ZOFARIN (Warfarin Sodium Tablets USP)

Antithrombotic agent (Vitamin K Antagonist), ATC code: B01AA03

ZOFARIN is a medication used to treat and prevent blood clots, as well as reduce the risk of stroke and heart attack. It contains the active ingredient warfarin sodium, which is a vitamin K antagonist. Warfarin works by reducing the activity of vitamin K in the body, which is needed to produce certain clotting factors in the blood. By doing so, warfarin helps to prevent the formation of blood clots.

Warfarin is a synthetic anti-coagulant of the coumarin series and acts by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II-60 hours, VII-4-6 hours, IX-24 hours, and X-48-72 hours.

The half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively.

ZOFARIN Therapeutic indications

Warfarin is indicated for the prophylaxis of systemic embolisation in patients with rheumatic heart disease and atrial fibrillation.
Warfarin is indicated for the prophylaxis after insertion of prosthetic heart valves.
Warfarin is indicated for the prophylaxis and treatment of venous thrombosis and pulmonary embolism.
Warfarin is indicated for transient cerebral ischaemic attacks.

ZOFARIN Posology and method of administration

Posology:

Adults and elderly patients: The typical induction dose of warfarin is 10 mg daily for 2 days, but this should be tailored to individual requirements. Baseline prothrombin measurements (PT) should be taken before beginning therapy with warfarin.

The daily maintenance dose of warfarin is usually 3 to 9 mg taken at the same time each day. The exact maintenance dose for an individual is dependent on the prothrombin time or other appropriate coagulation tests.

The maintenance dose is omitted if the prothrombin time is excessively prolonged.

Once the maintenance dose is stabilised in the therapeutic range, it is rarely necessary to alter it.

In emergencies, anticoagulant therapy should be initiated with heparin and warfarin together. Where there is less urgency, as in patients disposed to or at special risk of thromboembolism, anticoagulant therapy may be initiated with warfarin alone.

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

Control is established with INR monitoring at regular intervals and subsequent warfarin maintenance dosage further adjusted according to the results obtained.

Paediatric population: No data are available.

Method of administration:

Warfarin Tablets are for oral use

ZOFARIN Contraindications

Hypersensitivity to the active substance or to any of the excipients used in formulation.
Haemorrhagic stroke
Clinically significant bleeding
Within 72 hours of major surgery with risk of severe bleeding (for information on other surgery)
Within 48 hour postpartum. Pregnancy (first and third trimesters).
Drugs where interactions may lead to a significantly increased risk of bleeding.

ZOFARIN 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 stabilized 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. 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 minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding.

Haemorrhage: Haemorrhage can indicate an overdose of warfarin has been taken. 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. 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: 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.

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.

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

ZOFARIN 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.

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 contra-indicated 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.

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. Cholestyamine and sucralfate potentially decrease absorption of warfarin.

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.

Laboratory tests: Heparins and danaparoid may prolong the prothrombin time, therefore a sufficient time interval should be allowed after administration before performing the test.

ZOFARIN 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 dose of warfarin no effects on the breast feeding child are anticipated. Warfarin can be used during breast-feeding.

ZOFARIN Effects on ability to drive and use machines

Not relevant.

ZOFARIN 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; 1g/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 (e.g. 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.

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ZOFARIN (Warfarin Sodium Tablets USP)

ZOFARIN (Warfarin Sodium Tablets USP)

ZOFARIN Therapeutic indications