Warfarin Number 1 Causes of Hospital Emergencies--WP

ASPIRIN prevents MI, Cancer, and Alzheimer's disease
Celebrex and COX-2 inhibitors--American Heart Association Warnings
American Heart Association warns NSAIDs cause MI
COX-2 Inhibitors, their deadly mechanism
AHA on COX inhibitors
NSAIDs & Myocardial Infraction Risk--only ASPIRIN is safe
How VIOXX kills--jk
COX-2 INHIBITORS not as good as Ibuprofen
Continued Risk after taking VIOXX
HYDROCODONE--Opiates work for pain management
Acetaminophen, causes asthma, liver failure, & male infertility,
Acetaminophen causes male infertility
Liver failure Acetaminophen
Acetaminophen leading drug cause of liver damage
Acetaminophen increase ASTHMA risk 63%
Asthma risk and acetaminophen
Warfarin Number 1 Causes of Hospital Emergencies--WP

Elsewhere I have exposed the attack on the cheap and effective aspirin as a way to pave the way for the sales of Plavix, Warfarin and other antithrombotic drugs.  In addition to lower MI rate, aspirin also reduce risk for Alzheimer’s, cancer, and increase survival among cancer patient with stage I, II, & !!!

The appropriate dose of warfarin is difficult to establish because it can vary by a factor of 10 among patients, and the consequences of receiving an incorrect dose can be catastrophic. Clinical factors, demographic variables, and variations in two genes — CYP2C9 (full name: cytochrome P450, subfamily 2, subfamily C, polypeptide 9) and VKORC1 (full name: vitamin K epoxide reductase complex, subunit 1) — contribute significantly to the variability among patients in dose requirements for warfarin. 


http://www.worstpills.org/member/newsletter.cfm?n_id=777      Worstpills.org

There are an estimated annual 33,000 emergency hospitalizations per year from the taking of Warfarin. 

Authors of a recently published study in The New England Journal of Medicine (NEJM) found that “there were an estimated an estimated 99,628 emergency hospitalizations for adverse drug events in U.S. adults 65 years of age or older each year from 2007 through 2009.”

Nearly half of these hospitalizations were among adults 80 years of age or older. Almost two-thirds of these emergency hospitalizations were due to unintentional overdoses, either from drug doses that were too high or from drugs used at recommended doses in combination with other drugs that effectively increased the amount of the overdosed drug in the body.

It should be noted that many adverse-reaction deaths occur at home, such as those seen with DARVON, wherein patients, especially older adults, were found dead from the drug’s heart-toxic effects. Also, a large proportion of hospitalizations for adverse drug reactions do not occur through the emergency room, since many life-threatening reactions (such as liver toxicity, heart failure and other drug-induced diseases) may slowly worsen, leading to elective, not emergency, hospitalization.

The NEJM authors found that four drugs or drug classes were implicated alone or in combination in more than two-thirds of hospitalizations for adverse drug reactions: warfarin (COUMADIN, JANTOVEN; 33.3 percent), insulins (13.9 percent), oral antiplatelet agents (e.g., clopidogrel [PLAVIX] or aspirin; 13.3 percent) and oral hypoglycemic (diabetes) agents (10.7 percent).  {The numbers for aspirin are really much lower, for if there is a bleeding episode, most doctors will blame it on aspirin, even when the patient is taking several other drugs.  This is exactly what happened to my friend Danny Bronstein who was taking Warfarin, a tranquilizer at night, and an ADD medication during the dayj—jk.} 

“Thus,” they stated, “most of these emergency hospitalizations for recognized adverse drug events in older adults resulted from a few commonly used medications. Improved management of antithrombotic drugs [warfarin, aspirin, clopidogrel] and antidiabetic drugs [especially insulin] has the potential to reduce hospitalizations for adverse drug events in older adults.”

Of the 99,628 annual emergency hospitalizations, by far the largest category implicated was warfarin, with an estimated annual 33,000 emergency hospitalizations.

To help readers avoid possible adverse effects from drug mismanagement, below are excerpts from the updated WorstPills.org listings on warfarin and clopidogrel.

(Family: blood-clotting inhibitors)

About warfarin

Warfarin reduces the blood’s ability to clot (coagulate) and prevents blood clots from forming in the arteries and veins. It is prescribed to people who have a history of abnormal blood clots or who are at high risk of having abnormal clots.

Warfarin is a drug of considerable benefit after heart-valve replacement and in the prevention of blood clots from a type of heart-rhythm disturbance known as atrial fibrillation. It also reduces the risk of death, recurrent heart attacks and stroke after a heart attack.

Patients over 60 years of age should generally be taking less than the usual adult dose to lower the risk of heavy bleeding (hemorrhage). After a patient has taken warfarin for three months, a doctor should reevaluate the patient’s need to continue taking it.

