1. AVAPRO HISTORY
How was Avapro discovered?

Avapro is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. Irbesartan was discovered by Sanofi Research (now part of Sanofi-Aventis).

Irbesartan is jointly marketed by Sanofi-Aventis and Bristol-Myers Squibb under the trade names Avapro.

Sanofi-Synthelabo Inc. is the U.S. affiliate of the global pharmaceutical company Sanofi-Aventis.

Sanofi-Aventis group is Number 1 in Europe and Number 3 worldwide in the Pharmaceutical industry. This group is present in more than 100 countries throughout the 5 continents.

Sanofi-Synthelabo's principal area of business is ethical pharmaceuticals. The core therapeutic areas of Sanofi-Synthelabo are cardiovascular disease and thrombosis; diseases of the central nervous system; oncology; and internal medicine.

Bristol-Myers Squibb is a pharmaceutical and related health care products company whose mission is to extend and enhance human life.

At Bristol-Myers Squibb, our mission is to extend and enhance human life by providing the highest-quality pharmaceuticals and health care products. Our medicines are making a difference in the lives of millions of customers across the globe. And by living our mission and growing our company for well over a century, we are making a difference in the lives of our shareholders, employees and neighbors as well.

Bristol-Myers Squibb is one of premier 20 U.S. companies listed in the latest Global 100 Most Sustainable Corporations in the World. The new global business ranking identifies the top 100 companies that are most open to leading the way to a more sustainable world. 

Note: World-drugs.net sells generic version of Avapro

2.AVAPRO FACTS

Avapro works by preventing the action of a hormone in the body called angiotensin II.

Angiotensin II normally acts on special receptors in the body, with two main results. Firstly, it causes the peripheral blood vessels to narrow, and secondly, it stimulates the production of another hormone called aldosterone. Aldosterone causes salt and water to be retained by the kidneys, which increases the volume of fluid in the blood vessels.

Avapro blocks the receptors that angiotensin II acts on, and so prevents its actions. The main result of this is that the peripheral blood vessels are allowed to widen, which means that there is more space and less resistance in these blood vessels. This lowers the pressure inside the blood vessels.

Blocking the actions of angiotensin II also reduces the action of aldosterone on the kidneys. The result of this is an increase in the amount of fluid removed from the blood by the kidneys. This decreases the amount of fluid in the blood vessels, which also lessens the resistance and pressure in the blood vessels.

3.ABOUT AVAPRO MEDICATION

What is High Blood Pressure (Hypertension)?
High blood pressure, also known as hypertension, is a serious disease affecting your heart and blood vessels. It occurs when the blood exerts too much pressure against the walls of the blood vessels. In fact, that is what the term hypertension means: "too much" (hyper) "pressure" (tension). It affects upwards of 58 million people nationwide.

High blood pressure is serious because it places you at risk for certain life threatening and disabling conditions. If left untreated, High blood pressure could lead to heart attack, kidney disease, and/or stroke.

This happens because as your blood continuously exerts too much pressure against the walls of the blood vessels, it places extra stress on the heart and blood vessels.

Blood pressure is measured in two numbers, systolic (top or higher number) and diastolic (lower number). The higher number is the maximum pressure, which occurs when the heart beats (systole), and the lower number is the lowest pressure measured when the heart relaxes between beats (diastole), just before the next contraction. A systolic reading of 140 or greater and a diastolic reading of 90 or greater is considered high.

The normal blood pressure is less than 120/80. In fact, for every 20/10 increase in blood pressure, your risk of cardiovascular events, such as heart attack or stroke, is DOUBLED.

Symptoms of High Blood Pressure

High blood pressure is sometimes called the "silent killer" because the symptoms are rarely seen or felt. So, even though it might be upsetting to be told that you have High blood pressure, it's good that your doctor has discovered it. Treatment can help avoid the serious, long-term effects of High blood pressure.

What are antihypertensives?

Antihypertensives are medicines used to treat High blood pressure (hypertension). Although some patients do not need to take medication to control their High blood pressure, anyone who is prescribed medication needs to take it exactly as prescribed to avoid the serious medical problems associated with the condition. People taking Antihypertensives are also encouraged to make healthy lifestyle improvements, such as quitting smoking, losing weight and getting regular exercise. Furthermore, they are encouraged to speak with their physician before taking any prescription medications, such as narcotics, or over-the-counter medications, such as diet pills.

