Download Current Management of Basal Cell Carcinoma, Part 3

Supported by 3M Pharmaceuticals
Extensions
An Educational Newsletter for Physician Assistants and Nurse Practitioners in Dermatology
Editors’ Message
Current Management of
Basal Cell Carcinoma, Part 3: W
Pharmacological Options
By Roger I. Ceilley, M.D., and James Q. Del Rosso, D.O., F.A.O.C.D.
hen a patient
presents with
basal cell carcinoma (BCC), a number
of treatment modalities
are available to consider.
Despite new and intriguing therapeutic options, clinicians consider
several factors when deciding on the optimal
approach
for
each
patient.
Surgical approaches
have long been the standard of care, and data
suggest that clearance
rates and recurrence rates
for surgical excisions
remain the “gold standard.” Yet, surgery may be
contraindicated or undesirable in some cases.
Topical pharmacological approaches should be
considered as alternative
treatment options for
superficial BCC (sBCC).
Approved options include topical topical
5-fluorouracil (5-FU) and
imiquimod (see Table 1.)
W
Topical 5-Fluorouracil
(Efudex, Carac,
Fluoroplex)
Approved by the U.S.
Food and Drug Administration (FDA) for treat-
SPRING 2005
ment of superficial sBCC
when conventional (i.e.,
surgical) methods cannot
be used, 5-fluorouracil
(5-FU) is a chemotherapeutic agent that inhibits
DNA synthesis, thus pre-
5-FU, one small published
study focused on 44 sBCC
tumors treated with a
high concentration of this
drug. That is, 25% paste
with occlusion that was
changed once a week for
Topical pharmacological
approaches should be
considered as alternative
treatment options for
superficial BCC.
venting cellular proliferation of more rapidly
dividing cells.
Solution and cream formulations of 5% 5-FU are
administered twice daily
for at least 6 weeks,
although therapy may be
required for twice as long.
An initial clearance rate of
93% for sBCC was reported based on an old study.1
Efficacy data are limited.
While there are few
studies of efficacy or
recurrence rates with
3 weeks was associated
with a 21% 5-year recurrence rate.2
The literature suggests
that 5-FU may be more
effective in combination
with another treatment
modality, such as curettage
or cryotherapy.2,3 Light
curettage of 244 sBCC
lesions before the application of 25% 5-FU paste
resulted in a 5-year cumulative recurrence rate of
6% versus the 21% recurrence rate for 5-FU alone.2
e are pleased to present the Spring
2005 Extensions.
Our purpose in bringing you this quarterly
newsletter is to provide you with timely, relevant clinical information to help you provide
the best care to your patients.
In the lead section of this issue, beginning
on this page, we offer Part 3 of our three-part
series on treating basal cell carcinoma.
In the past two sections, we have covered
surgical options for this
disease (Part 1) and nonsurgical options (Part 2).
This time, we review
pharmacological options
for treating BCC.
In the litSCAN column
we look at a comparative
study of treatments for
both scalp psoriasis and Dr. James Del Rosso
nail psoriasis.
The regularly featured
column on Drug Actions,
and
InterReactions,
actions
provides
an
overview of treating superficial mycoses with oral
antifungal agents, which
Dr. Roger Ceilley
will represent the first of a
two-part series.
Lastly, we also offer an interesting Case of
the Month. Turn to page 7 to try and diagnose
this patient’s condition.
You are invited to submit a succinctly written summary of an interesting case along
with a digital photograph to [email protected].
Please forward to us any comments or
suggestions that you have regarding
Extensions. We hope to consistently achieve
our objectives of providing a publication that
is enjoyable to read, educational and clinically useful.
Professionally yours,
James Q. Del Rosso, D.O., F.A.O.C.D.
Roger I. Ceilley, M.D.
Co-editors
Table 1.
Topical 5-Fluorouracil
Topical Imiquimod 5% Cream
FDA status
Approved in treatment of sBCC
Approved for treatment of sBCC
and not approved for nBCC
Description
Cytotoxic agent that
causes tissue necrosis
Upregulation of immune
response resulting in
apoptosis of tumor cells.
