1.ALTACE HISTORY
(How was Altace discovered?)

Altace is marketed by Wyeth Pharmaceuticals and King Pharmaceuticals, Inc.

The FDA approved Altace in 1991.

King, based in Bristol, Tennessee, is a pharmaceutical company that develops, manufactures, markets and sells branded prescription pharmaceutical products. King, listed in the S&P 500 Index, seeks to identify promising opportunities in the pharmaceutical industry through the development, including through in-licensing arrangements and acquisitions, of novel branded prescription pharmaceutical products in attractive markets and the strategic acquisition of branded products that can benefit from focused promotion and marketing and product life-cycle management.

Wyeth Pharmaceuticals, a division of Wyeth, has leading products in the areas of women's health care, cardiovascular disease, central nervous system, inflammation, transplantation, hemophilia, oncology, vaccines and nutritional products. Wyeth is one of the world's largest research-driven pharmaceutical and health care products companies. It is a leader in the discovery, development, manufacturing, and marketing of pharmaceuticals, vaccines, biotechnology products and nonprescription medicines that improve the quality of life for people worldwide. The Company's major divisions include Wyeth Pharmaceuticals, Wyeth Consumer Healthcare, and Fort Dodge Animal Health.

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

2.ALTACE FACTS

Altace is a type of medicine used for controlling blood pressure called an ACE inhibitor.

ACE inhibitors work by blocking the action of a compound in the body called angiotensin-converting enzyme (ACE). Normally ACE produces another compound called angiotensin II, as part of the body's natural control of blood pressure. Angiotensin II has two actions. Firstly, it causes blood vessels to constrict and narrow, and secondly, it reduces the production of urine by the kidneys. Both these actions increase the pressure within the blood vessels.

As Altace blocks the action of ACE, it reduces the production of angiotensin II. This means that the blood vessels are allowed to relax to widen and more urine is produced by the kidneys. The overall effect of this is a drop in blood pressure. Altace can therefore be used to treat high blood pressure.

The reduced pressure within the blood vessels means that the heart doesn't have to work as hard to pump the blood around the body. Altace can therefore be used to improve the symptoms of heart failure, where the heart is not pumping as efficiently. It has also been shown to improve survival in people who are diagnosed with heart failure after suffering a heart attack. Altace is usually used in combination with a diuretic medicine to treat heart failure.  

3.ABOUT ALTACE 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 medications 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 changes, 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 urged 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.

Some common ACE inhibitors include

• Benazepril
• Captopril
• Enalapril
• Fosinopril
• Lisinopril
• Quinapril
• Ramipril

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 other causes, like lead poisoning or aortic coarctation, but you will be getting sick of hearing about such rare conditions. 

4.ALTACE EFFECTIVENESS
When is Altace best taken?

Following oral administration of Altace, peak plasma concentrations of Ramipril are reached within 0.5-1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery and is not significantly influenced by the presence of food in the GI tract.

Cleavage of the ester group (primarily in the liver) converts Ramipril to its active metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 1-2 hours after drug intake in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein binding of Ramipril is about 96.7% and that of Ramipril at about 95.3%, on the basis of in vitro studies, the degree of protein binding should be unaffected by age, hepatic dysfunction, or concentration (over the concentration range of 0.24-23.6 µmol/L).

Ramipril is almost completely metabolized to ramiprilat, which has much greater ACE inhibitor activity than Ramipril, and to the glucuronide conjugates of Ramipril and ramiprilat. Only trace amounts of an administered dose of Altace can be recovered in the urine as unchanged Ramipril, while about 20% of the dose of Altace is excreted as ramiprilat, 4% as ramipril glucuronide, and 8% as ramiprilat glucuronide.

The kinetics of Ramipril is approximately dose-proportional within the Altace dosage range of 10-80 mg.

The effective half-life of accumulation of Ramiprilat following multiple dosing of Ramipril hydrochloride is 10-11 hours. Thus, steady-state concentrations of Ramiprilat should be reached after 2 or 3 doses of Ramipril hydrochloride given once daily.

The kinetics did not change, and there was no significant accumulation during chronic administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios based on AUC and urinary recovery of ramiprilat were 1.19 and 1.27, respectively.

When dialysis was started two hours after ingestion of 10 mg of Ramipril, approximately 6% of ramiprilat was removed in 4 hours of dialysis. The parent compound, Ramipril, was not detected in the dialysate.

The disposition of Ramipril and ramiprilat in patients with mild-to-moderate renal insufficiency (creatinine clearance > 30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance </= 30 mL/min, peak ramiprilat levels and the initial (alpha phase) half-life increase, and time to steady state may be delayed.

Ramipril and ramiprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of ramiprilat excretion in healthy subjects. In patients with renal failure, biliary clearance may compensate to an extent for deficient renal clearance.

In patients with hepatic dysfunction due to cirrhosis, levels of ramiprilat are essentially unaltered. The pharmacokinetics of Ramipril and ramiprilat do not appear to be influenced by age.

