New Zealand - English - Medsafe (Medicines Safety Authority)
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NEW ZEALAND CONSUMER MEDICINE INFORMATION
Warfarin sodium tablets 1mg, 2 mg and 5 mg.
What is in this leaflet
Please read this leaflet carefully
before you start taking COUMADIN.
This leaflet answers some common
questions about COUMADIN.
It does not contain all the available
information. It does not take the
place of talking to your doctor or
All medicines have risks and
benefits. Your doctor has weighed
the risks of you taking COUMADIN
against the benefits they expect it
will have for you.
If you have any concerns about
taking this medicine, ask your
doctor or pharmacist.
Keep this leaflet with the
medicine. You may need to read it
What COUMADIN is
COUMADIN contains an active
ingredient called “warfarin”. It helps
to prevent blood from excessive
clotting or forming harmful clots.
This medicine belongs to a group of
medicines called anticoagulants.
Some people refer to anticoagulants
as ‘blood thinners’. Excessive
clotting sometimes occurs when
physical mobility is low. If excessive
clotting is not treated, it can lead to
serious health problems such as
strokes or heart attacks.
Ask your doctor if you have any
questions about why COUMADIN
has been prescribed for you.
Your doctor may have prescribed
COUMADIN for another reason.
There are two brands of warfarin
in New Zealand. They are called
COUMADIN and MAREVAN.
Do not change from one brand to
the other. You should not
combine these brands.
There is no evidence that
COUMADIN is addictive.
COUMADIN is available only with a
Before you use
When you must not take
Do not take COUMADIN during
Taking COUMADIN during
pregnancy may harm the
developing baby. If you are
considering becoming pregnant
while taking COUMADIN, tell your
doctor who can help you weigh the
benefits of taking COUMADIN
against the possible risks.
Do not take COUMADIN if you
have an allergy to:
any of the ingredients in
COUMADIN listed at the
end of this leaflet.
MAREVAN (another brand
Some of the symptoms of an
allergic reaction may include itchy
skin rash, difficulty breathing;
swelling of the face and tongue.
Do not take COUMADIN if you
have a history of bleeding
tendencies or abnormal blood
COUMADIN may make bleeding
Do not take COUMADIN if you
have moderate to severe high
blood pressure. The risk of
bleeding in this situation may be
increased by taking COUMADIN.
Do not take this medicine after
the expiry date printed on the
pack or if the packaging is torn or
shows signs of tampering.
If it has expired or is damaged,
return it to your pharmacist for
Do not take COUMADIN if the
packaging is torn or shows signs of
Before you start to use it
You must tell your doctor if you:
Are going to have any
Have recently had or are
going to undergo any
surgical procedures or
Are starting any sports
activities that may result in
Are going to travel or go on
Your doctor or pharmacist is best
able to advise you about combining
these situations with taking
Tell your doctor if you currently
have or have had any of the
following health or medical
Liver, kidney or intestinal
disease such as coeliac
High blood pressure
A deficiency in Protein C
An ulcer in your stomach or
Red or black bowel motions
Internal bleeding such as
bleeding in the brain
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Fits or convulsions
vomiting or fever
Sudden changes in weight
Have recently stopped
Your doctor will need to consider all
these factors when advising you
about taking COUMADIN.
Tell your doctor or pharmacist if
you are taking any other
medications, including those you
buy might from a chemist,
supermarket or health food shop.
Some commonly used medicines
and products that may interfere with
Any medication used to
treat arthritis (including
(NSAIDS such as
Some medications used to
treat blood clots, heart
attacks or angina
St John’s Wort
Other herbal preparations
(such as garlic, ginseng,
feverfew, gingko biloba and
Cranberry and grapefruit
Eating large amounts of
green leafy vegetables
and/or drastic changes in
These may be affected by
COUMADIN or may affect how well
COUMAIN works. You may need
different amounts of these or you
may need to take something
There are various other medicines
which interact with COUMARIN.
Your doctor and pharmacist have a
more complete list of medicines to
avoid while taking COUMADIN.
If you have not told your doctor
about any of these things tell
him/her before you take
How to take
How much to take
You should follow your doctor’s
directions exactly about how
much COUMADIN to take.
Different people require different
amounts of COUMADIN and the
dosage is adjusted to suit each
patient. Your directions should be
printed on the pharmacy label.
By using the results of a blood test,
your doctor will decide what amount
of COUMADIN you need. This
means that your doctor may
sometimes change your dose of
COUMADIN so that the dose is right
Each tablet has a score or break
line so that the tablets can be
halved if needed to provide the
exact dose your doctor has
prescribed for you.
When to take it
Take your medicine at about the
same time each day.
Taking it at the same time each day
will have the best effect. It will also
help you remember when to take it.
It does not matter if you take this
medicine before or after food.
How to take it
Swallow COUMADIN with a glass
of water. Do not crush or chew
How long to take it
You may not feel any differently
while taking COUMADIN from the
way you were prior to taking it.
However, COUMADIN will continue
to be prescribed while there is a risk
of excessive blood clotting.
Do not stop taking COUMADIN or
reduce your dose unless your
doctor advises you to do so.
If you forget to take
If you forget to take a dose of
COUMADIN, tell your doctor
Take the dose as soon as you
remember and then go back to
taking it as you would normally.
However, if it is less than 12 hours
till your next dose is due, skip the
missed dose and take your next
dose when you were meant to.