Finally, people with High blood pressure are recommended to be patient as the type and level of their medication are adjusted for optimal results. This is especially important because the vast majority of patients have no symptoms, making hypertension the silent killer.

There are a wide variety of Antihypertensives and combinations of different medications that are available, and it may take some time before the ideal treatment has been found and finely tuned to the patients needs.

Antihypertensives include:

Diuretics ("water pills")
Diuretics are sometimes called "water pills" because they work in the kidney and flush excess water and sodium from the body.

Beta Blockers
Beta-blockers reduce nerve impulses to the heart and blood vessels. This makes the heart beat slower and with less force. Blood pressure drops and the heart works less hard.

Alpha Blockers
Alpha-blockers reduce nerve impulses to blood vessels, which allows blood to pass more easily, causing the blood pressure to go down.

Alpha-Beta Blockers
Alpha-beta-blockers work the same way as alpha-blockers but also slow the heartbeat, as beta-blockers do. As a result, less blood is pumped through the vessels and the blood pressure goes down.

Nervous System Inhibitors
Nervous system inhibitors relax blood vessels by controlling nerve impulses. This causes the blood vessels to become wider and the blood pressure to go down.

Angiotensin Converting Enzyme (ACE) Inhibitors
Angiotensin converting enzyme (ACE) inhibitors prevent the formation of a hormone called angiotensin II, which normally causes blood vessels to narrow. The ACE inhibitors cause the vessels to relax and blood pressure goes down.

Calcium Channel Blockers
CCBs keep calcium from entering the muscle cells of the heart and blood vessels. This causes the blood vessels to relax and pressure goes down.

Angiotensin Receptor Blockers (formal medical name angiotensin-2-receptor antagonists, known as "sartans" for short). These agents are sometimes prescribed together, for instance an ACE inhibitor along with a calcium channel blocker.

Angiotensin antagonists shield blood vessels from angiotensin II. As a result, the vessels become wider and blood pressure goes down. 

Causes of High Blood Pressure

There are 2 main types of High blood pressure:

[1] Primary, Essential or Idiopathic. These 3 words all mean the same, & are medical terms for "unknown cause". 90% of cases of hypertension are of unknown cause.

There are a number of things that make it worse, one being stress & another being clogged arteries. Just like when a pipe is partly blocked with gunk it needs higher pressure to get fluid through it, so if your arteries are clogged with fat your heart steps up the pressure to get the blood through. A third factor is overweight. If you are too big you have a larger volume of small blood vessels so the heart has to pump harder & raise the pressure to supply them. A fourth is nicotine, a chemical in tobacco, which narrows arteries & so raises the pressure needed to get the blood through them. 

[2] Secondary hypertension. This means the High blood pressure is due to some known cause. Only 10% of cases have a known cause.

Some of these are:

[a] Kidney disease. If one of the kidneys has narrowing of the artery bringing its blood supply, or has damaged tubules, which can't handle your fluid & salt, you may get hypertension.

[b] Adrenal disease. The adrenal glands are a pair of small organs on the top of your kidneys. They produce lots of chemicals or hormones, which control salt & sugar in the body. One such hormone is aldosterone. This conserves salt, & if it conserves too much the blood pressure rises. Another is corticosteroid or steroid hormone. Too much of this will cause weight gain & grow too much body hair. This too can produce hypertension.

Another part of your adrenal gland produces adrenalin & nor-adrenalin. These are stress hormones, also called 'fight or flight' hormones. They will spit out adrenalin to make the heart pump faster, so more blood will go to your muscles ready for you to fight or run.

[c] Parathyroid disease. These are tiny glands in the neck, which produce a hormone controlling the calcium in your blood & bones. If they over act & pull too much calcium out of your bones into your blood, they may damage the kidneys or constrict your arteries causing High blood pressure.

[d] Other rare causes: The pituitary, a small gland at the base of the brain, produces growth hormone. Too much of this can make you grow to 7 feet or more [2.3 metres], or if it doesn't overact till late in life it can make your bones grow thicker instead of taller. It can also cause hypertension.

There are also other causes, like lead poisoning or aortic coarctation. 

4.AVAPRO EFFECTIVENESS
When is Avapro best taken?

