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Keep your heart healthy; February is American Heart Month

Friday, February 8th, 2008

In this month of love, with cards and shop windows adorned with heart-shaped items surrounding us, take a moment or two to appreciate your own heart.

Each day, it works tirelessly, without ceasing, steadily keeping lifeblood flowing through the veins and arteries of each and every human being. Quietly doing its job, the heart beats an average of 3.3 billion beats in a lifetime!

And how do we thank this hardworking muscle upon which our very lives depend? For many Americans, by feeding it cholesterol, saturated fats, refined sugars, and other harmful substances lacking the nutritive value a healthy heart needs to keep going, day in and day out, and with insufficient exercise and carrying weight that strains the body s hardest-working muscle.

Cardiovascular diseases, including stroke, are the No. 1 killers in the United States, according to information from the American Heart Association. Heart health or the lack of it, for many of us is one reason the president annually proclaims February as American Heart Month, at the request of Congress.

Coronary artery disease, or CAD, is the leading cause of death in every developed country, according to doctors Michael F. Roizen and Mehmet C. Oz, authors of You the Owner s Manual. Every American, Asian, and European has a 50 percent chance that his or her quality of life will be damaged by arterial aging disease.

A healthy heart pumps oxygenated blood to itself and the rest of the body, while bringing blood through organs to have toxins removed and back to the lungs for more oxygen. A heart weakened by disease or pumping inefficiently due to clogged arteries means a diminished quality of life and can lead to sudden death.

For optimum health, say Roizen and Oz, your body needs enough physical activity (exercise) to burn between 3,500 and 6,500 calories a week (or from 500 to about 950 a day).

The American Heart Association recommends, Don t eat more calories than you know you can burn up every day. For heart health, the association also suggests increasing the amount and intensity of physical activity to match the number of calories you take in.

Every body also needs about an hour each week of cardiovascular activity to elevate the heart rate to 80 percent or more of its age-adjusted maximum calculated at 220 minus one s age for an extended period of time. This can be in three 20-minute periods each week to obtain optimum health and for living younger, according to Roizen and Oz.

Exercise can be as simple as walking or as energetic as swimming or cycling. Another benefit of exercise is to maintain a healthy weight, as extra weight increases the risk of heart disease. A good guideline to follow is to keep a waist size of less than 40 inches for men or 35 inches for women.

Engaging in enough physical activity to be slightly out of breath, or enough to break a sweat during that time, is usually sufficient to maintain heart health and a healthy weight, provided a body is not overweight to begin with.

Keeping tabs on blood pressure and cholesterol levels also helps with heart health. A healthy pressure is 115/76, according to Roizen and Oz. Take steps if the pressure is too high and be guided by a doctor about the action to take.

Genetics and diet contribute to cholesterol levels. High HDL, or healthy cholesterol, can be caused by foods containing too much cholesterol, simple carbohydrates, and trans and saturated fats, or by genetics. High LDL, the unhealthy cholesterol, can run in families.

Avoiding most white foods, such as white bread, refined sugar, and white pasta, along with restricting saturated and trans fats to less than 20 grams daily, can lower LDL.

Among the things Roizen and Oz suggest for increasing healthy or HDL cholesterol are consuming healthy fats, such as a tablespoon of olive oil, 4 ounces of fish, or 12 walnuts daily; walking or another physical activity for 30 minutes a day; taking niacin; and having a drink of alcohol each night. A word of caution: Too much alcohol can cause aging of the immune system.

Diet plays a huge role in heart health. A diet rich in flavonoids, such as those found in nuts, teas, red wine, grapes, cranberries, onions, and tomatoes, along with conservative amounts of monounsaturated fats, like olive oil, and fatty fish like salmon and whitefish both high in omega-3 fatty acids, provides energy and nutrients for a healthy heart.

Other aids for a healthy heart may include a low dose of aspirin, as prescribed by a doctor. A good multivitamin can also help, and getting enough potassium from your diet, such as from melons, bananas, or avocados, is beneficial.

Choose foods like vegetables, fruits, whole-grain products, and fat-free or low-fat dairy products most often, the American Heart Association recommends. High in vitamins, minerals, and fiber, as well as calories, a variety of vegetables and fruits can help control weight and blood pressure. Whole-grain products contain fiber, which can help lower blood cholesterol and help you feel full, which in turn may help manage weight.

Generally, a healthy heart and cardiovascular system can be maintained with a plan including a healthy, low-fat diet, moderate exercise, and regular checks on blood pressure and cholesterol.

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Cholesterol is NOT the Critical Cause of Heart Disease

Monday, February 4th, 2008

Cholesterol is not the major culprit in heart disease or any disease. If it becomes oxidized it can irritate/inflame tissues in which it is lodged in, such as the endothelium (lining of the arteries). This would be one of numerous causes of chronic inflammation that can injure the lining of arteries. However, many good fats are easily oxidized such as omega-3 fatty acids, but it does not mean that you should avoid it at all costs.

Common sense would indicate that we should avoid the oxidation (rancidity) of cholesterol and fatty acids and not get rid of important life-giving molecules. Using the same conventional medical thinking that is being used for cholesterol would lead one to believe that doctors should reduce the risk of Alzheimer’s disease by taking out everybody’s brain.

In fact, cholesterol is being transported to tissues as part of an inflammatory response that is there to repair damage.

The fixation on cholesterol as a major cause of heart disease defies the last 15 years of science and deflects from real causes such as the damage (via glycation) that sugars such as glucose and fructose inflict on tissues, including the lining of arteries, causing chronic inflammation and resultant plaque.

Insulin & Leptin Resistance

Hundreds of excellent scientific articles have linked insulin resistance and more recently leptin resistance to cardiovascular disease much more strongly than cholesterol, and they are in fact at least partially responsible for cholesterol abnormalities. For instance, insulin and leptin resistance result in “small dense” LDL particles and a greater number of particles.

This is much more important than the total cholesterol number. Because of particle size shift to small and dense, the total LDL cholesterol could still be low even though the number of particles and the density of the particles is greater. Small, dense LDL particles can squeeze between the cells lining the inside of the arteries, the “gap junction” of the endothelium, where they can get struck and potentially oxidize, turn rancid, and cause inflammation of the lining of the arteries and plaque formation.

Importantly, many solid scientific studies have shown a mechanistic, causal effect of elevated insulin and leptin on heart and vascular disease, whereas almost all studies with cholesterol misleadingly only show an association. Association does not imply cause. For instance, something else may be causing lipid abnormalities such as elevated cholesterol and triglycerides, and also causing heart disease.

This “something else” is improper insulin and leptin signaling. Similarly, sugar does not cause diabetes; sugar is just listening to orders. Improper insulin and leptin signaling is the cause of diabetes. Likewise, cholesterol does not cause heart disease, but improper metabolic signals including improper signals to cholesterol (causing it to oxidize) and perhaps to the liver that manufactures the cholesterol, will cause heart and vascular disease and hypertension.

Removing cholesterol will do nothing to improve the underlying problems, the real roots of chronic disease, which will always have to do with improper communication, and the generals of metabolic communication are insulin and leptin. They are really what must be treated to reverse heart disease, diabetes, osteoporosis, obesity, and to some extent aging itself.

Cholesterol; Wrongly Accused?

Before we can begin to talk about the real cause and effective treatment for heart and blood vessel disease, we must first look at what is known, or I should say what we think we know. The first thing that comes to mind when one hears about heart disease is almost always cholesterol. Cholesterol and heart disease has been almost synonymous for the last half-century. Cholesterol has been portrayed as the Darth Vader to our arteries and our heart.