Do not try to make up for a missed
dose by taking more than one dose
Do not take a double dose to
make up for the dose that you
This may increase the chance of
you getting an unwanted side effect.
You should make a note in your
warfarin treatment booklet/record of
any missed or late doses. Tell your
doctor or nurse about the missed or
late doses at your next blood
appointment. If you are worried you
should contact your doctor or nurse
for any advice on increased
If you have trouble remembering
when to take COUMADIN, ask your
pharmacist for some hints.
While you are taking
Things you must do
If you are about to be started on
any new medicine, tell your
doctor and pharmacist that you
are taking COUMADIN
Tell any other doctors, dentists,
and pharmacists who treat you
that you are taking this medicine.
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If you are going to have surgery,
tell the surgeon or anaesthetist
that you are taking this medicine.
It may affect other medicines used
If you become pregnant while
taking this medicine, tell your
If you are about to have any
blood tests, tell your doctor that
you are taking this medicine.
It may interfere with the results of
It is recommended that you carry
identification with you, stating
that you are taking COUMADIN.
Keep all of your doctor’s
appointments so that your
progress can be checked.
Your doctor may do some tests
from time to time to make sure the
medicine is working and to prevent
unwanted side effects.
Tell your doctor if for any reason
you have not taken your
COUMADIN as prescribed,
otherwise your doctor may make
unnecessary changes to your dose.
Eat a normal balanced diet and do
not make any big changes in your
diet. This minimises the possibility
of your dietary habits interfering with
Things you must not do
Do not take COUMADIN to treat
any other complaints other than
that directed by your doctor. It
may not be safe to take
COUMADIN for another complaint.
Do not give your medicine to
anyone else, even if they have
the same condition as you. It may
not be safe to take COUMADIN for
Do not stop taking your medicine
or lower the dosage without
checking with your doctor.
Do not stop or start any other
medicines without checking with
your doctor. This includes
medicines that you buy without a
prescription from your pharmacy,
supermarket or health food shop.
Things to be careful of
There are two brands of warfarin
tablets. One is COUMADIN and
the other is MAREVAN. Do not
change from one brand to the
other. It may not be safe to change
In case of overdose
If you take too much
Immediately telephone your
doctor or the National Poisons
Centre (telephone 0800 POISON
or 0800 764 766) or go to accident
and emergency at your nearest
hospital, if you think that you or
anyone else may have taken too
much COUMADIN. Do this even if
there are no signs of discomfort
or poisoning. You may need
urgent medical attention.
Symptoms of an overdose may
include noticeable or abnormal
bleeding such as blood in bowel
motions or urine, heavy menstrual
bleeding, unusual bruising,
continual oozing of blood from
Tell your doctor or pharmacist as
soon as possible if you do not
feel well while you are taking
COUMADIN, even if you do not
think the problem is connected
with COUMADIN or if it is not
listed in this leaflet.
This medicine helps most people,
but it may have unwanted side
effects in a few people.
Early notification to your doctor
about such effects can help prevent
more serious complications by
allowing for prompt adjustments in
your COUMADIN therapy.
Tell your doctor or pharmacist if
you notice any of the following
and they worry you, particularly if
they remain or get worse over
Nausea, vomiting and/or
Prolonged, and sometimes
painful erection (priapism)
The above list includes some side
effects of your medicine.
Tell your doctor as soon as
possible if you notice any of the
Unexplained bruising or
pinpoint red spots on your
Pink, red or dark brown
urine (this may be due to
bleeding in the bladder or
Red or black tarry bowel
Unexplained nose bleeds or
Vomiting or coughing up
blood or particles that look
like coffee grounds (signs of
bleeding in the stomach or
Prolonged bleeding or
oozing blood from cuts and
Unusually heavy periods or
bleeding from the vagina
Blurred vision, slurred
speech, loss of movement,
vomiting, fits, loss of
consciousness as these
could be the sign of a bleed
in the brain
Yellowing of skin or whites
Painful blue/purple or
Painful swelling or
Painful skin rash
Severe skin wounds
A serious fall or injury.
The above list includes side effects
that which may indicate your clotting
levels are too low and that your
dose needs to be changed. These
side effects may require medical
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If any of the following happen,
tell your doctor immediately or
go to Accident and Emergency at
your nearest hospital:
Signs of an allergic reaction
which include shortness of
breath; wheezing or
difficulty breathing; swelling
of the face, lips, tongue or
other parts of the body;
rash, itching or hives on the
The above list includes very serious
side effects. You may need urgent
medical attention or hospitalisation.
These side effects are very rare
All medicines can have side
effects. Sometimes they are
serious, most of the time they are
not. You may need medical
treatment if you get some of the
Ask your doctor or pharmacist to
answer any questions you may
Tell your doctor or pharmacist if
you notice anything that is
making you feel unwell.
Other side effects not listed above
may also occur in some people. Tell
your doctor if you notice any other
Do not be alarmed by this list of
possible side effects. You may
not experience any of them.
Keep your tablets in the bottle
until it is time to take them
If you take the tablets out of the
bottle they may not keep well.
Keep your tablets in a cool dry
place where the temperature
stays below 30°C.
Do not store COUMADIN or any
other medicine in the bathroom or
near a sink. Do not leave it on a
window sill or in the car.
Heat and dampness can destroy
Keep it where children cannot
A locked cupboard at least one-and-
a half metres above the ground is a
good place to store medicines.
If your doctor tells you to stop
taking this medicine or the expiry
date has passed, ask your
pharmacist what to do with any
medicine that is left over.
