrations measured after the administration of a single oral dose of 100 mg to healthy male volunteers is depicted below:

Figure 5: Mean Sildenafil Plasma Concentrations in Healthy Male Volunteers

Absorption and Distribution

VIAGRA is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When VIAGRA is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.

Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.

Metabolism and Excretion

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects.

After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach.

Pharmacokinetics in Special Populations

Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [seeDOSAGE AND ADMINISTRATION, and Use In Specific Populations]

Renal Impairment: In volunteers with mild (CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered. In volunteers with severe (CLcr < 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment [seeDOSAGE AND ADMINISTRATION, and Use In Specific Populations].

In addition, N-desmethyl metabolite AUC and Cmax values significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with normal renal function.

Hepatic Impairment: In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied [seeDOSAGE AND ADMINISTRATION, and Use in Specific Populations].

Therefore, age > 65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil. A starting oral dose of 25 mg should be considered in those patients [see DOSAGE AND ADMINISTRATION].

Drug Interaction Studies

Effects of Other Drugs on VIAGRA

Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. The concomitant use of erythromycin or strong CYP3A4 inhibitors (e.g., saquinavir, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil [see DOSAGE AND ADMINISTRATION].

In vivo Studies

Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with VIAGRA (50 mg) to healthy volunteers.

When a single 100 mg dose of VIAGRA was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil Cmax and a 182% increase in sildenafil AUC. In addition, in a study performed in healthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Viagra (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Viagra had no effect on saquinavir pharmacokinetics. A stronger CYP3A4 inhibitor such as ketoconazole or itraconazole could be expected to have greater effect than that seen with saquinavir. Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

In another study in healthy male volunteers, co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with VIAGRA (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. VIAGRA had no effect on ritonavir pharmacokinetics [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels.

In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil Cmax . Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil.

Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of VIAGRA.

In healthy male volunteers, there was no evidence of a clinically significant effect of azithromycin (500 mg daily for 3 days) on the systemic exposure of sildenafil or its major circulating metabolite.

Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.

Effects of VIAGRA on Other Drugs
In Vitro Studies
Sildenafil is a weak inhibitor of the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 > 150 μM). Given sildenafil peak plasma concentrations of approximately 1 μM after recommended doses, it is unlikely that VIAGRA will alter the clearance of substrates of these isoenzymes.
In Vivo Studies
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.

In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.

VIAGRA (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).

Sildenafil at steady state, at a dose not approved for the treatment of erectile dysfunction (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in C max of bosentan (125 mg b.i.d.).

Clinical Studies

In clinical studies, VIAGRA was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. VIAGRA was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). VIAGRA was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. VIAGRA demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo.

Efficacy Endpoints in Controlled Clinical Studies

The effectiveness of VIAGRA was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function -IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered.

Efficacy Results from Controlled Clinical Studies

The effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 6, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received 100 mg, showed similar results. Figure 6 shows that regardless of the baseline levels of function, subsequent function in patients treated with VIAGRA was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline.

Figure 6: Effect of VIAGRA and Placebo on Maintenance of Erection by Baseline Score

The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 7. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions. Erectile dysfunction was attributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies. Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mg and 100 mg of VIAGRA, respectively, reported an improvement in their erections, compared to 24% on placebo. In the titration studies (n=644) (with most patients eventually receiving 100 mg), results were similar.

Figure 7: Percentage of Patients Reporting an Improvement in Erections

The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period.

In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of VIAGRA on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50-100 mg of VIAGRA vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on VIAGRA vs about 20% on placebo.

During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. At the end of the long-term study, 88% of patients reported that VIAGRA improved their erections.

Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured (again using a 5-point scale) in the IIEF. VIAGRA improved these aspects of sexual function: frequency, firmness and maintenance of erections; frequency of orgasm; frequency and level of desire; frequency, satisfaction and enjoyment of intercourse; and overall relationship satisfaction.

