Author:
Michael A. Mancano, Pharm.D.
Associate Professor of Clinical Pharmacy
Temple
University
School of Pharmacy
Philadelphia, Pennsylvania
Mailing Address:
Michael A. Mancano, Pharm.D.
Temple
University
School of Pharmacy
Department of Pharmacy Practice
3307 North Broad Street
Philadelphia, PA
19140
Business Phone:
215-707-4936
Home Phone:
856-489-3575
Fax: 215-707-3678
E-Mail:
mmancano@temple.edu
Behavioral Objectives:
After completing
this continuing education program, the participant should be able to:
1.
Explain
the pharmacokinetic complexities of warfarin metabolism.
2.
Recognize
clinically significant warfarin interactions and anticipate their potential
clinical impact.
3.
Discuss
the various mechanisms by which drugs can interact with warfarin.
4.
Identify
methods of prospectively minimizing the clinical impact of warfarin drug
interactions.
A number of medications can
interact with warfarin (Coumadin), in a clinically significant manner. This topic is confusing to many practitioners
because of the multitude of potential drug interactions with warfarin. Depending on the reference consulted, the
number of drugs potentially interacting with warfarin can be as high as
250. Extensive data are available
concerning clinically significant drug interactions with warfarin and
concomitantly administered prescription medications, over-the-counter
medications, certain types of foods and for natural products. This wide variety of possible interactions should
keep pharmacist’s on their toes with in order to keep patients on
anticoagulation therapy informed and safe from complications.
Background
Warfarin
is the most widely utilized oral anticoagulant drug in North America. Pharmacists would be hard-pressed to think of
a time when they have dispensed another oral anticoagulant for their patients
requiring anticoagulation. Warfarin is
an excellent anticoagulant because it has a predictable onset of action,
duration of effect and excellent bioavailability. The drug is easily monitored by utilizing the
prothrombin time (PT) or International Normalized Ratio (INR) laboratory tests
and has a clearly defined therapeutic range for specific anticoagulation
indications. Warfarin is usually
administered by the oral route, although an injectable preparation is available
in the United States
for use in patients not able to receive oral medication.
Warfarin
is a racemic mixture consisting of two stereoisomers, R-warfarin and
S-warfarin, in roughly equal amounts. Because each isomer has anticoagulant
activity, it is useful to think of warfarin as two anticoagulant
medications. The differences between the
stereoisomers are as follows; S-warfarin is approximately five times more
potent than R-warfarin. Each of the
stereoisomers of warfarin are metabolized by specific P-450 isoenzymes.
CYP450 enzymes are a group of
heme-containing enzymes located on the membrane of the smooth endoplasmic
reticulum of hepatocytes in the liver and in high concentrations on enterocytes
of the small intestine. P450 enzymes are
also located in small amounts in other tissues, specifically the kidney, lungs
and brain. CYP450 enzymes are important
in the metabolism of endogenous substances such as, steroids, hormones,
prostaglandins, lipids and fatty acids.
They are also important in the detoxification of exogenous compounds
such as drugs, especially after oral ingestion.
Basically, CYP450 enzymes are important in the oxidation, reduction and
hydrolysis reactions that make a drug more water-soluble and more readily
excreted in the urine or bile.
S-warfarin is primarily
metabolized via CYP2C9, while R-warfarin is partially metabolized by CYP1A2 and
CYP3A4. Therefore certain interacting
drugs can selectively affect the P-450 metabolism of S-warfarin or R-warfarin
or both while others affect the metabolism of both isomers. In general, drugs that affect the metabolism
of S-warfarin present a greater risk of complication due to S-warfarin’s
increased anticoagulant potency.
However, clinically significant interactions with the R-isomer have been
reported also. A list of the mechanisms
by which drugs may interact with warfarin are included in Table 1.
Mechanisms of
Interaction:
Pharmacokinetic
Interactions
Alteration of
Absorption
The therapeutic
response to warfarin can be influenced by pharmacokinetic factors due to
differences in intestinal absorption or the metabolic clearance of
warfarin. Medications which can reduce
the absorption of warfarin, as well as other medications, are cholestyramine
(Questran) and colestipol (Colestid).
Inhibition of
S-warfarin Clearance
As noted,
medications can inhibit the metabolic clearance of warfarin in a
stereoselective or nonstereoselective manner.
Examples of medications that inhibit the clearance of S-warfarin via
inhibition of the CYP2C9 isoenzyme include trimethoprim/sulfamethoxazole
(Bactrim, Septra) and metronidazole (Flagyl).
