1.MEVACOR HISTORY
(How was Mevacor discovered?)

Mevacor is a product of Merck Pharmaceuticals.

The US FDA approved Mevacor in August 1987.

2.MEVACOR FACTS

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first.

Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines in over 20 therapeutic categories.

Merck & Co. aims at helping to improve the health and well being of people everywhere by discovering, developing and bringing to market breakthrough medicines. Their priorities are focused on turning cutting-edge science into breakthrough medicines that address significant unmet needs, and thus have the potential to become important medical advances. 

3.ABOUT MEVACOR MEDICATION

What is cholesterol and what does it have to do with heart disease?

Cholesterol is a waxy, fat-like material that is found in all parts of the body. It comes from two sources: the liver produces it, and we consume it in meat and dairy products.

Cholesterol is a chemical that can do both good and harm in the body. On the good side, Cholesterol plays important roles in the structure of cells and in the production of hormones. But too much Cholesterol in the blood can lead to heart and blood vessel disease. To complicate matters, not all Cholesterol contributes to heart and blood vessel problems.

One type, called high-density lipoprotein (HDL) Cholesterol, or "good Cholesterol," actually lowers the risk of these problems. High-density lipoproteins (HDL) remove cholesterol from the bloodstream. The other type, low-density lipoprotein (LDL) Cholesterol, or "bad Cholesterol," is the type that threatens people's health. Low-density lipoproteins (LDL) deliver Cholesterol to the body. To travel through the bloodstream, Cholesterol must attach itself to a protein. The combination of a protein and a fatty substance like Cholesterol is called a lipoprotein.

Many factors may contribute to the fact that some people have higher Cholesterol levels than others. A diet high in certain types of fats is one factor. Medical problems such as poorly controlled diabetes, an under active thyroid gland, an overactive pituitary gland, liver disease or kidney failure also may cause high Cholesterol levels. And some people have inherited disorders that prevent their bodies from properly using and eliminating fats. This allows Cholesterol to build up in the blood.

Treatment for high Cholesterol levels usually begins with changes in habits. By losing weight, stopping smoking, exercising more and reducing the amount of fat and Cholesterol in the diet, many people can bring their Cholesterol levels down to acceptable levels. However, some may need to use Cholesterol-reducing drugs to reduce their risk of health problems.

While some Cholesterol is needed for good health, too much Cholesterol in your blood can raise your risk of having a heart attack or stroke.

The extra Cholesterol in your blood may be stored in your arteries (blood vessels) and cause them to narrow. (This is called atherosclerosis.) Large deposits of Cholesterol can completely block an artery, so the blood cannot flow through.

If an artery that supplies blood to your heart becomes blocked, a heart attack can occur. If an artery that supplies blood to your brain becomes blocked, a stroke can occur.

Cholesterol Levels:

Total cholesterol level

• Less than 200 is best.
• Between 200 to 239 is borderline high.
• 240 or more means you're at increased risk for heart disease.

LDL cholesterol levels

• Less than 130 is best.
• Between 130 to 159 is borderline high.
• 160 or more means you're at higher risk for heart disease.

HDL cholesterol levels

• Less than 40 means you're at higher risk for heart disease.

60 or higher reduces your risk of heart disease.

What are Cholesterol Lowering agents?

Cholesterol-reducing drugs are medicines that lower the amount of Cholesterol in the blood.

Bile acid sequestrants

They are drugs that act by binding with the bile produced by the liver. Bile helps the digestion and absorption of fats in the intestine. By blocking the digestion of fats, bile acid sequesterants prevent the formation of Cholesterol. Drugs in this class include:

• Cholestyramine,
• Colestipol, and
• Colesevelam 

HMG-CoA inhibitors, often called "statins,"

They are drugs that block an enzyme called "3-hydroxy-3-methyl-glutaryl-coenzyme A reductase." This blocks one of the steps in converting fat to Cholesterol. These are the most effective Cholesterol lowering agents available and in recent years have received increased attention for their benefits beyond helping patients with high Cholesterol. In 2003, researchers reported that people with heart failure but no coronary artery disease received benefits after only 14 weeks of statin therapy. In addition, some research has connected the drugs to reduced risk for depression and dementia.

Drugs in this group include:

• Mevacor,
• Cerivastatin,
• Fluvastatin,
• Lovastatin,
• Pravastatin,
• Simvastatin, and
• Rosuvastatin

Fibric acid derivatives

They include

• Clofibrate,
• Gemfibrozil, and
• Fenofibrate.

Although these drugs are less effective than the statins at lowering total Cholesterol, they may be able to lower the low-density lipoprotein (LDL) Cholesterol while raising the high-density lipoprotein (HDL) Cholesterol. They probably act by inhibiting lipoprotein lipase activity.

4. Niacin, or vitamin B-3, also is effective in lowering cholesterol levels. Although the normal vitamin dose of niacin is only 20 mg, the dose required to reduce cholesterol levels is at least 500 mg each day. Niacin probably helps reduce cholesterol by inhibiting very low-density lipoprotein (VLDL) secretion in the bloodstream. 

How does Mevacor work?

