OBSERVATION

Diltiazem Induces Severe

Photodistributed Hyperpigmentation
Case Series, Histoimmunopathology, Management, and Review of the Literature
Rao N. Saladi, MD; Steven R. Cohen, MD; Robert G. Phelps, MD; Andrea N. Persaud, MD; Donald Rudikoff, MD

Background: Diltiazem hydrochloride is a commonly
prescribed benzothiazepine calcium channel blocker for
the treatment of cardiovascular disease. Recently, 8 cases
of diltiazem-induced photodistributed hyperpigmenta-
tion occurring predominantly in elderly African Ameri-
can women were reported. Here, we report occurrence
for the first time in a light-skinned African American
woman and a Hispanic woman. We also report this find-
ing in an African American man. Biopsy specimens of hy-
perpigmented areas were obtained for histopathologic
evaluation and marker studies. Photospectrometry analy-
sis for diltiazem was performed to analyze the photoab-
sorption properties of this drug.
Observations: Routine laboratory examination results
were normal in all patients. Serologic test results for
antinuclear antibodies, including Sjögren antibodies
anti-Ro (SS-A) and anti-La (SS-B), were negative. Histo-
pathologic analysis of the skin biopsy specimens
revealed a sparse lichenoid infiltrate, prominent pigmen-
tary incontinence, and numerous melanophages in the
dermis. There was no increase in dermal mucin sugges-
tive of lupus. The mononuclear cells in the specimens
were strongly positive for CD3, weakly positive for
CD68, and either weakly positive or negative for CD79a.
All specimens were negative for Alcian blue staining.
Photospectrometry analysis of diltiazem showed an
absorption range within the UV-B spectrum.
Conclusions: Photospectrometry analysis revealed dil-
tiazem could demonstrate a photosensitizing effect within
the UV-B range. Discontinuation of therapy with diltia-
zem is the most effective modality in resolving hyper-
pigmentation. Avoidance of sun exposure and consis-
tent use of sunscreens and sun-protective clothing are
indicated for patients undergoing diltiazem therapy.
Arch Dermatol. 2006;142:206-210

Author Affiliations:
Departments of Dermatology
(Drs Saladi, Cohen, Phelps,
Persaud, and Rudikoff ) and
Dermatopathology (Drs Saladi
and Phelps), Mount Sinai
School of Medicine,
New York, NY.
T
HE US F OOD AND D RUG
Administration approved
3 new calcium channel
blockers (nifedipine, ver-
apamil hydrochloride, and
diltiazem hydrochloride) in the 1970s and
1980s for treating cardiovascular dis-
eases. Diltiazem, a benzothiazepine, is a
widely prescribed agent used in treating
hypertension and angina. Adverse effects
of the drug include rare cutaneous erup-
tions such as maculopapular rashes, urti-
caria, and pruritus.1-3 Even rarer severe ad-
verse effects include subacute cutaneous
lupus erythematosus, Stevens-Johnson
syndrome,4 toxic epidermal necrolysis,1
and vasculitis. 5 Photosensitivity reac-
tions of the skin associated with dil-
tiazem rarely have been reported.1,2,6-8
Diltiazem-induced photodistributed hy-
perpigmentation has been reported, until
now, in 8 cases occurring mostly in Afri-
can American women.9-12 We report oc-
currence for the first time in a light-
skinned African American woman and a
Hispanic woman. We also report this find-
ing in an African American man.
REPORT OF CASES
All 4 patients were seen at dermatology
clinics affiliated with the Mount Sinai
School of Medicine in New York, with a
chief complaint of increased pigmenta-
tion on the face. The demographic char-
acteristics of the individual patients are
described in Table 1. Duration of pig-
mentation ranged from 6 to 24 months.
There were no associated local or sys-
temic symptoms. The patients’ medical
histories were remarkable for hyperten-
sion treated with diltiazem but no use of
other medications that could be impli-
cated as a cause for hyperpigmentation.
Physical examination in all patients
revealed diffuse slate-gray to gray-blue
pigmented macules and patches on the
face, neck, and forearms (Figure 1).
Perifollicular accentuation was noted

