(Family: blood-clotting inhibitors)
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
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)
- severe allergies
- ulcers or other lesions of the gastrointestinal
tract, respiratory tract or urinary tract
- kidney or liver problems
- infectious disease
- vitamin K deficiency
- alcohol dependence
- severe inflammation of blood vessels
- subacute bacterial endocarditis (infection of the
- recent injury
- 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
Take the drug at the same time(s)
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.
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
- unexplained bruising
- unusually heavy bleeding from cuts or wounds
- unusually heavy or unexpected menstrual bleeding
- abdominal pain or swelling
- sudden light-headedness
- loss of consciousness
- blood in urine
- bloody or tarry stools
- 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
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
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
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
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
Take the drug at the same time(s)
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.
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
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
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
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,
Regulatory actions surrounding
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).