Mevacor decreases the production of LDL cholesterol by blocking the action of the enzyme in the liver (called HMG-CoA reductase) that is responsible for its production. This decreases the amount of cholesterol in the liver cells, which causes them to take up LDL cholesterol from the blood. The decreased cholesterol production and increased removal of LDL cholesterol from the blood ultimately results in lowered blood cholesterol levels.

Mevacor also causes a small decrease in the production of other 'bad fats' in the blood called triglycerides, and a small increase in the level of HDL cholesterol. This results in lowered levels of 'bad fats' and raised levels of 'good fats' in the blood. 

4.MEVACOR EFFECTIVENESS
(When is Mevacor best taken?)

Mevacor is a lactone, which is readily hydrolyzed in vivo to the corresponding b-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the b-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of Mevacor.

Following an oral dose of Mevacor in man, 10% of the Mevacor dose was excreted in urine and 83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. Plasma concentrations of total radioactivity peaked at 2 hours and declined rapidly to about 10% of peak by 24 hours post dose. Absorption of Mevacor, estimated relative to an intravenous reference dose, in each of four animal species tested, and averaged about 30% of an oral dose. In animal studies, after oral dosing of Mevacor, Mevacor had high selectivity for the liver, where it achieved substantially higher concentrations than in non-target tissues. Mevacor undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of Mevacor, the availability of drug to the general circulation is low and variable. In a single Mevacor dose study in four hypercholesterolemic patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation as active inhibitors. Following administration of Mevacor tablets the coefficient of variation, based on between-subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory activity in the general circulation.

Both Mevacor and its b-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers. 

The major active metabolites present in human plasma are the b-hydroxyacid of Mevacor, its 6¢-hydroxy derivative, and two additional metabolites. Peak plasma concentrations of both active and total inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic dose range is 10 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by a single dose study employing Mevacor tablet dosages from 60 to as high as 120 mg. With a once-a-day dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state between the second and third days of therapy and were about 1.5 times those following a single dose. When Mevacor was given under fasting conditions, plasma concentrations of total inhibitors was on average about two-thirds those found when lovastatin was administered immediately after a standard test meal.

5.MEVACOR EFFECTS ON SPECIAL POPULATION
(How do different people react to Mevacor?)

Pregnancy

Safety in pregnant women has not been established. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with Mevacor during pregnancy, treatment should be immediately discontinued as soon as pregnancy is recognized. Mevacor should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards.

Nursing Mothers

It is not known whether Mevacor is excreted in human milk. Because a small amount of another drug in this class is excreted in human breast milk and because of the potential for serious adverse reactions in nursing infants, women taking Mevacor should not nurse their infants.

Pediatric Use

Safety and effectiveness in patients 10-17 years of age have been evaluated in controlled clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in girls who were at least 1 year post-menarche. Patients treated with Mevacor had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In these limited controlled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. Mevacor has not been studied in pre-pubertal patients or patients younger than 10 years of age.

Geriatric Use

A pharmacokinetic study with Mevacor showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age; however, clinical study experience in the elderly indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large clinical studies conducted with Mevacor, 21% of patients were 65 years of age. Lipid-lowering efficacy with Mevacor was at least as great in elderly patients compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg/day dosage range.

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

Renal Insufficiency : Renal disease has no influence on the plasma concentrations or LDL-C reduction of Mevacor; thus, dose adjustment in patients with renal dysfunction is not necessary.

Hemodialysis : While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of Mevacor since the drug is extensively bound to plasma proteins.

Hepatic Insufficiency : In patients with chronic alcoholic liver disease, plasma concentrations of Mevacor are markedly increased. 

7.OTHER/ALTERNATE USES OF MEVACOR
(What else does Mevacor treat?)

Mevacor is used to reduce the amounts of LDL (bad) cholesterol, total cholesterol, triglycerides (another type of fat), and apolipoprotein B (a protein needed to make cholesterol) in your blood. Mevacor is also used to increase the level of HDL (good) cholesterol in your blood. These actions are important in reducing the risk of hardening of the arteries, which can lead to heart attacks, stroke, and peripheral vascular disease.

8.ADVERSE/SIDE EFFECTS of MEVACOR
(What are the side effects of Mevacor?)

Mevacor is generally well tolerated; adverse reactions usually have been mild and transient.

In Phase III controlled clinical studies involving 613 patients treated with Mevacor, the adverse experience profile was similar to that shown below for the 8,245-patient EXCEL study.

Persistent increases of serum transaminases have been noted. About 11% of patients had elevations of CK levels of at least twice the normal value on one or more occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported.

Expanded Clinical Evaluation of Lovastatin (EXCEL) Study

Mevacor was compared to placebo in 8,245 patients with hypercholesterolemia in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical adverse experiences reported as possibly, probably or definitely drug-related in? 1% in any treatment group are shown in the table below. For no event was the incidence on drug and placebo statistically different.

Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to 1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on drug and placebo was not statistically different.

Body as a Whole : chest pain;

Gastrointestinal : acid regurgitation, dry mouth, vomiting;

Musculoskeletal : leg pain, shoulder pain, arthralgia;

Nervous System/Psychiatric : insomnia, paresthesia;

Skin : alopecia, pruritus;

Special Senses : eye irritation.