In studies in rats given 14 C- Ramipril, Ramipril and its metabolites crossed the blood-brain barrier only to an extremely low extent. Multiple doses of Ramipril did not result in accumulation in any tissue except the lung, where, as with other ACE inhibitors in similar studies, there was a slight increase in concentration due to slow elimination in that organ. 

5.ALTACE EFFECTS ON SPECIAL POPULATION
(How do different people react to Altace?

Nursing Mothers
Ingestion of single 10 mg oral dose of Altace resulted in undetectable amounts of Altace and its metabolites in breast milk. However, because multiple doses of Altace may produce low milk concentrations that are not predictable from single doses of Altace, women receiving Altace should not breast feed.

Geriatric Use
Of the total number of patients who received Altace in U.S. clinical studies of Altace 11.0% were 65 and over while 0.2% were 75 and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pediatric Use
Safety and effectiveness of Altace in pediatric patients have not been established. Irreversible kidney damage has been observed in very young rats given a single dose of Altace.

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

Impaired Renal Function:
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including Altace, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. 

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of Altace and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Ramipril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of Ramipril and/or discontinuation of the diuretic may be required. 

Hyperkalemia:
In clinical trials, hyperkalemia (serum potassium greater than 5.7 mEq/l) occurred in approximately 1% of hypertensive patients receiving Altace. In most cases, these were isolated values, which resolved despite continued therapy. None of these patients was discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Altace.

Cough:
Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors always resolving after discontinuation of therapy. Altace induced cough should be considered in the differential diagnosis of cough.

Impaired Liver Function:
Since Altace is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of Ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function. However, since the renin-angiotensin system may be activated in patients with severe liver cirrhosis and/or ascites, particular caution should be exercised in treating these patients.

Surgery/Anesthesia:
In patients undergoing surgery or during anesthesia with agents that produce hypotension, Ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

7.OTHER/ALTERNATE USES OF ALTACE
(What else does Altace treat?)

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

8.ADVERSE/SIDE EFFECTS of ALTACE
What are the side effects of Altace?

Hypertension: Altace has been evaluated for safety in over 4,000 patients with hypertension; of these, 1,230 patients were studied in US controlled trials, and 1,107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in Altace and placebo patients. The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving Altace in US placebo-controlled trials were: headache (5.4%), “dizziness” (2.2%) and fatigue or asthenia (2.0%), but only the last was more common in Altace patients than in patients given placebo. Generally, the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 to 20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of US patients treated with Altace. The most common reasons for discontinuation were: cough (1.0%), “dizziness” (0.5%), and impotence (0.4%).

Of observed side effects considered possibly or probably related to study drug that occurred in US placebo-controlled trials in more than 1% of patients treated with Altace, only asthenia (fatigue) was more common on Altace than placebo (2% vs. 1%).

PATIENTS IN US PLACEBO CONTROLLED STUDIES
	ALTACE (n=651)		Placebo (n=286)
	n	%	n	%
Asthenia (Fatigue)	13	2	2	1

In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome in the Altace group, not attributed at that time to Altace. As these studies were carried out before the relationship of cough to ACE inhibitors was recognized, recognized, some of these events may represent Altace-induced cough. In a later 1-year study, increased cough was seen in almost 12% of Altace patients, with about 4% of patients requiring discontinuation of treatment.

Heart Failure Post Myocardial Infarction: Adverse reactions considered possibly/probably related to study drug that occurred in more than one percent of patients and more frequently on Altace are shown below.

Percentage of Patients with Adverse Events Possibly/ Probably Related to Study Drug
Placebo-Controlled (AIRE) Mortality Study
Adverse Event
Ramipril (N=1004)	Placebo (N=982)
Hypotension	11	5
Cough Increased	8	4
Dizziness	4	3
Angina Pectoris	3	2
Nausea	2	1
Postural Hypotension	2	1
Syncope	2	1
Vomiting	2	0.5
Vertigo	2	0.7
Abnormal Kidney Function	1	0.5
Diarrhea	1	0.4

Other adverse experiences reported in controlled clinical trials (in less than 1% of Altace patients), or rarer events seen in postmarketing experience, include the following

Body As a Whole : Anaphylactoid reactions.

Cardiovascular : Symptomatic hypotension (reported in 0.5% of patients in US trials), syncope and palpitations.

Hematologic : Pancytopenia, hemolytic anemia and thrombocytopenia.

Renal : Some hypertensive patients with no apparent pre-existing renal disease have developed minor, usually transient, increases in blood urea nitrogen and serum creatinine when taking Altace, particularly when Altace was given concomitantly with a diuretic. Acute renal failure.

Angioneurotic Edema : Angioneurotic edema has been reported in 0.3% of patients in US clinical trials.

Gastrointestinal : Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased salivation and taste disturbance.

Dermatologic : Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome.

Neurologic and Psychiatric : Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances.

Miscellaneous : As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has been reported.

Other: arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain.

Post-Marketing Experience : In addition to adverse events reported from clinical trials, there have been rare reports of hypoglycemia reported during Altace therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The casual relationship is unknown.