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 Table 1. Demographic Characteristics of Cases of Photodistributed Hyperpigmentation After Diltiazem Therapy*

Case No./Sex/ Fitzpatrick Onset After Initiation of Diltiazem

Source Age, y/Race Skin Phototype Hydrochloride Therapy, mo Distribution
Saladi et al 1/F/67/B VI 15 Face, neck, forearms
Saladi et al 2/M/67/B VI 10 Face, neck
Saladi et al 3/F/50/H III 6 Face, neck, forearms
Saladi et al 4/F/82/W 77/I 1½ Face
Scherschun et al,9 2001 5/F/49/B V 6 Face, neck, chest, forearms, hands
Scherschun et al,9 2001 6/F/72/B IV 11 Face, neck, chest
Scherschun et al,9 2001 7/F/56/B V 8 Face, neck
Scherschun et al,9 2001 8/F/71/B V 7 Face, neck, forearms
Chawla and Goyal,10 2002 9/F/57/B V 24 Face, neck, back, shins
Boyer et al,11 2003 10/M/71/B VI 12 Face, neck
11/M/49/H IV 24 Face, neck
Kuykendall-Ivy et al, 12 2004 12/F/66/B V 6 Face, neck, hands

Abbreviations: B, black; H, Hispanic; W, white.

*Cases 1 through 4 are the authors’ cases, and cases 5 through 12 are previously reported cases.

A B C

D E
F
Figure 1. Distinctive appearance of photodistributed
hyperpigmentation in patients undergoing diltiazem
hydrochloride therapy (A-I). Hyperpigmentation is
consistent with the sun-exposed areas of the face,
neck, and forearms. The pigmentation ranges from
slate-gray to gray-blue and dark brown. Perifollicular
accentuation was noted in some patients.

G H I

clinically in several patients (Figure 1). A sharply
demarcated hyperpigmented patch demonstrating a V
shape was noted in 3 of 4 patients on the upper chest or
neck (Figure 1). No periorbital edema or erythema and
no periungual erythema or telangiectasia were present.
After query, patients revealed a mild to moderate history
of exposure to sunlight during diltiazem therapy.
Results of routine laboratory testing in all patients, in-
cluding a complete blood cell count, liver function tests,
serum urea nitrogen and creatinine levels, complete meta-
bolic profile, and thyroid function tests, were all normal.
Serologic test results for antinuclear antibodies, including
Sjögren antibodies anti-Ro (SS-A) and anti-La (SS-B), were
negative.
Skin biopsy specimens of the hyperpigmented areas
were obtained, and histopathologic evaluation and marker
studies were conducted. Histopathologic findings were
similar in all patients. Specimens showed a thinned epi-