One randomized, double-blind, flexible-dose, placebo-controlled study included only patients with erectile dysfunction attributed to complications of diabetes mellitus (n=268). As in the other titration studies, patients were started on 50 mg and allowed to adjust the dose up to 100 mg or down to 25 mg of VIAGRA; all patients, however, were receiving 50 mg or 100 mg at the end of the study. There were highly statistically significant improvements on the two principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on VIAGRA compared to placebo. On a global improvement question, 57% of VIAGRA patients reported improved erections versus 10% on placebo. Diary data indicated that on VIAGRA, 48% of intercourse attempts were successful versus 12% on placebo.

One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA. On a global improvement question, 83% of patients reported improved erections on VIAGRA versus 12% on placebo. Diary data indicated that on VIAGRA, 59% of attempts at sexual intercourse were successful compared to 13% on placebo.

Across all trials, VIAGRA improved the erections of 43% of radical prostatectomy patients compared to 15% on placebo.

Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies (total n=179) and two titration studies (total n=149) showed 84% of VIAGRA patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA. Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for VIAGRA and 29% for placebo.

Efficacy Results in Subpopulations in Controlled Clinical Studies

A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. VIAGRA was effective in a broad range of ED patients, including those with a history of coronary artery disease, hypertension, other cardiac disease, peripheral vascular disease, diabetes mellitus, depression, coronary artery bypass graft ( CABG), radical prostatectomy, transurethral resection of the prostate (TURP) and spinal cord injury, and in patients taking antidepressants/antipsychotics and anti-hypertensives/ diuretics.

PATIENT INFORMATION

VIAGRA®
(vi-AG-rah)
(sildenafil citrate) Tablets
What is the most important information I should know about VIAGRA?
VIAGRA can cause your blood pressure to drop suddenly to an unsafe level if it is taken with certain other medicines. Do not take VIAGRA if you take any other medicines called "nitrates." Nitrates are used to treat chest pain ( angina). A sudden drop in blood pressure can cause you to feel dizzy, faint, or have a heart attack or stroke.

Do not take VIAGRA if you take medicines called guanylate cyclase stimulators which include:

Tell all your healthcare providers that you take VIAGRA. If you need emergency medical care for a heart problem, it will be important for your healthcare provider to know when you last took VIAGRA.

Stop sexual activity and get medical help right away if you get symptoms such as chest pain, dizziness, or nausea during sex.

Sexual activity can put an extra strain on your heart, especially if your heart is already weak from a heart attack or heart disease. Ask your doctor if your heart is healthy enough to handle the extra strain of having sex.

VIAGRA does not protect you or your partner from getting sexually transmitted diseases, including HIV-the virus that causes AIDS.
What is VIAGRA?
VIAGRA is a prescription medicine used to treat erectile dysfunction (ED). You will not get an erection just by taking this medicine. VIAGRA helps a man with erectile dysfunction get and keep an erection only when he is sexually excited (stimulated).

VIAGRA is not for use in women or children.

It is not known if VIAGRA is safe and effective in women or children under 18 years of age.
Who should not take VIAGRA? Do not take VIAGRA if you:

take medicines called nitrates (such as nitroglycerin)

use street drugs called "poppers" such as amyl nitrate or amyl nitrite, and butyl nitrate

take any medicines called guanylate cyclase stimulators such as riociguat (Adempas)

are allergic to sildenafil, as contained in VIAGRA and REVATIO, or any of the ingredients in VIAGRA. See the end of this leaflet for a complete list of ingredients in VIAGRA.

What should I tell my healthcare provider before taking VIAGRA?
Before you take VIAGRA, tell your healthcare provider if you:

have or have had heart problems such as a heart attack, irregular heartbeat, angina, chest pain, narrowing of the aortic valve or heart failure

have had heart surgery within the last 6 months

have pulmonary hypertension

have had a stroke

have low blood pressure, orhigh blood pressure that is not controlled

have a deformed penis shape

have had an erection that lasted for more than 4 hours

have problems with your blood cells such as sickle cell anemia, multiple myeloma, or leukemia

have retinitis pigmentosa, a rare genetic (runs in families) eye disease

have ever had severe vision loss, including an eye problem called non-arteritic anterior ischemic optic neuropathy (NAION)

have bleeding problems

have or have had stomach ulcers

have liver problems

have kidney problems or are having kidney dialysis

have any other medical conditions

Tell your healthcare provider about all the medicines you take*, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