Who should not use warfarin

Do not use warfarin if you have or have had eclampsia or preeclampsia; blood disorders; or severe, uncontrolled high blood pressure. You should not use warfarin if you have or have had recent surgery, an aneurysm or dissecting aorta, a threatened or incomplete abortion, confirmed or suspected cerebrovascular hemorrhage or active bleeding.

Before you use warfarin

Tell your doctor about any other drugs you take (including aspirin, herbs, vitamins and other nonprescription products) and whether you have or have had:

  • allergies to drugs
  • heart problems (including atrial fibrillation, myocardial infarction or stroke)
  • thromboembolism
  • severe allergies
  • ulcers or other lesions of the gastrointestinal tract, respiratory tract or urinary tract
  • kidney or liver problems
  • diverticulitis
  • vasculitis
  • infectious disease
  • vitamin K deficiency
  • alcohol dependence
  • severe inflammation of blood vessels
  • subacute bacterial endocarditis (infection of the heart)
  • diabetes
  • recent injury
  • childbirth
  • spinal puncture
  • a fall or blow to the body or head
  • wounds from trauma, ulcers or surgery
  • fever lasting more than a couple of days
  • an intrauterine device (IUD)
  • heavy or unusual menstrual bleeding
  • medical or dental surgery
  • severe or continuing diarrhea

How to take warfarin

It is very important that you take warfarin exactly on schedule, since failing to take this drug properly can cause serious adverse effects (see “Side effects” below). While taking warfarin, patients should be monitored with regular blood tests to ensure that the most effective dose of the drug is being taken.

If you miss a dose, take it as soon as you remember, but skip it if you don’t remember until the next day. Do not take double doses. Keep a record of missed doses and give the list to your doctor at each visit.

Do not share your medication with others.

Take the drug at the same time(s) each day.

Store at room temperature with lid on tightly. Do not store in the bathroom. Do not expose to heat, moisture or strong light. Keep out of reach of children.

Side effects

Call your doctor immediately if you experience: abnormal bleeding; bloody, cloudy or dark urine; difficult or painful urination or sudden decrease in the amount of urine; dizziness or fainting; swelling of the ankles, feet or legs; unusual weight gain; blue or purple toes; chills, fever, sore throat or unusual tiredness; yellow eyes or skin; nausea or vomiting; diarrhea; skin rash, hives or itching; sores or white spots in mouth or throat; sores on skin; stomach cramps or pain; loss of appetite; nervousness; confusion; blurred vision; chest pain; or difficulty breathing.

Call your doctor if these symptoms continue: bloated stomach or gas, cold intolerance, diarrhea, lossof appetite, nausea or vomiting,stomach cramps or pain.

Skin necrosis. Australia’s Adverse Drug Reactions Advisory Committee (ADRAC) has received nine reports of death of skin tissue (skin necrosis) with warfarin use, of which three were fatal. In four cases, the onset occurred within seven days of commencing warfarin, but in three cases, the first symptoms occurred three to eight weeks after starting warfarin.

Risk of tendinitis when used with fluoroquinolone antibiotics. In 2006, we petitioned the Food and Drug Administration (FDA) to add a warning to the product label of all fluoroquinolone antibiotics to alert doctors to the risk of tendinitis, including a warning of the possibility of complete tendon rupture, which can occur when fluoroquinolones are used with warfarin. The class of fluoroquinolone antibiotics includes drugs such as ciprofloxacin (CIPRO). The onset of symptoms is sudden and has occurred as soon as 24 hours after starting treatment with a fluoroquinolone. Most people have recovered completely after one to two months.

Signs of overdose

If you suspect an overdose (see the signs below), call (800) 222-1222 to contact your poison control center:

  • bleeding gums when brushing teeth
  • nosebleeds
  • unexplained bruising
  • unusually heavy bleeding from cuts or wounds
  • unusually heavy or unexpected menstrual bleeding
  • abdominal pain or swelling
  • sudden light-headedness
  • weakness
  • loss of consciousness
  • backaches
  • blood in urine
  • bloody or tarry stools
  • constipation
  • headache
  • joint pain
  • stiffness or swelling
  • blood or material that looks like coffee grounds expelled when coughing or vomiting
  • pinpoint red spots on skin


Warfarin can interact with nearly all drugs and some dietary supplements. Its anti-clotting action is very difficult to control when other drugs are added or subtracted, or when another drug’s dose is changed. Another medication may either increase or decrease warfarin’s action (see “Warfarin: Interactions” box below). 

If you are taking warfarin, you should notify your doctor before taking any product containing acetaminophen. Acetaminophen may interact with warfarin to increase the risk of bleeding, a risk that rises with increasing doses of acetaminophen.