Advantages
• FDA approved
• Patient-applied therapy
• Usually minimal symptomatology
• Patient-applied therapy
Limitations
• Only approved for sBCC
• Efficacy data limited
• Local skin reactions with
symptomatology common
• Local skin reactions common
• Approved only for sBCC
Proposed dosing regimen
b.i.d. ≥ 3 to 6 weeks
Approved regimen 5 times per
week for 6 weeks
Clearance rates
Estimated sBCC 93% (data limited;
actual clearance rate unknown)1
sBCC 81% to 88% 6,7
Recurrence rates
Lack of long-term data
Lack of long-term data
Topical application of
5-FU is associated with
adverse inflammatory reactions at the site of application
that are related to the cytotoxic mechanism of action of
the drug. Erythema, crusting
and pain are consistently
noted. Dyspigmentation and
persistent erythema may
occur. These reactions may
be severe in some cases.2
The role of topical 5-FU as
a monotherapy may be limited, but it may be a useful
adjunct to other therapies.
Further investigation is warranted to help clinicians
understand its most efficient
role in treating sBCC tumors.
Topical Imiquimod
(Aldara)
Imiquimod was recently
FDA approved for treatment
of sBCC.4 This agent works by
forming a ligand with surface
receptors on immune surveillance cells (dendrite cells) in
skin, which triggers a series of
immunomodulatory events.
The result is upregulation
of both innate and adaptive
2
When treating sBCC with
topical imiquimod,
the more intense the
inflammatory response,
the greater the clinical and
histologic clearance rates.
immune response within the
field of application, eliciting
a Th1 lymphocytic response
and increased secretion of
both alpha- and gammainterferon.4,5
There is some evidence that
imiquimod 5% cream may
induce Fas (CD95) receptormediated apoptosis in BCC
cells.5 Normally, BCC cells do
not express Fas receptor
(FasR), thus avoiding tumor
apoptosis as there is no FasR
on tumor cell surfaces to ligand to T lymphocytes infiltrating the BCC.
In a vehicle-controlled
study topical imiquimod
induced the expression of
FasR on BCC cells, resulting
in ligand formation with predominantly T-helper (CD-4+)
lymphocytes attempting to
infiltrate and destroy the
tumor (tumor apoptosis).5
Open-label, randomized,
parallel trials of imiquimod
for
the
treatment
of
sBCC randomized patients
to 6 weeks or 12 weeks of
treatment, once a day three
times a week, or twice a day
three times a week.6 With
12 weeks of therapy, the
histological clearance rates
were 87%, 81%, and 52%,
respectively. Interestingly, the
6-week cure rate data were
essentially identical to results
reported in the 12-week
study groups. This data suggest that 6 weeks of treatment is sufficient for clinical
efficacy.
Two identical, randomized,
vehicle-controlled Phase III
studies (n=724) examined
imiquimod 5% cream used for
6 weeks to treat sBCC with
patients treated either five times
a week or seven times a week.7
The study’s primary endpoint was a composite of clinical and histologic clearance
at 12 weeks post-treatment.
The clinical and histologic
clearance rate was 75% in the
five-times-a-week
group
(n=185) and 73% in the
seven-times-a-week
group
(n=179).
When data were separated
to study histologic clearance
rates alone, it was found that
82% of the five-times-a-week
group had histologic clearance versus 79% of the seventimes-a-week group.
The vehicle groups had low
composite clearance rates
(histologic and clinical) of
2% and histologic clearance
of 3%.
Analysis of response of
sBCC to imiquimod treatment suggests there was a significant correlation between
histologic clearance rate and
the intensity of local skin
reactions (such as erythema,
erosion, crusting, scabbing).
When treating sBCC with topical imiquimod, the more
intense the inflammatory
response, the greater the clinical and histologic clearance
rates.
with visible signs of skin
inflammation that are usually
associated with little to no
symptomatology. The most
commonly reported local
reactions include erythema,
crusting, flaking, itching and
skin erosion.6
Although patients do not
tend to discontinue treatment because of skin reactions, the intensity of the
inflammatory response correlates with the frequency of
dosing.6,9,10
This woman’s BCC was resolved after 1 month of treatment
with imiquimod. Photo courtesy of James Q. Del Rosso.
Studies have found that
use of imiquimod is associated
with visible signs of
skin inflammation that are
usually associated with little
to no symptomatology.
Treating Nodular Basal
Cell Carcinoma
Although
not
FDA
approved for nodular BCC
(nBCC), imiquimod has
undergone limited study for
treatment of small nBCC
lesions not located in highrisk anatomic sites.8
In one study, daily treatment with imiquimod seven
times a week for 6 or 12 weeks
resulted in histologic clearance rates of nBCC of 71%
and 76%, respectively.8
As with sBCC trials, all
nBCC treatment sites were
excised after completion of
imiquimod to carefully assess
histologic clearance.
