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WARFARIN TABLETS 3MG

Active substance(s): WARFARIN SODIUM / WARFARIN SODIUM / WARFARIN SODIUM

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SUMMARY OF PRODUCT CHARACTERISTICS
1.

NAME OF THE MEDICINAL PRODUCT
Warfarin 3mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 3 mg warfarin sodium (as clathrate).
Excipients with known effect:
Each tablet contains 124.850 mg lactose.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Round blue uncoated tablet, scored and marked 'W3' on one side with
company logo on reverse.
The score line is only to facilitate breaking for ease of swallowing and not to
divide into equal doses.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications
For prophylaxis against venous thrombosis and pulmonary embolism, and for
use in the treatment of these conditions to prevent their extension. For the
prophylaxis of systemic embolisation in patients with rheumatic heart disease
and atrial fibrillation.

4.2

Posology and method of administration
Posology
An initial daily dose of 10mg on the first two days. Subsequent daily doses
should be adjusted according to the results of the prothrombin time or other
appropriate coagulation tests. The single daily maintenance requirement is
usually between 5mg and 12mg, but can vary between 2mg and 30mg.
The maintenance dose is omitted if the prothrombin time is excessively
prolonged.

Use in elderly patients: The elderly are generally more sensitive to the effects
of warfarin and often require a smaller dose on a weight for weight basis than
younger patients.
Target INR
By referring to the target INR (see below), the dosage of warfarin can be
adjusted depending on the deviation of the patient’s INR from the target value.
An INR within 0.5 INR units of the target is considered to be generally
satisfactory.
The following target INR values are based on guidelines from The British
Society for Haematology:
Indication
Pulmonary embolus
Proximal deep vein thrombosis
Calf vein thrombosis in non-surgical patients with
no persistent risk factors
Post-operative calf vein thrombosis without
persistent risk factors
Recurrence of venous thromboembolism when no
longer on warfarin therapy
Recurrence of venous thromboembolism whilst on
warfarin therapy
Symptomatic inherited thrombophilia
Antiphospholipid syndrome
Non-rheumatic atrial fibrillation
Atrial fibrillation due to rheumatic heart disease,
congenital heart disease, thyrotoxicosis
Cardioversion
Mural thrombus
Cardiomyopathy
Mechanical prosthetic heart valve

Target INR
2.5
2.5
2.5
2.5
2.5
3.5
2.5
3.5
2.5
2.5
2.5
2.5
2.5
3.5

Method of administration
Warfarin tablets are for oral administration.
4.3

Contraindications


Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1.

Haemorrhagic stroke (see section 4.4 for further details)

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 4.6)

Drugs where interactions may lead to a significantly increased risk of
bleeding (see section 4.5)

4.4

Special warnings and precautions for use
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.
Patients should be given a patient-held information booklet (‘warfarin card’)
and informed of symptoms for which they should seek medical attention.
Commencement of therapy
Monitoring
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 stabilised 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.
Thrombophilia
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).
Risk factors for bleeding include high intensity of anticoagulation (INR >4.0),
age ≥65, highly variable INRs, history of gastrointestinal bleeding,
uncontrolled hypertension, cerebrovascular disease, serious heart disease, risk
of falling, anaemia, malignancy, trauma, renal insufficiency, 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 falling.
Any concomitant anti-platelet drugs should be used with caution due to an
increased risk of bleeding.
Haemorrhage
Haemorrhage can indicate an overdose of warfarin has been taken. For advice
on treatment of haemorrhage see section 4.9.
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 infarcted 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 after ischaemic stroke is
justified. Warfarin 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.
Calciphylaxis
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 or 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 taking 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.
Surgery
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 surgery.

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 postoperative 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, eg, tooth
extraction.
Active peptic ulceration
Due to a high risk of bleeding, patients with active peptic ulcers should be
treated with caution. Such patients should be reviewed regularly and informed
of how to recognise bleeding and what to do in the event of bleeding
occurring.
Interactions
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.

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.
Additional circumstances where changes in dose may be required
The following also may exaggerate the effect of warfarin tablets, and
necessitate a reduction of dosage:




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
Diarrhoea
Vomiting

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 warranted.
Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this
medicine.

4.5

Interaction with other medicinal products 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 consulted 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 warfarin.
Drugs which should be avoided if possible

The following examples should be avoided, or administered with caution with
increased clinical and laboratory monitoring:


Clopidogrel



NSAIDs (including aspirin and cox-2 specific NSAIDS)



Sulfinpyrazone



Thrombin inhibitors such as bivalirudin, dabigatran



Dipyridamole



Unfractionated heparins and heparin derivatives, low molecular weight
heparins



Fondaparinux, rivaroxaban



Glycoprotein IIb/IIIa receptor antagonists such as eptifibatide, tirofiban and
abciximab



Prostacyclin



SSRI and SNRI antidepressants



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 is increased. Warfarin may initially be given with a heparin
in the initial treatment of thrombosis, until the INR is in the correct range.

