1 COUMADIN HISTORY
(How was Coumadin discovered?)

Coumadin is a product of Bristol-Myers Squibb.

The US FDA approved Coumadin in July 1999.

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

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

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

2.COUMADIN FACTS

Coumadin tablets contain the active ingredient warfarin sodium, which is a type of medicine called an oral anticoagulant. It is used to stop blood clots forming within the blood vessels.

Blood clots normally only form to stop bleeding that has occurred as a result of injury to the tissues. The clotting process is complicated and begins when blood cells called platelets clump together at the site of damage and produce chemicals that activate clotting factors in the blood. Clotting factors are proteins that are produced by the liver. Vitamin K is essential for their production. The activated clotting factors cause a protein called fibrin to be converted into another called fibrinogen. Fibrinogen binds the platelets together, forming a blood clot. This is the body's natural way of repairing itself.

Sometimes, however, a blood clot can form abnormally within the blood vessels. This is known as a thrombus and can be dangerous because the clot may detach and travel in the bloodstream, where it becomes known as an embolus. The clot may eventually get lodged in a blood vessel, thereby blocking the blood supply to a vital organ such as the heart, brain or lungs. This is known as a thromboembolism.

Some people have an increased tendency for blood clots to form within the blood vessels. This is usually due to a disturbance in the blood flow within the blood vessels. For example, fatty deposits on the walls of the blood vessels (atherosclerosis) can disrupt the blood flow, giving a tendency for platelets to clump together and start off the clotting process. Slow blood flow in the leg and pelvic veins can also result in clots forming (deep vein thrombosis). These clots can break off and travel to the lungs (pulmonary embolism). A type of fast irregular heartbeat called atrial fibrillation can also disrupt blood flow and may lead to blood clots forming in the heart. Heart valve disease can have the same effect, particularly if artificial heart valves have been fitted. Clots in the heart can detach and travel to the brain, causing a stroke. Warfarin is used to reduce the risk of blood clots forming inside the blood vessels in conditions such as these.

Coumadin works by preventing the vitamin K dependent production of the clotting factors described above. Coumadin prevents the production of these clotting factors by inhibiting the action of vitamin K. Without these clotting factors fibrin cannot be converted into fibrinogen and blood clots are therefore less likely to occur.

Coumadin takes about three days to produce its full anticoagulant effect because, while it prevents the production of new clotting factors, it takes about this long for clotting factors that have already been produced to be used up. For this reason, when treating blood clots such as deep vein thrombosis (DVT) or pulmonary embolism, a faster acting injectable anticoagulant, such as a heparin, is often used as well to begin with.

The anticoagulant effect of Coumadin is measured in terms of the prothombin time, which is the time taken for blood clotting to occur in a sample of blood to which calcium and a substance known as thromboplastin have been added. This time is expressed as the International Normalised Ratio (INR). Your doctor will take regular blood samples and adjust your dose of warfarin as necessary to make your INR fall into the range that has been shown to be effective at preventing blood clots in your particular condition.

3.ABOUT COUMADIN MEDICATION

What are anticoagulants?

Anticoagulants decrease the clotting ability of the blood and therefore help to prevent harmful clots from forming in the blood vessels. These medicines are sometimes called blood thinners, although they do not actually thin the blood. They also will not dissolve clots that already have formed, but they may prevent the clots from becoming larger and causing more serious problems. They are often used as treatment for certain blood vessel, heart, and lung conditions.

In order for an anticoagulant to help you without causing serious bleeding, it must be used properly and all of the precautions concerning its use must be followed exactly. Be sure that you have discussed the use of this medicine with your doctor. It is very important that you understand all of your doctor's orders and that you are willing and able to follow them exactly.

Anticoagulants are available only with your doctor's prescription, in the following dosage forms: 

What is coagulation?