The latest recommendation given by a so-called panel of “experts” recommends that a person’s cholesterol be as low as possible, in fact to a level so low they say it cannot be achieved by diet, exercise, or any known lifestyle modification. Therefore, they say cholesterol-lowering drugs; particularly the so-called “statins” need to be given to anyone at high risk of heart disease. Since heart disease is the number one killer in this country that would include most adults and even many children. The fact that this might add to the $26 billion in sales of statin drugs last year I’m sure played no role in their recommendations.

Or did it?

Expert Conflict of Interests

Major consumer groups think so. They found out that eight of the nine “experts” that made the recommendations were on the payroll of pharmaceutical companies that manufacture those drugs. Major scientific organizations have chastised medical journals for allowing the pharmaceutical industry to publish misleading results and half-truths. There is a major push under way to force the pharmaceutical industry (and others) to publish results of all of their studies, and not just the ones that appear positive. The studies that showed negative results would be forced to be published also.

It could be that lowering cholesterol might not be as healthy as we are being told. More and more studies are coming out showing just how unhealthy lowering cholesterol might be, particularly by the use of statin drugs. In particular, statin drugs have been shown to be harmful to muscles causing considerable damage. A common symptom of this damage is muscular aches and pains that many patients experience on cholesterol-lowering drugs, however most do not realize that these drugs are to blame.

Hmm…isn’t the heart a muscle?

Statin Drugs Actually Increase Heart Disease

Indeed, low cholesterol levels have been shown to worsen patients with congestive heart failure, a life-threatening condition where the heart becomes too weak to effectively pump blood. Statin drugs have been shown to also cause nerve damage and to greatly impair memory. One reason that statin drugs have these various serious side effects is that they work by inhibiting a vital enzyme that manufactures cholesterol in the liver. However, the same enzyme is used to manufacture coenzyme Q10, which is a biochemical needed to transfer energy from food to our cells to be used for the work of staying alive and healthy.

Statin drugs are known to inhibit our very important production of coenzyme Q10. Importantly, while many cardiologists insist that lowering cholesterol is correlated with a reduction in the risk of heart attacks; few can say that there is a reduction in the risk of mortality (death). That has been much harder to show. In other words it has never been conclusively shown that lowering cholesterol saves lives. In fact, several large studies have shown that lowering cholesterol into the range currently recommended is correlated with an increased risk of dying, especially of cancer.

No Such Thing as Good and Bad Cholesterol

Because the correlation of total cholesterol with heart disease is so weak, many years ago a stronger correlation was sought. It was found that there is so-called “good cholesterol” called HDL, and that the so-called “bad cholesterol” was LDL. HDL stands for high-density lipoprotein, and LDL stands for low-density lipoprotein. Notice please that LDL and HDL are lipoproteins — fats combined with proteins. There is only one cholesterol. There is no such thing as a good or a bad cholesterol. Cholesterol is just cholesterol. It combines with other fats and proteins to be carried through the bloodstream, since fat and our watery blood do not mix very well.

Fatty substances therefore must be shuttled to and from our tissues and cells using proteins. LDL and HDL are forms of proteins and are far from being just cholesterol. In fact we now know there are many types of these fat and protein particles. LDL particles come in many sizes and large LDL particles are not a problem. Only the so-called small dense LDL particles can potentially be a problem, because they can squeeze through the lining of the arteries and if they oxidize, otherwise known as turning rancid, they can cause damage and inflammation. Thus, you might say that there is “good LDL” and “bad LDL.” Also, some HDL particles are better than others. Knowing just your total cholesterol tells you very little. Even knowing your LDL and HDL levels do not tell you very much.

A mistake that is rarely made in the hard-core sciences such as physics seems to be frequently made in medicine. This is confusing correlation with cause. There may be a weak correlation of elevated cholesterol with heart attacks, however this does not mean it is the cholesterol that caused the heart attack. Certainly gray hair is correlated with getting older; however one could hardly say that the gray hair caused one to get old. Using hair dye to reduce the gray hair would not really make you any younger. Neither it appears would just lowering your cholesterol.

Perhaps something else is causing both the gray hair and aging. Even if elevated cholesterol were significant and heart disease (which I question) perhaps something else is causing the elevated cholesterol and also causing the heart disease.

Let’s look little more at cholesterol or, as Paul Harvey was fond of saying, “the rest of the story.” First and foremost, cholesterol is a vital component of every cell membrane on Earth. In other words, there is no life on Earth they can live without cholesterol. That will automatically tell you that, in of itself, it cannot be evil. In fact it is one of our best friends. We would not be here without it. No wonder lowering cholesterol too much increases one’s risk of dying. Cholesterol also is a precursor to all of the steroid hormones. You cannot make estrogen, testosterone, cortisone, and a host of other vital hormones without cholesterol.

Cholesterol Is The Hero, Not The Villain.

It was determined many years ago that the majority of cholesterol in your bloodstream comes from what your liver is manufacturing and distributing. The amount of cholesterol that one eats plays little role in determining your cholesterol levels. It is also known that HDL shuttles cholesterol away from tissues, and away from your arteries, back to your liver. That is why HDL is called the “good cholesterol;” because it is supposedly taking cholesterol away from your arteries. But let’s think about that.

* Why does your liver make sure that you have plenty of cholesterol?
* Why is HDL taking cholesterol back to your liver?
* Why not take it right to your kidneys, or your intestines to get rid of it?

It is taking it back to your liver so that your liver can recycle it; put it back into other particles to be taken to tissues and cells that need it. Your body is trying to make and conserve the cholesterol for the precise reason that it is so important, indeed vital, for health.

One function of cholesterol is to keep your cell membranes from falling apart. As such, you might consider cholesterol your cells “superglue.” It is a necessary ingredient in any sort of cellular repair. The coronary disease associated with heart attacks is now known to be caused from damage to the lining of those arteries. That damage causes inflammation. The coronary disease that causes heart attacks is now considered to be caused mostly from chronic inflammation.

What Is Inflammation?

Think of what happens if you were to cut your hand. Within a fraction of a second, chemicals are released by the damaged tissue to initiate the process known as inflammation. Inflammation will allow that little cut to heal, and indeed to keep you from dying. The cut blood vessels constrict to keep you from bleeding too much. Blood becomes “thicker” so that it can clot. Cells and chemicals from the immune system are alerted to come to the area to keep intruders such as viruses and bacteria from invading the cut. Other cells are told to multiply to repair the damage so that you can heal. When the repair is completed, you have lived to be careless another day, though you may have a small scar to show for your troubles.

We now know that similar events take place within the lining of our arteries. When damage occurs to the lining of our arteries (or even elsewhere) chemicals are released to initiate the process of inflammation. Arteries constrict, blood becomes more prone to clot, white blood cells are called to the area to gobble up damaged debris, and cells adjacent to those damaged are told to multiply. Ultimately, scars form, however inside our arteries we call it plaque. And the constriction of our arteries and the “thickening” of our blood further predisposes us to high blood pressure and heart attacks.

So Where Might Cholesterol Fit Into All Of This?

When damage is occurring and inflammation is being initiated, chemicals are being released so that that damage can be repaired. One could speculate that to replace damaged, old and worn-out cells the liver needs to be notified to either recycle or manufacture cholesterol since no cell, human or otherwise, can be made without it. In this case, cholesterol is being manufactured and distributed in your bloodstream to help you repair damaged tissue and in fact to keep you alive.

If excessive damage is occurring such that it is necessary to distribute extra cholesterol through the bloodstream, it would not seem very wise to merely lower the cholesterol and forget about why it is there in the first place. It would seem much smarter to reduce the extra need for the cholesterol — the excessive damage that is occurring, the reason for the chronic inflammation.