Further study is needed
with nBCC and topical
imiquimod therapy.
Imiquimod produces an
inflammatory response in
order to treat the tumor.
Studies have found that use
of imiquimod is associated
Using Imiquimod as
Adjunctive Therapy
A double-blind, vehiclecontrolled study had 20
nBCC patients use topical
imiquimod or vehicle cream
once daily for a month after
electrodesiccation and curettage (ED&C). Imiquimod
reduced the frequency of
residual tumor with ED&C
compared with ED&C as a
monotherapy. The use of
imiquimod after curettage
without use of electrodesiccation appears to minimize
scarring, thus optimizing cosmetic results without apparent
loss
of
efficacy.11
Additional studies and longterm follow-up are warranted.
2.
3.
4.
5.
6.
7.
8.
Promising Therapies
Pharmacological approaches
for BCC offer promise as
monotherapy and adjuvant
therapy. Topical 5-FU and
imiquimod are approved for
sBCC. Both are expected to
produce local skin reactions.
Data are more limited with
topical 5-FU. Long-term cure
rates are lacking with both
agents, although time and
further study will provide this
information for the medical
community. • • •
9.
10.
References
1.
EFUDEX® (fluorouracil) topical
solutions and cream (product
pamphlet). Costa Mesa, CA:
ICN Pharmaceuticals, Inc.
2000.
11.
Epstein E. Fluorouracil paste
treatment of thin basal cell carcinomas. Arch Dermatol 1985;
121: 207-213.
Tsuji T, Otake N, Nishimura M.
Cryosurgery and topical fluorouracil: a treatment method for
widespread basal cell epithelioma in basal cell nevus
syndrome. J Dermatol 1993; 20:
507-513.
Stanley MA. Imiquimod and the
imidazoquinolones: mechanism
of action and therapeutic potential. Clin Exp Dermatol 2002; 27:
571-577.
Berman B, Sullivan T, De Araujo
T et al. Expression of Fasreceptor on basal cell carcinomas after treatment with
imiquimod 5% cream or vehicle. Br J Dermatol 2003;
149(suppl 66): 59-61.
Marks R, Gebauer K, Shumack
S et al. Imiquimod 5% cream in
the treatment of superficial basal
cell carcinoma: results of a multicenter 6-week dose-response
trial. J Am Acad Dermatol 2001;
44: 807-813.
Geisse J, Caro I, Lindholm J et
al. Imiquimod 5% cream for the
treatment of superficial basal
cell carcinoma: results from two
phase III, randomized, vehiclecontrolled studies. J Am Acad
Dermatol 2004; 50: 722-733.
Shumack S, Robinson J, Kossard
S et al. Efficacy of topical 5%
imiquimod cream for the treatment of nodular basal cell carcinoma: comparison of dosing
regimens. Arch Dermatol 2002;
138: 1165-1171.
Huber A, Huber JD, Skinner RB
Jr. Et al. Topical imiquimod
treatment for nodular basal cell
carcinomas: an open-label
series. Dermatol Surg 2004; 30:
429-430.
Geisse JK, Rich P, Pandya A, et
al. Imiquimod 5% cream in the
treatment of superficial basal
cell carcinoma: a double-blind,
randomized, vehicle-controlled
study. J Am Acad Dermatol 2002;
47: 390-398.
Personal communication with
Dr. James M. Spencer and the
author.
3
litSCAN
Selected Abstract Reviews from
Current Dermatology Literature.
By Roger I. Ceilley, M.D.
n this issue, litSCAN focuses on psoriasis, including a
review of comparative studies of treatments for scalp psoriasis and nail psoriasis.
I
Scalp Psoriasis:
Clobetasol Shampoo
vs. Calcipotriol
Solution
Reygagne P, Mrowietz U,
Decroix J, et al. Clobetasol
propionate shampoo 0.05%
and calcipotriol solution
0.005%: A randomized comparison of efficacy and safety
in subjects with scalp psoriasis.
J
Dermatol
Treat.
2005;16:31-36.
The scalp is frequently
involved in patients presenting with psoriasis vulgaris.
Treatment challenges include
finding therapy that is effective, convenient to use and
cosmetically acceptable.
