1. ZETIA HISTORY
(How was Zetia discovered?)

Zetia is a product of Merck & Co 

The FDA approved Zetia in October 2002. 

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

2.ZETIA FACTS

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

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

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

3.ABOUT ZETIA MEDICATION

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

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

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

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

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

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

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

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

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

Cholesterol Levels:

Total cholesterol level

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

LDL cholesterol levels

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

HDL cholesterol levels

• Less than 40 means you're at higher risk for heart disease.
• 60 or higher reduces your risk of heart disease.

What are Cholesterol Lowering agents?

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

• Bile acid sequestrants

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

• Cholestyramine,
• Colestipol, and
• Colesevelam.  

•  HMG-CoA inhibitors, often called "statins,"

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

Drugs in this group include:

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

Fibric acid derivatives

They include

• Clofibrate,
• Gemfibrozil, and
• Fenofibrate.

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

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

How does Zetia work?
Zetia works by preventing cholesterol from being absorbed from the small intestine into the bloodstream. Zetia prevents cholesterol and other plant sterols that are consumed in the diet from being absorbed into the bloodstream. Zetia also prevents cholesterol released from the bile duct into the intestine from being reabsorbed into the bloodstream. The overall result is a reduction in cholesterol levels in the blood. 

4.ZETIA EFFECTIVENESS
When is Zetia best taken?

After oral administration, Zetia is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of Zetia to fasted adults, mean Zetia peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. Zetia has variable bioavailability; the coefficient of variation, based on inter-subject variability, was 35 to 60% for AUC values.

Effect of Food on Oral Absorption
Concomitant food administration (high fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as Zetia 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high fat meals. Zetia can be administered with or without food.

Distribution
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%)to human plasma proteins.

Metabolism and Excretion
Zetia is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated.

In humans, Zetia is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.

Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.

Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Zetia was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose. 

5.ZETIA EFFECTS ON SPECIAL POPULATION
(How do different people react to Zetia?

Geriatric Patients
In a multiple dose study with Zetia given 10 mg once daily for 10 days, plasma concentrations for total Zetia were about 2-fold higher in older (65 years) healthy subjects compared to younger subjects.

Pediatric Patients
In a multiple dose study with Zetia given 10 mg once daily for 7 days, the absorption and metabolism of Zetia were similar in adolescents (10 to 18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available.

Gender
In a multiple dose study with Zetia given 10 mg once daily for 10 days, plasma concentrations for total Zetia were slightly higher (<20%) in women than in men.

Race
Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Blacks and Caucasians. There were too few patients in other racial or ethnic groups to permit further pharmacokinetic comparisons

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

Hepatic Insufficiency

After a single 10-mg dose of Zetia, the mean area under the curve (AUC) for total Zetia was increased approximately 1.7-fold in patients with mild hepatic insufficiency, compared to healthy subjects. The mean AUC values for total Zetia were increased approximately 3-4 fold and 5-6 fold, respectively, in patients with moderate or severe hepatic impairment. In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic insufficiency, the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, Zetia is not recommended in these patients.

Renal Insufficiency
After a single 10-mg dose of Zetia in patients with severe renal disease, the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9). 

7.OTHER/ALTERNATE USES OF ZETIA
(What else does Zetia treat?)

Zetia can also be used to treat people with a rare inherited disorder called homozygous sitosterolaemia, where there are raised levels of plant sterols that are similar to cholesterol in the blood. In this case Zetia is used on its own, together with a cholesterol-lowering diet.

8.ADVERSE/SIDE EFFECTS of ZETIA
(What are the side effects of Zetia?)

Zetia has been evaluated for safety in more than 4700 patients in clinical trials. Clinical studies of Zetia (administered alone or with an HMG-CoA reductase inhibitor) demonstrated that Zetia was generally well tolerated. The overall incidence of adverse events reported with Zetia was similar to that reported with placebo, and the discontinuation rate due to adverse events was also similar for Zetia and placebo.

Monotherapy
Adverse experiences reported in ³2% of patients treated with Zetia and at an incidence greater than placebo in placebo-controlled studies of Zetia, regardless of causality assessment, are shown in the Table below.

Clinical Adverse Events Occurring in 2% of Patients Treated with Zetia and at an Incidence Greater than Placebo, Regardless of Causality

Body System/Organ Class Adverse Event	Placebo (%) n = 795	Zetia 10 mg (%) n = 1691
Body as a whole – general disorders
Fatigue	1.8	2.2
Gastro-intestinal system disorders
Abdominal pain	2.8	3.0
Diarrhea	3.0	3.7
Infection and infestations
Infection viral	1.8	2.2
Pharyngitis	2.1	2.3
Sinusitis	2.8	3.6
Musculo-skeletal system disorders
Arthralgia	3.4	3.8
Back pain	3.9	4.1
Respiratory system disorders
Coughing	2.1	2.3

The frequency of less common adverse events was comparable between Zetia and placebo.

Combination with an HMG-CoA reductase Inhibitor

Zetia has been evaluated for safety in combination studies in more than 2000 patients.

In general, adverse experiences were similar between Zetia administered with HMG-CoA reductase inhibitors and HMG-CoA reductase inhibitors alone. However, the frequency of increased transaminases was slightly higher in patients receiving Zetia administered with HMG-CoA reductase inhibitors than in patients treated with HMG-CoA reductase inhibitors alone. Clinical adverse experiences reported in 2% of patients and at an incidence greater than placebo in four placebo-controlled trials where Zetia was administered alone or initiated concurrently with various HMG-CoA reductase inhibitors, regardless of causality assessment, are shown in Table below.

Clinical Adverse Events occurring in ³2% of Patients and at an Incidence Greater than Placebo, Regardless of Causality, in Zetia/Statin Combination Studies 

Body System/Organ Class Adverse Event	Placebo (%) n=259	ZETIA 10 mg (%) n=262	All Statins** (%) n=936	ZETIA + All Statins** (%) n=925
Body as a whole – general disorders
Chest pain	1.2	3.4	2.0	1.8
Dizziness	1.2	2.7	1.4	1.8
Fatigue	1.9	1.9	1.4	2.8
Headache	5.4	8.0	7.3	6.3
Gastro-intestinal system disorders
Abdominal pain	2.3	2.7	3.1	3.5
Diarrhea	1.5	3.4	2.9	2.8
Infection and infestations
Pharyngitis	1.9	3.1	2.5	2.3
Sinusitis	1.9	4.6	3.6	3.5
Upper respiratory tract infection	10.8	13.0	13.6	11.8
Musculo-skeletal system disorders
Arthralgia	2.3	3.8	4.3	3.4
Back pain	3.5	3.4	3.7	4.3
Myalgia	4.6	5.0	4.1	4.5

Post-marketing Experience
The following adverse reactions have been reported in post-marketing experience:
Hypersensitivity reactions, including angioedema and rash.