So Why Take Cholesterol-Lowering Drugs?

The pharmaceutical companies thought that you might think that. They went back to the drawing board. They did more “research” and found (coincidentally) that statin drugs had anti-inflammatory effects. Therefore we’re currently being told to stay on our cholesterol-lowering drugs because now they work by reducing inflammation and perhaps not even by reducing cholesterol, and in fact perhaps in spite of it. Aspirin reduces inflammation for a lot less money. So does vitamin E, and fish oil, and dietary changes without the dangers of drugs and having many other benefits instead.

What About Triglycerides?

Triglycerides are just medical terminology for fat. A person with high triglycerides has a lot of fat in the bloodstream. Triglycerides are generally measured when a person has fasted overnight. High fasting triglycerides are either from manufacturing too much, or using (burning) too little. In other words, what high triglycerides are telling you is that you are making too much fat and you are unable to burn it. This indeed is a major problem. The inability to burn fat underlies virtually all of the chronic diseases of aging, and in fact may contribute to the rate of aging itself.

As such, one might think that the control all fat burning and storage might be very important in heart disease, and the other diseases of aging such as diabetes, obesity, osteoporosis, and even cancer. Indeed, this appears to very much be the case. The two hormones that to a major extent control our ability to burn and store fat, insulin and leptin, appear to play a major role in all of the chronic diseases of aging. I would call them the most important hormones, indeed chemicals in the entire body. But that is a story for next time.

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Keeping Cholesterol Down

Thursday, January 31st, 2008

There’s new scrutiny of statins, which are the most popular prescription drug ever that’s been marketed as a cholesterol-lowering medication.

As Businessweek reports: “The drugs are thought to be so essential that, according to the official government guidelines from the National Cholesterol Education Program, 40 million Americans should be taking them. Some researchers have even suggested-half-jokingly-that the medications should be put in the water supply, like fluoride for teeth.”

This week, CBS News partnered with Businessweek, which reported today that statins don’t necessarily help patients in the way they are thought to. Read our partner story from Businessweek here.

While it is possible that it is in your best interest to use cholesterol-lowering medication, medical experts suggest ways to lower your cholesterol without drugs – making simple lifestyle changes.

The American Heart Association’s Web gives simple recommendations in a checklist for lowering cholesterol. It suggests taking simple measures: exercising regularly, eating a heart-healthy diet and making certain lifestyle choices, such as avoiding tobacco smoking.

Eating healthy

The American Heart Association offers some information on cholesterol, your body and your diet.

Some of your cholesterol is made by your body. The food you eat is responsible for the rest. Food products from animals contain cholesterol – including meats, poultry, shellfish, eggs, butter, cheese and whole or 2 percent milk. And any type of food can also contain saturated fats and trans fats, which cause your body to make more cholesterol.

The American Heart Association recommends that you keep your intake of total fat to between 25 percent and 35 percent, your saturated fat consumption to less than 7 percent and your intake of trans fat to less than 1 percent of your total daily calories.

At the same time, limit your intake of cholesterol from food to less than 300 mg per day. People with high LDL (bad) blood cholesterol levels or who are taking cholesterol medication should consume less than 200 mg of cholesterol per day.

Eat at least 25 to 30 grams of dietary fiber each day – preferably from whole grains, fruits, vegetables and legumes. To combat high blood pressure and for overall cardiovascular health, also limit sodium to 2,300 mg or less per day.

But a heart-healthy diet isn’t just about what you shouldn’t eat. It also means eating a diet rich in vegetables and fruits, with whole grains, high-fiber foods, lean meats and poultry, fish at least twice a week, and fat-free or 1 percent fat dairy products. Also, the diet should be low in saturated fat, trans fat and cholesterol.

But can a bowl of cereal help prevent a heart attack? The Mayo Clinic suggests the best foods to lower your cholesterol and protect your heart. A partial list from the Mayo Clinic is below.

Oatmeal

Oatmeal contains soluble fiber, which reduces your “bad” cholesterol. Soluble fiber is also found in such foods as kidney beans, brussels sprouts, apples, pears, psyllium, barley and prunes.

Walnuts and almonds

Studies have shown that walnuts can significantly reduce blood cholesterol. Rich in polyunsaturated fatty acids, walnuts also help keep blood vessels healthy and elastic. Almonds appear to have a similar effect, resulting in a marked improvement within just four weeks.

Fish including omega-3 fatty acids

Studies in the 1970s showed that Greenland Eskimos had a lower rate of heart disease than did other individuals living in Greenland at the same time. Analysis of dietary differences between the groups showed that the Eskimos ate less saturated fat and more omega-3 fatty acids found in fish and whale and seal meat. Research since that time has supported the heart-healthy benefits of eating fish. If you can’t dine with the Eskimos, other good sources of omega-3 fatty acids include flaxseed, walnuts, canola oil and soybean oil.

Soy

Long thought to have cholesterol-lowering effects, a recent meta-analysis by the American Heart Association’s Nutrition Committee showed soy protein actually has very little impact on reducing cholesterol levels. In January 2006, the American Heart Association issued a statement saying the cardiovascular health benefits of soy protein are minimal at best. No benefit was seen on HDL, triglycerides, or blood pressure and even with a large intake of soy, only a small impact on LDL was seen.

Stay away from smoke

The American Heart Association advises the following:
Cigarette and tobacco smoke, high blood cholesterol, high blood pressure, physical inactivity, obesity and diabetes are the six major independent risk factors for coronary heart disease that you can modify or control. Cigarette smoking is so widespread and significant as a risk factor that the Surgeon General has called it “the leading preventable cause of disease and deaths in the United States.”

Cigarette smoking increases the risk of coronary heart disease by itself. When it acts with other factors, it greatly increases risk. Smoking increases blood pressure, decreases exercise tolerance and increases the tendency for blood to clot. Smoking also increases the risk of recurrent coronary heart disease after bypass surgery.

Keep up physical activity

Physical inactivity is a major risk factor for heart disease, according to The American Heart Association, which recommends getting at least 30 minutes of physical activity, preferably every day but at least more days than not.

You don’t need to get your minutes all at once – it’s fine to break up your activity into 10-minute sessions or 15-minute sessions. For some people, regular physical activity affects blood cholesterol level by increasing the level of HDL (good) cholesterol. A higher HDL level is linked with a lower risk of heart disease. Physical activity can also help control other risk factors for heart disease: weight, diabetes and high blood pressure. Aerobic exercise (exercise that uses oxygen to provide energy to large muscles) raises your heart and breathing rates, which help your heart to work more efficiently at rest as well as during physical activity. Vigorous, regular physical activity such as brisk walking, jogging and swimming also condition your lungs.

Even mild activities, if done daily, can help. You can benefit from simple things like walking, gardening, housework or dancing. Talk to your doctor about getting started, especially if you’ve been inactive.

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Do Cholesterol Drugs Do Any Good?

Wednesday, January 30th, 2008

Research suggests that, except among high-risk heart patients, the benefits of statins such as Lipitor are overstated Martin Winn’s cholesterol level was inching up. Cycling up hills, he felt chest pain that might have been angina. So he and his doctor decided he should be on a cholesterol-lowering medication called a statin. He was in good company. Such drugs are the best-selling medicines in history, used by more than 13 million Americans and an additional 12 million patients around the world, producing $27.8 billion in sales in 2006. Half of that went to Pfizer (PFE) for its leading statin, Lipitor. Statins certainly performed as they should for Winn, dropping his cholesterol level by 20%. “I assumed I’d get a longer life,” says the retired machinist in Vancouver, B.C., now 71. But here the story takes a twist. Winn’s doctor, James M. Wright, is no ordinary family physician. A professor at the University of British Columbia, he is also director of the government-funded Therapeutics Initiative, whose purpose is to pore over the data on particular drugs and figure out how well they work. Just as Winn started on his treatment, Wright’s team was analyzing evidence from years of trials with statins and not liking what it found.

