New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Warfarin sodium 5 mg
Available from:
Mylan New Zealand Ltd
INN (International Name):
Warfarin sodium 5 mg
5 mg
Pharmaceutical form:
Active: Warfarin sodium 5 mg Excipient: Brilliant blue FCF Lactose Magnesium stearate Maize starch Quinoline yellow Stearic acid
Units in package:
Blister pack, 50 tablets
Prescription type:
Manufactured by:
Chemoswed AB
Therapeutic indications:
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.
Product summary:
Package - Contents - Shelf Life: Blister pack, - 50 tablets - 36 months from date of manufacture stored at or below 30°C - Bottle, glass, - 50 tablets - 36 months from date of manufacture stored at or below 30°C - Bottle, plastic, HDPE with Clic loc II 28 mm child resistant cap - 50 tablets - 36 months from date of manufacture stored at or below 30°C
Authorization number:
Authorization date:

Page 1 of 4



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



used for

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


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

doctor’s prescription.

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

of warfarin)

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

tendencies worse

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 breastfeeding

Are going to have any

dental treatment

Have recently had or are

going to undergo any

surgical procedures or


Are starting any sports

activities that may result in

traumatic injury

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

Bleeding tendencies

Page 2 of 4

Fits or convulsions

Thyroid problems

Heart problems

Psychiatric problems

Severe diabetes

Infections, diarrhoea,

vomiting or fever


Severe allergies

Warfarin resistance

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

COUMADIN include:


Any medication used to

treat arthritis (including

glucosamine and



(NSAIDS such as

naproxen, fenopron,

indomethacin, ibuprofen,


Some medications used to

treat blood clots, heart

attacks or angina



Some antibiotics

Vitamin C

Vitamin K

St John’s Wort

Other herbal preparations

(such as garlic, ginseng,

feverfew, gingko biloba and


Drinking alcohol

Cranberry and grapefruit


Eating large amounts of

green leafy vegetables

and/or drastic changes in

dietary habits.

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

for you.

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

the tables.

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

per day.

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

monitoring requirements.

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.

Page 3 of 4

If you are going to have surgery,

tell the surgeon or anaesthetist

that you are taking this medicine.

It may affect other medicines used

during surgery.

If you become pregnant while

taking this medicine, tell your

doctor immediately.

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

some tests.

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

another complaint.

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

surface injuries

Side effects

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


Hair loss

Skin rash


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

bleeding gums

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,

numbness, dizziness,

headache, nausea,

vomiting, fits, loss of

consciousness as these

could be the sign of a bleed

in the brain

Yellowing of skin or whites

of eyes

Painful blue/purple or

mottled toes

Swollen ankles

Painful swelling or


Stomach pain

Chest Pain

Joint Pain

Painful skin rash

Severe skin wounds

Persistent diarrhoea

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


Page 4 of 4

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

side effects.

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.

After taking



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

some medicines.

Keep it where children cannot

reach it.

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.

Product description

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

break line.

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

break line.

Each bottle of COUMADIN tablets

contains 50 tablets.


Active ingredient(s):

COUMADIN tablets contain either

1mg, 2 mg or 5mg warfarin as the

active ingredient.

Inactive ingredient(s):

Lactose anhydrous

Maize starch

Stearic acid

Magnesium stearate

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

Zealand by:

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)

Page 1 of 16



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


Therapeutic indications

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

Page 2 of 16

* 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.


Initial dose

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.

Maintenance dose

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.

Laboratory control

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

to, during,

or immediately following dental or surgical procedures,

adjusting the


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.

Page 3 of 16

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

be discontinued.



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

bleeding of;

gastrointestinal, genitourinary or respiratory tract;

cerebrovascular haemorrhage;

aneurysms- cerebral, dissecting aorta;

pericarditis and pericardial effusions;

bacterial endocarditis

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

patient cooperation









uncontrollable bleeding

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.

Paediatric Use:

Safety and effectiveness in children below the age of 18 have not been established.

Page 4 of 16


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.

Ischaemic stroke

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


Page 5 of 16

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.

Dental surgery

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

with warfarin.

Thyroid disorders

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

Acute illness

Cessation of smoking

The following may reduce the effect of warfarin tablets, and require the dosage to be increased:

Weight gain



Other warnings

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 information

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


Endogenous factors


Collagen disease

Congestive heart failure


Elevated temperature

Hepatic disorders


Infectious hepatitis


Poor nutritional state


Vitamin K deficiency

Exogenous factors:




Aminosalicylic acid

Amiodarone hydrochloride

Anabolic steroids

Anaesthetics, inhalation


Anti-thyroid drugs




Chloral hydrate*






COUMADIN overdosa








Ethacrynic acid



Fluoroquinolone antibiotics




Hepatotoxic drugs



Influenza virus vaccine


Mefenamic acid





Monoamine oxidase inhibitors

Moricizine hydrochloride*

Nalidixic acid


Narcotics, prolonged















Sulfonamides - long acting



Thyroid compounds

Thryoid drugs





Page 8 of 16


other medications affecting blood elements which may modify haemostasis

dietary deficiencies

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

PT response:

Endogenous factors:


hereditary coumarin/warfarin resistance



Exogenous factors:

Adrenocortical steroids







Chloral hydrate*



COUMADIN underdosage







Moricizine hydrochloride*


Oral contraceptives







Vitamin C


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.

Page 9 of 16

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.

Pharmacodynamic interactions

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

laboratory monitoring:



Fondaparinux rivaroxaban

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.

Page 10 of 16

Metabolic interactions

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,

fluconazole etc.)









Paracetamol (prolonged regular use


Statins (not pravastatin; predominantly

associated with Fluvastatin),




Examples of drugs which antagonise the effect of warfarin





Oral contraceptives




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

not recommended.

Page 11 of 16

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

of warfarin.

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

monitoring advisable.


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.

Laboratory tests

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

diarrhoea occurs.

Page 12 of 16


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.


Undesirable effects

Potential adverse reactions to COUMADIN may include:

MedDRA system organ class

Adverse Reaction

Infections and Infestation


Immune system disorders


Nervous system disorders






Vascular disorders


Respiratory, thoracic and mediastinal disorders

Haemothorax, epistaxis

Gastrointestinal disorders







diarrhoea; nausea; vomiting; melaena

Page 13 of 16

Hepatobiliary disorders

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,

ulcer, etc.

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



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)

Page 14 of 16

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


Pharmacodynamic 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.

Page 15 of 16


Pharmacokinetic properties

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

Maize starch


Stearic acid

Magnesium stearate

Brilliant blue FCF (5mg only)

Quinoline yellow (1 and 5 mg only)

Amaranth (1 and 2 mg only)

Indigo carmine (2 mg only).


Shelf life

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

Prescription Medicine

Page 16 of 16

8. Sponsor Details

Mylan New Zealand Ltd

PO Box 11183



Telephone 09-579-2792

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

All sections

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

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