Studying short-applicationtime therapy. This investigatorblinded study sought to evaluate, in moderate to severe psoriasis, the efficacy and safety of
clobetasol propionate 0.05%
shampoo short contact therapy
(application once a day and
left on the scalp for 15 minutes
followed by rinsing) compared
to calcipotriol 0.005% solution
applied twice daily and left on
the scalp. A total of 120
patients were randomized to a
clobetasol propionate shampoo 0.05% or a calcipotriol
solution 0.005% treatment
arm.
The study measured global
severity score (GSS) on a scale
of 0 (none) to 5 (very severe)
and total severity score (TSS),
which was the sum of scores for
erythema, desquamation and
plaque thickening assessed by
4
the investigator on a scale from
0 (none) to 3 (severe). Pruritus
was assessed using the same
TSS-type measure and safety
was evaluated based on skin
atrophy, telangiectasia, burning sensation on scalp, neck or
face, and burning of the eyes.
Patients were evaluated at
baseline, 2 weeks, and 4 weeks.
Analyzing the results. After
exclusions and dropouts, a perprotocol population was established for clobetasol propionate group (n=73) and the
calcipotriol group (n=64). The
joint primary outcome measures of GSS and TSS improved
in both groups, with greater
improvement in the clobetasol
propionate group. When data
were analyzed by intention-totreat, clobetasol propionate
shampoo
had
markedly
improved TSS and GSS scores
versus calcipotriol. Secondary
efficacy variables (erythema,
plaque thickening, adherent
desquamation, pruritus) improved in both groups with
more pronounced improvement in the clobetasol propionate group. Both investigators’ and patients’ assessments
showed a significantly higher
percentage of patients in the
clobetasol propionate group
rated as “clear” or “almost
clear” by the end of the study
(p=0.003 for investigators and
p=0.009 for subjects).
Adverse events occurred
more frequently in the calcipotriol group; 17 patients
reported a treatment-related
adverse event and 23 more
reported any adverse event.
By contrast, in the clobetasol
propionate group, one subject reported a treatmentrelated adverse event and
eight reported any adverse
event. There was no significant
difference in telangiectasia,
and skin atrophy was not commonly observed. Calcipotrioltreated patients more frequently reported a burning
sensation. Eight subjects in
each group reported ocular
stinging at baseline, but none
rated it as severe.
Author commentary. Despite
its relatively short contact
time (15 minutes once daily),
clobetasol propionate shampoo achieved superior results
when compared to calcipotri-
Study methods. Fifty four
patients with severe psoriasis
and nail involvement were
matched for severity of nail disease, age, sex, and cyclosporin
dosage. Group A (n=21) included patients treated with cyclosporine alone (3.5 mg/kg/day)
for 3 months. Group B (n=33)
patients were treated with the
same course and dose of
cyclosporin, plus they received
topical calcipotriol cream twice
daily. A dermatologist evaluated
the results at 3 months on a
scale of + to +++ (with + meaning least involvement).
Despite its short contact time . . .
clobetasol propionate shampoo
achieved superior results
compared with calcipotriol.
ol solution. The shorter contact time may help minimize
systemic absorption of clobetasol propionate and mitigate
potential side effects without
compromise of efficacy.
Fewer adverse events were
reported with clobetasol propionate shampoo.
Treating Nail
Psoriasis:
Combination Therapy
or Monotherapy?
Feliciani C, Zampetti A,
Forleo P et al. Nail psoriasis:
combined therapy with systemic cyclosporine and topical calcipotriol. J Cutan Med
Surg. 2004; 122-125.
Nail psoriasis is notoriously
refractory to therapy; however,
new treatments have been considered over the past few years,
including topical calcipotriol, a
vitamin D analog, and
cyclosporin, a systemic immunosuppressive agent. In this
study, the efficacy of oral
cyclosporin used in combination with calcipotriol cream
was compared to cyclosporin
alone for nail psoriasis.
Analyzing the results. Both
groups exhibited improvement, with combination therapy showing better overall
results in both milder and
severe presentations of nail
psoriasis. Improvement in clinical appearance of nail lesions
occurred in 47% of patients in
Group A (p≤0.15) versus 79%
in Group B (p≤0.0004). No
patient dropped out from the
study due to adverse effects. A
significant number of patients
(52% in Group A and 21% in
Group B) did not respond to
therapy. At 3 months, follow-up
data indicated a persistent clinical response in Group B participants.
Author commentary. Both
groups contained subjects
who did and did not show
improvement.
Combination therapy produced better results in responders and yielded a lower percentage of non-responders.