Avapro is an orally active agent that does not require biotransformation into an active form. The oral absorption of Avapro dose is rapid and complete with an average absolute bioavailability of 60–80%. Following oral administration of Avapro dose, peak plasma concentrations of Irbesartan are attained at 1.5–2 hours after dosing. Food does not affect the bioavailability of Avapro.

Avapro exhibits linear pharmacokinetics over the therapeutic Avapro dose range.

The terminal elimination half-life of Avapro averaged 11–15 hours. Steady-state concentrations are achieved within 3 days. Limited accumulation of Avapro (<20%) is observed in plasma upon repeated once-daily Avapro dosing.

Metabolism and Elimination
Avapro is metabolized via glucuronide conjugation and oxidation. Following oral or intravenous administration of 14C-labeled Irbesartan, more than 80% of the circulating plasma radioactivity is attributable to unchanged Irbesartan. The primary circulating metabolite is the inactive irbesartanglucuronideconjugate (approximately 6%). The remaining oxidative metabolites do not add appreciably to Avapro pharmacologic activity.

Avapro and its metabolites are excreted by both biliary and renal routes. Following either oral or intravenous administration of 14C-labeled Irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as Irbesartan or irbesartan glucuronide.

In vitro studies of Irbesartan oxidation by cytochrome P450 isoenzymes indicated Irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was negligible. Irbesartan was neither metabolized by, nor did it substantially induce or inhibit, isoenzymes commonly associated with drug metabolism. There was no induction or inhibition of 3A4.

Distribution
Avapro is 90% bound to serum proteins (primarily albumin and a1-acid glycoprotein) with negligible binding to cellular components of blood. The average volume of distribution is 53–93 liters. Total plasma and renal clearances are in the range of 157–176 and 3.0–3.5 mL/min, respectively. With repetitive Avapro dosing, Avapro accumulates to no clinically relevant extent. 

5.AVAPRO EFFECTS ON SPECIAL POPULATION
How do different people react to Avapro?

Pregnancy
Avapro should not be used in Pregnancy Categories C (first trimester) and D (second and third trimester).

Nursing Mothers
It is not known whether Avapro is excreted in human milk, but Avapro or some metabolite of Avapro is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric: The pharmacokinetics of Avapro were studied in hypertensive children (age 6-12, n=9) and adolescents (age 13-16, n=12) following single and multiple daily Avapro doses of 2 mg/kg (maximum dose of 150 mg per day) for 4 weeks. Accumulation with repeated Avapro doses was limited (18%) in both age groups. Clearance rates, AUC values, and Cmax values were comparable to adults receiving 150 mg daily. Avapro pharmacokinetics have not been investigated in patients <6 years of age. 

Gender: No gender related differences in pharmacokinetics were observed in healthy elderly (age 65–80 years) or in healthy young (age 18–40 years) subjects. In studies of hypertensive patients, there was no gender difference in half-life or accumulation, but somewhat higher plasma concentrations of Avapro were observed in females (11–44%). No gender-related dosage adjustment is necessary. 

Geriatric: In elderly subjects (age 65–80 years), Avapro elimination half-life was not significantly altered, but AUC and Cmax values were about 20–50% greater than those of young subjects (age 18–40 years). No dosage adjustment is necessary in the elderly. 

Race: In healthy black subjects, Irbesartan AUC values were approximately 25% greater than whites; there were no differences in Cmax values.

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

Renal Insufficiency:
The pharmacokinetics of Avapro were not altered in patients with renal impairment or in patients on hemodialysis. Avapro is not removed by hemodialysis. No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also volume depleted. 

Hepatic Insufficiency:
The pharmacokinetics of Avapro following repeated oral administration were not significantly affected in patients with mild to moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency. 

7.OTHER/ALTERNATE USES OF AVAPRO
(What else does Avapro treat?)

Avapro may be used for other purposes as prescribed by your physician.

8.ADVERSE/SIDE EFFECTS of AVAPRO
What are the side effects of Avapro?

Hypertension
Avapro has been evaluated for safety in more than 4300 patients with hypertension and about 5000 subjects overall. This experience includes 1303 patients treated for over 6 months and 407 patients for 1 year or more. Treatment with Avapro was well-tolerated, with an incidence of adverse events similar to placebo. These events generally were mild and transient with no relationship to the dose of Avapro.

In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event was required in 3.3% of patients treated with Avapro, versus 4.5% of patients given placebo.

