Practice Gap
The topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are US Food and Drug Administration approved for the treatment of atopic dermatitis.1 In addition, these 2 drugs are utilized off label for many other dermatologic conditions, including vitiligo, psoriasis, and periorificial dermatitis. They can be used safely for prolonged periods and on sensitive areas, including the face.
Treatment with a TCI provides advantages over topical steroids, which can cause atrophy, telangiectasia, dyspigmentation, ocular hypertension, cataracts, and tachyphylaxis after prolonged use. Adverse events resulting from use of a TCI most commonly include transient burning, warmth, and erythema in areas of application. Patients typically acclimate to these effects after a few consecutive days of use.
Localized flushing after alcohol ingestion is a known potential side effect of TCIs1; however, this association may be underappreciated and underreported to patients.
Counseling Patients Taking TCIs
Topical calcineurin inhibitors cause alcohol-induced flushing on areas of application (Figures 1 and 2) in approximately 3.4% to 6.9% of patients.1 The reaction has been reported with both topical TCIs but more often is noted with tacrolimus.2,3 Typically, flushing begins 2 to 4 weeks after treatment is initiated and within 5 to 20 minutes after alcohol intake.4 The phenomenon is self-limited; erythema typically resolves in 20 to 60 minutes.
FIGURE 1. A man with atopic dermatitis that requires application of a topical calcineurin inhibitor (tacrolimus ointment 0.1%) to the entire face. A, Patient prior to ingesting alcohol. B and C, Twelve minutes after consuming 1 beer (12 oz), the patient exhibited profound flushing of the entire face, with sharp demarcation at the neck where the topical calcineurin inhibitor was not applied. He denied a history of alcohol intolerance.
Topical calcineurin inhibitors are hypothesized to cause alcohol-induced flushing by locally inhibiting acetaldehyde dehydrogenase, an enzyme necessary for alcohol metabolism. This leads to accumulation of acetaldehyde, a by-product of alcohol metabolism, which indirectly causes concentrated vasodilation by means of prostaglandins, histamines, and other vasodilatory mediators. The combination of ethanol and a TCI also might induce release of neuropeptides, which could cause vasodilation.4
Alcohol-related flushing commonly is seen among individuals who are aldehyde dehydrogenase 2 (ALDH2) deficient; it is sometimes accompanied by nausea, headache, and tachycardia. The same pathway is implicated in disulfiram reactions, to a more intense and systemic degree, to discourage alcohol intake.
Oral calcineurin inhibitors are not reported to cause generalized flushing, perhaps because of differences in the relative dose. For example, topical tacrolimus 0.1% is 1 mg/g that is applied to a relatively small body surface area; oral calcineurin inhibitors are dosed at a range of 1 to 15 mg for an entire person.