Combination therapy may produce better long-term results,
possibly owing to the action of
calcipotriol on keratinocyte
cell growth control.
Drug Actions, Reactions,
and Interactions
Treating Superficial Mycoses with Oral Antifungal
Agents, Part 1
By James Q. Del Rosso, D.O., F.A.O.C.D.
onsidering the widespread prevalence of
superficial
mycotic
infections and associated oral
antifungal use, it is important
to revisit the subject of potential drug interactions and oral
antifungal agents. Due to variations in metabolic pathways,
significant differences in the
potential for interactions are
present when comparing griseofulvin, terbinafine (Lamisil),
ketoconazole (Nizoral) and the
triazoles, itraconazole (Sporanox) and fluconazole (Diflucan). Overall, as compared to
the oral azole antifungal
agents, terbinafine is associated with the most favorable
safety profile with regard to
clinically significant drug interactions.
The following provides an
overview of potential drug
interactions related to the
selection of specific oral antifungal agents. Emphasis will
be placed on supportive data,
clinical significance and management suggestions for the
clinician when selecting oral
antifungal therapy for onychomycosis and other superficial mycotic infections. This
article also includes one case
study, with more illustrative
case studies to come in part 2
(Summer Extensions issue).
C
Major Drug Interaction
Mechanisms
The majority of clinically significant drug interactions
involve either alterations in
gastrointestinal absorption or
hepatic metabolism.
Absorption. In cases involving
gastrointestinal absorption,
interaction occurs when
absorption of itraconazole
(capsules) or ketoconazole
(tablets) is impaired by concurrent administration of a
second drug or compound
that decreases gastric acidity.
Decreased gastric acidity may
be caused by ingestion of
antacids, H-2 blocker antihistamines such as cimetidine
(Tagamet), ranitidine (Zantac)
and famotidine (Pepcid) and
proton pump inhibitors such
as omeprazole (Prilosec),
rabeprazole (Aciphex), lansoprazole (Prevacid), and pantoprazole (Protonix).
Metabolism. Metabolic interactions occur through either
enzyme inhibition or enzyme
induction. Enzyme inhibition
occurs when the hepatic
metabolism of one drug is
decreased by a second drug
that the patient is ingesting.
The most common hepatic
enzyme associated with drug
metabolism is cytochrome 3A4
(CYP 3A4). Other enzymes
with lesser degrees of involvement, but still with important
roles in the metabolism of specific drugs include CYP 2C9,
CYP 2D6 and CYP 1A2. A
major example of enzyme
inhibition is the decreased
metabolism of certain HMG
CoA reductase inhibitors (simvastatin, lovostatin, atorvastatin). which are cholesterollowering agents metabolized
by CYP 3A4, caused by itraconazole or ketoconazole,
both of which are inhibitors of
CYP 3A4. The inhibition of
CYP 3A4 by itraconazole or
ketoconazole
results
in
increased serum levels of simvastatin (Zocor), lovastatin
(Mevacor) or atorvastatin
(Lipitor), ultimately placing
the patient at increased risk of
severe myopathy and rhabodomyolysis. Another example of enzyme inhibition is
decreased metabolism of
phenytoin (Dilantin) a drug
metabolized by CYP 2C9,
caused by fluconazole, an
inhibitor of CYP 2C9. As a
result, significantly increased
phenytoin serum levels have
been documented during concomitant administration of fluconazole, leading to clinically
evident phenytoin toxicity.
Enzyme induction occurs
when an administered drug
increases the metabolic activity of an enzyme responsible
for the metabolism of another
drug. A clinically relevant
example is the co-administration of phenytoin and itraconazole. Phenytoin increases
the hepatic metabolism of itraconazole resulting in its accelerated clearance. The possible
outcome of this interaction is
inadequate therapeutic response to itraconazole because less is systemically available. Treatment failure related
to induction of itraconazole
metabolism by phenytoin has
been reported.
Exploring a Patient Case
History. A 53-year-old Hispanic male presents with a 6year history of onychomycosis
of both large toenails and multiple smaller toenails. Fungal
culture obtained from the
right large toenail confirms
the presence of Trichophyton
rubrum. Bilateral plantar tinea
pedis is also noted on examination. The patient has a history of diabetes, hypertension
and anxiety with difficulty
sleeping. Past medical history
and recent evaluation within
the last month of a serum
chemistry panel are otherwise
unremarkable. The patient is
highly motivated regarding his
interest in treating onychomycosis and is very embarrassed
by the condition.