Yes, Wright saw, the drugs can be life-saving in patients who already have suffered heart attacks, somewhat reducing the chances of a recurrence that could lead to an early death. But Wright had a surprise when he looked at the data for the majority of patients, like Winn, who don’t have heart disease. He found no benefit in people over the age of 65, no matter how much their cholesterol declines, and no benefit in women of any age. He did see a small reduction in the number of heart attacks for middle-aged men taking statins in clinical trials. But even for these men, there was no overall reduction in total deaths or illnesses requiring hospitalization—despite big reductions in “bad” cholesterol. “Most people are taking something with no chance of benefit and a risk of harm,” says Wright. Based on the evidence, and the fact that Winn didn’t actually have angina, Wright changed his mind about treating him with statins—and Winn, too, was persuaded. “Because there’s no apparent benefit,” he says, “I don’t take them anymore.”

Wait a minute. Americans are bombarded with the message from doctors, companies, and the media that high levels of bad cholesterol are the ticket to an early grave and must be brought down. Statins, the message continues, are the most potent weapons in that struggle. The drugs are thought to be so essential that, according to the official government guidelines from the National Cholesterol Education Program (NCEP), 40 million Americans should be taking them. Some researchers have even suggested—half-jokingly—that the medications should be put in the water supply, like fluoride for teeth. Statins are sold by Merck (MRK) (Mevacor and Zocor), AstraZeneca (AZN) (Crestor), and Bristol-Myers Squibb (BMY) (Pravachol) in addition to Pfizer. And it’s almost impossible to avoid reminders from the industry that the drugs are vital. A current TV and newspaper campaign by Pfizer, for instance, stars artificial heart inventor and Lipitor user Dr. Robert Jarvik. The printed ad proclaims that “Lipitor reduces the risk of heart attack by 36%…in patients with multiple risk factors for heart disease.”

So how can anyone question the benefits of such a drug?

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Oatmeal’s War on Cholesterol

Saturday, January 26th, 2008

It’s been 10 years since the Food and Drug Administration agreed to allow claims that oatmeal can reduce cholesterol.

Since then, research has confirmed that oats do indeed reduce bad LDL cholesterol, while also helping reduce blood pressure, weight gain and the risk of Type 2 diabetes, according to a review article in the American Journal of Lifestyle Medicine.

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Lipitor Complete Information

Thursday, January 24th, 2008

DESCRIPTION

Lipitor (atorvastatin calcium) is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.

Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is (C33H34FN2O5)2Ca•3H2O and its molecular weight is 1209.42.

Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile, slightly soluble in ethanol, and freely soluble in methanol.

Lipitor tablets for oral administration contain 10, 20, 40 or 80 mg atorvastatin and the following inactive ingredients: calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion.

CLINICAL PHARMACOLOGY

Mechanism of Action

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk.

In animal models, Lipitor lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL; Lipitor also reduces LDL production and the number of LDL particles. Lipitor reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s).

A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C.

Lipitor reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Lipitor also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Lipitor reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Lipitor reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia.

Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Pharmacodynamics

Atorvastatin as well as some of its metabolites are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage rather than systemic drug concentration correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response (see DOSAGE AND ADMINISTRATION).

Pharmacokinetics and Drug Metabolism

Absorption

Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration (see DOSAGE AND ADMINISTRATION).

Distribution

Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk (see CONTRAINDICATIONS, Pregnancy and Lactation, and PRECAUTIONS, Nursing Mothers).

Metabolism

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following coadministration with erythromycin, a known inhibitor of this isozyme (see PRECAUTIONS, Drug Interactions). In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion

Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.

Special Populations

Geriatric

Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults (see PRECAUTIONS section; Geriatric Use subsection).

Gender

Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with LIPITOR between men and women.

Renal Insufficiency

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary (see DOSAGE AND ADMINISTRATION).

Hemodialysis

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

Hepatic Insufficiency

In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease (see CONTRAINDICATIONS).

Clinical Studies
Prevention of Cardiovascular Disease

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of Lipitor (atorvastatin calcium) on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40–80 years of age (mean of 63 years), without a previous myocardial infarction and with TC levels ≤251 mg/dl (6.5 mmol/l). Additionally all patients had at least 3 of the following cardiovascular risk factors: male gender (81.1%), age >55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality (14.3%), proteinuria/albuminuria (62.4%). In this double-blind, placebo-controlled study patients were treated with anti-hypertensive therapy (Goal BP <140/90 mm Hg for non-diabetic patients, <130/80 mm Hg for diabetic patients) and allocated to either Lipitor 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years.

The effect of 10 mg/day of Lipitor on lipid levels was similar to that seen in previous clinical trials.

Lipitor significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the Lipitor group) or nonfatal MI (108 events in the placebo group vs. 60 events in the Lipitor group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for Lipitorvs. 3.0% for placebo), p=0.0005. The risk reduction was consistent regardless of age, smoking status, obesity or presence of renal dysfunction. The effect of Lipitor was seen regardless of baseline LDL levels. Due to the small number of events, results for women were inconclusive.

Lipitor also significantly decreased the relative risk for revascularization procedures by 42%. Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for Lipitor and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17).

In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of Lipitor (atorvastatin calcium) on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% White, 68% male), ages 40–75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL≤ 160 mg/dL and TG ≤600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the study. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either Lipitor 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint.

Baseline characteristics of subjects were: mean age of 62 years, mean HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52mg/dL.

The effect of Lipitor 10 mg/ day on lipid levels was similar to that seen in previous clinical trials.

Lipitor significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the LIPITOR group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48,0.83) (p=0.001). An effect of Lipitor was seen regardless of age, sex, or baseline lipid levels.

Effect of Lipitor 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS.

Lipitor significantly reduced the risk of stroke by 48% (21 events in the Lipitor group vs 39 events in the placebo group), HR 0.52, 95% CI (0.31,0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the Lipitor group vs 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death.

There were 61 deaths in the Lipitor group vs 82 deaths in the placebo group, (HR 0.73, p=0.059).

In the Treating to New Targets Study (TNT), the effect of Lipitor 80 mg/day vs. Lipitor 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level <130 mg/dL after completing an 8-week, open-label, run-in period with Lipitor 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of LIPITOR and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98 and 47 mg/dL during treatment with 80 mg of LIPITOR and 99, 177, 152, 129 and 48 mg/dL during treatment with 10 mg of Lipitor.

Treatment with Lipitor 80 mg/day significantly reduced the rate of MCVE (434 events in the 80mg/day group vs 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69,0.89), p=0.0002 (see Figure 3 and Table 1). The overall risk reduction was consistent regardless of age (<65, ≥65) or gender.

Of the events that comprised the primary efficacy endpoint, treatment with LIPITOR 80 mg/day significantly reduced the rate of nonfatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 1). Of the predefined secondary endpoints, treatment with Lipitor 80 mg/day significantly reduced the rate of coronary revascularization, angina and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF.

There was no significant difference between the treatment groups for all-cause mortality (Table 1). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke were numerically smaller in the Lipitor 80 mg group than in the Lipitor 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the Lipitor 80 mg group than in the Lipitor10 mg treatment group.