What it looks like
COUMADIN tablets are available in
3 different strengths:
Each strength has a different colour
so it is easy to tell them apart. Be
sure you are taking the right tablet
by checking the colour and strength.
COUMADIN 1mg is a round light
tan tablet with a score or break line
on one side with COUMADIN above
the break line and a ‘1’ below the
COUMADIN 2mg is a round
lavender tablet with a score or
break line on one side with
COUMADIN above the break line
and a ‘2’ below the break line.
COUMADIN 5mg is a round green
tablet with a score or break line on
one side with COUMADIN above
the break line and a ‘5’ below the
Each bottle of COUMADIN tablets
contains 50 tablets.
COUMADIN tablets contain either
1mg, 2 mg or 5mg warfarin as the
Amaranth ((123) in
COUMARIN 1mg and 2 mg
Indigo carmine (132) in
COUMARIN 2 mg only
Brilliant blue FCF (133) in
Coumarin 5 mg only
Quinoline yellow (104) in
COUMARIN 1 mg and 5mg
This medicine does not contain
sucrose, gluten or tartrazine.
If you want to know
Should you have any questions
regarding this product, please
contact your pharmacist or doctor.
Who supplies this
COUMADIN is supplied in New
Mylan New Zealand Ltd,
PO Box 11183,
Telephone: (09) 579 2792
Date of Preparation
26 September 2019.
(Based on Coumadin datasheet
dated 26 September 2019)
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NEW ZEALAND DATA SHEET
1. Product Name
COUMADIN 1 mg, 2 mg and 5 mg tablets
COUMADIN is not to be marketed as substitutable for any other warfarin product as if the two
products were bioequivalent
2. Qualitative and Quantitative Composition
Each COUMADIN tablet contains 1 mg, 2 mg or 5 mg of warfarin.
Excipients with known effect: lactose.
For the full list of excipients, see Section 6.1.
3. Pharmaceutical Form
Tablets, 1 mg - A beige/tan coloured, shallow, biconvex tablet. One face is bisected and embossed
with a numerical "1" and the word "Coumadin". The other face is plain.
Tablets, 2 mg - A lavender coloured, shallow, biconvex tablet. One face is bisected and embossed
with a numerical "2" and the word "Coumadin". The other face is plain.
Tablets, 5 mg - A green coloured, shallow, biconvex tablet. One face is bisected and embossed with
a numerical "5" and the word "Coumadin". The other face is plain.
All the tablets can be divided into equal doses.
4. Clinical Particulars
COUMADIN is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension,
pulmonary embolism, thromboembolism associated with atrial fibrillation, and as an adjunct in the
prophylaxis of systemic embolism after myocardial infarction.
Dose and method of administration
The administration and dosage of COUMADIN must be individualised for each patient according to
the particular patient's sensitivity to the drug. The dosage should be adjusted based upon the results
of the one stage prothrombin time (PT). Different thromboplastin reagents vary substantially in their
responsiveness to sodium warfarin-induced effects on prothrombin time. To define the appropriate
therapeutic regimen, it is important to be familiar with the sensitivity of the thromboplastin reagent
used in the laboratory and its relationship to the International Reference Preparation (IRP)*, a
sensitive thromboplastin reagent prepared from human brain
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* A system of standardizing the prothrombin time in oral anticoagulant control was introduced by the
World Health Organisation in 1983. It is based upon the determination of an International Normalised
Ratio (INR) which provides a common basis for communication of PT results and interpretations of
therapeutic ranges. The INR is derived from calibrations of commercial thromboplastin reagents
against a sensitive human brain thromboplastin, the International Reference Preparation (IRP). For
the three commercial rabbit brain thromboplastins currently used in North America, a PT ratio of 1.3
to 2.0 is equivalent to an INR of 2.0 to 4.0. For other preparations the INR can be calculated as:
INR = (observed PT ratio)
Where the ISI (International Sensitivity Index) is the calibration factor and is available from the
manufacturers of the thromboplastin reagent.
The dosing of COUMADIN must be individualised according to patient's sensitivity to the drug as
indicated by the INR and/or PT ratio. Use of a large loading dose may increase the incidence of
haemorrhage and other complications, does not offer more rapid protection against thrombi
formation, and is not recommended. Low initiation doses are recommended for elderly and/or
debilitated patients and patients with increased sensitivity to COUMADIN (see Section 4.4). It is
recommended that COUMADIN therapy be initiated with a dose of 2 to 5 mg per day with dosage
adjustments based on the results of INR and/or PT ratio determinations.
Most patients are satisfactorily maintained at a dose of 2 to 10 mg daily. Flexibility of dosage is
provided by breaking scored tables in half. The individual dose and interval should be gauged by the
patient's prothrombin response.
Duration of therapy
The duration of therapy in each patient should be individualised. In general, anticoagulant therapy
should be continued until the danger of thrombosis and embolism has passed.
The prothrombin time (PT) reflects the depression of vitamin K dependent Factors VII, IX, X and II.