This risk has been found to increase tenfold in people taking 28 or more regular-strength acetaminophen tablets per week, or the equivalent of 18 or more extra-strength tablets per week, compared to those taking warfarin and no acetaminophen. A regular-strength acetaminophen tablet contains 325 milligrams (mg) of acetaminophen, and an extra-strength tablet contains 500 mg of the drug. Results published from a prospective randomized, parallel, double-blind, placebo-controlled study of 45 patients found that acetaminophen (at a dose of 2 or 3 grams a day, administered for 10 days) increased the anticoagulant effect of warfarin in stable patients.

The U.K. Medicines and Healthcare products Regulatory Agency (MHRA) has received seven reports suggesting an interaction between warfarin and the dietary supplement glucosamine, according to the MHRA and the U.K. Committee on Safety of Medicines. In those cases, patients who previously had a stable international normalized ratio (INR, which is a measurement of how properly one’s blood clots) while receiving warfarin experienced an INR increase (potentially dangerous abnormal thinning of the blood) after they started receiving glucosamine supplements. ADRAC reported in February 2008 that it had received 10 reports of an increase in INR values associated with warfarin and glucosamine use.


The following drugs may cause clinically significant interactions when used together with warfarin. Make sure to tell your doctor and pharmacist about all of the drugs and dietary supplements you are taking and whether you take any of the following:acetaminophen (alone and in combination), ACHROMYCIN, alcohol (if concomitant liver disease), ALURATE, amiodarone, amobarbital, amoxicillin, amoxicillin and clavulanate, amoxicillin/tranexamic rinse, AMOXIL, ANTABUSE, ANTURANE, aprobarbital, ARAVA, aspirin (alone and in combination), ATROMID-S, AUGMENTIN, azathioprine, azithromycin, AZULFIDINE, BACTRIM, BIAXIN, bosentan, butabarbital, BUTAZOLIDIN, BUTISOL, carbamazepine, CARBATROL, CARDIZEM, CARDIZEM CD, CELEBREX, celecoxib, CELEXA, CHIBROXIN, chloral hydrate, chloramphenicol, chlordiazepoxide, CHLOROMYCETIN, cholestyramine, CIPRO, ciprofloxacin, citalopram, clarithromycin, CLINORIL, clofibrate, COMTAN, CORDARONE, COTRIM, cotrimoxazole, DARVON, DARVON-N, dextropropoxyphene, dicloxacillin, DIFLUCAN, DILACOR XR, DILANTIN, diltiazem, disopyramide, disulfiram, DIULO, DURAQUIN, DYCILL, DYNAPEN, EASPRIN, ECOTRIN, EES, EMPIRIN, entacapone, ERYTHROCIN, erythromycin, felbamate, FELBATOL, FELDENE, fenofibrate, FLAGYL, FLOXIN, fluconazole, fluvastatin, fluvoxamine, FORTOVASE, gatifloxacin, gemfibrozil, GENUINE BAYER ASPIRIN, griseofulvin, IMURAN, INDERAL, INDERAL LA, INDOCIN, indomethacin, INH, interferon, INTRON A, INVIRASE, isoniazid, itraconazole, KALETRA, LAMISIL, leflunomide, LESCOL, LESCOL XL, LEVAQUIN, levofloxacin, LIBRIUM, LOCHOLEST, LOPID, LUMINAL, LUVOX, mephobarbital, mesalamine, metharbital, metolazone, metronidazole, MICARDIS, miconazole oral gel, miconazole topical gel, miconazole vaginal suppositories, MONISTAT 1, MONISTAT 3, MONISTAT 7, MONISTAT-DERM, nafcillin, nalidixic acid, NEGGRAM, NOCTEC, norfloxacin, NOROXIN, NORPACE, NORVIR, ofloxacin, PACERONE, PANMYCIN, pentobarbital, phenobarbital, phenylbutazone, phenytoin, piroxicam, propafenone, propoxyphene, propranolol, QUESTRAN, QUESTRAN LIGHT, QUINAGLUTE DURA-TABS, QUINIDEX, quinidine, REQUIP, ribavirin, RIFADIN, rifampin, RIMACTANE, ritonavir, rofecoxib, ROFERON-A, ropinirole, RYTHMOL, salicylates (topical), saquinavir, secobarbital, secobarbital and amobarbital, SEPTRA, sertraline, simvastatin, SOLFOTON, SPORANOX, sulfasalazine, sulfinpyrazone, sulindac, TEGRETOL, telmisartan, TEQUIN, terbinafine, tetracycline, TIAZAC, TOLECTIN, tolmetin, TRACLEER, tramadol, TRICOR, trimethoprim and sulfamethoxazole, TYLENOL, ULTRAM, VFEND, VIOXX, voriconazole, ZAROXOLYN, ZITHROMAX, ZOCOR, ZOLOFT

When using warfarin

Wear a medical identification bracelet or carry a card stating that you take warfarin.