In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with Lipitor 80 mg/day was compared to treatment with simvastatin 20–40 mg/day in 8,888 subjects up to 80 years of age with a history of CHD to assess whether reduction in CV risk could be achieved. Patients were mainly male (81%), white (99%) with an average age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76% were on statin therapy. In this prospective, randomized, open-label, blinded endpoint (PROBE) trial with no run-in period, subjects were followed for a median duration of 4.8 years. The mean LDL-C, TC, TG, HDL and non-HDL cholesterol levels at Week 12 were 78, 145, 115, 45 and 100 mg/dL during treatment with 80 mg of Lipitor and 105, 179, 142, 47 and 132 mg/dL during treatment with 20–40 mg of simvastatin.

There was no significant difference between the treatment groups for the primary endpoint, the rate of first major coronary event (fatal CHD, nonfatal MI and resuscitated cardiac arrest): 411 (9.3%) in the Lipitor 80 mg/day group vs. 463 (10.4%) in the simvastatin 20–40 mg/day group, HR 0.89, 95% CI ( 0.78,1.01), p=0.07.

There were no significant differences between the treatment groups for all-cause mortality: 366 (8.2%) in the Lipitor 80 mg/day group vs. 374 (8.4%) in the simvastatin 20–40 mg/day group. The proportions of subjects who experienced CV or non-CV death were similar for the Lipitor 80 mg group and the simvastatin 20–40 mg group.

Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)

Lipitor reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in patients with hypercholesterolemia and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy.

Lipitor is effective in a wide variety of patient populations with hypercholesterolemia, with and without hypertriglyceridemia, in men and women, and in the elderly. Experience in pediatric patients has been limited to patients with homozygous FH. In two multicenter, placebo-controlled, dose-response studies in patients with hypercholesterolemia, Lipitor given as a single dose over 6 weeks significantly reduced total-C, LDL-C, apo B, and TG.

In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25th and 75th percentile) percent changes from baseline in HDL-C for atorvastatin 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7(0, 17), 7.8(0, 16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled data demonstrated consistent and significant decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.

In three multicenter, double-blind studies in patients with hypercholesterolemia, Lipitor was compared to other HMG-CoA reductase inhibitors. After randomization, patients were treated for 16 weeks with either Lipitor 10 mg per day or a fixed dose of the comparative agent.

The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 3 is not known. Table 3 does not contain data comparing the effects of atorvastatin 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the studies summarized in the table are not necessarily interchangeable.

Hypertriglyceridemia (Fredrickson Type IV)

The response to Lipitor in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below. For the atorvastatin-treated patients, median (min, max) baseline TG level was 565 (267–1502).

Dysbetalipoproteinemia (Fredrickson Type III)

The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia (Fredrickson Type III)

Homozygous Familial Hypercholesterolemia

In a study without a concurrent control group, 29 patients ages 6 to 37 years with homozygous FH received maximum daily doses of 20 to 80 mg of Lipitor. The mean LDL-C reduction in this study was 18%. Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients

In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10–17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (FH) or severe hypercholesterolemia were randomized to Lipitor (n=140) or placebo (n=47) for 26 weeks and then all received Lipitor for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline LDL-C ≥ 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first- or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5–385.0 mg/dL) in the Lipitor group compared to 230.0 mg/dL (range: 160.0–324.5 mg/dL) in the placebo group. The dosage of Lipitor (once daily) was 10 mg for the first 4 weeks and up-titrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of Lipitor-treated patients who required up-titration to 20 mg after Week 4 during the double-blind phase was 80 (57.1%).

Lipitor significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26 week double-blind phase.

The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0–242.0 mg/dL) in the Lipitor group compared to 228.5 mg/dL (range: 152.0–385.0 mg/dL) in the placebo group during the 26 week double-blind phase.

The safety and efficacy of doses above 20 mg have not been studied in controlled trials in children. The long-term efficacy of Lipitor therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

INDICATIONS AND USAGE

Prevention of Cardiovascular Disease

In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, Lipitor is indicated to:

* Reduce the risk of myocardial infarction
* Reduce the risk of stroke
* Reduce the risk for revascularization procedures and angina

In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, Lipitor is indicated to:

* Reduce the risk of myocardial infarction
* Reduce the risk of stroke

In patients with clinically evident coronary heart disease, Lipitor is indicated to:

* Reduce the risk of non-fatal myocardial infarction
* Reduce the risk of fatal and non-fatal stroke
* Reduce the risk for revascularization procedures
* Reduce the risk of hospitalization for CHF
* Reduce the risk of angina

Hypercholesterolemia

Lipitor is indicated:

1. as an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb);
2. as an adjunct to diet for the treatment of patients with elevated serum TG levels(Fredrickson Type IV);
3. for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet;
4. to reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable;
5. as an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present:

a.
LDL-C remains ≥ 190 mg/dL or
b.
LDL-C remains ≥ 160 mg/dL and:
* there is a positive family history of premature cardiovascular disease or
* two or more other CVD risk factors are present in the pediatric patient

Therapy with lipid-altering agents should be a component of multiple-risk-factor intervention in individuals at increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other nonpharmacological measures has been inadequate (see National Cholesterol Education Program (NCEP) Guidelines.

After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.

Prior to initiating therapy with LIPITOR, secondary causes for hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, and alcoholism) should be excluded, and a lipid profile performed to measure total-C, LDL-C, HDL-C, and TG. For patients with TG <400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation: LDL-C = total-C - (0.20 × [TG] + HDL-C). For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation.

LIPITOR has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).

CONTRAINDICATIONS

Active liver disease or unexplained persistent elevations of serum transaminases.

Hypersensitivity to any component of this medication.

Pregnancy and Lactation

Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women. Therefore, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers. ATORVASTATIN SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug, therapy should be discontinued and the patient apprised of the potential hazard to the fetus.

WARNINGS

Liver Dysfunction

HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.

One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin.

It is recommended that liver function tests be performed prior to and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with atorvastatin. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of >3 times ULN persist, reduction of dose or withdrawal of atorvastatin is recommended.

Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin (see CONTRAINDICATIONS).

Skeletal Muscle

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class.

Uncomplicated myalgia has been reported in atorvastatin-treated patients (see ADVERSE REACTIONS). Myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, combination of ritonavir plus saquinavir or lopinavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin, clarithromycin, a combination of ritonavir plus saquinavir or lopinavir plus ritonavir, immunosuppressive drugs, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs (See DRUG INTERACTIONS). Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.

Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

PRECAUTIONS
General

Before instituting therapy with atorvastatin, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, and weight reduction in obese patients, and to treat other underlying medical problems (see INDICATIONS AND USAGE).

Information for Patients

Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

Drug Interactions

The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin or cytochrome P450 3A4 inhibitors (e.g. cyclosporine, erythromycin, clarithromycin, and azole antifungals) (see WARNINGS, Skeletal Muscle).

Inhibitors of cytochrome P450 3A4

Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4.

Clarithromycin

Concomitant administration of atorvastatin 80 mg with clarithromycin (500 mg twice daily) resulted in a 4.4-fold increase in atorvastatin AUC (see WARNINGS, Skeletal Muscle, and DOSAGE AND ADMINISTRATION).

Erythromycin

In healthy individuals, plasma concentrations of atorvastatin increased approximately 40% with co-administration of atorvastatin and erythromycin, a known inhibitor of cytochrome P450 3A4 (see WARNINGS, Skeletal Muscle).

Combination of Protease Inhibitors

Concomitant administration of atorvastatin 40 mg with ritonavir plus saquinavir (400 mg twice daily) resulted in a 3-fold increase in atorvastatin AUC. Concomitant administration of atorvastatin 20 mg with lopinavir plus ritonavir (400 mg+100 mg twice daily) resulted in a 5.9-fold increase in atorvastatin AUC (see WARNINGS, Skeletal Muscle, and DOSAGE AND ADMINISTRATION).