Medication History. Current
daily systemic medications
used by the patient are
hydrochlorothiazide and nifedipine for hypertension, metformin and glipizide for diabetes and alprazolam as a
sedative-hypnotic agent.
The clinician is considering
oral antifungal treatment in
combination with large toenail
debridement. What potentially
significant drug interactions
may be identified prior to initiation of therapy?
Drug Interaction Case
Summary
This case illustrates potentially significant drug interactions
between certain oral antifungal
agents and calcium channel
blockers, oral hypoglycemic
agents and benzodiazepine
sedative-hypnotic agents. Here
is a closer look at some potential problems.
Calcium Channel Blockers. As
with many other calcium channel
blockers,
nifedipine
(Procardia) is metabolized in
the liver by CYP 3A4.
Clearance of nifedipine is
decreased by itraconazole or
ketoconazole due to enzyme
inhibition of CYP 3A4.
Other calcium channel
blockers that may be affected
in a similar fashion are
felodipine (Plendil), isradipine (Dynacirc) and verapamil.
Consequences of the interaction between itraconazole or
ketoconazole with nifedipine
5
(or other similarly metabolized calcium channel blockers) include marked peripheral edema and decrease in
blood pressure. Cautious concurrent use or avoidance of coadministration with itraconazole or ketoconazole is recommended.
Due to inhibition of CYP
3A4, fluconazole, especially at
higher doses (>200 mg daily),
may potentially cause the same
interaction effect as itraconazole and ketoconazole.
As terbinafine does not
affect CYP 3A4, interaction
with nifedipine or other similarly metabolized calcium
channel blockers is not
expected. There are no
reports of interaction of
terbinafine with calcium channel blockers. In vivo studies
support the absence of interaction between terbinafine
and nifedipine.
There are no apparent interactions between griseofulvin
and calcium channel blockers.
Hypoglycemic Agents. Interactions between terbinafine
and any of the currently available agents used to treat diabetes, including insulin and
oral hypoglycemic agents,
have not been reported. Drug
interactions with terbinafine
are not anticipated after consideration of what is known
regarding involved pathways
of metabolism. Based on
routes of metabolism and
available data, itraconazole
and ketoconazole do not
appear to interact with insulin,
metformin, oral sulfonylureas
such as glyburide and glipizide,
rosiglitazone (Avandia) and
netaglinide
(Starlix).
As
repaglinide (Prandin) and
pioglitazone (Actos) are metabolized by CYP 3A4, potential
for hypoglycemia due to interaction with itraconazole and
ketoconazole exists.
Fluconazole, especially at
higher doses, is also capable of
inhibiting CYP 3A4 with potential to produce interactions similar to those associated with itraconazole and ketoconazole.
Interaction between fluconazole and several oral hypoglycemic agents, such as sulfonylureas (for example, glipizide, glyburide), rosiglitazone
and netaglinide may occur due
to inhibition of the metabolic
enzyme CYP 2C9. The clinical
outcome of these agents interacting with fluconazole is
enhanced risk of hypoglycemia.
There are no known interactions between hypoglycemic
agents and griseofulvin.
Sedative-Hypnotic
Agents.
Patients treated with benzodiazepine sedative-hypnotic agents metabolized by CYP 3A4,
specifically triazolam (Halcion), midazolam (Versed)
and alprazolam (Xanax),
should not co-ingest itraconazole, ketoconazole, and probably fluconazole at doses >200
mg daily. The CYP 3A4 inhibition associated with itraconazole or ketoconazole results in
elevated serum levels of the
aforementioned
benzodiazepines, ultimately enhancing
sedation and somnolence.
Similar interaction does not
occur with co-administration of
terbinafine due to absence of
CYP 3A4 inhibition. Griseofulvin does not appear to interact
with benzodiazepine sedativehypnotic agents.
Management
Suggestions.
From the perspective of potential drug interaction risk, and
based on the confirmed diagnosis of dermatophyte onychomycosis, oral terbinafine is
the optimal choice for treatment in this patient.
Although griseofulvin is
approved for the treatment of
onychomycosis, it would not
be considered to be a viable
option due to its poor efficacy
and the availability of newer
more effective oral antifungal
agents. If terbinafine is not tolerated, concomitant use of
interacting drugs that are not
contraindicated warrants careful monitoring and possible
dosage adjustment. The combination of oral antifungal
therapy and debridement is
likely to optimize the response
to therapy by reducing physical factors that promote treatment failure, such as extensive
onycholysis, lateral plate
involvement, marked nail
plate thickening and dermatophyoma.