There are several modifications of the one-stage PT and the physician should become familiar with
the specific method used in his laboratory. The degree of anticoagulation indicated by any range of
prothrombin times may be altered by the type of thromboplastin used; the appropriate therapeutic
range must be based on the experience of each laboratory. The PT should be determined daily after
the administration of the initial dose until PT results stabilise in the therapeutic range. Intervals
between subsequent PT determinations should be based upon the physician's judgment of the
patient's reliability and response to COUMADIN in order to maintain the individual within the
therapeutic range. Acceptable intervals for PT determinations are normally within the range of one
to four weeks after a stable dosage has been determined. To ensure adequate control, it is
recommended that additional prothrombin time tests are done when other warfarin products are
interchanged with COUMADIN and also if other medications are co-administered with COUMADIN
(see Section 4.4).
Treatment during dentistry and surgery
The management of patients who undergo dental and surgical procedures requires close liaison
between attending physicians, surgeons and dentists. In patients who must be anticoagulated prior
or immediately following dental or surgical procedures,
COUMADIN to maintain the PT at the low end of the therapeutic range, may safely allow for
continued anticoagulation. The operative site should be sufficiently limited and accessible to permit
the effective use of local procedures for haemostasis. Under these conditions, dental and surgical
procedures may be performed without undue risk of haemorrhage.
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Conversion from heparin therapy
Since the onset of the COUMADIN effect is delayed, heparin is preferred initially for rapid
anticoagulation. Conversion to COUMADIN may begin concomitantly with heparin therapy or may
be delayed 3 to 6 days. As heparin may affect the PT, patients receiving both heparin and
COUMADIN should have blood for PT determination, drawn at least:
5 hours after the last IV bolus dose of heparin, or
4 hours after cessation of a continuous IV infusion of heparin, or
24 hours after the last subcutaneous heparin injection.
When COUMADIN has produced the desired therapeutic range or prothrombin activity, heparin may
Anticoagulation is contraindicated in any localized or general physical condition or personal
circumstance in which the hazard of haemorrhage might be greater than the potential clinical benefits
of anticoagulation, such as:
Known hypersensitivity to warfarin or to any of the excipients listed in Section 6.1
Haemorrhagic stroke and/or bleeding tendencies associated with active ulceration or overt
gastrointestinal, genitourinary or respiratory tract;
aneurysms- cerebral, dissecting aorta;
pericarditis and pericardial effusions;
Clinically significant bleeding
Within 72 hours of major surgery with risk of severe bleeding (for information on other surgery
see Section 4.4).
Within 48 hours postpartum
Pregnancy (first and third trimesters see Section 4.4).
Drugs where interactions may lead to a significantly increased risk of bleeding (see Section
Threatened abortion, eclampsia and preeclampsia
Inadequate laboratory facilities or unsupervised senility, alcoholism, psychosis, or lack of
Miscellaneous: major regional, lumbar block anaesthesia and malignant hypertension.
Special warnings and precautions for use
It cannot be emphasised too strongly that treatment of each patient is a highly individualized matter.
Dosage should be controlled by periodic determinations of prothrombin time or other suitable
coagulation tests. Determinations of whole blood clotting and bleeding times are not effective
measures for control of therapy.
Most adverse events reported with warfarin are a result of over anticoagulation therefore it is
important that the need for therapy is reviewed on a regular basis and therapy discontinued when
no longer required.
Safety and effectiveness in children below the age of 18 have not been established.
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When warfarin is started using a standard dosing regimen the INR should be determined daily or on
alternate days in the early days of treatment. Once the INR has established in the target range the
INR can be determined at longer intervals.
INR should be monitored more frequently in patients at an increased risk of over coagulation e.g.
patients with severe hypertension, liver or renal disease. Patients for whom adherence may be
difficult should be monitored more frequently.
Patients with protein C deficiency are at risk of developing skin necrosis when starting warfarin
treatment. In patients with protein C deficiency, therapy should be introduced without a loading dose
of warfarin even if heparin is given. Patients with protein S deficiency may also be at risk and it is
advisable to introduce warfarin therapy slowly in these circumstances.
Risk of haemorrhage
The most frequently reported adverse effect of all oral anticoagulants is haemorrhage. Warfarin
should be given with caution to patients where there is a risk of serious haemorrhage (e.g.
concomitant NSAID use, recent ischaemic stroke, bacterial endocarditis, previous gastrointestinal
bleeding, severe or moderate hepatic or renal insufficiency).
Risk factors for bleeding include high intensity of anticoagulation (INR > 4.0) age ≥ 65, high variable
INRs, history of gastrointestinal bleeding, uncontrolled hypertension, cerebrovascular disease,
serious heart disease, risk of failing, anaemia, malignancy, trauma, renal insufficiency, indwelling
catheters, concomitant drugs (see Section 4.5). All patients treated with warfarin should have INR
monitored regularly. Those at high risk of bleeding may benefit from more frequent INR monitoring,
careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be
instructed on measures to minimise risk of bleeding and to report immediately to physicians, signs
and symptoms of bleeding.
Checking the INR and reducing or omitting doses depending on INR level is essential following
consultation with anticoagulation services if necessary. If the INR is found to be too high, reduce
dose or stop warfarin treatment; sometimes it will be necessary to reverse anticoagulation. INR
should be checked within 2-3 days to ensure that it is failing.
Any concomitant anti-platelet drugs should be used with caution due to an increased risk of bleeding.
Unexpected bleeding at therapeutic levels should always be investigated and INR monitored.
Anticoagulation following an ischaemic stroke increases the risk of secondary haemorrhage into the
infracted brain. In patients with atrial fibrillation long term treatment with warfarin is beneficial, but
the risk of early recurrent embolism is low and therefore a break in treatment should be re-started 2-
14 days following ischaemic stroke, depending on the size of the infarct and blood pressure. In
patients with large embolic strokes, or uncontrolled hypertension, warfarin treatment should be
stopped for 14 days.