Itraconazole

Concomitant administration of atorvastatin (20 to 40 mg) and itraconazole (200 mg) was associated with a 2.5–3.3-fold increase in atorvastatin AUC.

Diltiazem hydrochloride

Co-administration of atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma concentrations of atorvastatin.

Cimetidine

Atorvastatin plasma concentrations and LDL-C reduction were not altered by co-administration of cimetidine.

Grapefruit juice

Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day).

Cyclosporine

Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g. cyclosporine) can increase the bioavailability of atorvastatin. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in an 8.7-fold increase in atorvastatin AUC. In cases where co-administration of atorvastatin with cyclosporine is necessary, the dose of atorvastatin should not exceed 10 mg (see WARNINGS, Skeletal Muscle).

Inducers of cytochrome P450 3A4

Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (eg efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

Antacid

When atorvastatin and Maalox® TC suspension were coadministered, plasma concentrations of atorvastatin decreased approximately 35%. However, LDL-C reduction was not altered.

Antipyrine

Because atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isozymes are not expected.

Colestipol

Plasma concentrations of atorvastatin decreased approximately 25% when colestipol and atorvastatin were coadministered. However, LDL-C reduction was greater when atorvastatin and colestipol were coadministered than when either drug was given alone.

Digoxin

When multiple doses of atorvastatin and digoxin were coadministered, steady-state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.

Oral Contraceptives

Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.

Warfarin

Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

Amlodipine

In a drug-drug interaction study in healthy subjects, co-administration of atorvastatin 80 mg and amlodipine 10 mg resulted in an 18% increase in exposure to atorvastatin which was not clinically meaningful.

Endocrine Function

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if an HMG-CoA reductase inhibitor is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

CNS Toxicity

Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0–24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0–24) based on the maximum recommended human dose of 80 mg/day.

CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0–24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose.

A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0–24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose.

In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test.

Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years.

Pregnancy
Pregnancy Category X

See CONTRAINDICATIONS

Safety in pregnant women has not been established. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m2).

In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day. Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took lovastatin with dextroamphetamine sulfate during the first trimester of pregnancy. Lipitor should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking Lipitor, it should be discontinued and the patient advised again as to the potential hazards to the fetus.

Nursing Mothers

Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother’s milk. Because of the potential for adverse reactions in nursing infants, women taking Lipitor should not breast-feed (see CONTRAINDICATIONS).

Pediatric Use

Safety and effectiveness in patients 10–17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months duration in adolescent boys and postmenarchal girls. Patients treated with LIPITOR had an adverse experience profile generally similar to that of patients treated with placebo, the most common adverse experiences observed in both groups, regardless of causality assessment, were infections. Doses greater than 20 mg have not been studied in this patient population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in boys or on menstrual cycle length in girls (see CLINICAL PHARMACOLOGY, Clinical Studies section; ADVERSE REACTIONS, Pediatric Patients (ages 10–17 years); and DOSAGE AND ADMINISTRATION, Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10–17 years of age). Adolescent females should be counseled on appropriate contraceptive methods while on Lipitor therapy (see CONTRAINDICATIONS and PRECAUTIONS, Pregnancy). Lipitor has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age.

Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled study of patients with homozygous FH including 8 pediatric patients (see CLINICAL PHARMACOLOGY, Clinical Studies: Homozygous Familial Hypercholesterolemia).

Geriatric Use

The safety and efficacy of atorvastatin (10–80 mg) in the geriatric population (≥65 years of age) was evaluated in the ACCESS study. In this 54-week open-label trial 1,958 patients initiated therapy with atorvastatin 10 mg. Of these, 835 were elderly (≥65 years) and 1,123 were non-elderly. The mean change in LDL-C from baseline after 6 weeks of treatment with atorvastatin 10 mg was –38.2% in the elderly patients versus –34.6% in the non-elderly group.

The rates of discontinuation due to adverse events were similar between the two age groups. There were no differences in clinically relevant laboratory abnormalities between the age groups.

Use in Patients with Recent Stroke or TIA

In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where Lipitor 80 mg vs placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the Lipitor 80 mg group compared to placebo. Subjects with hemorrhagic stroke on study entry appeared to be at increased risk for hemorrhagic stroke.

ADVERSE REACTIONS

Lipitor is generally well-tolerated. Adverse reactions have usually been mild and transient. In controlled clinical studies of 2502 patients, <2% of patients were discontinued due to adverse experiences attributable to atorvastatin. The most frequent adverse events thought to be related to atorvastatin were constipation, flatulence, dyspepsia, and abdominal pain.

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

In ASCOT (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 10,305 participants treated with LIPITOR 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated with Lipitor was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up.

Collaborative Atorvastatin Diabetes Study (CARDS)

In CARDS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 2838 subjects with type 2 diabetes treated with LIPITOR 10 mg daily (n=1428) or placebo (n=1410), there was no difference in the overall frequency of adverse events or serious adverse events between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported.

Treating to New Targets Study (TNT)

In TNT (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 10,001 subjects with clinically evident CHD treated with Lipitor 10 mg daily (n=5006) or Lipitor 80 mg daily (n=4995), there were more serious adverse events and discontinuations due to adverse events in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥3 × ULN twice within 4–10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 × ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%).

Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL)

In IDEAL (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 8,888 subjects treated with Lipitor 80 mg/day (n=4439) or simvastatin 20–40 mg daily (n=4449), there was no difference in the overall frequency of adverse events or serious adverse events between the treatment groups during a median follow-up of 4.8 years.

The following adverse events were reported, regardless of causality assessment in patients treated with atorvastatin in clinical trials. The events in italics occurred in ≥2% of patients and the events in plain type occurred in <2% of patients.

Body as a Whole: Chest pain, face edema, fever, neck rigidity, malaise, photosensitivity reaction, generalized edema.

Digestive System: Nausea, gastroenteritis, liver function tests abnormal, colitis, vomiting, gastritis, dry mouth, rectal hemorrhage, esophagitis, eructation, glossitis, mouth ulceration, anorexia, increased appetite, stomatitis, biliary pain, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, gum hemorrhage, stomach ulcer, tenesmus, ulcerative stomatitis, hepatitis, pancreatitis, cholestatic jaundice.

Respiratory System: Bronchitis, rhinitis, pneumonia, dyspnea, asthma, epistaxis.

Nervous System: Insomnia, dizziness, paresthesia, somnolence, amnesia, abnormal dreams, libido decreased, emotional lability, incoordination, peripheral neuropathy, torticollis, facial paralysis, hyperkinesia, depression, hypesthesia, hypertonia.

Musculoskeletal System: Arthritis, leg cramps, bursitis, tenosynovitis, myasthenia, tendinous contracture, myositis.

Skin and Appendages: Pruritus, contact dermatitis, alopecia, dry skin, sweating, acne, urticaria, eczema, seborrhea, skin ulcer.

Urogenital System: Urinary tract infection, hematuria, albuminuria, urinary frequency, cystitis, impotence, dysuria, kidney calculus, nocturia, epididymitis, fibrocystic breast, vaginal hemorrhage, breast enlargement, metrorrhagia, nephritis, urinary incontinence, urinary retention, urinary urgency, abnormal ejaculation, uterine hemorrhage.

Special Senses: Amblyopia, tinnitus, dry eyes, refraction disorder, eye hemorrhage, deafness, glaucoma, parosmia, taste loss, taste perversion.

Cardiovascular System: Palpitation, vasodilatation, syncope, migraine, postural hypotension, phlebitis, arrhythmia, angina pectoris, hypertension.