VIAGRA may affect the way other medicines work, and other medicines may affect the way VIAGRA works causing side effects. Especially tell your healthcare provider if you take any of the following:

medicines called nitrates (see "What is the most important information I should know about VIAGRA?")

medicines called guanylate cyclase stimulators, such as riociguat (Adempas)

medicines called alpha blockers such as Hytrin (terazosin HCl), Flomax (tamsulosin HCl), Cardura (doxazosin mesylate), Minipress (prazosin HCl), Uroxatral (alfuzosin HCl), Jalyn (dutasteride and tamsulosin HCl), or Rapaflo (silodosin). Alpha-blockers are sometimes prescribed forprostate problems or high blood pressure. In some patients, the use of VIAGRA with alpha-blockers can lead to a drop in blood pressure or tofainting.

medicines called HIV protease inhibitors, such as ritonavir (Norvir), indinavir sulfate (Crixivan), saquinavir (Fortovase or Invirase) or atazanavir sulfate (Reyataz)

some types of oral antifungal medicines, such as ketoconazole (Nizoral), and itraconazole (Sporanox)

some types of antibiotics, such as clarithromycin (Biaxin), telithromycin (Ketek), or erythromycin

other medicines that treat high blood pressure

other medicines or treatments for ED

VIAGRA contains sildenafil, which is the same medicine found in another drug called REVATIO. REVATIO is used to treat a rare disease called pulmonary arterial hypertension (PAH). VIAGRA should not be used with REVATIO or with other PAH treatments containing sildenafil or any other PDE5 inhibitors (such as Adcirca [tadalafil]).

Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.
How should I take VIAGRA?

Take VIAGRA exactly as your healthcare provider tells you to take it.

Your healthcare provider will tell you how much VIAGRA to take and when to take it.

Your healthcare provider may change your dose if needed.

Take VIAGRA about 1 hour before sexual activity. You may take VIAGRA between 30 minutes to 4 hours before sexual activity if needed.

VIAGRA can be taken with or without food. If you take VIAGRA after a high fat meal (such as a cheeseburger and french fries), VIAGRA may take a little longer to start working

Do not take VIAGRA more than 1 time a day.

If you accidentally take too much VIAGRA, call your doctor or go to the nearest hospital emergency room right away.

What are the possible side effects of VIAGRA?
VIAGRA can cause serious side effects. Rarely reported side effects include:

an erection that will not go away (priapism). If you have an erection that lasts more than 4 hours, get medical help right away. If it is not treated right away,priapism can permanently damage your penis.

sudden vision loss in one or both eyes. Sudden vision loss in one or both eyes can be a sign of a serious eye problem called non-arteritic anterior ischemic optic neuropathy (NAION). Stop taking VIAGRA and call your healthcare provider right away if you have sudden vision loss in one or both eyes.

sudden hearing decrease or hearing loss. Some people may also have ringing in their ears (tinnitus) or dizziness. If you have these symptoms, stop taking VIAGRA and contact a doctor right away.

The most common side effects of VIAGRA are:

headache

flushing

upset stomach

abnormal vision, such as changes in color vision (such as having a blue color tinge) and blurred vision

stuffy or runny nose

muscle pain

nausea

dizziness

rash

In addition, heart attack, stroke, irregular heartbeats and death have happened rarely in men taking VIAGRA. Most, but not all, of these men had heart problems before taking VIAGRA. It is not known if VIAGRA caused these problems.

Tell your healthcare provider if you have any side effect that bothers you or does not go away.

These are not all the possible side effects of VIAGRA. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1800-FDA-1088.
How should I store VIAGRA?

Store VIAGRA at room temperature between 68°F to 77°F (20°C to 25°C).
Keep VIAGRA and all medicines out of the reach of children. General information about the safe and effective use of VIAGRA.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use VIAGRA for a condition for which it was not prescribed. Do not give VIAGRA to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about VIAGRA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about VIAGRA that is written for health professionals.

For more information, go to www.viagra.com, or call 1-888-4VIAGRA
What are the ingredients in VIAGRA?
Active ingredient: sildenafil citrate

Inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake

This Patient Information has been approved by the U.S. Food and Drug Administration.