Be very careful doing activities that may cause cuts or bleeding (such as shaving or cooking).

Consult with your doctor immediately if any signs of bleeding occur.

Do not drink alcohol. Eat a normal, balanced diet. Do not change your diet or take nutritional supplements or vitamins without first checking with your doctor.

If you plan to have any surgery, including dental, tell your doctor that you take this drug.

Do not take any other drugs, including nonprescription products (aspirin, cold remedies, antacids, laxatives), or change the dose of drugs you are taking without consulting your doctor.

Be sure to schedule regular doctor visits for blood tests. Ask your doctor which of these tests should be done periodically while you are taking this drug:

  • prothrombin time, now measured by the INR (INR should be checked daily for the first week, weekly until a therapeutic level is achieved and then monthly)
  • complete blood count
  • stool tests for possible blood loss
  • urine tests for possible blood loss

Pregnancy and breast-feeding warnings

You should not take warfarin while nursing. Warfarin should not be used if you are pregnant or are thinking of becoming pregnant. Severe malformations have occurred in infants of mothers taking this drug.

Regulatory actions surrounding warfarin

2006: The FDA announced on Oct. 10 that it would require that an agency-approved Medication Guide, which provides information about drug safety, accompany all new and refill prescriptions for the blood thinner warfarin.
Warfarin is one of a limited number of drugs for which the FDA requires an FDA-approved Medication Guide to be dispensed when the prescription is filled. An FDA advisory committee has unanimously recommended that all drugs be accompanied by such medication guides, but at present, less than 5 percent of drugs are. The other 95 percent of drugs are accompanied by unregulated, often dangerously incomplete, information leaflets not approved by the FDA.

2010: In January, the FDA issued information on the dosage and administration of warfarin. The advisory emphasized that the dose of warfarin must be individualized and that lab monitoring is necessary. The appropriate dose of warfarin is influenced by various factors, stated in the advisory, and not all of the factors leading to the variability in warfarin dose are known.

(Family: adenosine diphosphate blockers, blood-clotting inhibitors)

Limited Use: offers limited benefit or benefits certain people or conditions

About clopidogrel

Clopidogrel is approved by the FDA to reduce the risk of a new heart attack or stroke in patients with a history of a recent heart attack or stroke. The drug has also been approved by the FDA for a condition known as acute coronary syndrome in patients who may be treated with medicines, with a stent (a metal device placed in a coronary vessel to keep it open) or with bypass surgery to reduce the rate of heart attack, stroke and cardiovascular death. Acute coronary syndrome consists of unstable chest pain (angina) and changes in the electrocardiogram (EKG or ECG) that suggest a heart attack.

Because the retail cost of clopidogrel is at least 100 times greater than the cost of aspirin and is no better than aspirin in preventing a second heart attack or stroke, its use should be limited to those who cannot take aspirin. The long-term use of clopidogrel in the management of patients with acute coronary syndromes is unclear. Long-term clopidogrel may be no better than aspirin.

FDA Boxed Warning

There is reduced effectiveness in patients who are poor metabolizers of PLAVIX. Poor metabolizers do not effectively convert PLAVIX to its active form in the body.

Inform health care professionals that tests are available to identify genetic differences in CYP2C19 function.

Advise health care professionals to consider use of other anti-platelet medications or alternative dosing strategies for PLAVIX in patients identified as poor metabolizers.

Who should not use clopidogrel

Do not use if you have or have had an intracranial hemorrhage or a peptic ulcer.

Before you use clopidogrel

Tell your doctor if you have or have had an allergy to this drug, bleeding problems, liver disease, stomach ulcers, recent surgery or trauma. Also tell your doctor if you are pregnant or breast-feeding and if you are taking any other drugs, including aspirin, herbs, vitamins and other nonprescription products.

How to take clopidogrel

If you miss a dose, take it as soon as you remember, but skip it if it is almost time for the next dose. Do not take double doses.

Do not share your medication with others.

Take the drug at the same time(s) each day.

Store at room temperature with the lid on tightly. Do not store in the bathroom. Do not expose to heat, moisture or strong light. Keep out of reach of children.

Side effects

Call your doctor immediately if you experience: black, tarry stools; blood in urine or stools; chest pain; coughing; fainting; fever, chills, sneezing or sore throat; frequent, painful or difficult urination; generalized pain; sudden or severe headaches; irregular heartbeat; joint pain; nosebleeds; red or purple spots on the skin; runny nose; shortness of breath; skin blistering, flaking or peeling; severe stomach pain; swelling of the feet or lower legs; ulcers, sores or white spots in the mouth; unusual bleeding or bruising; vomiting of blood or material that looks like coffee grounds; or sudden weakness.