For surgery where there is no risk of severe bleeding, surgery can be performed with an INR of < 2.5.
For surgery where there is a risk of severe bleeding, warfarin should be stopped 3 days prior to
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Where it is necessary to continue anticoagulation e.g. risk of life- threatening thromboembolism, the
INR should be reduced to < 2.5 and heparin therapy should be started.
If surgery is required and warfarin cannot be stopped 3 days beforehand, anticoagulation should be
reversed with low-dose vitamin K.
The timing for re-instating warfarin therapy depends on the risk of post-operative haemorrhage. In
most instances warfarin treatment can be re-started as soon as the patient has an oral intake.
Warfarin need not be stopped before routine dental surgery, e.g. tooth extraction.
Many drugs and foods interact with warfarin and affect the prothrombin time (see Section 4.5). Any
change to medication, including self-medication with OTC products, warrants increased monitoring
of the INR. Patients should be instructed to inform their doctor before they start to take any additional
medications including over the counter medicines, herbal remedies or vitamin preparations.
Calciphylaxis is a rare syndrome of vascular calcification with cutaneous necrosis, associated with
high mortality. The condition is mainly observed in patients with end-stage renal disease on dialysis
but also in patients with known risk factors such as protein C or S deficiency, hyperphosphataemia,
hypercalcaemia or hypoalbuminaemia. Rare cases of calciphylaxis have been reported in patients
receiving warfarin, also in the absence of renal disease. In case calciphylaxis is diagnosed,
appropriate treatment should be started, and consideration should be given to stopping treatment
The rate of warfarin metabolism depends on thyroid status. Therefore, patients with hyper- or hypo-
thyroidism should be closely monitored on starting warfarin therapy.
Necrosis appears to be associated with local thrombosis and usually appears within a few days of
the start of anticoagulant therapy. In severe cases of necrosis treatment through debridement or
amputation of the affected tissue, breast or penis has been reported. Careful diagnosis is required
to determine whether necrosis is caused by an underline disease. Warfarin therapy should be
discontinued when warfarin suspected to be the cause of developing necrosis and heparin therapy
may be considered for anticoagulation. Although various treatments have been attempted, no
treatment for necrosis has been considered uniformly effective. See below for information on
predisposing conditions. These and other risks associated with anticoagulant therapy must be
weighed against the risk of thrombosis or embolization in untreated cases.
Purple toes syndrome
Anticoagulation therapy with COUMADIN may enhance the release of atheromatous plaque emboli,
therapy increasing the risk of complications from systemic cholesterol microembolization, including
the “purple toes syndrome”.
Discontinuation of COUMADIN therapy is recommended when such phenomena are observed.
Systemic artheroemboli and cholesterol microemboli can present with a variety of signs and
symptoms including purple toes syndrome, livedo reticularis, rash, gangrene, abrupt and intense
pain in the leg, foot or toes, foot ulcers, myalgia, penile gangrene, abdominal pain, flank or back
pain, haematuria, renal insufficiency, hypertension, cerebral ischemia, spinal cord infarction,
Page 6 of 16
pancreatitis, symptoms simulating polyarteritis or any other sequelae of vascular compromise due
to embolic occlusion. The most commonly involved visceral organs are the kidneys followed by the
pancreas, spleen and liver. Some cases have progressed to necrosis or death.
Purple toes syndrome is a complication of oral anticoagulation characterized by a dark, purplish or
mottled colour of the toes, usually occurring between 3-10 weeks, or later, after the initiation of
therapy with warfarin or related compounds. Major features of this syndrome include purple colour
of plantar surfaces and sides of the toes that blanches on moderate pressure and fades with
elevation of the legs; pain and tenderness of the toes; waxing and waning of the colour over time.
While the purple toes syndrome is reported to be reversible, some cases progress to gangrene or
necrosis which may require debridement of the affected area or may lead to amputation.
Additional circumstances where changes in dose may be required
The following also may exaggerate the effect of warfarin tablets and necessitate a reduction of
Loss of weight
Cessation of smoking
The following may reduce the effect of warfarin tablets, and require the dosage to be increased:
Acquired or inherited warfarin resistance should be suspected if larger than usual daily doses of
warfarin are required to achieve the desired anticoagulant effect.
Genetic variability particularly in relation to CYP2C9 and VKORC1 can significantly affect dose
requirements for warfarin. If a family association with these polymorphisms is known extra care is
Heparin prolongs the one-stage prothrombin time. When heparin and COUMADIN are administered
concomitantly, refer to Section 4.2; Conversion from heparin therapy for recommendations.
Known or suspected deficiency in protein C:
This hereditary or acquired condition, which should be suspected if there is a history of recurrent
episodes of thromboembolic disorders in the patient or in the family, has been associated with an
increased risk of developing necrosis following warfarin administration. Tissue necrosis may occur
in the absence of protein C deficiency. It has been reported that concurrent anticoagulation therapy
with heparin for 5 to 7 days during initiation of therapy with COUMADIN may minimise the incidence
of this reaction. Warfarin therapy should be discontinued when warfarin is suspected to be the cause
of developing necrosis and heparin therapy may be considered for anticoagulation.