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Viagra (Sildenafil Citrate): Side Effects, Interactions, Warning, Dosage & Uses

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Learn about Viagra (Sildenafil Citrate) may treat, uses, dosage, side effects, drug interactions, warnings, patient labeling, reviews, and related medications.

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Blood sugar levels in diagnosing diabetes

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Blood sugar levels in diagnosing diabetes

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Types of glucose transporters and their location

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American Diabetes Association - Glucose Metabolism and Regulation

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American Diabetes Association - Glucose Metabolism and Regulation

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Abstract

Insulin and glucagon are potent regulators of glucose metabolism. For decades, we have viewed diabetes from a bi-hormonal perspective of glucose regulation. This perspective is incomplete and inadequate in explaining some of the difficulties that patients and practitioners face when attempting to tightly control blood glucose concentrations. Intensively managing diabetes with insulin is fraught with frustration and risk. Despite our best efforts, glucose fluctuations are unpredictable, and hypoglycemia and weight gain are common. These challenges may be a result of deficiencies or abnormalities in other glucoregulatory hormones. New understanding of the roles of other pancreatic and incretin hormones has led to a multi-hormonal view of glucose homeostasis.

HISTORICAL PERSPECTIVE

The recent discovery of additional hormones with glucoregulatory actions has expanded our understanding of how a variety of different hormones contribute to glucose homeostasis. In the 1950s, glucagon was characterized as a major stimulus of hepatic glucose production. This discovery led to a better understanding of the interplay between insulin and glucagon, thus leading to a bi-hormonal definition of diabetes. Subsequently, the discovery of a second β-cell hormone, amylin, was first reported in 1987. Amylin was determined to have a role that complemented that of insulin, and, like insulin, was found to be deficient in people with diabetes. This more recent development led to a view of glucose homeostasis involving multiple pancreatic hormones.

This enhanced understanding of glucose homeostasis will be central to the design of new pharmacological agents to promote better clinical outcomes and quality of life for people with diabetes. This review will focus on the more recently discovered hormones involved in glucose homeostasis and is not intended to be a comprehensive review of diabetes therapies.

NORMAL PHYSIOLOGY

Plasma glucose concentration is a function of the rate of glucose entering the circulation (glucose appearance) balanced by the rate of glucose removal from the circulation (glucose disappearance). Circulating glucose is derived from three sources: intestinal absorption during the fed state, glycogenolysis, and gluconeogenesis. The major determinant of how quickly glucose appears in the circulation during the fed state is the rate of gastric emptying. Other sources of circulating glucose are derived chiefly from hepatic processes: glycogenolysis, the breakdown of glycogen, the polymerized storage form of glucose; and gluconeogenesis, the formation of glucose primarily from lactate and amino acids during the fasting state.

Glycogenolysis and gluconeogenesis are partly under the control of glucagon, a hormone produced in the α-cells of the pancreas. During the first 8-12 hours of fasting, glycogenolysis is the primary mechanism by which glucose is made available ( Figure 1A). Glucagon facilitates this process and thus promotes glucose appearance in the circulation. Over longer periods of fasting, glucose, produced by gluconeogenesis, is released from the liver.

Glucoregulatory hormones include insulin, glucagon, amylin, GLP-1, glucose-dependent insulinotropic peptide (GIP), epinephrine, cortisol, and growth hormone. Of these, insulin and amylin are derived from the β-cells, glucagon from the α-cells of the pancreas, and GLP-1 and GIP from the L-cells of the intestine.

The glucoregulatory hormones of the body are designed to maintain circulating glucose concentrations in a relatively narrow range. In the fasting state, glucose leaves the circulation at a constant rate. To keep pace with glucose disappearance, endogenous glucose production is necessary. For all practical purposes, the sole source of endogenous glucose production is the liver. Renal gluconeogenesis contributes substantially to the systemic glucose pool only during periods of extreme starvation. Although most tissues have the ability to hydrolyze glycogen, only the liver and kidneys contain glucose-6-phosphatase, the enzyme necessary for the release of glucose into the circulation. In the bi-hormonal model of glucose homeostasis, insulin is the key regulatory hormone of glucose disappearance, and glucagon is a major regulator of glucose appearance. After reaching a post-meal peak, blood glucose slowly decreases during the next several hours, eventually returning to fasting levels. In the immediate post-feeding state, glucose removal into skeletal muscle and adipose tissue is driven mainly by insulin. At the same time, endogenous glucose production is suppressed by 1) the direct action of insulin, delivered via the portal vein, on the liver, and 2) the paracrine effect or direct communication within the pancreas between the α- and β-cells, which results in glucagon suppression ( Figure 1B).