Metabolic and Nutritional Disorders: Peripheral edema, hyperglycemia, creatine phosphokinase increased, gout, weight gain, hypoglycemia.

Hemic and Lymphatic System: Ecchymosis, anemia, lymphadenopathy, thrombocytopenia, petechia.

Postintroduction Reports

Adverse events associated with Lipitor therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, fatigue, and tendon rupture.

Pediatric Patients (ages 10–17 years)

In a 26-week controlled study in boys and postmenarchal girls (n=140), the safety and tolerability profile of Lipitor 10 to 20 mg daily was generally similar to that of placebo (see CLINICAL PHARMACOLOGY, Clinical Studies section and PRECAUTIONS, Pediatric Use).

OVERDOSAGE

There is no specific treatment for atorvastatin overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

DOSAGE AND ADMINISTRATION

The patient should be placed on a standard cholesterol-lowering diet before receiving Lipitor and should continue on this diet during treatment with Lipitor.

Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)

The recommended starting dose of Lipitor is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of Lipitor is 10 to 80 mg once daily. Lipitor can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of Lipitor should be individualized according to patient characteristics such as goal of therapy and response (see NCEP Guidelines, summarized in Table 7). After initiation and/or upon titration of Lipitor, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.

Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should total-C be used to monitor therapy.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10–17 years of age)

The recommended starting dose of Lipitor is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy (see NCEP Pediatric Panel Guidelines1, CLINICAL PHARMACOLOGY, and INDICATIONS AND USAGE). Adjustments should be made at intervals of 4 weeks or more.

Homozygous Familial Hypercholesterolemia

The dosage of Lipitor in patients with homozygous FH is 10 to 80 mg daily. LIPITOR should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Concomitant Lipid Lowering Therapy

Lipitor may be used in combination with a bile acid binding resin for additive effect. The combination of HMG-CoA reductase inhibitors and fibrates should generally be avoided (see WARNINGS, Skeletal Muscle, and PRECAUTIONS, Drug Interactions for other drug-drug interactions).

Dosage in Patients With Renal Insufficiency

Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin; thus, dosage adjustment in patients with renal dysfunction is not necessary (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

Dosage in Patients Taking Cyclosporine, Clarithromycin or A Combination of Ritonavir plus Saquinavir or Lopinavir plus Ritonavir

In patients taking cyclosporine, therapy should be limited to Lipitor 10 mg once daily. In patients taking clarithromycin or in patients with HIV taking a combination of ritonavir plus saquinavir or lopinavir plus ritonavir, for doses of atorvastatin exceeding 20 mg appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed (see WARNINGS, Skeletal Muscle, and PRECAUTIONS, Drug Interactions).

HOW SUPPLIED

Lipitor (atorvastatin calcium) is supplied as white, elliptical, film-coated tablets of atorvastatin calcium containing 10, 20, 40 and 80 mg atorvastatin.

10 mg tablets: coded “PD 155″ on one side and “10″ on the other.

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High Cholesterol May Have Muscle-Building Benefits.

Monday, January 21st, 2008

For years, doctors have routinely reminded their patients to lower high cholesterol levels. Now, a new study suggests that having cholesterol levels that are too low might actually lead to a reduction in muscle gain during exercise.

High cholesterol is linked to coronary heart disease and an increased risk of heart attack.

But the study, conducted by researchers at Texas A&M University, finds that the most impressive gains in muscle strength were achieved by study participants who had the highest cholesterol levels, rather than the lowest.

Those with low levels of cholesterol were taking cholesterol-lowering medications.

Fifty men and women between the ages of 60 and 69 were studied. They followed an exercise regimen that included stretching, riding a stationary bike and weightlifting three times a week for 12 weeks. All ate similar meals.

“One possible explanation is through cholesterol’s important role in the inflammation process,” the study’s lead investigator Steven Riechman, an assistant professor of health and kinesiology, said in a release.

“As you exercise, your muscles can become sore because they are rebuilding muscle mass. More cholesterol may result in a more robust inflammatory response. We know that inflammation in some areas, such as near the heart, is not good, but for building muscles it may be beneficial, and cholesterol appears to aid in this process.”

The scientists believe that cholesterol has an important role in muscle tissue repair — critical in building muscle mass. It shows that there is still a lot about cholesterol that we don’t know, Riechman said.

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Foods That Prevent High Cholesterol

Monday, January 21st, 2008

Cholesterol is thought to become a problem for people over 40. Although this is not strictly true (as some children and young adults can also have high cholesterol), it is often the consequence of eating the wrong types of foods for many years. Certainly the metabolism has begun to slow down and the person is probably not as active as they used to be. They are probably well advanced in a career and have responsibilities, like a mortgage and children to raise, so it becomes easy to lose focus of their personal wellbeing at the expense of the family. Thus 40 seems to be a good age to start considering personal health issues. This article will cover what high cholesterol is and some foods that prevent high cholesterol.

According to the American Heart Association, normal cholesterol levels should be less than 200mg/dl (milligrams per deciliter of blood). Anything from 200 – 239mg/dl is considered borderline high. Anything over 239mg/dl is considered high. The only way you can determine this level is by having a blood test. Your doctor can administer the blood test and advise you on possible treatment if your numbers are high.

In most cases the treatment is simple. Modifying your diet and taking on more exercise will help to lower your high cholesterol. In some cases drugs may be used, but they are only prescribed in cases where the reading is extremely high or the diet/exercise has had no affect on reducing the cholesterol level.

In terms of food to eat it is also simple. You don’t need to go on any fad diet, just stick to a balanced diet that gives you the required vitamins and minerals. It should give you a good balance between carbohydrates, proteins and some fats.

Animals fats are the primary cause of excess cholesterol so you should avoid high fat dairy products. You should trim the fat off meat and look into eating leaner types and cuts of meat.

In terms of fats, you should restrict your fat intake to mono and polyunsaturated fats, like olive oil. You should avoid saturated fats and trans fats. These types of fats are often found in processed foods hence the reason to avoid packaged or processed foods. Fresh foods are best. This applies to meats but more so to vegetables and fruits. You should get as much fresh vegetables as you can. Steaming or boiling is best. This is the basic guideline for a balanced diet that will reduce or at least stabilize your cholesterol level. There are other foods that can actively reduce it.

Soluble fiber which can be found in oatmeal or porridge is thought to be good for reducing cholesterol. It works on two fronts. It prevents the absorption of cholesterol into the bloodstream. It cannot be completely metabolized by the body and is excreted, however, as it passes through the digestive system it attaches to LDL cholesterol thus helping to reduce the overall reading.

Another product that actively prevents high cholesterol is spreads that contain plant sterols. Plant sterols are the plant equivalent of animal sterols (or cholesterol) so they compete with animal sterols when they are being absorbed into the small intestine. Plant sterols are also added to things like fruit juices and yogurts.

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Cholesterol Reducers Help

Monday, January 21st, 2008

Almost all of the more than two million Canadians with diabetes should be taking cholesterol-lowering drugs, according to a major new study.

Researchers who pooled data from 14 studies involving more than 90,000 people say cholesterol reducers known as statins lower the risk of heart attack and stroke in people with diabetes by about one-third — even in those whose risk of a major “vascular event” is as low as one per cent per year.

Reporting today in the journal The Lancet, researchers say their study shows “convincingly” that most people with diabetes should consider taking statins.

“I know it sounds drastic but this is a group of people we can’t be complacent about,” says Dr. Colin Baigent, a professor of epidemiology at the University of Oxford and a member of the Cholesterol Treatment Trialists’ Collaborators.