Call your doctor if these symptoms continue: abdominal or stomach pain, anxiety, back pain, constipation, diarrhea, depression, dizziness, fever, chills, headache, heartburn, insomnia, itching, joint pain, leg cramps, muscle aches, nausea or vomiting, numbness or tingling or skin rash.

Clopidogrel and the blood disorder thrombotic thrombocytopenic purpura (TTP). TTP is a life-threatening adverse effect that is characterized by a breakdown of red blood cells, low levels of cells that help stop bleeding (platelets), fever, mental changes and kidney problems. Clopidogrel and ticlopidine (TICLID), a close chemical relative of clopidogrel, have been linked to TTP. In the two-year period between March 1998 and March 2000, TTP was identified in 11 patients from an active surveillance program that involved blood banks around the U.S. Between the end of 1997 and the fourth quarter of 2001, the FDA received 16 reports of TTP. (It is not known if these 16 reports included the 11 previously mentioned.)

Clopidogrel in research studies

Cardiovascular events. Researchers have struggled to show that clopidogrel is better than aspirin in preventing certain cardiovascular incidents such as heart attack and stroke, and they have been largely unsuccessful in doing this.

A single clinical trial was the basis for the FDA approval of clopidogrel for preventing a second heart attack or stroke. In this trial, clopidogrel was directly compared to aspirin. The difference between clopidogrel and aspirin was very small but statistically significant, favoring clopidogrel. A critique of the trial concluded by saying that the result “leaves open questions about whether such a difference is clinically meaningful or, in fact, reproducible.”

The trial did not show clopidogrel to be superior to aspirin in preventing a second heart attack or stroke. The fact that clopidogrel is no better than aspirin in preventing a second heart attack or stroke did not stop its manufacturer from advertising it as a better drug overall. This resulted in the FDA warning Bristol-Myers Squibb/Sanofi in April 2001 about its false and misleading promotion of clopidogrel as being superior to aspirin.

In the August 1999 issue of the journal Stroke, researchers compared the benefits of clopidogrel to aspirin in reducing stroke, heart attack and death from diseases of the blood vessels, concluding that these two drugs work in different ways to prevent platelet aggregation, and currently there is no evidence that one way is better than the other.

Also, an NEJM study published on April 20, 2006, found that clopidogrel, when given in combination with aspirin, was overall no more effective than aspirin alone in reducing the rate of heart attacks, strokes or deaths from cardiovascular causes.

In a study examining the management of acute coronary syndromes, clopidogrel was found to be marginally better than aspirin by only 2.1 percent. However, in statistically significant results, there were more patients with major bleeding episodes (defined as needing a transfusion of at least two units of blood) in those taking clopidogrel. In this study, 1 percent more patients taking clopidogrel had a major bleeding episode compared to the aspirin-treated patients, but there was no statistically significant difference between those taking clopidogrel or aspirin inregard to episodes of life-threatening bleeding.

A further analysis of the trial mentioned immediately above found that in patients with acute coronary syndrome who were taking aspirin, adding clopidogrel was beneficial, compared to a placebo, in reducing major cardiovascular events. However, it has been noted that beyond 30 days, there was no significant advantage to treatment with clopidogrel over a placebo in regard to cardiovascular death or nonfatal heart attack.

Effect decreased when combined with omeprazole (PRILOSEC). A study published in 2008, investigating the effect of the heartburn drug omeprazole (a proton pump inhibitor [PPI]) on the action of clopidogrel plus aspirin therapy, found that omeprazole significantly decreased the effect of clopidogrel, meaning that clopidogrel could then be less effective in preventing strokes and heart attacks. Physicians should be aware of this association, since this drug combination is widely prescribed. Patients also should be made aware of this drug interaction, since omeprazole is available over the counter without a prescription.

In 2009, the FDA issued information concerning the use of clopidogrel and omeprazole. According to the FDA release, the concurrent use of clopidogrel and omeprazole resulted in a reduction in the effectiveness of clopidogrel. The FDA release also stated that separating the administration time of the dose of each drug did not reduce the harmful interaction of this therapy.

According to the FDA, “Other drugs that are expected to have a similar effect and should be avoided in combination with clopidogrel include: cimetidine, fluconazole,
ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine and ticlopidine.”

Genetic factors. Published medical literature shows that clopidogrel is less effective in some patients than it is in others. This may be due to genetic factors that influence how the body metabolizes clopidogrel or the effect that certain other drugs (such as PPIs) have on the effectiveness of clopidogrel. The FDA is working with the manufacturer to obtain more information on this.