β-CELL HORMONES

Insulin

Until recently, insulin was the only pancreatic β-cell hormone known to lower blood glucose concentrations. Insulin, a small protein composed of two polypeptide chains containing 51 amino acids, is a key anabolic hormone that is secreted in response to increased blood glucose and amino acids following ingestion of a meal. Like many hormones, insulin exerts its actions through binding to specific receptors present on many cells of the body, including fat, liver, and muscle cells. The primary action of insulin is to stimulate glucose disappearance.

All of these actions reduce blood glucose. Other actions of insulin include the stimulation of fat synthesis, promotion of triglyceride storage in fat cells, promotion of protein synthesis in the liver and muscle, and proliferation of cell growth.

Insulin action is carefully regulated in response to circulating glucose concentrations. Insulin is not secreted if the blood glucose concentration is ≤ 3.3 mmol/l, but is secreted in increasing amounts as glucose concentrations increase beyond this threshold. Postprandially, the secretion of insulin occurs in two phases: an initial rapid release of preformed insulin, followed by increased insulin synthesis and release in response to blood glucose. Long-term release of insulin occurs if glucose concentrations remain high.

Amylin

Isolated from pancreatic amyloid deposits in the islets of Langerhans, amylin was first reported in the literature in 1987. Amylin, a 37-amino acid peptide, is a neuroendocrine hormone coexpressed and cosecreted with insulin by pancreatic β-cells in response to nutrient stimuli. When secreted by the pancreas, the insulin-to-amylin molar ratio in the portal circulation is approximately 50:1. Because of hepatic extraction of insulin, this ratio falls to ∼ 20:1 in the peripheral circulation.

Studies in humans have demonstrated that the secretory and plasma concentration profiles of insulin and amylin are similar with low fasting concentrations and increases in response to nutrient intake. In healthy adults, fasting plasma amylin concentrations range from 4 to 8 pmol/l rising as high as 25 pmol/l postprandially. In subjects with diabetes, amylin is deficient in type 1 and impaired in type 2 diabetes.

Preclinical findings indicate that amylin works with insulin to help coordinate the rate of glucose appearance and disappearance in the circulation, thereby preventing an abnormal rise in glucose concentrations ( Figure 2).

Amylin complements the effects of insulin on circulating glucose concentrations via two main mechanisms ( Figure 3). Amylin suppresses post-prandial glucagon secretion, thereby decreasing glucagon-stimulated hepatic glucose output following nutrient ingestion. This suppression of post-prandial glucagon secretion is postulated to be centrally mediated via efferent vagal signals. Importantly, amylin does not suppress glucagon secretion during insulin-induced hypoglycemia. Amylin also slows the rate of gastric emptying and, thus, the rate at which nutrients are delivered from the stomach to the small intestine for absorption. In addition to its effects on glucagon secretion and the rate of gastric emptying, amylin dose-dependently reduces food intake and body weight in animal models ( Table 1).

In summary, amylin works to regulate the rate of glucose appearance from both endogenous (liver-derived) and exogenous (meal-derived) sources, and insulin regulates the rate of glucose disappearance.

α-CELL HORMONE: GLUCAGON

Glucagon is a key catabolic hormone consisting of 29 amino acids. It is secreted from pancreatic α-cells. Described by Roger Unger in the 1950s, glucagon was characterized as opposing the effects of insulin. Glucagon plays a major role in sustaining plasma glucose during fasting conditions by stimulating hepatic glucose production.

Unger was the first to describe the diabetic state as a "bi-hormonal" disease characterized by insulin deficiency and glucagon excess. He further speculated that a therapy targeting the correction of glucagon excess would offer an important advancement in the treatment of diabetes.