The coagulation of blood is a complex process during which blood forms solid clots. It is an important part of haemostasis whereby a damaged blood vessel wall is covered by a fibrin clot to stop hemorrhage and aid repair of the damaged vessel. Disorders in coagulation can lead to increased hemorrhage and/or thrombosis and embolism.

Coagulation is extremely similar in all mammals, with all mammals using a combined cellular and serine protease mechanism. The system in humans is the most extensively researched and therefore the best known. This matter focuses on human blood coagulation. 

4.COUMADIN EFFECTIVENESS
(When is Coumadin best taken?)

Coumadin is a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2-5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.

Absorption

Coumadin is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours.

Distribution

There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin solution. Coumadin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the race-mate. Concentrations in fetal plasma approach the maternal values, but Coumadin has not been found in human milk. Approximately 99% of the drug is bound to plasma proteins.

Metabolism

The elimination of Coumadin is almost entirely by metabolism. Coumadin is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of Coumadin that have been identified include dehydrowarfarin, two diastereoisomer alcohols, .4-, 6-, 7-, 8- and 10-hydroxywarfarin. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9,2C19,2C8,2C18, 1A2,and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin.

Excretion

The terminal half-life of Coumadin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little Coumadin is excreted unchanged in urine. Urinary excretion is in the form of metabolites. 

5.COUMADIN EFFECTS ON SPECIAL POPULATION
(How do different people react to Coumadin?)

Geriatric Patients:

Plasma concentrations of the main circulating metabolite are significantly higher in elderly (>75 years) compared to young healthy volunteers. No Coumadin dosage adjustment is needed for the elderly.

Renally Impaired Patients:

After repeated doses of Coumadin per day, plasma levels of the main circulating metabolite were lower in patients with severe renal impairment compared to subjects with moderate renal impairment or healthy subjects.

Gender:

No significant difference was observed in the plasma levels of the main circulating metabolite between males and females. In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in prolongation of bleeding time. In the large, controlled clinical study, the incidence of clinical outcome events, other adverse clinical events, and abnormal clinical laboratory parameters was similar in men and women.

Race:

Pharmacokinetic differences due to race have not been studied.

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

Renal Dysfunction

Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure.

Hepatic Dysfunction

Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.

7.OTHER/ALTERNATE USES OF COUMADIN
(What else does Coumadin treat?)

Coumadin is used to reduce risk of atherothrombotic events (eg further heart attacks) in people who have had a heart attack or an Ischemic stroke and in people with unstable angina.

8.ADVERSE/SIDE EFFECTS of COUMADIN
(What are the side effects of Coumadin?)

Potential adverse reactions to Coumadin may include:

Fatal or nonfatal hemorrhage from any tissue or organ. This is a consequence of the anticoagulant effect. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as paralysis; paresthesia; headache, chest, abdomen, joint, muscle or other pain; dizziness; shortness of breath, difficult breathing or swallowing; unexplained swelling; weakness; hypotension; or unexplained shock. Therefore, the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints, which do not indicate an obvious diagnosis. Bleeding during anticoagulant therapy does not always correlate with PT/INR.

Bleeding which occurs when the PT/INR is within the therapeutic range warrants diagnostic investigation since it may unmask a previously unsuspected lesion, e.g., tumor, ulcer, etc.

Necrosis of skin and other tissues.

Adverse reactions reported infrequently include: hypersensitivity/allergic reactions, systemic cholesterol microembolization, purple toes syndrome, hepatitis, cholestatic hepatic injury, jaundice, elevated liver enzymes, vasculitis, edema, fever, rash, dermatitis, including bullous eruptions, urticaria, abdominal pain including cramping, flatulence/bloating, fatigue, lethargy, malaise, asthenia, nausea, vomiting, diarrhea, pain, headache, dizziness, taste perversion, pruritus, alopecia, cold intolerance, and paresthesia including feeling cold and chills.

Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin therapy. The clinical significance of this event is unknown.

Priapism has been associated with anticoagulant administration, however, a causal relationship has not been established.