Points to Remember
• A complete medication
history is very important prior
to choosing an oral antifungal
agent in order to proactively
identify potentially deleterious
drug interactions.
• In almost all cases, a viable
and safe oral antifungal alter-
Hallmark Interaction
Within dermatology, the clinical significance of drug interactions has been made evident by the withdrawal from the
marketplace of the “non-sedating” antihistamines, terfenadine (Seldane) and astemizole (Hismanal), due to the
increased propensity for prolongation of the QTc interval with subsequent ventricular arrhythmia when these agents were
co-administered with erythromycin, ketoconazole or itraconazole. This “hallmark interaction” is directly related to inhibition of the cytochrome (CYP) 3A4 metabolic pathway by several macrolide antibiotics and azole antifungal agents.
Due to the predominant role of CYP 3A4 in the metabolism of approximately half of drugs currently available on the
market, the potential for widespread impact related to CYP 3A4 inhibition, as well as other less predominant CYP metabolic isoenzymes, has received significant notoriety.
6
native exists that allows for
treatment of the patient without exposure to the risk of a
harmful drug interaction. Due
to differences in absorption
and metabolism, terbinafine
can be safely used in the
majority of situations where a
potential interaction with an
azole agent is identified.
• Despite the potential for
interactions via CYP 2D6 inhibition, there has been a conspicuous paucity of drug interactions reported in association
with terbinafine use based on
pharmacosurveillance and literature review. Published literature supports that clinically significant interactions associated
with terbinafine use are rare.
References
1.
Physicians’
Desk
Reference,
Thompson Publishers, Montvale,
New Jersey 2003.
2.
Gupta AK, Ryder JE. The use of
oral antifungal agents to treat onychomycosis.
Dermatol
Clin
2003;21:469.479.
3.
Elewski BE. Large-scale epidemiological study of the causal agents
of onychomycosis: mycological
findings from the multicenter
onychomycosis
study
of
Dermatol
Arch
terbinafine.
1997;133:1317-1318.
4.
Dominguez-Cherit J, Teixeira F,
Arenas R. Combined surgical and
systemic treatment of onychomycosis. Br J Dermatol 1999;140:778780.
Goodfield M, Evans EGV.
5.
Combined treatment with surgery
and short duration oral antifungal
therapy in patients with limited
dermatophyte toenail infection.
J Dermatol Treat 2000;11:259-262.
6.
Darkes MJM, Scott LJ, Goa KL.
Terbinafine: a review of its use in
onychomycosis in adults. Am J
Clin Dermatol 2003;4:39-65.
7.
Katz HI. Drug interactions of the
newer oral antifungal agents. Br J
Dermatol 1999;141 (Suppl):26-32.
Shear N, Drake L, Gupta AK, et al.
8.
The implications and management of drug interactions with
itraconazole, fluconazole and
Case of the Month
By Vanessa Benes, P.A.-C., Steve Hawkes, P.A.-C., James Q. Del Rosso, D.O., F.A.O.C.D.
Case Study
A 56-year-old female presented with fever, malaise, and diffuse erythema which she states began
on her face and neck and spread rapidly over the next 1 to 2 days to the trunk and extremities (figure at left). She relates “feeling fine” prior to the eruption and reports no change in personal use
products or over-the-counter medications. Past medical history is remarkable for osteoarthritis of the
hands treated with naproxen over the past 6 years, Type-II diabetes treated with dietary control, metformin and glyburide over the past 5 years, and recent inframammary and vaginal candidiasis treated over the past 10 days with itraconazole. Closer inspection of the eruption reveals multiple
monomorphic nonfollicular small pustules. Physical examination revealed no evidence of pharyngitis or mucosal abnormality and absence of palpable adenopathy and organomegaly. Bacterial culture obtained from three representative unroofed pustules was negative. A complete blood cell count
revealed leukocytosis with predominance of neutrophils without a shift. of Skin biopsy revealed
spongiform pustule formation with papillary dermal edema and a mixed perivascular infiltrate with
the presence of some eosinophils observed. What is your diagnosis?