Inhibition of S-warfarin’s clearance by these and other compounds would
serve to potentiate warfarin’s effect on PT/INR, possibly placing the patient
at increased risk of bleeding complications.
Inhibition of
R-warfarin Clearance
Medications
such as cimetidine (Tagamet) and omeprazole (Prilosec) have been shown to
inhibit CYP3A4 and therefore inhibit the metabolic clearance of
R-warfarin. While R-warfarin is
pharmacologically less potent than S-warfarin it is prudent to consider these
interactions because they may alter PT/INR to a clinically important extent.
Inhibition of R-
and S-warfarin Clearance
An example of a medication the
inhibits the clearance of S-warfarin and R-warfarin is amiodarone
(Cordarone). Due to its ability to
inhibit the metabolism of both warfarin stereoisomers, it is recommended that a
30% to 50% reduction in warfarin dosage be implemented when amiodarone is added
to a patient’s therapy while they are receiving warfarin or when a dose of
amiodarone is increased.
Induction of
Warfarin Metabolism
The
induction of hepatic CYP450 isoenzymes by concomitant administration of certain
medications can lead to a diminished anticoagulant effect of warfarin. While this type of interaction may not seem
to be as life threatening as a serious bleeding complication, the development
of a clot in an anticoagulated patient may lead to severe morbidity and even
mortality. Potentially detrimental
outcomes of clot formation include; stroke, pulmonary embolism and myocardial
infarction. The anticoagulant effect of
warfarin is diminished via CYP450 enzyme induction by medications such as
barbiturates, rifamycins, and carbamazepine.
Pharmacodynamic
Effects
The
effects of warfarin can be influenced by pharmacodynamic factors as evidenced
by differences in anticoagulant response to given concentrations of
warfarin. The dose response relationship
of warfarin has been shown to differ significantly between “healthy patients”
and can vary to an even greater extent among “sick patients”. Many reasons may account for this variability
in warfarin response. Relevant
pharmacodynamic mechanisms are discussed below.
Alteration in
Dietary Vitamin K Content
Fluctuations
in vitamin K intake occur in both healthy and sick patients. Increased intake of dietary vitamin K in
quantities sufficient to reduce the anticoagulant response to warfarin can
occur in patients on weight reduction diets.
These individuals may ingest a diet rich in vitamin K-containing green
vegetables or vitamin K containing dietary supplements. Additionally, those patients receiving
intravenous parenteral nutrition containing vitamin K may experience a
diminished anticoagulant effect.
Conversely, the effects of warfarin can be potentiated in sick patients
with poor vitamin K intake and in states of fat and vitamin malabsorption. Warfarin potentiation can also occur in a
healthy patient who regularly ingests vitamin K containing foods and abruptly
changes their dietary habits. See Table
2 for a list of common foods and their Vitamin K content.
Inhibition of the
Synthesis of Vitamin K Dependent Clotting Factors
Patients
with hepatic disease or dysfunction can experience a potentiation in response
to warfarin due to impaired synthesis of the normal clotting factors. These patients require careful warfarin
dosage titration and frequent INR monitoring.
The anticoagulant response of warfarin can be increased also by second
and third generation cephalosporin antibiotics because they inhibit steps in
the synthesis of vitamin K.
Increasing
Metabolic Clearance of Vitamin K Dependent Coagulation Factors
Patients
experiencing hypermetabolic states such as those produced by fever or
hyperthyroidism can have an increased response to warfarin therapy. This exaggerated response is most likely due
to the increased catabolism of the vitamin K dependent clotting factors. Patients treated with levothyroxine experience
increased catabolism of vitamin K-dependent clotting factors which could put
the patient at risk for excessive bleeding.
Interference With
Other Pathways of Hemostasis
Medications
such as aspirin and the NSAIDs, and high doses of penicillin and moxalactam can
increase the risk of warfarin related bleeding by inhibiting platelet
function. Aspirin posses the most
significant risk due to its common use and its prolonged effect on platelets. The proposed mechanism of interaction
involves the possibility that salicylates displace warfarin from plasma
protein-binding sites. However, the
transient nature of the interaction make the significance of this mechanism
questionable as compared to aspirin’s intrinsic effect on platelets. Aspirin and NSAIDs can also produce gastric
erosions that increase the risk of serious upper gastrointestinal
bleeding. Some of the available NSAIDs
may have a lesser effect on coagulation than aspirin.