Periodic determination of prothrombin time or other suitable coagulation test is
Numerous factors, alone or in combination, including travel, changes in diet, environment, physical
state and medication may influence response of the patient to anticoagulants. It is generally good
Page 7 of 16
practice to monitor the patient's response with additional prothrombin time determinations in the
period immediately after discharge from the hospital, and whenever other medications are initiated,
discontinued or taken haphazardly. The following factors are listed for your reference, however, other
factors may also affect the anticoagulant response.
The following factors, alone or in combination, may be responsible for INCREASED PT
Congestive heart failure
Poor nutritional state
Vitamin K deficiency
Influenza virus vaccine
Monoamine oxidase inhibitors
Sulfonamides - long acting
Page 8 of 16
other medications affecting blood elements which may modify haemostasis
prolonged hot weather
unreliable prothrombin time determinations
* Increased and decreased prothrombin time responses have been reported.
The following factors, alone or in combination, may be responsible for DECREASED
hereditary coumarin/warfarin resistance
diets high in vitamin K (e.g. large amounts of green leafy vegetables, dairy products fortified
with vitamin K)
unreliable PT determinations
* Increased and decreased prothrombin time responses have been reported.
Because a patient may be exposed to a combination of the above factors, the net effect of
COUMADIN on PT response may be unpredictable. More frequent PT monitoring is therefore
advisable. Medications of unknown interaction with warfarin are best regarded with caution. When
these medications are started or stopped, more frequent PT monitoring is advisable.
Warfarin may also affect the action of other drugs. Hypoglycaemic agents (chlorpropamide and
tolbutamide) and anticonvulsants (phenytoin and phenobarbital) may accumulate in the body as a
result of interference with either their metabolism or excretion.
It has been reported that concomitant administration of warfarin and ticlopidine may be associated
with cholestatic hepatitis.
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Special risk patients:
Caution should be observed when warfarin sodium is administered to certain patients such as the
elderly or debilitated or when administered in any situation or physical condition where added risk of
haemorrhage is present.
Intramuscular (IM) injections of concomitant medications should be confined to the upper extremities,
which permits easy access for manual compression, inspections for bleeding and use of pressure
Caution should be observed when COUMADIN (or warfarin) is administered concomitantly with
anticoagulation dosage is required. In addition to specific drug interactions that might affect PT,
NSAID's, including aspirin, can inhibit platelet aggregation, and can cause gastrointestinal bleeding,
peptic ulceration and/or perforation.
Interaction with other medicines and other forms of interaction
Warfarin has a narrow therapeutic range and care is required with all concomitant therapy. The
individual product information for any new concomitant therapy should be considered for specific
guidance on warfarin dose adjustment and therapeutic monitoring. If no information is provided the
possibility of an interaction should be considered. Increased monitoring should be considered when
commencing any new therapy if there is any doubt as to the extent of interaction.
Drugs which are contraindicated
Concomitant use of drugs used in the treatment or prophylaxis of thrombosis or other drugs with
adverse effects on haemostasis may increase the pharmacological effect of warfarin, increasing the
risk of bleeding.
Fibrinolytic drugs such as streptokinase and alteplase are contraindicated in patients receiving
Drugs which should be avoided if possible
The following examples should be avoided or administered with caution with increased clinical and
Glycoprotein IIb/IIIa receptor antagonists such as eptifibatide, tirofiban and abciximab
NSAIDs (including aspirin and cox-2 specific NSAIDs)
SSRI and SNRI antidepressants
Thrombin inhibitors such as bivalirudin, dabigatran
Unfractionated heparins and heparin derivatives, low molecular weight heparins
Other drugs which inhibit haemostasis, clotting or platelet action
Low-dose aspirin with warfarin may have a role in some patients but the risk of gastrointestinal
bleeding in increased. Warfarin may initially be given with a heparin in the initial treatment of
thrombosis, until the INR is in the correct range.
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Warfarin is a mixture of enantiomers which are metabolised by different CYPP450 cytochromes.
R-warfarin is metabolised primarily by CYP1A2 and CYP3A4. S-warfarin is metabolised primarily by
CYP2C9. The efficacy of warfarin is affected primarily when the metabolism of S-warfarin is altered.
Drugs that compete as substrates for these cytochromes or inhibit their activity may increase warfarin
plasma concentration and INR, potentially increasing the risk of bleeding. When these drugs are co-
administered, warfarin dosage may need to be reduced and the level of monitoring increased.
concentrations and INR, potentially leading to reduced efficacy. When these drugs are co-
administered, warfarin dosage may need to be increased and the level of monitoring increased.
There is a small subset of drugs for which interactions are known; however, their clinical effect on
the INR is variable. In these cases, increased monitoring or starting and stopping therapy is advised.
Care should also be taken when stopping or reducing the dose of a metabolic inhibitor or inducer,
once patients are stable on this combination (offset effect).
Listed below are drugs which are known to interact with warfarin in a clinically significant way.
Examples of drugs which potentiate the effect of warfarin
Azole antifungals (ketoconazole,
Paracetamol (prolonged regular use
Statins (not pravastatin; predominantly
associated with Fluvastatin),
Examples of drugs which antagonise the effect of warfarin
Examples of drugs with variable effect
Other drug interactions
Broad spectrum antibiotics may potentiate the effect of warfarin by reducing the gut flora which
produces vitamin K. Similarly, orlistat may reduce absorption of vitamin K, cholestyramine and
sucralfate potentially decrease absorption of warfarin.