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 A B
C D
208.0 239.0
1.034 0.627
1.034
ABS
– 0.013
200 220 240 260 280 300 320 340 360 380
Wavelength, µm
Figure 3. Photospectrometer graph of diltiazem hydrochloride showing the
absorption range (220-300 nm) within the UV-B spectrum (290-320 nm).
ABS indicates absorbance.
dermis with effaced rete ridges and focal interface vacu-
olar changes with small groups of hyaline globules in the
uppermost papillary dermis. There were sparse lichen-
oid changes with interstitial and superficial perivas-
cular infiltrates of inflammatory cells, predominantly
composed of lymphocytes. Prominent pigmentary in-
continence and numerous melanophages were seen in the
dermis (Figure 2A and B). Some biopsy specimens
showed perifollicular accentuation, colloid bodies, and
association with apoptotic keratinocytes and hydropic
changes of the follicular epidermis (Figure 2C). How-
ever, none of the biopsy specimens showed increased der-
mal mucin that might suggest lupus; they were negative
for Alcian blue staining. The infiltrating mononuclear cells
were strongly CD3 positive (Figure 2D), weakly CD68
positive, and weakly positive or negative for CD79a cells.
The CD3-positive cells also showed striking perifollicu-
lar extension (Figure 2D).
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Figure 2. Histoimmunopathology of diltiazem
hydrochloride–induced hyperpigmented sites. A and
B, There is sparse perifollicular and focally lichenoid
infiltrate in the dermis, with numerous
melanophages. The infiltrate has a striking
perifollicular distribution often associated with
follicular plugging (original magnification ⫻10).
C, Some specimens were associated with apoptotic
keratinocytes (arrows) and hydropic changes of the
follicular epidermis (original magnification ⫻20).
D, The infiltrate is strongly CD3 positive and
demonstrated lichenoid perivascular and
perifollicular patterns (original magnification ⫻10).
Scale bar is 50 µm.
COMMENT
Photosensitivity reactions associated with the use of dil-
tiazem were reported previously. These cutaneous ad-
verse effects include erythema, pruritus, and/or lichen-
oid eruptions, which mostly develop soon after exposure
to the sun.2,7,8 However, photodistributed hyperpigmen-
tation associated with the use of diltiazem recently has
been reported (Table 1). Analysis of all these reported
cases in the literature showed that onset of pigmentary
changes developed within 6 to 24 months after use of dil-
tiazem. Patient age ranged between 49 and 77 years. Dis-
400 tribution of hyperpigmentation was consistent with sun-
exposed areas of the face, neck, and forearms, with lesser
pigmentation on the lower chest, back, and shins. Pig-
mentation was mild to severe with a slate-gray, gray-
blue, or dark brown appearance.
To determine the photoabsorption spectrum of dil-
tiazem, photospectrometry analysis of the drug was per-
formed. The results showed diltiazem’s absorption range
to be 220 to 300 nm, within the UV-B spectrum
(Figure 3). These results correlate with previous data
showing no absorption in the UV-A spectrum.9 Al-
though the UV-A range is thought to be the major con-
tributory factor for photosensitivity reactions, several
drugs (eg, tetracyclines, thiazides)13 exert photosensi-
tivity properties in the UV-B range (5%-10% UV-B co-
exists in sunlight).14,15 Furthermore, the pattern of pho-
todistributed pigmentation and history of mild to
moderate sun exposure during diltiazem therapy in the
patients in our study also supports diltiazem’s photosen-
sitizing effect. In efforts to elicit the causal mechanism,
Scherschun et al9 demonstrated that persistent darken-
ing of hyperpigmented patches occurred in patients
exposed only to UV-A. However, electron microscopic
evaluation did not reveal drug or metabolite deposits in
the skin biopsy specimens; therefore, the authors thought
diltiazem may exert its photosensitizing properties
through other mechanisms. Several diltiazem metabo-
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lites have been identified; however, the specific metabo-
lites involved in the adverse effects of the skin are not Table 2. Analytical Observations and Management
yet known.16 of Diltiazem-Induced Photodistributed Hyperpigmentation
Generally, for a drug to be regarded as a photosensi-
Characteristic Specific Data
tizer, the absorption wavelength of the drug should be
within the range of UV-B (290-320 nm), UV-A (320- Total No. of cases reported 12
400 nm), and/or visible light (⬎400 nm).13,15 Drugs that Ethnicity, ratio African American/all other ethnic
groups (⬇4:1)
induce photodistributed hyperpigmentation are acti- F/M, ratio 3:1
vated metabolically (via solar radiation) forming free radi- Mean age, y 63 (range, 49-77)
cals and reactive intermediates that covalently bind to cel- Hyperpigmentation
lular proteins and DNA. This binding is considered critical Site of distribution Predominantly on sun-exposed
in eliciting drug immunotoxicity by producing various (photodistributed) areas: face,