Antimicrobials
Agents
Cotrimoxazole (Bactrim,
Septra)
Trimethoprim
/ sulfamethoxazole can potentiate warfarin’s hypoprothrombinemic effect,
possibly placing the patient at increased risk of bleeding complications. Sulfonamides appear to impair the hepatic
metabolism of warfarin via inhibition of CYP2C9. Other contributory factors to this
interaction may include the competition for protein binding sites between
sulfamethoxazole and warfarin and the fact that fever associated with infection
may enhance the catabolism of clotting factors.
Since
fever has been shown to enhance the break down of clotting factors; the
infection that the sulfonamide is being prescribed to treat could enhance
warfarin’s effect. However, the
relevance of fever in affecting warfarin’s actions may be diminished by the
fact that fever would be expected to dissipate as the infection resolves with
appropriate antimicrobial treatment.
In the
practical management of a patient facing the potential interaction of an
antibiotic with warfarin pharmacists are faced with several options. One option is to consider the use of a
non-interacting antimicrobial agent to treat the infection. Secondly, if the use of cotrimoxazole is
unavoidable, careful monitoring of the patient’s warfarin therapy for several
days should be recommended.
Additionally, the dose of warfarin may need to be reduced or even
temporarily discontinued based on the patients response to therapy.
Education
of patients regarding the signs and symptoms of bleeding is an important
measure for pharmacists to help to minimize the risk of hemorrhagic
complications. Lastly, if a dosage
reduction of warfarin is initiated due to cotrimoxazole therapy, pharmacists
must be vigilant to ensure a proper adjustment back to an appropriate dose of
warfarin to assure continued anticoagulation.
Erythromycin and
Clarithromycin
There
have been numerous reports describing the enhancement of the anticoagulant
effects of warfarin when given in combination with erythromycin or
clarithromycin. In patients receiving
these agents, prothrombin times have increased up to two fold after seven days
of therapy. Fortunately, there are few
reports of bleeding complications due to the interaction.
In a
randomized study, erythromycin produced a modest, fourteen percent reduction in
the clearance of warfarin. These small increases
in prothrombin time appear to be inconsistent with the dramatic increases noted
in earlier case reports.
The
clinical importance of this interaction likely depends on many patient-specific
factors including fever, low dietary vitamin K, age, rate of warfarin
clearance, concurrent therapy and ability to shunt warfarin metabolism to
uninhibited pathways.
As
mentioned earlier, the selection of an alternative antimicrobial agent may be
advisable to avoid this problem. This
interaction has not be observed with azithromycin (Zithromax) or dirithromycin
(Dynabac), but like erythromycin, caution is advised with concurrent
clarithromycin (Biaxin) therapy.
Metronidazole (Flagyl)
Metronidazole
can increase the hypoprothrombinemic response to warfarin, and bleeding has
resulted in patients receiving warfarin and metronidazole concomitantly. Metronidazole appears to inhibit the
metabolism of the more active S-isomer of warfarin via inhibition of the CYP2C9
isoenzyme, but has no effect on the R-isomer.
It is
advisable to avoid the combination of warfarin and metronidazole unless the
benefit of therapy truly outweighs the risk of bleeding. If a patient must receive this combination
then increased monitoring of the patient’s INR should be undertaken. As mentioned earlier, pharmacist’s should
make patients aware of the signs and symptoms of major bleeding to minimize the
risk of hemorrhagic complications.
The
typical scenario involves a patient stabilized on warfarin therapy who requires
initiation of a course of metronidazole therapy. However, there are cases where a patient is
already receiving metronidazole and warfarin is to be initiated. In these instances the use of conservative
warfarin doses is recommended until the patient reaches a stable maintenance
dose.
Azole Antifungal
Agents
Fluconazole (Diflucan),
Itraconazole (Sporanox), Ketoconazole (Nizoral) & Miconazole (Monistat)
The
anticoagulant effect of warfarin may be increased when azole antifungal agents
are administered concomitantly with warfarin.
Two-fold (fluconazole) and three-fold (ketoconazole) increases in
prothrombin time have been reported in the medical literature. Even low doses of fluconazole, 100 mg daily
for seven days, have been implicated to reduce warfarin clearance.
While the
azole antifungal agents exert their antifungal effect by inhibiting fungal
cytochrome P450; human CYP450 enzymes appear to be affected as well. The ability of fluconazole to inhibit drug
metabolism by CYP3A4 pathways has been shown to require large doses while doses
of only 100 mg daily can inhibit warfarin metabolism. These observations suggest that the CYP2C9
isoenzyme is affected since it is the primary isoenzyme responsible for
S-warfarin metabolism.