Increased INR has been reported in patients taking glucosamine and warfarin. This combination is
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Interactions with herbal products
Herbal preparations containing St John’s Wort (Hypericum perforatum) must not be used whilst
taking warfarin due to a proven risk of decreased plasma concentrations and reduced clinical effects
Many other herbal products have a theoretical effect on warfarin; however most of these interactions
are not proven. Patients should generally avoid taking any herbal medicines or food supplements
whilst taking warfarin and should be told to advise their doctor if they are taking any, as more frequent
Acute ingestion of a large amount of alcohol may inhibit the metabolism of warfarin and increase
INR. Conversely, chronic heavy alcohol intake may induce the metabolism of warfarin. Moderate
alcohol intake can be permitted.
Interactions with food and food supplements
Individual case reports suggest a possible interaction between warfarin and cranberry juice in most
cases leading to an increase in INR or bleeding event. Patients should be advised to avoid cranberry
products. Increased supervision and INR monitoring should be considered for any patient taking
warfarin and regular cranberry juice.
Limited evidence suggests that grapefruit juice may cause a modest rise in INR in some patients
taking warfarin. Certain foods such as liver, broccoli, brussels sprouts and green leafy vegetables
contain large amounts of vitamin K. Sudden changes in diet can potentially affect control of
anticoagulation. Patients should be informed of the need to seek medical advice before undertaking
any major changes in diet.
Many other food supplements have a theoretical effect on warfarin; however most of these
interactions are not proven. Patients should be told to advise their doctor if they are taking any, as
more frequent monitoring is advisable.
Heparins and danaparoid may prolong the prothrombin time, therefore a sufficient time interval
should be allowed after administration before performing the test.
Information for patients:
The objective of anticoagulant therapy is to control the coagulation mechanism so that thrombosis
is prevented, while avoiding spontaneous bleeding. Effective therapeutic levels with minimal
complications are in part dependent upon cooperative and well-instructed patients who communicate
effectively with their physician. Various COUMADIN patient educational guides are available to
physicians on request. Patients should be advised: Strict adherence to prescribed dosage schedule
is necessary. Do not take or discontinue any other medication, except on advice of physician.
Avoid alcohol, salicylates (e.g. aspirin and topical analgesics), large amounts of green leafy
vegetables, dairy products fortified with vitamin K and/or drastic changes in dietary habits, because
they may affect COUMADIN therapy. COUMADIN may cause a red-orange discolouration of alkaline
urine. The patient should notify the physician if any illness, such as diarrhoea, infection or fever
develops or if any unusual symptoms, such as pain, swelling or discomfort appear or if prolonged
bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds or bleeding of gums
from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools or
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Fertility, pregnancy and lactation
COUMADIN is contraindicated in women who are or may become pregnant because the drug passes
through the placental barrier and may cause fatal haemorrhage to the foetus in utero.
Furthermore, there have been reports of birth malformations in children born to mothers who have
been treated with warfarin during pregnancy. Embryopathy characterized by nasal hypoplasia with
or without stippled epiphyses (chondrodysplasia punctata) has been reported in pregnant women
exposed to warfarin during the first trimester. Central nervous system abnormalities also have been
reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum,
Dandy-Walker malformation and midline cerebellar atrophy.
Warfarin is contraindicated in pregnancy in the first and third trimester. Women of child-bearing age
who are taking warfarin tablets should use effective contraception during treatment.
Ventral midline dysplasia characterized by optic atrophy and eye abnormalities has been observed.
Mental retardation, blindness and other central nervous system abnormalities have been reported in
association with second and third trimester exposure. Although rare, teratogenic reports following in
utero exposure to warfarin include urinary tract anomalies such as single kidney, asplenia,
anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart
disease, polydactyly, deformities of toes, diaphragmatic hernia and corneal leukoma.
Spontaneous abortion and still birth are known to occur, and a higher risk of foetal mortality is
associated with the use of warfarin.
Women of childbearing potential who are candidates for anticoagulant therapy should be carefully
evaluated and the indications critically reviewed with the patient. If the patient becomes pregnant
while taking this drug she should be apprised of the potential risks to the foetus and the possibility
of termination of the pregnancy should be discussed in light of those risks.
Warfarin is excreted in breast milk in small amounts. However, at therapeutic dose of warfarin no
effects on the breast-feeding child are anticipated. Warfarin can be used during breast-feeding.
Potential adverse reactions to COUMADIN may include:
MedDRA system organ class
Infections and Infestation
Immune system disorders
Nervous system disorders
Respiratory, thoracic and mediastinal disorders
diarrhoea; nausea; vomiting; melaena
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Jaundice; hepatic dysfunction; rash; alopecia;
purple; purple toes syndrome; erythematous
swollen skin patches leading to ecchymosis
infarction and skin
Skin and subcutaneous disorders
Frequency ‘not known’: Calciphylaxis
Renal and urinary disorders
Unexplained drop in haematocrit; haemoglobin
Haemorrhage from any tissue or organ. This is a consequence of the anticoagulant effect.
The signs and symptoms will vary according to the location and degree or extent of the
unexplained swelling; or unexplained shock.
Therefore, the possibility of haemorrhage should be considered in evaluating the condition
of any anticoagulated patient with complaints which do not indicate an obvious diagnosis.
Bleeding during anticoagulant therapy does not always correlate with prothrombin activity.
(see Section 4.9)
Bleeding which occurs when the prothrombin time is within the therapeutic range warrants
diagnostic investigation since it may unmask a previously unsuspected lesion e.g. tumour,
Necrosis of skin and other tissues (see Section 4.4).
