Dermatologists and other physicians frequently prescribe
medications off-label for the treatment of cutaneous
disease.1,2 Off-label prescribing refers to prescription
of a drug in a way that diverges from FDA-approved
use. It may represent first-line therapy, be incorporated into
treatment guidelines, or serve solely as a last resort.3 The ability
to prescribe off-label empowers physicians to innovate within
the scope of clinical practice, especially when standard treatments
fail.3 This may offer considerable benefits for patient
care. Off-label prescribing avoids the expenses of running
clinical trials and obtaining FDA approval for a new indication,
which provide pharmaceutical companies with little motivation
to seek new approvals for existing medications. In addition, the
low incidence and prevalence rates of many dermatologic conditions
do not always support extensive research.1 On the other
hand, although off-label prescribing is legal and common, there
are concerns regarding safety and efficacy that may need to be
addressed, as well as issues of cost to the healthcare system.3,4
The field of dermatology is in a unique position to repurpose
existing therapies for cutaneous conditions, given the broad
variety of pathophysiologic processes affecting the skin. This
review covers five medications that have been adapted for novel
off-label use within dermatology. We include a brief history
of each drug, followed by mechanisms of action, current use in
dermatologic practice, and adverse effect profiles.
Dapsone
First synthesized in 1908 during experiments on dye chemistry,5
dapsone is a sulfone drug that possesses both antimicrobial
and anti-inflammatory activities. However, dapsone’s medical
applications were not discovered for nearly 30 years, when
it was shown to possess antistreptococcal activity in mice.6
About a decade later sulfones were implemented for leprosy7
and dermatitis herpetiformis,8 paving the way for further dermatologic
applications.
Like sulfonamide antibiotics, dapsone acts bacteriostatically via
competitive inhibition of dihydropteroate synthetase (competing
with para-aminobenzoic acid for the enzyme active site),
thereby decreasing downstream production of folic acid.9 Its anti-
inflammatory mechanism is much more complex and enables
translation of dapsone to numerous neutrophil-mediated and autoimmune
processes.10 These effects are varied and incompletely
characterized, but foremost among them is reversible inhibition of myeloperoxidase, preventing cellular damage by hypochlorous
acid produced by both neutrophils and eosinophils.11
Dapsone is ideally suited for broad off-label use in dermatology
because of its combination antimicrobial-antiprotozoal effects,
formidable anti-inflammatory activity, long-term (even lifelong)
safety, steroid-sparing properties, and low cost.12 Currently,
dapsone is only approved by the FDA for dermatitis herpetiformis
and as a component of leprosy multidrug therapy. Its
off-label uses in dermatology stretch much further: dapsone is
recommended as first-line therapy for acropustulosis infantilis,
13 cicatricial pemphigoid,14 erythema elevatum diutinum,15
IgA pemphigus,16 linear IgA dermatosis,17 prurigo pigmentosa,
18 recurrent neutrophilic dermatosis of the dorsal hands,19
and subcorneal pustulosis.13 It may be employed as adjunctive
therapy in a number of diseases, and reports of use exist for
many other conditions, with variable results.10,20,21 Dosing of
dapsone for chronic inflammatory dermatoses is highly individualized,
generally beginning at 50-100 mg daily; if treatment
goal is not attained after 4-6 weeks, the dose may be titrated up
to 150-300 mg daily, according to patient tolerability.12
The most common adverse effects associated with dapsone
include methemoglobinemia and hemolysis.10 Severe anemia
may occur in persons with glucose-6-phosphate dehydrogenase
deficiency. Accordingly, all patients should be screened
for this enzyme deficiency prior to initiation of therapy. Cimetidine,
by acting as a cytochrome P450 inhibitor, has been shown
to reduce methemoglobin formation and may increase adherence
among patients receiving more than 200 mg daily.22
Doxepin
The first phenothiazine compound was synthesized in 1883 during
chemical dye experiments, but no medicinal use was found for
this class of drugs until 1952, when exciting results were reported
on the use of chlorpromazine for psychosis. This spurred a series
of experiments on the emerging class of tricyclic antidepressants,
resulting in the creation of doxepin in the early 1960s.23
Tricyclic antidepressants such as doxepin act primarily by inhibiting
reuptake of serotonin and norepinephrine, increasing the
synaptic concentrations of those neurotransmitters. However,
there are numerous off-target effects that occur with use of this
class of drugs, mediated largely via muscarinic and histamine
receptors.24 Doxepin has 56 times the affinity of hydroxyzine and
nearly 800 times that of diphenhydramine for the H1 receptor.25
Pruritus is a very common dermatologic complaint. Given doxepin’s
well known activity at histamine H1 receptors, topical
doxepin formulations are FDA-approved for pruritus secondary
to eczematous dermatitis. Doxepin has found more extensive
use as a systemic agent prescribed to patients suffering
from psychodermatoses, especially neurotic excoriations, as