The
interaction causes potentiation of anticoagulant effects within days, requiring
frequent monitoring of INR values when adding, discontinuing or changing the
dose of an azole antifungal agent. The
monitoring should continue until the patient’s level of anticoagulation
stabilizes. An adjustment of the
anticoagulant dose should be made as needed based on patient response.
Interactions
between warfarin and vaginally or cutaneously applied azole antifungal agents
have been reported and patients who use both products should be monitored closely.
Acetaminophen (Tylenol)
Of all
the potential interactions between warfarin and other drugs, the interaction
with acetaminophen is probably the most confusing for pharmacists and
patients. The published data on the
interaction is conflicting but acetaminophen appears to increase the
anticoagulant effect of warfarin in a dose-dependent manner.
Approximately
thirty percent of patients stabilized on warfarin ingesting approximately two
grams of acetaminophen daily can experience an intensification of warfarin
response. An interaction between
acetaminophen and warfarin appears more likely with daily acetaminophen doses
of greater then 2 grams daily for a week or more. Maximal effects on the anticoagulant response
have occurred one to three weeks after starting acetaminophen. Occasional doses of acetaminophen do not
appear likely to interact with warfarin.
Patients
receiving warfarin should be counseled to limit their intake of
acetaminophen-containing products.
Patients should also be reminded to check with their pharmacist if they
are unsure if a product contains acetaminophen.
Many over-the-counter products contain acetaminophen as an ingredient
and should therefore be avoided.
Aspirin-containing products should not be used as an alternative to
acetaminophen. Aspirin is undesirable
due to its adverse effects on the gastric mucosa and platelet inhibition
effects.
Coagulation
parameters should be monitored more frequently (e.g. once or twice weekly) when
a patient is starting or stopping chronic acetaminophen therapy. This is especially true if ingesting more
then the two gram daily limit.
Amiodarone
(Cordarone)
An
interaction that can lead to bleeding complications in patients receiving
warfarin is amiodarone. Pharmacists
should be aware of this potential interaction and be prepared to recommend
appropriate dosage adjustments to minimize this complication.
Amiodarone is an example of a
medication the inhibits the clearance of S-warfarin and R-warfarin. Remember that the S-stereoisomer of warfarin
is approximately five times more potent than the R-stereoisomer. S-warfarin is primarily metabolized via
CYP2C9, while R-warfarin is partially metabolized by CYP1A2 and CYP3A4. Amiodarone reduces the metabolism of warfarin
primarily via inhibition of CYP2C9 but it also has inhibitory effects on
CYP3A4. Due to this dual inhibition of
the metabolism of warfarin’s stereoisomers, it is recommended that the dosage
of warfarin be reduced if amiodarone is to be added to a patient’s drug
regimen.
Amiodarone
may enhance the anticoagulant effect of warfarin by 50% to 100% while reducing
warfarin’s clearance by 35% to 65%.
Following the initiation of amiodarone therapy to a patient receiving
warfarin, the increased anticoagulant effect can begin within one week. The effects of the interaction on
anticoagulant action stabilizes in approximately one month after initiation of
concomitant therapy. However due to
amiodarone’s long half-life this effect may persist for several months after
amiodarone is discontinued.
Amiodarone
may interact with warfarin via an additional mechanism. Since amiodarone contains iodine in each
tablet, amiodarone-induced hyperthyroidism can further enhance the
anticoagulant effect of warfarin.
Hyperthyroidism is associated with sensitivity to warfarin leading to an
increased warfarin effect.
In a
patient receiving warfarin who is to begin amiodarone therapy, a pharmacist’s
intervention can significantly reduce the patient’s risk of bleeding
complications. Typically a 30% to 50%
reduction in the warfarin dose is required when amiodarone is initiated. Pharmacists can recommend close monitoring of
the patient’s INR for the first two to four weeks of amiodarone therapy and
adjust the dose of warfarin accordingly.
If amiodarone is discontinued in
a patient who was stabilized on the combination, additional INR monitoring is
indicated. The onset and duration of
this interaction may be delayed in some patients due to amiodarone’s long half-life. Therefore, close monitoring should continue
for several months following the discontinuation of amiodarone with appropriate
adjustments made to the patient’s warfarin dose.
Cimetidine
(Tagamet)
Cimetidine
can increase the anticoagulant effects of warfarin via inhibition of warfarin
metabolism by isoenzyme CYP2C9. The
interaction is dose related in that patients receiving 400 mg per day or less
are unlikely to experience significant adverse effects. In fact, a single 800 mg dose of cimetidine
at bedtime is not likely to result in an interaction with warfarin. However, patients receiving larger doses of
cimetidine given two or more times per day may experience an adverse drug
interaction.
