Interactions : אינטראקציות

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 metabolized 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 the 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.
There are limited data on possible drug interactions with glucosamine, but increments in the INR parameter have been reported with oral vitamin K antagonists. Patients treated with oral vitamin K antagonists should therefore be closely monitored at the time of initiation or termination of glucosamine therapy.
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.