Metabolic interactions
Warfarin is a mixture of enantiomers which are metabolised by different CYPP450
cytochromes. R-warfarin is metabolised primarily by CYP1A2 and CYP3A4. Swarfarin 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 concentrations 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.
Conversely, drugs which induce these metabolic pathways may decrease warfarin
plasma 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 are a small subsets of drugs for which interactions are known; however their
clinical effect on the INR is variable. In these cases increased monitoring on 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
allopurinol, capecitabine, erlotinib, disulfiram, azole antifungals
(ketoconazole, fluconazole etc)
omeprazole, paracetamol (prolonged regular use), propafenone, amiodarone,
tamoxifen, methylphenidate
zafirlukast, fibrates, statins (not pravastatin; predominantly associated with
fluvastatin)
erythromycin, sulfamethoxazole, metronidazole
Examples of drugs which antagonise the effect of warfarin
Barbiturates, primidone, carbamazepine, griseofulvin, oral contraceptives,
rifampicin, azathioprine, phenytoin
Examples of drugs with variable effect
Corticosteroids, nevirapine, ritonavir

Other drug interactions
Broad spectrum antibiotics may potentiate the effect of warfarin by reducing the gut
flora which produce 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.

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 is advisable.

Alcohol
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 generally avoid taking any food
supplements whilst taking warfarin, and 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.

4.6

Fertility, pregnancy and lactation
Pregnancy:

Based on human experience warfarin causes congenital malformations and
foetal death when administered during pregnancy.
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.
Breast-feeding:
Warfarin is excreted in breast milk in small amounts. However, at therapeutic
doses of warfarin no effects on the breast-feeding child are anticipated.
Warfarin can be used during breast-feeding.

4.7

Effects on ability to drive and use machines
Warfarin has no influence on the ability to drive and use machines.

4.8

Undesirable effects
The following adverse reactions are classified by system organ class and
ranked under heading of frequency using the following convention: very
common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to
<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known –
cannot be estimated from the available data.
MedDRA system
organ class

Frequency

Adverse Reaction

Infections and
infestations

Not known

Fever

Immune system
disorders

Not known

Hypersensitivity

Nervous system
disorders

Not known

Vascular disorders

Not known

Cerebral haemorrhage;
Cerebral subdural
haematoma
Haemorrhage

Respiratory,
thoracic and
mediastinal
disorders

Not known

Haemothorax,
epistaxis

Gastrointestinal
disorders

Not known

Hepatobiliary
disorders
Skin and
subcutaneous tissue
disorders

Not known

Renal and urinary
disorders
Investigations

Not known

Not known

Not known

Gastrointestinal
haemorrhage, rectal
haemorrhage,
haematemesis;
pancreatitis; diarrhoea;
nausea; vomiting;
melaena
Jaundice; hepatic
dysfunction
Rash; alopecia;
purpura; ‘purple toes’
syndrome;
erythematous swollen
skin patches leading to
ecchymosis, infarction
and skin necrosis;
calciphylaxis
Haematuria
Unexplained drop in
haematocrit;
haemoglobin
decreased

Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.
4.9

Overdose

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
Stop warfarin treatment, 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.
Discuss with local haematologist or National 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)

Where rapid re-anticoagulation is desirable (eg, valve 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 overdose.
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 adults, 0·015–0·030 mg/kg (15–30
micrograms/kg) for children by slow intravenous injection or 5 mg by mouth
(for partial reversal of anticoagulation give smaller oral doses of
phytomenadione eg, 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 ofwarfarin and make reestablishment of anticoagulation difficult.



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:

a)

there is no active bleeding and the patient has ingested more than 0·25
mg/kg;

OR

b)

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 and consider
further vitamin K1.

5

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties
Pharmacotherapeutic group: Antithrombotic agents, Vitamin K antagonists
ATC code: B01AA03
Mechanism of action
Warfarin is a coumarin anticoagulant which depresses the hepatic vitamin Kdependent synthesis of coagulation factors II (Prothrombin), VII, IX and X. It
acts indirectly, with no effect on existing clots.

5.2

Pharmacokinetic properties
Absorption
Warfarin Sodium is readily absorbed from the gastro-intestinal tract; it can
also be absorbed through the skin.
Distribution
It is extensively bound to plasma proteins and its plasma half-life is about 37
hours. It crosses the placenta but does not occur in significant quantities in
breast milk. Warfarin is administered as a racemic mixture.
Biotransformation
The s-isomer is reported to be more potent; the R and S isomers are both
metabolised in the liver, though at different rates; the stereo-isomers may also
be affected differently by other drugs.
Elimination
The inactive metabolites are excreted in the urine following reabsorption from
the bile.

5.3.

Preclinical Safety Data
No further relevant information other than that which is included in other
sections of the Summary of Product Characteristics.

Pharmaceutical Particulars
6.1.

List of Excipients (Qualitative)

Lactose, Maize Starch, Sodium Starch Glycollate, Magnesium Stearate, Indigo
Carmine Lake ( E132 ), Alumina.

6.2.

Incompatibilities

None known

6.3

Shelf life
Securitainers: 5 years
Blister packs: 3 years

6.4

Special precautions for storage
Store below 25°C
Store in the original package in order to protect from light and moisture.

6.5

Nature and contents of container
Polypropylene securitainers with tamper evident lid.
Pack size : 100 tablets, 500 tablets.
Blister strips of 14 tablets.
Pack size: 28 tablets, 56 tablets,
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
Mercury Pharma International Ltd
4045, Kingswood Road,
City West Business Park,
Co Dublin, Ireland

8.

MARKETING AUTHORISATION NUMBER
PL 02848/0186

9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
22 November 1995

10

DATE OF REVISION OF THE TEXT
08/09/2016

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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