The
response to this interaction may vary considerably from patient to patient with
most patients developing modest changes in the anticoagulant effect and other
patients experiencing large increases.
In general, patients receiving cimetidine and warfarin typically
experience a gradual increase in INR over approximately one to two weeks. When cimetidine is discontinued it may take
approximately one week for the INR to return to pre-cimetidine levels.
While
this interaction has a wide interpatient variability it is easy to avoid by
recommending a change in therapy. The
other H2 blockers currently available are unlikely to effect
warfarin’s anticoagulant effect.
Ranitidine (Zantac), famotidine (Pepcid) and nizatidine (Axid) are
reasonable alternatives. A proton pump inhibitor
may be initiated in place of cimetidine, however omeprazole (Prilosec) can
inhibit CYP2C9 in a dose-related manner.
While the usual 20 mg dose of omeprazole may produce only a slight
increase in INR, it seems likely that at least an occasional patient on
warfarin will manifest a clinically important drug interaction. Therefore lansoprazole (Prevacid),
esomeprazole (Nexium), rabeprazole (Aciphex), pantoprazole (Protonix) would be
excellent alternative choices if a proton pump inhibitor is needed in patients
receiving warfarin therapy.
Thyroid Hormone
Replacement
Pharmacists
should be aware of the potential interaction between warfarin and levothyroxine
(Synthroid), which could lead to excessive bleeding. Patients at greatest risk are those who have
been stabilized on warfarin therapy and then placed on levothyroxine therapy to
reverse hypothyroidism. These patients
are at risk for amplified anticoagulant effects due to increased vitamin
K-dependent clotting factor catabolism.
Conversely, patients with untreated hypothyroidism usually require
higher warfarin dosages to achieve a therapeutic INR due to a slower rate of
clotting factor catabolism.
Stabilized,
anticoagulated patients receiving warfarin who are to begin receiving
levothyroxine therapy should be closely observed for clinical signs of bleeding
and have their INRs monitored. In
summary, the dose of warfarin may need to be decreased during levothyroxine
therapy. Conversely, if a patient
receiving warfarin and levothyroxine is to have their levothyroxine therapy
discontinued, the dose of warfarin may need to be increased. The above changes should be made based on the
patient’s clinical response and concomitant INR monitoring.
Aspirin, NSAIDs
& COX2 Inhibitors
Aspirin &
NSAIDs
Aspirin
increases the risk of bleeding in patients receiving warfarin. This effect is due to inhibition of platelet
function by aspirin and possibly by producing gastric erosion. In addition, the ability of the highly
protein bound aspirin to displace warfarin from plasma protein binding sites may
play a role in the interaction mechanism.
Due to the transient nature of the protein binding displacement
interaction, it is of questionable clinical significance when compared with
aspirin’s antiplatelet effects and aspirin’s ability to produce gastrointestinal
bleeding.
While small doses of aspirin can
interact with warfarin, larger doses are likely to have an intrinsic
hypoprothrombinemic effect thus enhancing the anticoagulant effect of
warfarin. The risk of clinically
important bleeding is increased when high doses of aspirin are used in
combination with high-intensity warfarin therapy. Nonacetylated salicylates such as choline
salicylate, magnesium salicylate, salsalate, and sodium salicylate appear to be
safer choices with oral anticoagulants.
The nonacetylated salicylates have minimal effects on platelet function
and tend to produce less gastrointestinal damage.
Since all
NSAIDs inhibit platelet function, cause gastrointestinal erosion, and probably
increase the risk of gastrointestinal bleeding in patients receiving warfarin,
this combination should be initiated only after careful consideration of the
risk versus benefit. Aspirin should be
combined with warfarin only when used intentionally for additive anticoagulant
effects. Some NSAIDs such as ibuprofen
(Motrin), naproxen (Naprosyn) and diclofenac (Voltaren) may be less likely to
increase oral anticoagulant-induced hypoprothrombinemia than others. Acetaminophen is a reasonable substitute when
analgesic or antipyretic effects are needed, however, as mentioned earlier,
warfarin does interact with chronically dosed acetaminophen.
When
NSAIDs and warfarin are combined, patients should be monitored closely for
evidence of bleeding, especially gastrointestinal. In addition, careful monitoring of the INR
should also be initiated.