In placebo-controlled clinical trials, the following adverse event experiences reported in at least 1% of patients treated with Avapro (n=1965) and at a higher incidence versus placebo (n=641), excluding those too general to be informative and those not reasonably associated with the use of drug because they were associated with the condition being treated or are very common in the treated population include: diarrhea (3% vs. 2%), dyspepsia/heartburn (2% vs. 1%), and fatigue (4% vs.3%).

The following adverse events occurred at an incidence of 1% or greater in patients treated with Avapro, but were at least as frequent or more frequent in patients receiving placebo: abdominal pain, anxiety/nervousness, chest pain, dizziness, edema, headache, influenza, musculoskeletal pain, pharyngitis, nausea/vomiting, rash, rhinitis, sinus abnormality, tachycardia and urinary tract infection.

Avapro use was not associated with an increased incidence of dry cough, as is typically associated with ACE inhibitor use. In placebo controlled studies, the incidence of cough in Avapro treated patients was 2.8% versus 2.7% in patients receiving placebo.

The incidence of hypotension or orthostatic hypotension was low in Irbesartan treated patients (0.4%), unrelated to dosage, and similar to the incidence among placebo treated patients (0.2%). Dizziness, syncope, and vertigo were reported with equal or less frequency in patients receiving Irbesartan compared with placebo.

In addition, the following potentially important events occurred in less than 1% of the 1965 patients and at least 5 patients (0.3%) receiving Avapro in clinical studies, and those less frequent, clinically significant events (listed by body system). It cannot be determined whether these events were causally related to Avapro:

Body as a Whole: fever, chills, facial edema, upper extremity edema;

Cardiovascular : flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, arrhythmic/conduction disorder, cardio-respiratory arrest, heart failure, hypertensive crisis;

Dermatologic : pruritus, dermatitis, ecchymosis, erythema face, urticaria;

Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout;

Gastrointestinal: constipation, oral lesion, gastroenteritis, flatulence, abdominal distention;

Musculoskeletal/Connective Tissue: extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, joint stiffness, bursitis, muscle weakness;

Nervous System : sleep disturbance, numbness, somnolence, emotional disturbance, depression, paresthesia, tremor, transient ischemic attack, cerebrovascular accident;

Renal/Genitourinary: abnormal urination, prostate disorder;

Respiratory: epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea, wheezing;

Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain, conjunctivitis, other eye disturbance, eyelid abnormality, ear abnormality. 

Nephropathy in Type 2 Diabetic Patients
In clinical studies in patients with hypertension and type 2 diabetic renal disease, the adverse drug experiences were similar to those seen in patients with hypertension with the exception of an increased incidence of orthostatic symptoms (dizziness, orthostatic dizziness, and orthostatic hypotension) observed in IDNT (proteinuria 900 mg/day, and serum creatinine ranging from 1.0-3.0 mg/dL). In this trial, orthostatic symptoms occurred more frequently in the Avapro group (dizziness 10.2%, orthostatic dizziness 5.4%, orthostatic hypotension 5.4%) than in the placebo group (dizziness 6.0%, orthostatic dizziness 2.7%, orthostatic hypotension 3.2%).

Post-Marketing Experience
The following have been very rarely reported in post-marketing experience: urticaria; angioedema (involving swelling of the face, lips, pharynx, and/or tongue); increased liver function tests; jaundice. Hyperkalemia has been rarely reported.

Laboratory Test Findings

Hypertension
In controlled clinical trials, clinically important differences in laboratory tests were rarely associated with administration of Avapro (Irbesartan).

Creatinine, Blood Urea Nitrogen : Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.7% of patients with essential hypertension treated with Avapro alone versus 0.9% on placebo.

Hematologic : Mean decreases in hemoglobin of 0.2 g/dL were observed in 0.2% of patients receiving Avapro compared to 0.3% of placebo treated patients. Neutropenia (<1000 cells/mm3) occurred at similar frequencies among patients receiving Avapro (0.3%) and placebo treated patients (0.5%).

Nephropathy in Type 2 Diabetic Patients
Hyperkalemia: In IDNT (proteinuria 900 mg/day, and serum creatinine ranging from 1.0-3.0 mg/dL), the percent of patients with hyperkalemia (>6 mEq/L) was 18.6% in the Avapro group vs.6.0% in the placebo group. Discontinuations due to hyperkalemia in the Avapro group were 2.1% vs.0.4% in the placebo group.