Type 2 diabetes, which accounts for about 90 per cent of the disease, strikes in middle age and is associated with a high risk of heart attack and stroke that increases with time. Cardiovascular disease accounts for up to 80 per cent of deaths in people with diabetes.

The study “confirms what we thought” and supports guidelines published by the Canadian Diabetes Association that the vast majority of people with diabetes should take a cholesterol-lowering drug, says Dr. Gary Lewis, Canada Research Chair in Diabetes and professor of medicine and physiology at the University of Toronto.

“We’re not saying that every single diabetic patient should be on a statin,” says Lewis, who was part of the committee that made the guidelines. But it’s believed fewer than half are. “The numbers are never as good as you would like them to be.”

The number of Canadians with diabetes is expected to increase to three million by 2010.

Cholesterol is a type of fat. Low-density lipoproteins, or LDL cholesterol, is called the “bad” cholesterol because the cells in the coronary artery walls take it up, causing narrowing.

Cholesterol is measured in units called millimoles per litre of blood.

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Trans Fatty Acids (‘Trans Fat) and Heart Disease and Stroke

Friday, January 18th, 2008

A lot of discussion and media attention has focused on the health effects of trans fat, but it is difficult to make sense of how or if trans fat can be eaten as part of a healthy diet. The Heart and Stroke Foundation of Canada is a leader in educating the public about the importance of eating a healthy and balanced diet. The following position statement was developed to help the public better understand trans fat, personal food choices, and their relationship to heart disease and stroke.

FACTS

* Your diet can influence your risk for heart disease and stroke. Eating habits that will lower your risk include eating a high-fibre, lower-fat diet, eating lots of vegetables and fruit, and eating portions of food that are in line with your level of physical activity.
* Lowering trans fat and saturated fat in your diet will help reduce your risk for heart disease and stroke.
* Simply lowering or eliminating trans fat in packaged food will not necessarily make the food we eat more nutritious. You should also be aware of the salt and sugar content of foods and the overall number of calories.
* Your overall risk of heart disease or stroke is determined by ALL of your risk factors . There are risk factors that you can and cannot control.
o Risk factors that you can control include: smoking, physical inactivity, high blood pressure, high blood cholesterol, obesity and diabetes.
o Risk factors that you can’t control include: age, gender, family history and ethnicity.
* You can reduce your risk of heart disease and stroke by knowing and controlling as many risk factors as possible.

RECOMMENDATIONS

The Heart and Stroke Foundation of Canada recommends that:

1. The Federal government implement the recommendations in the Final Report of the Trans Fat Task Force (2006)†, which was co-Chaired by the Heart and Stroke Foundation of Canada and Health Canada.
2. Accurate information about the nutritional value of foods and the health effects of lowering trans fat be made available to the public, to help consumers make informed and healthy choices.
3. Trans fat in processed foods be replaced as soon as possible and where feasible by healthy alternatives such as monounsaturated and polyunsaturated fats rather than with equal amounts of saturated fat.
4. Canadians consume a healthy, balanced diet that includes:
* foods from the four food groups in Canada’s Food Guide to Healthy Eating;
* 20-35% of total calories from fat (about 45-75 grams/day for a woman and about 60-105 grams/day for a man);
* more polyunsaturated fat , especially omega-3 fatty acids (fatty fish, flaxseed, canola oil, soybean oil, nuts, liquid egg products, etc.) and monounsaturated fat (olive oil, canola oil, avocados, nuts etc.); and
* lower amounts of trans fat and saturated fat.

BACKGROUND INFORMATION

Unsaturated fat, Saturated fat and Trans fat

Unsaturated fat
Unsaturated fat can help lower low density lipoprotein (LDL) cholesterol (‘bad’ cholesterol) levels. There are two types of unsaturated fat: monounsaturated and polyunsaturated.

Monounsaturated fat lowers LDL-cholesterol levels. It is found mainly in olive and canola oils and some soft, non-hydrogenated margarines.

There are two types of polyunsaturated fat: Omega-3 and Omega-6 fats:

* Omega-3 fat helps prevent blood from sticking and clotting and also helps lower triglycerides, decreasing the risk of heart disease and stroke. Omega-3 fat is found in fatty fish such as salmon, mackerel, herring and sardines as well as in flax and some newer products such as Omega-3 liquid eggs.
* Canadian diets tend to include high amounts of Omega-6 fat. This fat is liquid at room temperature and is found in foods that come from plants. Safflower, sunflower and corn oils are examples of Omega-6 fat. This fat is also found in some non-hydrogenated margarines and some nuts and seeds such as almonds, pecans, brazil nuts, sunflower seeds and sesame seeds. Omega-6 fat helps lower LDL-cholesterol (‘bad’ cholesterol), but when eaten in large amounts is thought to lower high density lipoprotein (HDL) cholesterol (“good” cholesterol). Omega-6 fat should be eaten in moderation since it still contributes to total amount of calories you eat.

Saturated fat
Saturated fat is solid at room temperature and generally comes from animal sources such as meat, poultry, and dairy foods. Plant sources of saturated fat are coconut oil, palm oil and palm kernel oil. Saturated fat can raise LDL-cholesterol (‘bad’ cholesterol) levels. Reducing your consumption of saturated fat is an important step in lowering your risk for heart disease and stroke. You can reduce the amount of saturated fat you eat by choosing lean meats, removing the skin from chicken and using lower fat dairy products. In addition, any cooking method that allows fat to drain off (e.g. broiling, grilling, roasting on a rack) helps further reduce the amount of saturated fat you eat.

Trans fat
A healthy diet limits the amount of trans fat. Trans fat is created when an unsaturated fat is processed or hydrogenated. Like saturated fat, trans fat raises LDL-cholesterol (‘bad’ cholesterol) levels. Trans fat is found in partially hydrogenated margarines, as well as in many crackers, cookies and commercially baked products, usually listed as “partially hydrogenated” or “vegetable oil shortening” in the ingredients. Partially hydrogenated products are the biggest source of trans fat in the Canadian diet. Trans fats can also be found in deep fried foods from fast food outlets.

To help you identify trans fat and other ingredients in foods, there will be a new Nutrition Facts table on food labels in Canada by December 2005 for large food companies, and by December 2007 for smaller food companies. These tables will help you identify and limit your intake of products high in trans fat. In the meantime we advise you to look for the words “partially hydrogenated” or “vegetable oil shortening” in the ingredient list and to limit the amount of these types of oils in your diet.

For more information on heart healthy eating, visit www.heartandstroke.ca. To learn about our Health Check™ food information program, which will help you identify healthy food choices at the grocery store and other retailers, visit www.healthcheck.org.

NOTE
The Heart and Stroke Foundation of Canada recognizes that the life-long heart health of Canadians is affected by both individual and social factors. Individual factors include genetic make-up, personal health choices and actions, and social support. Social factors include the social, economic and environmental conditions in which Canadians live, work, learn and play.

The Foundation encourages Canadians to make heart-healthy choices and encourages governments and the private sector to develop policies and programs that support healthy communities and reduce inequalities that negatively affect health and well-being.

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Lipitor

Archive for the ‘brain’ Category

Keep your heart healthy; February is American Heart Month

Cholesterol is NOT the Critical Cause of Heart Disease

Keeping Cholesterol Down

Do Cholesterol Drugs Do Any Good?

Oatmeal’s War on Cholesterol

Lipitor Complete Information

High Cholesterol May Have Muscle-Building Benefits.

Foods That Prevent High Cholesterol

Cholesterol Reducers Help

Trans Fatty Acids (‘Trans Fat) and Heart Disease and Stroke

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