Bleeding ulcers. Research published in the Jan. 20, 2005, NEJM found “an astonishingly high rate of bleeding ulcers” in patients taking clopidogrel compared to patients taking aspirin plus the antiulcer/heartburn drug esomeprazole (NEXIUM). No safety advantage was found for clopidogrel over aspirin plus esomeprazole in ulcer bleeding.

When using clopidogrel

Do not exceed the prescribed dose.
Tell any doctor, dentist, emergency medical technician, pharmacist or surgeon whose care you are under that you take clopidogrel. This is especially important for any surgery, including dental.

Pregnancy and breast-feeding warnings

You should not take clopidogrel while nursing. Clopidogrel should not be used if you are pregnant or are thinking of becoming pregnant. Severe malformations have occurred in infants of mothers taking this drug.


The following drugs, biologics (e.g., vaccines, therapeutic antibodies) and foods are listed in Evaluations of Drug Interactions 2003 as causing “highly clinically significant” or “clinically significant” interactions when used together with any of the drugs in clopidogrel’s class. In some classes with multiple drugs, the interaction may have been reported for one but not all drugs in the class, but we include the interaction because the drugs in this class are similar to one another. We also have included potentially serious interactions listed in the drug’s FDA-approved product label or in published medical journal articles. There may be other drugs, especially those in the families of the drugs listed below, that also will react with this drug to cause severe adverse effects. Make sure to tell your doctor and pharmacist the drugs you are taking and whether you take any of these interacting drugs:

acemetacin, ANSAID, atorvastatin, CLINORIL, COUMADIN, DAYPRO, DEMADEX, diclofenac, DILANTIN, enoxaparin, eptifibatide, etodolac, FELDENE, fenbufen, fenoprofen, flurbiprofen, fluvastatin, ibuprofen, indomethacin, INTEGRILIN, ketoprofen, ketorolac, LESCOL, LIPITOR, LODINE, LOVENOX, meclofenamate, mefenamic acid, meloxicam, MOBIC, nadroparin, NALFON, naproxen, NOLVADEX, ORINASE, ORUVAIL, oxaprozin, phenytoin, piroxicam, PONSTEL, sulindac, tamoxifen, tiaprofenic acid, tolbutamide, TOLECTIN, tolfenamic acid, tolmetin, TORADOL, torsemide, VOLTAREN, warfarin

Regulatory actions surrounding clopidogrel

In response to an action letter request by the FDA, the manufacturer of clopidogrel revised the “Precautions” section of the product label to include the following statement: “In patients with recent TIA [transient ischemic attack] or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and PLAVIX has not been shown to be more effective than PLAVIX alone, but the combination has been shown to increase major bleeding.”

2010: In March, the FDA issued an advisory that a boxed warning has been added to the product information for clopidogrel (see "Clopidogrel Interactions box above).



Warfarin is an acronym derived from the name of the patent holder Wisconsin Alumni Research Foundation.  Following the report of hemorrhagic disorder in cattle, the cause was found to be spoiled sweet clover silage, and the hemorrhagic agent was identified in 1939.  In 1948 a more potent synthetic congener was synthetiaed and marketed as a very effective rodenticide. Goodman & Gilman 11th edition 2006, p. 1475


The list of drugs and other factors that may affect the action of warfarin and related anticoagulants is prodigious and expanding.  Warfarin acts as an antagonist of vitamin K. (G&G 1477) Bleeding is the major toxicity of orgal anticoagulant drugs. Especially serious episodes involve sites where irreversible damage mayu result from compression of vital structures (e.g., intracranial, pericardial, verve sheath, or spinal cord).  Although the reported incidence of major bleeding episodes varies considerably, it is generally less than 5% per year in patients treated with a target INR of 2 to 3.  The risk of intracranial hemorrhage increases dramatically with an INR greater than 3, especially in older patients. G&G 1478  


Oral anticoagulants are used to prevent the progression or recurrence of acute dep vein thrombosis or pulmonary embolism following an initial course of herparin [Heparin is a glycosaminoglycan found in the secretory granules of mast cells.  Heparin increases the rate of the thrombin-antithrombin reaction at least a thousand fold.  It is used to initiate treatment of venous thrombosis and pulmonary embolism because of its rapid onset of action.  G&G 1471-72]    



Drug Interactions: Warfarin (COUMADIN)

     Worst Pills Best Pills Newsletter article December, 2007 http://www.worstpills.org/member/newsletter.cfm?n_id=565

These days, prescription drugs often become popular after drug companies inundate health professionals and the public with advertising (especially on television).

But after the initial hype, some of these drugs are doomed to extinction due to toxicity – sometimes unanticipated, and sometimes known but hidden or downplayed by those with a vested interest. Other drugs languish over time, and still others are superceded by newer drugs that are more effective and/or less toxic.

