Tretinoin and Warfarin Interaction: What Patients and Clinicians Need to Know

What the labels say

The Jantoven (warfarin) label's drug interaction section includes tables of CYP2C9, CYP1A2 and CYP3A4 inhibitors and inducers, a table of drugs that raise bleeding risk, and separate discussions of antibiotics, antifungals, botanicals and vitamin K in food. The label notes that its tables should not be considered all-inclusive [2].

Topical tretinoin is applied to the skin, and the Renova label does not name warfarin as an interacting drug. It warns against using the product with drugs known to be photosensitizers, giving thiazides, tetracyclines, fluoroquinolones, phenothiazines and sulfonamides as examples, because of the possibility of augmented phototoxicity; warfarin is not among the examples listed [1]. The Renova label lists hypersensitivity to any of its components as its contraindication and says to discontinue if hypersensitivity is noted [1].

An interaction that is not documented in a label is not the same as one that has been ruled out.

How much tretinoin reaches the blood

The Renova label reports that transdermal absorption of tretinoin from various topical formulations ranged from 1% to 31% of the applied dose, depending on whether it was applied to healthy skin or dermatitic skin [1]. For a 0.05% oil-in-water emulsion cream, absorption was less than 2% after a single application (7 healthy men) and after daily applications for 28 days (7 healthy men), and the extent of bioavailability was less after repeated application [1]. No percutaneous absorption study was conducted with the 0.02% Renova cream itself [1].

What the warfarin label says to watch

Warfarin carries a boxed warning for bleeding: the label says it can cause major or fatal bleeding and says to perform regular INR monitoring in all treated patients. It calls for more frequent INR monitoring when other drugs are started or stopped, including short-term drugs such as antibiotics and antifungals [2]. That instruction covers drug changes in general; it does not single out tretinoin.

• The label gives a target INR of 2.5 (range 2.0 to 3.0) for venous thromboembolism and for non-valvular atrial fibrillation, and 3.0 (range 2.5 to 3.5) for tilting disk and bileaflet mechanical valves in the mitral position [2].
• An INR above 4.0 appears to give no added benefit in most patients and is linked to more bleeding [2].
• The label says maintaining the INR in the therapeutic range does not eliminate the risk of bleeding [2].

The label also says patients should be instructed on bleeding prevention and to report signs and symptoms of bleeding [2].

Using both

On the tretinoin side, the Renova label describes local irritation such as erythema, pruritus, burning, stinging and peeling, and says exposure to sunlight and sunlamps should be avoided or minimized during use, with sunscreens of at least SPF 15 and protective clothing [1]. It also says not to use the cream if the patient is sunburned or has eczema or other chronic skin conditions of the face [1].