Hepatic glucose production, which is primarily regulated by glucagon, maintains basal blood glucose concentrations within a normal range during the fasting state. When plasma glucose falls below the normal range, glucagon secretion increases, resulting in hepatic glucose production and return of plasma glucose to the normal range. This endogenous source of glucose is not needed during and immediately following a meal, and glucagon secretion is suppressed. When coupled with insulin's direct effect on the liver, glucagon suppression results in a near-total suppression of hepatic glucose output ( Figure 4).

In the diabetic state, there is inadequate suppression of postprandial glucagon secretion (hyperglucagonemia) resulting in elevated hepatic glucose production ( Figure 4). Importantly, exogenously administered insulin is unable both to restore normal postprandial insulin concentrations in the portal vein and to suppress glucagon secretion through a paracrine effect. This results in an abnormally high glucagon-to-insulin ratio that favors the release of hepatic glucose. These limits of exogenously administered insulin therapy are well documented in individuals with type 1 or type 2 diabetes and are considered to be important contributors to the postprandial hyperglycemic state characteristic of diabetes.

INCRETIN HORMONES GLP-1 AND GIP

The intricacies of glucose homeostasis become clearer when considering the role of gut peptides. By the late 1960s, Perley and Kipnis and others demonstrated that ingested food caused a more potent release of insulin than glucose infused intravenously. This effect, termed the "incretin effect," suggested that signals from the gut are important in the hormonal regulation of glucose disappearance. Additionally, these hormonal signals from the proximal gut seemed to help regulate gastric emptying and gut motility.

Several incretin hormones have been characterized, and the dominant ones for glucose homeostasis are GIP and GLP-1. GIP stimulates insulin secretion and regulates fat metabolism, but does not inhibit glucagon secretion or gastric emptying. GIP levels are normal or slightly elevated in people with type 2 diabetes. While GIP is a more potent incretin hormone, GLP-1 is secreted in greater concentrations and is more physiologically relevant in humans.

GLP-1 also stimulates glucose-dependent insulin secretion but is significantly reduced postprandially in people with type 2 diabetes or impaired glucose tolerance. GLP-1 stimulates insulin secretion when plasma glucose concentrations are high but not when plasma glucose concentrations approach or fall below the normal range. Derived from the proglucagon molecule in the intestine, GLP-1 is synthesized and secreted by the L-cells found mainly in the ileum and colon. Circulating GLP-1 concentrations are low in the fasting state. However, both GIP and GLP-1 are effectively stimulated by ingestion of a mixed meal or meals enriched with fats and carbohydrates. In contrast to GIP, GLP-1 inhibits glucagon secretion and slows gastric emptying.

GLP-1 has many glucoregulatory effects ( Table 1 and Figure 3). In the pancreas, GLP-1 stimulates insulin secretion in a glucose-dependent manner while inhibiting glucagon secretion. Animal studies have demonstrated that the action of GLP-1 occurs directly through activation of GLP-1 receptors on the pancreatic β-cells and indirectly through sensory nerves. GLP-1 has a plasma half-life of about 2 minutes, and its disappearance is regulated primarily by the enzyme dipeptidyl peptidase-IV (DPP-IV), which rapidly cleaves and inactivates GLP-1.

Infusion of GLP-1 lowers postprandial glucose as well as overnight fasting blood glucose concentrations. The postprandial effect of GLP-1 is partly due to inhibition of glucagon secretion. Yet while GLP-1 inhibits glucagon secretion in the fed state, it does not appear to blunt glucagon's response to hypoglycemia. GLP-1 helps regulate gastric emptying and gastric acid secretion, perhaps by signalling GLP-1 receptors in the brain and thereby stimulating efferent tracts of the vagus nerve. As gastric emptying slows, the postprandial glucose excursion is reduced. Administration of GLP-1 has been associated with the regulation of feeding behavior and body weight. In addition, there have been reported observations of GLP-1 improving insulin sensitivity and enhancing glucose disposal.

Of significant and increasing interest is the role GLP-1 may have in preservation of β-cell function and β-cell proliferation. In animal studies, GLP-1 has been shown to enhance functional β-cell mass.