But occasionally a drug has staying power and continues to be used over the decades. Warfarin (COUMADIN) is such a drug. It debuted on the U.S. market in 1954, and last year about 24 million prescriptions were filled in U.S. pharmacies for this important drug.

What is warfarin used for?
Warfarin has been used as an anticoagulant (“blood thinner”) to reduce the chances of blood clots in high-risk individuals. If blood clots form, they can break off from inside the blood vessel in which they formed and travel throughout the body, sometimes blocking blood flow within vital organs such as the lungs and brain.

Who uses warfarin?
The drug is commonly used in patients with a tendency to form blood clots in their legs (deep venous thrombosis). If these clots travel to the lungs, they can cause what is known as a pulmonary embolism, which is frequently fatal.

Warfarin is also used in patients with abnormal heart rhythms such as atrial fibrillation, which can cause clots to form in the heart and then travel to the brain, resulting in a stroke.

In addition, the drug is used to prevent second heart attacks in some patients who have already had one, to prevent clots in patients with artificial heart valves and to treat a number of other blood clotting problems.

What side effects does warfarin have?
Although warfarin has saved many lives, its one big drawback is that, by reducing blood clotting, it increases the risk of bleeding. Often the bleeding is easy to find, such as in the urine, stool or skin, and it serves as an early warning sign to the patient to have his or her blood checked for excessive “thinning.”

Sometimes, however, the bleeding is serious or life-threatening but can be difficult to detect, such as bleeding from the stomach or bleeding into the brain, especially when there is a smaller amount of bleeding that does not cause symptoms. Keep in mind that serious bleeding is uncommon, and as long as clotting has not been slowed too much, the benefit of warfarin for well-established indications often outweighs the risks.

How can the risk of bleeding be minimized?
Although the risk of bleeding in people taking warfarin cannot be completely reduced, even with optimal management, patients taking the drug are less likely to have bleeding problems if they follow dosage directions very carefully, and have their blood tested to measure the degree of clotting inhibition exactly as they have been advised.

Minimizing the risk of warfarin-induced bleeding, however, also requires that patients pay close attention to drug interactions because some of these can raise the International Normalized Ratio (INR; see Box) into a range that is too high, with an unnecessarily increased risk of bleeding. Other interactions may lower the INR below the desired range and thereby put the patient at risk of clotting.

The International Normalized Ratio (INR) is a test applied to a sample of a patient’s blood to determine how “thin” it is. The normal value in people not using warfarin ranges from 0.8 to 1.2. Higher numbers indicate thinner blood, so the number increases with warfarin use.

Therefore, the likelihood that dangerous clotting will occur decreases with these higher numbers.

For most patients who use warfarin, the desired INR range is between 2 and 3. Their dose of the drug will be adjusted until their test result is somewhere in that range. An INR higher than that may increase the chance of bleeding, and a ratio lower than that may not protect patients from the clotting for which they are using the drug.

The first step in avoiding bad interactions between warfarin and other drugs is never to start, stop or change the dosage of any prescription, non-prescription or alternative medication without informing the health professional who is managing your warfarin treatment. Many patients are prescribed drugs by several different health care professionals: general physicians, specialists, dentists, nurse practitioners, physician assistants and others. The only way a patient can be sure that the person managing their warfarin therapy will know all of his or her medications (prescription or not) is if the patient provides an up-to-date list of all of these drugs and/or dietary supplements.

Is bleeding the only risk with warfarin drug interactions?
No. Some drugs interfere with the blood-thinning effects of warfarin, cause the INR to decrease and may actually increase the risk of having a clot. This can be just as dangerous as drug interactions that increase bleeding risk.

Can over-the-counter (OTC) medications interact with warfarin?
Absolutely. In fact, one of the most common serious warfarin drug interactions occurs when people on warfarin take common OTC painkillers such as aspirinibuprofen (ADVIL, MEDIPREN, MOTRIN, NUPRIN), or naproxen (ALEVE, ANAPROX, NAPROSYN). Combining warfarin with these painkillers increases the risk of serious stomach bleeding. While doctors sometimes use warfarin and aspirin together for additive blood thinning, it should only be done after careful consideration of the benefit versus risk balance, because the risk is clearly increased.

The take-home message is not to take any OTC medication – and especially any painkiller – without checking first with the person who is managing your warfarin therapy.

Can “alternative” medicines interact with warfarin?
Yes. Some complementary and alternative medications (CAMs) have been shown to interact with warfarin. For some dietary supplements (such as ginkgo) the risk of bleeding may be increased, while other dietary supplements (such as St. John’s Wort) may inhibit the blood thinning effect of warfarin and increase the risk of clotting. (See Table 1 for some dietary supplements that may interact with warfarin.)