COX2
Inhibitors
In patients receiving celecoxib
(Celebrex) and warfarin there have been post-marketing reports of increases in
prothrombin time, sometimes associated with bleeding. These adverse bleeding events have
predominantly occurred in elderly patients.
Initial trials studied the effects of celecoxib on the anticoagulant
effect of warfarin in a group of healthy subjects. In these trials, celecoxib did not alter the
anticoagulant effect of warfarin as determined by prothrombin time. While it is acceptable for patients on
warfarin therapy to receive celecoxib, increased monitoring is warranted. Reports suggest that celecoxib has no effect
on platelet aggregation or bleeding time at therapeutic doses. However, anticoagulant activity (prothrombin
time and INR) should be monitored, particularly in the first few days after
initiating or changing celecoxib therapy in patients receiving warfarin or
similar agents.
Rofecoxib (Vioxx) has increased
the prothrombin time, (measured as INR) in patients receiving warfarin. In patients stabilized on warfarin therapy,
rofecoxib administration was associated with an increase in INR of
approximately 8%. For patients receiving
warfarin and rofecoxib concomitantly, standard monitoring of prothrombin time
is recommended when therapy with rofecoxib is initiated or changed,
particularly in the first few days after initiation or dosage change.
Barbiturates
Phenobarbital,
Amobarbital (Amytal), Butabarbital
(Butisol), Mephobarbital (Mebaral) Pentobarbital (Nembutal), Primidone (Mysoline), Secobarbital (Seconal)
Phenobarbital
increases the metabolism of warfarin via hepatic enzyme induction, thereby
inhibiting its anticoagulant effects.
This interaction may cause a patient who has become stabilized on
warfarin therapy to become under-anticoagulated following the initiation of
phenobarbital therapy. All of the above
barbiturates have been shown to decrease the anticoagulant effect of warfarin
presumably via a similar mechanism.
The use
of a barbiturate as a sedative/hypnotic should be discouraged in a patient
receiving warfarin therapy. However, if
the barbiturate is being utilized for seizure control this interaction may need
to be managed carefully. If the patient
must receive combination therapy with these agents, monitoring for
anticoagulant response should be increased with the dosage of warfarin being
altered as needed.
Patients
stabilized on the combination of a barbiturate and warfarin should be advised
not to stop taking their barbiturate or change its dosage without consulting
with their physician or pharmacist. This
is an important issue because of the risk of bleeding complications if the
barbiturate is decreased in dosage or discontinued without proper warfarin
downward dosage titration.
Bile Acid Sequestrants
Cholestyramine
(Questran) Colestipol (Colestid)
Cholestyramine
and colestipol may diminish the anticoagulant effect of warfarin by binding to
warfarin in the gastrointestinal tract and decreasing its absorption. While this mechanism of interaction seems
rather simplistic there may also be another mechanism at work. Cholestyramine and colestipol may also
interfere with the enterohepatic recirculation of warfarin. This was demonstrated by the fact that even
an intravenous form of warfarin exhibited increased clearance when
concomitantly administered with cholestyramine.
To
minimize this interaction, the administration of warfarin should be at least
two hours before or six hours after the binding resin is administered. While this may diminish the magnitude of the
interaction, warfarin may still be affected by the binding resin during its
enterohepatic recirculation. Probably
the most practical advice to manage this interaction is to advise the patient
to be consistent with their administration times of each of the agents. This will result in a relatively consistent
interaction occurring on a daily basis that is reasonably predictable.
The
patient’s prothrombin time should be monitored if one of the binding resins is
initiated, discontinued or if a dosage change is undertaken. There is some evidence that colestipol may
effect warfarin to a lesser extent than cholestyramine, however it would be
prudent to exercise the same level of caution in patients receiving either
agent. To date, Colesevelam (Welchol) was found to have no significant effect on
the bioavailability of warfarin and may be a viable alternative to if a bile
acid sequestrant is desired.
Carbamazepine (Tegretol)
Carbamazepine
appears to enhance the metabolism of warfarin by inducing hepatic microsomal
enzymes. The elimination half-life of
warfarin can be decreased by up to fifty percent in patients receiving
carbamazepine. Conversely, if a patient
stabilized on the combination of carbamazepine and warfarin is to have carbamazepine
discontinued, a resultant decrease in warfarin metabolism would be
expected.
This
interaction may have a delayed onset due to the fact that it is an enzyme
induction interaction and the hepatic microsomal enzymes must have time to
increase in number. While the onset of
the interaction is delayed, by approximately one to two weeks, it is still
prudent to monitor a patients prothrombin time when beginning, stopping or
adjusting the dose of carbamazepine in patient’s receiving warfarin. Based on the patient’s prothrombin time test
results, the warfarin dosage should be adjusted as needed.