DIABETES PATHOPHYSIOLOGY

Our understanding of the pathophysiology of diabetes is evolving. Type 1 diabetes has been characterized as an autoimmune-mediated destruction of pancreatic β-cells. The resulting deficiency in insulin also means a deficiency in the other cosecreted and colocated β-cell hormone, amylin. As a result, postprandial glucose concentrations rise due to lack of insulin-stimulated glucose disappearance, poorly regulated hepatic glucose production, and increased or abnormal gastric emptying following a meal.

Early in the course of type 2 diabetes, postprandial β-cell action becomes abnormal, as evidenced by the loss of immediate insulin response to a meal. Peripheral insulin resistance coupled with progressive β-cell failure and decreased availability of insulin, amylin, and GLP-1 contribute to the clinical picture of hyperglycemia in diabetes.

Abnormal gastric emptying is common to both type 1 and type 2 diabetes. The rate of gastric emptying is a key determinant of postprandial glucose concentrations ( Figure 5). If gastric emptying is accelerated, then the presentation of meal-derived glucose to the circulation is poorly timed with insulin delivery. In individuals with diabetes, the absent or delayed secretion of insulin further exacerbates postprandial hyperglycemia. Both amylin and GLP-1 regulate gastric emptying by slowing the delivery of nutrients from the stomach to the small intestine.

REPLACEMENT OF INSULIN

For the past 80 years, insulin has been the only pharmacological alternative, but it has replaced only one of the hormonal compounds required for glucose homeostasis. Newer formulations of insulin and insulin secretagogues, such as sulfonylureas and meglitinides, have facilitated improvements in glycemic control. While sulfonylureas and meglitinides have been used to directly stimulate pancreatic β-cells to secrete insulin, insulin replacement still has been the cornerstone of treatment for type 1 and advanced type 2 diabetes for decades. Advances in insulin therapy have included not only improving the source and purity of the hormone, but also developing more physiological means of delivery.

Clearly, there are limitations that hinder normalizing blood glucose using insulin alone. First, exogenously administered insulin does not mimic endogenous insulin secretion. In normal physiology, the liver is exposed to a two- to fourfold increase in insulin concentration compared to the peripheral circulation. Peripherally injected insulin does not approach this ratio, thus resulting in inadequate hepatic glucose suppression. Second, insulin's paracrine suppression of glucagon is limited in diabetes and inadequately compensated for by peripherally delivered insulin ( Figures 1C, 1D). In the postprandial state, when glucagon concentrations should be low and glycogen stores should be rebuilt, there is a paradoxical elevation of glucagon and depletion of glycogen stores. And finally, therapeutically increasing insulin doses results in further peripheral hyperinsulinemia, which may predispose the individual to hypoglycemia and weight gain. As demonstrated in the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study, intensified care is not without risk. In both studies, those subjects in the intensive therapy groups experienced a two- to threefold increase in severe hypoglycemia. Additionally, intensification of diabetes management was associated with weight gain.

REGULATION OF GLUCAGON ACTION

Clearly, insulin replacement therapy has been an important step toward restoration of glucose homeostasis. But it is only part of the ultimate solution. The vital relationship between insulin and glucagon has suggested additional areas for treatment. With inadequate concentrations of insulin and elevated concentrations of glucagon in the portal vein, glucagon's actions are excessive, contributing to an endogenous and unnecessary supply of glucose in the fed state. To date, no pharmacological means of regulating glucagon exist and the need to decrease postprandial glucagon secretion remains a clinical target for future therapies.

AMYLIN ACTIONS

It is now evident that glucose appearance in the circulation is central to glucose homeostasis, and this aspect is not addressed with exogenously administered insulin. Amylin works with insulin and suppresses glucagon secretion. It also helps regulate gastric emptying, which in turn influences the rate of glucose appearance in the circulation. A synthetic analog of human amylin that binds to the amylin receptor, an amylinomimetic agent, is in development.

GLP-1 ACTIONS

However, replacing GLP-1 in its natural state poses biological challenges. In clinical trials, continuous subcutaneous or intravenous infusion was superior to single or repeated injections of GLP-1 because of the rapid degradation of GLP-1 by DPP-IV.