Other adverse reactions are infrequent and consist of alopecia, urticaria, dermatitis, fever,
nausea, diarrhoea, abdominal cramping, systemic cholesterol microembolisation, purple toes
syndrome, cholestatic hepatic injury, and hypersensitivity reactions.
relationship has not been established.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows
continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked
to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.
Signs and Symptoms
Suspected or overt abnormal bleeding (i.e. appearance of blood in stools or urine, haematuria,
excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from
superficial injuries) are early manifestations of anticoagulation beyond a safe and satisfactory level.
The benefit of gastric decontamination is uncertain. If the patient presents within 1 hour of ingestion
of more than 0.25 mg/kg or more than the patient’s therapeutic dose, consider activated charcoal
(50 g for adults; 1 g/kg for children)
In cases of life-threatening haemorrhage:
30-50 units/kg or (if no concentrate available) fresh frozen plasma 15 mL/kg. Discuss with local
haematologist or Poisons Information Service or both.
Non life-threatening haemorrhage
Where anticoagulation can be suspended give slow intravenous injection of phytomenadione
(vitamin K1) 10-20 mg for adults (250 micrograms/kg for a child)
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Where rapid re-anticoagulation is desirable (e.g. value replacements) give prothrombin complex
concentrate (factors II, VII, IX and X) 30-50 units/kg or (if no concentrate available) fresh frozen
plasma 15 mL/kg.
Monitor INR to determine when to restart normal therapy. Monitor INR for at least 48 hours post
For patients on long-term warfarin therapy without major haemorrhage
INR > 8.0, no bleeding or minor bleeding – stop warfarin, and give phytomenadione (vitamin
K1) 0.5 -1 mg for adult; 15-30 micrograms/kg for children by slow intravenous injection or 5
phytomenadione e.g. 0.5 - 2.5 mg using the intravenous preparation orally); repeat dose of
phytomenadione if INR still too high after 24 hours. Large doses of phytomenadione may
completely reverse the effects of warfarin and make re- establishment of anticoagulation
INR 6.0 – 8.0, no bleeding or minor bleeding – stop warfarin, restart when INR < 5.0.
INR < 6.0 but more than 0.5 units above target value reduce dose or stop warfarin, restart
when INR < 5.0
For patients, NOT on long-term anticoagulants without major haemorrhage:
Measure the INR (prothrombin time) at presentation and sequentially every 24 – 48 hours after
ingestion depending on the initial dose and initial INR.
If the INR remains normal for 24 – 48 hours and there is no evidence of bleeding, there should
be no further monitoring necessary.
Give vitamin K1 (phytomenadione) if;
There is no active bleeding and the patient has ingested more than 0.25 mg/kg;
the prothrombin time is already significantly prolonged (INR > 4.0)
The adult dose of vitamin K1 is 10 – 20 mg orally (250 micrograms/kg body weight for a child). Delay
oral vitamin K1 at least 4 hours after any activated charcoal has been given.
Repeat INR at 24 hours after and consider further vitamin K1.
For further advice on management of overdose please contact the National Poisons Information
Centre (0800 POISON or 0800 764 766).
5. Pharmacological Properties
Pharmacotherapeutic group: Antithrombotic agents; ATC code: B01AA03
COUMADIN (warfarin sodium) is a vitamin K dependent factor anticoagulant. Warfarin is the coined
generic name for 3-(α- acetonyl-benzyl)-4- hydroxycoumarin.
COUMADIN and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K
dependent coagulation factors. The resultant in vivo effect is a sequential depression of Factors VII,
IX, X and II activities. The degree of depression is dependent upon the dosage administered.
Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischaemic
tissue damage. However, once a thrombosis has occurred, anticoagulant treatment aims to prevent
further extension of the formed clot and prevents secondary thromboembolic complications which
may result in serious and possible fatal sequelae.
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After oral administration, absorption is essentially complete, and maximal plasma concentrations are
reached in 1 to 9 hours. Approximately 97% is bound to albumin within the long-lasting response
curve. COUMADIN is metabolized by hepatic, microsomal enzymes to inactive metabolites that are
excreted into the bile, reabsorbed and excreted into the urine.
Coumadin is a potent drug with a half-life of 2½ days; therefore, its effects may become more
pronounced as daily maintenance doses overlap.
An anticoagulant effect generally occurs within 24 hours; however, peak anticoagulant effect may
be delayed 72 to 96 hours.
5.3 Preclinical safety data
reproductive effects of COUMADIN have not been evaluated.
6. Pharmaceutical Precautions
List of excipients
Brilliant blue FCF (5mg only)
Quinoline yellow (1 and 5 mg only)
Amaranth (1 and 2 mg only)
Indigo carmine (2 mg only).
1 mg: 36 months
2 mg: 36 months
5 mg: 36 months
Special precautions for storage
Store at or below 30°C.
Nature and contents of container
Bottle, plastic, HDPE with Clic loc II 28 mm child resistant cap – 50 tablets
7. Medicines Schedule
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8. Sponsor Details
Mylan New Zealand Ltd
PO Box 11183
9. Date of First Approval
14 September 2006
10. Date of Revision of the Text
26 September 2019
Summary table of changes
Summary of new information
To Mylan format- correction of typographical, grammatical and
other administrative errors
Reorganisation of factors affecting PT into alphabetical order.
Sponsor details to Mylan New Zealand Ltd