Ethanol
Ethanol
can interact with warfarin in various ways specifically related to the amount
and frequency of the ethanol exposure.
Ethanol can increase the anticoagulant effect of warfarin following an
acute ethanol intoxication. This is most
likely due to an inhibition of warfarin’s metabolism by the large amount of
ethanol present during acute intoxication.
Small amounts of ethanol, defined
as two drinks per day or less, seems to have little or no effect on warfarin’s
level of anticoagulation in most patients.
This is an important fact because given the small amounts of ethanol
present in medications, it appears unlikely that a clinically significant drug
interaction would manifest. Likewise, an
occasional small amount of ethanol with a meal probably poses no significant
risk to patients.
Patients who are chronic heavy
drinkers may experience an increase in warfarin metabolism, thereby potentially
decreasing warfarin’s anticoagulant effect.
This increase in warfarin metabolism is possibly due to ethanol-induced
stimulation of hepatic microsomal enzymes.
Griseofulvin (Grisactin)
Griseofulvin
appears to decrease the anticoagulant activity of warfarin. While there have been a number of case
reports describing patients who have initiated griseofulvin therapy and
experienced a decreased anticoagulant effect of warfarin, the exact mechanism
of this interaction is unknown. It is
postulated that perhaps griseofulvin has enzyme inducing properties and this
may be the explanation for the interaction.
Whatever the case the onset of this interaction is very gradual, so it
may be several weeks or longer for the maximal effect of griseofulvin to be
seen.
As for a
number of inducing interactions, it is recommended that coagulation parameters
be monitored whenever griseofulvin is initiated, dose adjusted or discontinued
in patients receiving warfarin. Since
the effect of griseofulvin may be gradual, it is prudent to monitor the
anticoagulant response of warfarin until it is stable, while adjusting the dose
of warfarin as dictated by test results.
Phenytoin
(Dilantin)
Phenytoin
is involved with an interesting interaction with warfarin. When phenytoin therapy is initiated in a
patient receiving chronic warfarin therapy, a transient increase in the
anticoagulant effect of warfarin may be observed. However, after approximately one to two weeks
of concomitant therapy an inhibition of the anticoagulant effect of warfarin
may be observed. This may lead to the
patient requiring a larger dose of warfarin to maintain adequate
anticoagulation.
The
inhibition of warfarin’s anticoagulant effect is most likely due to phenytoin’s
enzyme inducing effects. However, the enhanced
anticoagulant effect of warfarin seen at the initiation of phenytoin therapy
may be due to phenytoin displacement of protein bound warfarin.
Based on
the potential for interaction with warfarin when phenytoin therapy is
initiated, it would be prudent to monitor anticoagulation parameters if
phenytoin is initiated, dose adjusted or discontinued. The dose of warfarin would then be adjusted
based on anticoagulant response and appropriate lab results.
Rifamycins
Rifampin
(Rifadin, Rimactane), Rifabutin
(Mycobutin), Rifapentine (Priftin)
Rifampin
can decrease the anticoagulant action of warfarin. Rifampin can cause this decrease in
anticoagulant effect by inducing hepatic microsomal enzymes. Rifampin induction of warfarin’s metabolism
is considered to be maximal at five to ten days after the initiation of
rifampin. Additional members of the
rifamycin class are also expected to interact with warfarin in a similar
manner. Pharmacists should note that
products such as, Rifater and Rifamate also contain rifampin, however it is in
combination with isoniazid. The
combination of any these agents with warfarin should be avoided unless
absolutely necessary.
An
anticipated increase in the dosage of warfarin is expected due to rifampin’s
enzyme induction properties. Dosage
adjustments of greater then fifty percent of the warfarin dose may be required
in some patients receiving this combination.
Close monitoring of coagulation parameters is recommended whenever
rifampin is initiated, dose adjusted or discontinued. Close monitoring of coagulation parameters
should be continued for up to three weeks after rifampin is discontinued from a
patient’s regimen due to the slow reversal of rifampin’s enzyme inducing
properties.
Herbal Products
Interactions with herbal products
are of particular concern to pharmacists because they are often uninformed as
to what herbal products are being utilized by their patients. The widespread use of these products is more
prevalent than realized. Pharmacists
should ask patients if they are taking herbal or natural products. By asking this question directly one can be
assured of receiving the appropriate response.
This may be due to the fact that many patients do not consider herbal or
natural products to be “drugs” and often neglect to divulge their use unless
asked directly.