Keep in mind that dietary supplements are generally not standardized, so different brands may interact differently because the amount of active ingredient (and in some cases “inactive” ingredients) may not be the same. Moreover, even different lots of the same brand may vary substantially as to content.

In short, patients on warfarin are rarely, if ever, justified in taking dietary supplements. (The same can be said for patients not taking warfarin, but that is a different story.)

Which prescription medications interact with warfarin?
Unfortunately, there is a very long list of prescription meds that interact with warfarin (See Tables 2 & 3). Part of the problem is that there are several ways that medications can interact with this drug. The most common is when another medication throws a monkey wrench into the body’s normal machinery for getting rid of warfarin from the body (see Table 2). Unless the blood is tested and the warfarin dose is adjusted accordingly, warfarin will accumulate, the blood will become too thin and bleeding may result. A good example is the commonly used antibiotic with the unwieldy name, trimethoprim and sulfamethoxazole (BACTRIM, COTRIM, SEPTRA); it can dramatically increase the blood-thinning effects of warfarin and increase bleeding risk.

Other medications can have the opposite effect from the monkey wrench, and ramp up the warfarin-gobbling machinery into “turbo” mode. This means that warfarin is being destroyed too fast so warfarin levels are reduced, the patient’s INR goes below the desired range, and the patient is more at risk of having a serious blood clot. Examples of drugs that can do this are found in Table 3.

Proper clotting involves both the production of chemicals called clotting factors (it is this process that warfarin inhibits) and the activity of small particles suspended in the blood called platelets. Some medications can interfere with the function of the blood’s platelets. Platelets normally help prevent bleeding by sticking together and plugging up leaks in blood vessels. When a patient’s blood has already been thinned by warfarin, the platelet’s job becomes even more important. A recent study confirmed that antiplatelet medications such as aspirin or NSAIDs caused a substantial increase in serious stomach bleeding in people taking warfarin.

Still other drugs can also affect the ability of the liver to manufacture these clotting factors. Thus these other drugs may join with warfarin to gang up on the liver to further suppress the production of these important clotting chemicals. If the blood becomes too thin, the patient may bleed. It is likely that thyroid replacement hormones act in this way. The thyroid-warfarin interaction is one of the most common of all drug interactions, and it is important to note that the risk of this interaction occurs primarily when thyroid medication is started, stopped or its dosage is adjusted. A person on stable doses of warfarin and thyroid replacement medication is not likely to have problems from the interaction.

What You Can Do  
Make sure the person managing your warfarin therapy is fully aware of all of the medications you are taking, including prescription and over-the-counter medications and dietary supplements.

Note that the drugs listed in Tables 12 and 3 represent most of the established and important drug interactions involving warfarin. But due to the rapidly changing nature of medical knowledge, new warfarin drug interactions are regularly discovered. So be sure to consult with your health professional if you have any questions regarding interactions of warfarin with any other medications.

able 1. Selected Dietary Supplements That May Interact With Warfarin

Possible Increased Risk of Bleeding

Possible Increased Risk of Clotting

Dong Quai
Ginkgo Biloba

Coenzyme Q10
Green Tea
St. John’s Wort

Table 2. Selected Prescription and Over-the Counter Medications That May Increase Risk of Bleeding with Warfarin

Generic Name


Acetaminophen (especially large doses)


Alcohol (large amounts)








































































































Thyroid hormone




Trimethoprim and sulfamethoxazole








Table 3. Selected Prescription and Over-the-Counter Medications That May Increase Risk of Clotting with Warfarin

Generic Name











































Below is another company funded study with market goals, in this case to get those.  Notice the failure to mention side effects, and the article source--jk.

New England Journal of Medicine:


Source: the International Warfarin Pharmacogenetics Consortium at 300 Pasteur Dr., Ln. 301, Mailstop 5120, Stanford, CA 94305,

Warfarin Dosing
The appropriate dose of warfarin is difficult to establish because it can vary by a factor of 10 among patients, and the consequences of receiving an incorrect dose can be catastrophic. Clinical factors, demographic variables, and variations in two genes — CYP2C9 (full name: cytochrome P450, subfamily 2, subfamily C, polypeptide 9) and VKORC1 (full name: vitamin K epoxide reductase complex, subunit 1) — contribute significantly to the variability among patients in dose requirements for warfarin. In 2007, the Food and Drug Administration added pharmacogenetic information to the warfarin product label but did not propose a specific method for using genetic information to predict the dose required for individual patients.*



Background Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base.

Methods Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators.

Results In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring &#8804;21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring &#8805;49 mg per week).

Conclusions The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.




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Disclaimer:  The information, facts, and opinions provided here is not a substitute for professional advice.  It only indicates what JK believes, does, or would do.  Always consult your primary care physician for any medical advice, diagnosis, and treatment.