Document: spc-doc_PL 20416-0169 change

• spc-doc_PL 02848-0186
• spc-doc_PL 20416-0169

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NAME OF THE MEDICINAL PRODUCT

Warfarin Tablets 3 mg

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 3.0 mg of warfarin sodium For excipients, see 6.1

3.    PHARMACEUTICAL FORM

Tablets

Flat bevelled edged, blue tablets engraved with company logo on one side and with a breakline, and A324 on the other side.

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

Prophylaxis of systemic embolism in rheumatic heart disease and atrial fibrillation. Prophylaxis and treatment of venous thrombosis and pulmonary embolism. Transient cerebral ischaemic attacks. Prophylaxis of thromboembolism after insertion of prosthetic heart valve.

4.2    Posology and method of administration

Route of administration: Oral

A baseline coagulation screen and liver function tests should be performed before initiating warfarin therapy.

Adults:

The typical induction dose is 10mg daily for 2 days but this should be tailored to individual requirements. The daily maintenance dose is usually 3 to 9mg taken at the same time each day. The exact maintenance dose depends on the prothrombin time or other appropriate coagulation tests.

Control tests should be made at regular intervals and the maintenance dose should be adjusted according to the results obtained. Once the maintenance dose is established, it is rarely necessary to alter it.

In emergencies, anticoagulant therapy should be initiated with heparin and warfarin together.

Concomitant therapy with heparin affects the results of control tests, and should be discontinued at least six hours before the first test is carried out.

Elderly: As for adults, but dosage may need to be lowered as the elderly are generally

more sensitive to the effects of warfarin and often require a smaller dose. Children: Dosage for children has not been established.

4.3 Contra-indications

Known hypersensitivity to warfarin or to any of the excipients.

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).

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

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 anitcoagulation 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.

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 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.

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.

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.

4.5 Interaction with other medicinal products and other forms of interactions

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 the 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 contrainidicated 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. 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 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 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 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:

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.

Colestyramine 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 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 Use during 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 should use effective contraception during treatment. Lactation

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

None Known

4.8 Undesirable effects

MedDRA system organ class	Adverse reaction
Infections and infestations	Fever
Immune system disorders	Hypersensitivity
Nervous system disorders	Cerebral haemorrhage; cerebral subdural haematoma
Vascular disorders	Haemorrhage
Respiratory, thoracic and mediastinal disorders	Haemothorax, epistaxis
Gastrointestinal disorders	Gastroinestinal haemorrhage; rectal haemorrhage; haematemesis; pancreatitis; diarrhoea; nausea; vomiting; melaena
Hepatobiliary disorders	Jaundice; hepatic dysfunction
Skin and subcutaneous tissue disorders	Rash; alopecia; purpura; ‘purple toes’ syndrome; erythematous swollen skin patches leading to ecchymosis, infarction and skin necrosis Frequency ‘not known’: Calciphylaxis
Renal and urinary disorders	Haematuria
Investigations	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 (1530 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 of warfarin and make re-establishment 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

Pharmacotherapeutic group: B01A A03

5.1. Pharmacodynamic properties

Warfarin is a synthetic 4-hydroxycoumarin derivative which acts by preventing the formation of active procoagulation factors II, VII, IX and X in the liver by inhibiting the vitamin K-mediated gamma-carboxylation of precursor proteins. Full therapeutic activity is not achieved until circulating coagulation factors have been removed by normal catabolism. This occurs at different rates for each factor, with factor VII having the shortest half-life. Warfarin has no direct thrombolytic effect, though it may limit the extension of existing thrombi.

5.2. Pharmacokinetic properties

Warfarin is almost completely absorbed from the gastro-intestinal tract with its rate, but not extent of absorption decreased by food. Peak plasma concentrations are reached within 2 -8 hours. Peak therapeutic effect, which must await catabolism of circulating coagulation factors, is not achieved for 24 - 36 hours.

Warfarin is highly protein bound (97%) to albumin. Its mean half-life is about 44 hours, but there is a 12 fold variation in half-life between individuals.

Warfarin undergoes oxidative biotransformation in the liver producing warfarin alcohols which have some minor anticoagulant activity. Enterohepatic re-cycling occurs. Less than 1% of the drug is excreted unchanged in the urine.

5.3. Preclinical safety data

There are no other pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6.    PHARMACEUTICAL PARTICULARS

6.1.    List of Excipients

Lactose Sucrose Maize starch Magnesium stearate Pregelatinised starch

Dispersed Indigo Carmine Lake 15009 (E132)

6.2. Incompatibilities

None known.

6.3 Shelf life

Opaque plastic containers: 36 months Blister packs: 36 months Special precautions for storage

Blister packs: Do not store above 25°C. Store in the original package. Tablet containers: Do not store above 25°C. Store in the original container.

6.5 Nature and contents of container

Warfarin tablets are packed in the following:

1.    Opaque plastic containers composed of polypropylene tubes and polyethylene tamper-evident closures in pack sizes of 50, 100, 250, 500 and 1000.

2.    Opaque plastic containers with child resistant/tamper evident caps, composed of polypropylene and/or polyethylene with a packaging inclusion of standard polyether foam or polyethylene filler in pack sizes of 28 and 100.

3.    Blister packs composed of aluminium foil and white opaque PVC with PVDC coating subsequently packed in cartons of 28 (14 tablets per strip) and 100 (10 tablets per strip).

6.6. Instructions for Use, Handling and Disposal

No special instructions for use/handling.

7    MARKETING AUTHORISATION HOLDER

Crescent Pharma Limited

Units 3 & 4, Quidhampton Business Units

Polhampton Lane

Overton

Hants

RG25 3ED

United Kingdom

8.    MARKETING AUTHORISATION NUMBER

PL 20416/0169

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/11/2003

10 DATE OF REVISION OF THE TEXT

05/09/2016