In the United
States sales of herbs and supplements have
topped $1.5 billion. Many consumers turn to alternative therapies because they
are dissatisfied with conventional medicine and want to take more control over
their health care decisions. It is
estimated that more than 60 million Americans use herbal products and vitamins
to supplement their diet. This increase
is especially noticeable among senior citizens.
In light of these facts, pharmacists should be aware of potential herbal
/ natural product interactions when counseling their patients receiving
warfarin.
Dong Quai
Dong quai
is recommended primarily by modern herbalists for the treatment of many
gynecological ailments. It has been
utilized for menstrual cramps, irregular menstrual flow, weakness during
menstruation and for relief of the symptoms of menopause. Dong quai has been recommended for the
treatment of selected non-gynecologic conditions, as well.
Dong quai has been noted to have
an effect on blood clotting and approximately six coumarin derivatives have
been isolated from dong quai. A recent
case report describes a patient who was stabilized on warfarin therapy
experienced a two-fold increase in their INR after taking dong quai. Pharmacists should be aware that patients
receiving warfarin may experience an increased anticoagulant effect if they
begin taking dong quai.
A patient who is taking warfarin
should be discouraged from initiating dong quai. Discuss the increased risk of bleeding with
this combination. It would also be
prudent to advise against the use of dong quai in patients receiving
antiplatelet agents due to the potential for bleeding complications with
concomitant therapy.
Ginkgo Biloba
Ginkgo
biloba is an herbal medication that has been employed for the treatment of a
number of conditions. Ginkgo has been
utilized to treat anxiety, stress, tinnitus, vertigo, headache, diabetic
retinopathy, dementia, circulatory disorders, asthma, and for its antioxidant
effects and for memory improvement.
Components
of ginkgo extract known as ginkgolides have been shown to inhibit platelet
activating factor. This inhibition can
lead to an inhibition of platelet aggregation and can decrease blood viscosity. Isolated cases of bleeding have been reported
following ginkgo biloba use, with and without concurrent warfarin therapy. Cases of ocular bleeding and subdural
hematoma have been reported in patients receiving ginkgo biloba alone, however
a true cause-and-effect relationship has not been established in these
cases.
Due to
the risk of bleeding complications, patients receiving warfarin therapy should
be advised against initiating ginkgo biloba.
Ginseng
Ginseng,
like many other herbal products, has been utilized for a wide variety of
conditions and ailments. Ginseng is
considered an adaptogen in that it is purported to help the body adapt to
internal and external stressors.
Therefore, it has been utilized for the prevention and treatment of
fatigue and stress. Ginseng has also
been utilized for its purported effects on blood pressure, enhancing the immune
system, menopausal symptoms, impotence, infertility and
hypercholesteremia.
Ginseng may affect platelet
adhesiveness and blood coagulation. It
has been reported that ginseng has demonstrated both increased and decreased
effects on blood coagulation. Therefore,
patients receiving warfarin should avoid ginseng due to its potential for an
altered warfarin response. A recent case
report has documented a fifty percent reduction in INR in a patient receiving
warfarin who initiated ginseng. If a
patient initiates ginseng in spite of warnings, it is prudent to recommend
increased monitoring of the patient’s INR to detect ginseng’s possible
potentiation or inhibition of warfarin’s anticoagulant effects.
St.
John’s Wort
St.
John’s Wort is currently one of the most popular
herbal products on the market. While its
predominant use is as an antidepressant, St. John’s
Wort has been utilized as an antianxiety agent and as a antiviral agent.
It has
been suggested that St. John’s Wort
is an enzyme inducer of the CYP2C9 and CYP3A4 isoenzymes. Both of these isoenzymes play a part in the
metabolism of warfarin with CYP2C9 responsible for the metabolism of S-warfarin
and CYP3A4 responsible for the metabolism of R-warfarin. Because St. John’s
Wort is an enzyme inducer, it may enhance the hepatic metabolism of warfarin,
thereby decreasing its anticoagulant effect.
If a
patient receiving warfarin seeks advice concerning the use of St.
John’s Wort for depression, it is prudent to suggest
alternate therapy with a prescription antidepressant that does not interact
with warfarin.
In summary, pharmacists should
ask patients about their use of herbal or natural products before starting any
new medication. Since the ingredients of
many herbal products are not standardized it is imperative to know the exact
product the patient is receiving.
Additionally, it is possible that some herbal products contain a
combination of herbs or ingredients other than those listed on the label that
may interact with the patient’s prescription medications.