To circumvent this intensive and expensive mode of treatment, clinical development of compounds that elicit similar glucoregulatory effects to those of GLP-1 are being investigated. These compounds, termed incretin mimetics, have a longer duration of action than native GLP-1. In addition to incretin mimetics, research indicates that DPP-IV inhibitors may improve glucose control by increasing the action of native GLP-1. These new classes of investigational compounds have the potential to enhance insulin secretion and suppress prandial glucagon secretion in a glucose-dependent manner, regulate gastric emptying, and reduce food intake. Lastly, incretin mimetics may also play a role in preservation of β-cell function and β-cell proliferation.

SUMMARY

Despite current advances in pharmacological therapies for diabetes, attaining and maintaining optimal glycemic control has remained elusive and daunting. Intensified management clearly has been associated with decreased risk of complications. Yet, despite this scientific understanding, the average hemoglobin A 1c in patients with diabetes in the United States is > 9%.

Glucose regulation is an exquisite orchestration of many hormones, both pancreatic and gut, that exert effect on multiple target tissues, such as muscle, brain, liver, and adipocyte. While health care practitioners and patients have had multiple therapeutic options for the past 10 years, both continue to struggle to achieve and maintain good glycemic control. Currently available therapies do not perfectly address many of the abnormalities and/or deficiencies of type 1 or type 2 diabetes.

There remains a need for new interventions that complement our current therapeutic armamentarium without some of their clinical short-comings such as the risk of hypoglycemia and weight gain. These evolving therapies offer the potential for more effective management of diabetes from a multi-hormonal perspective ( Figure 3) and are now under clinical development.

Footnotes

Stephen L. Aronoff, MD, FACP, FACE, is a partner and clinical endocrinologist at Endocrine Associates of Dallas and director at the Research Institute of Dallas in Dallas, Tex. Kathy Berkowitz, APRN, BC, FNP, CDE, and Barb Schreiner, RN, MN, CDE, BC-ADM, are diabetes clinical liaisons with the Medical Affairs Department at Amylin Pharmaceuticals, Inc., in San Diego, Calif. Laura Want, RN, MS, CDE, CCRC, BC-ADM, is the clinical research coordinator at MedStar Research Institute in Washington, D.C.

Note of disclosure: Dr. Aronoff has received honoraria for speaking engagements from Amylin Pharmaceuticals, Inc., and Eli Lilly and Company and research support from Amylin, Lilly, and Novo Nordisk. Ms. Berkowitz and Ms. Schreiner are employed by Amylin. Ms. Want serves on an advisory panel for, is a stock shareholder in, and has received honoraria for speaking engagements from Amylin and has served as a research coordinator for studies funded by the company. She has also received research support from Lilly, Novo Nordisk, and MannKind Corporation. Amylin Pharmaceuticals, Inc., is developing synthetic amylin and incretin hormone products, and Mannkind Corporation is developing an inhaled insulin system for the treatment of diabetes.

View Abstract

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Glucose Metabolism and Regulation: Beyond Insulin and Glucagon

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Insulin and glucagon are potent regulators of glucose metabolism. For decades, we have viewed diabetes from a bi-hormonal perspective of glucose regulation. This perspective is incomplete and inadequate in explaining some of the difficulties that patients and practitioners face when attempting to tightly control blood glucose concentrations.

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Mechanism of Action of Insulin                                    (aka main mode of mechanism) 

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Mechanism of Action of Insulin                                    (aka main mode of mechanism) 

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Visit us (http://www.khanacademy.org/science/healthcare-and-medicine) for health and medicine content or (http://www.khanacademy.org/test-prep/mcat) for MCAT related content. These videos do not provide medical advice and are for informational purposes only. The videos are not intended to be a substitute for professional medical advice, diagnosis or treatment.

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Julia
https://play.google.com/store/apps/details?id=uk.ac.exeter.DiabetesDiagnostics&hl=en_GB

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Diabetes Diagnostics - Apps on Google Play

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The Diabetes Diagnostics app is a clinical aid for the differential diagnosis of diabetes subtypes. The app combines information from national and international diabetes guidelines, the MODY clinical prediction calculator, and expert opinion from world leaders in monogenic diabetes to provide a resource to help guide diabetes classification.