neck, and forearms
enzymatic reactions that trigger a cascade of events, in-
Mean time of ⬇12 mo after diltiazem hydrochloride
cluding a release of erythrogenic and pigmentary media- appearance therapy
tors that result in phototoxic and hyperpigmentary drug Color/appearance Slate-gray, gray-blue, dark brown,
reactions.13 Drugs that induce photosensitivity hyper- reticulated, macules, patches
pigmentation include antimicrobial agents (tetracy- Prevention
clines), diuretic agents, psychotropic drugs, antima- Sun exposure Limit during diltiazem hydrochloride
therapy
larial agents, nonsteroidal anti-inflammatory drugs, Photoprotective Use broad-spectrum UV-A/UV-B
cardiovascular drugs, cytotoxic drugs, and other agents.13,17,18 measures sunscreen and adequate covering
Diltiazem-induced photodistributed hyperpigmentation of sun-exposed areas from the start
may be similar to other drug-induced photodistributed hy- of diltiazem hydrochloride therapy
perpigmentation. Amiodarone, chlorpromazine hydro- Treatment Discontinue treatment with diltiazem
hydrochloride and/or use topical
chloride, imipramine hydrochloride, and desipramine hy- bleaching agents or chemical peels
drochloride also induce slate-gray macules or patches.19-21
However, diltiazem-induced photodistributed hyperpig-
mentation can be distinguished from minocycline hydro-
chloride–induced hyperpigmentation and argyria.9 Mino- Some conclusions can be drawn on the basis of the
cycline hyperpigmentation appeacrs in areas of cutaneous cases reported (Table 1 and Table 2 ). Diltiazem-
inflammation, typically in acne scars.22 Argyria induces slate- induced photodistributed hyperpigmentation has been
gray pigmentation not only in sun-exposed areas but also found in other ethnic groups and skin types, but dark-
in the lunulae of nails, mucous membranes, and sclerae.23 skinned individuals and women were more prone to
Patients undergoing treatment with calcium channel block- hyperpigmentation. The association of drug-induced hy-
ers such as diltiazem have developed drug-induced sub- perpigmentation in darker skin has never been under-
acute cutaneous lupus erythematosus. These patients had stood. Results of previous reports and our case series in-
positive serologic test results and characteristic subacute dicate that only patients with severe hyperpigmentation
cutaneous lupus erythematosus histoimmunopathologic seek dermatological care. Family practitioners, inter-
findings.24,25 nists, cardiologists, and dermatologists who care for pa-
Prevention of diltiazem-induced photodistributed hy- tients using diltiazem should be aware of diltiazem-
perpigmentation can be achieved by initiating photopro- induced hyperpigmentation and its association with sun
tective measures, including use of broad-spectrum sun- exposure. We recommend that these patients limit their
screens containing UV-A and UV-B blockers with a sun sun exposure, wear sun-protective clothing, and use
protection factor of 15 or greater and behavioral modi- broad-spectrum sunscreen from the start of diltiazem
fication by limiting sun exposure and wearing sun- therapy.
protective clothing. Sunscreen use should be initiated at
the beginning of diltiazem therapy. If hyperpigmenta-
tion develops during diltiazem therapy, discontinua- Accepted for Publication: July 15, 2005.
tion of diltiazem is the most effective remedy. Better reso- Correspondence: Donald Rudikoff, MD, Department
lution of hyperpigmentation gradually has been observed of Dermatology, Mount Sinai Medical Center, 1425
in patients discontinuing diltiazem9-12 than in those Madison Ave, Campus Box 1047, New York, NY 10029
using topical bleaching agents or chemical peels while (RNAhybrid@aol.com).
continuing therapy.12 Application of topical bleaching Financial Disclosure: None.
agents (hydroquinone cream) may be useful in reduc- Acknowledgment: We thank Jane B. Hilfer, MD, and
ing the hyperpigmentation across time. In the patients Sapna R. Palep, BS, for their assistance in this project.
in our study, use of 4% hydroquinone cream caused
partial resolution across time. The patient showed com- REFERENCES
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Correction

Error in Figure. In the Study by Juarez et al titled “Analysis of

T-Cell Receptor Gene Rearrangement for Predicting Clinical
Outcome in Patients With Cutaneous T-Cell Lymphoma: A
Comparison of Southern Blot and Polymerase Chain Reaction
Methods,” published in the September issue of the ARCHIVES
(2005;141:1107-1113), an error occurred in the Figure on
page 1110. In the Figure, 2 line markers in the figure key
were reversed. The line markers should have indicated that
the poorest survival was in the patients with T3/T4 disease,
not the patients with T2 disease. The corrected Figure is
reproduced here.

1.0

0.9

0.8

0.7
Cumulative Survival

0.6

0.5

0.4

0.3

0.2 T1 Censored (n = 25)

T2 Censored (n = 19)
0.1
T3/T4 Censored (n = 11)

0 5 10
Time, y

Figure. Cumulative survival by skin stage category.

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