Diagnosis and Discussion
The clinical presentation, skin biopsy features and laboratory results support a diagnosis of acute generalized exanthematous pustulosis (AGEP). This eruption is most often drug-induced developing within the first few days to weeks of initiating therapy, and is most
often confused with acute diffuse pustular psoriasis. A variety of drugs have been reported as causes of AGEP, most commonly beta-lactam antibiotics. Rare sporadic reports have been associated with oral antifungal agents, including itraconazole and terbinafine. AGEP is a
well-defined entity, although it is an uncommon association with any of the drugs reported to be related to its development. Therefore, a
high index of suspicion for drug-induced disease is vital to the management of the patient.
Due to the temporal relationship apparent in this case, itraconazole was suspected and the drug was withdrawn. Over the next week,
the fever, malaise and overall “toxic appearance” of the patient rapidly and progressively dissipated. The skin eruption faded, ultimately
resulting in superficial exfoliation (“sloughing”) within 2 weeks of stopping itraconazole. The exfoliation is often characterized by epidermal
sheets and represents the sequelae of marked papillary dermal edema.
Submission Instructions
Do you have a case you would like to see published in this column? If so, please send a write-up (about 250 words) and a high-resolution image (at least 266 dpi) of the patient’s condition.
Please send materials to Larisa Hubbs, Extensions, 83 General Warren Blvd., Suite 100, Malvern, PA 19355 or e-mail them to
[email protected].
9.
10.
11.
12.
terbinafine.
Dermatology
2000;201:196-203.
Katz HI, Gupta AK. Oral antifungal drug interactions: a mechanistic approach to understanding
their cause. Dermatol Clin
2003;21:543-563.
Stockley IH. General considerations
and an outline of some basic interaction mechanisms. In: Stockley IH
(Ed), Drug Interactions, Fifth Edition.
London, Pharmaceutical Press,
1999, pp 1-14.
Gupta AK, Katz HI, Shear NH.
Drug interactions with itraconazole, fluconazole and terbinafine
and their management. J Am Acad
Dermatol 1999;41:237-249.
Neuvonen PJ, Kantola T, Kivisto
KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP 3A4 inhibitor
13.
14.
15.
16.
itraconazole. Clin Pharmacol Ther
1998;63:332-341.
Ducharme MP, Slaughter RL,
Warbasse LH, et al. Itraconazole
and hydroxyitraconazole serum
concentrations are reduced more
than ten-fold by phenytoin. Clin
Pharmacol Ther 1995;58:617-624.
Stockley IH. Antibiotic and antiinfective agents. In: Stockley IH
(Ed), Drug Interactions, Fifth Edition.
London, Pharmaceutical Press,
1999, p 153.
Tailor SA, Gupta AK,Walter SE, et
al. Peripheral edema due to
nifedipine-itraconazole reaction: a
case report. Arch Dermatol
1996;132:350-352.
Neuvonen PJ, Suhonen R.
Itraconazole
interacts
with
felodipine. J Am Acad Dermatol
1995;33:134-135.
17.
18.
19.
20.
21.
Hall M, Monka C, Krupp P, et al.
Safety of oral terbinafine: results of
a postmarketing surveillance study
in 25,884 patients. Arch Dermatol
1997;133:1213-1219.
Penzak SR, Gubbins PO, Gurley
BJ, et al. Grapefruit juice decreases
the systemic availability of itraconazole in healthy volunteers. Ther
Drug Monitor 1999;21:304-309.
Hansten PD, Horn JR. Drug
Interactions Analysis and Management.
Facts & Comparisons, St. Louis,
Missouri, 2003.
Sachs MK, Blanchard LM, Green
PJ. Interaction of itraconazole and
Clin
Infect
Dis
digoxin.
1993;14:400-403.
Aldermann CP, Allcroft PD.
Digoxin-itraconazole interaction:
possible
mechanisms.
Ann
Pharmacother 1997;31:438-440.
22.
23.
24.
25.
26.
Kaukonen KM, Olkkola KT,
Neuvonen
PJ. Itraconazole
increases plasma concentrations of
quinidine. Clin Pharmacol Ther
1997;62:510-517.
McNulty RM, Lazar JA, Sketch
M. Transient increase in plasma
quinidine concentration during
ketoconazole-quinidine therapy.
Clin Pharm 1989;8:222-225.
The Medical Letter. November 24,
2003,Volume 45 (Issue 1170):93-96
Shapiro LE, Knowles SR, Shear
NH. Drug interactions of clinical
significance for the dermatologist:
recognition and avoidance. Am J
Clin Dermatol 2003;4:623-639.
Van der Kuy PH, Hooymans PM.
intoxication
Nortriptyline
induced by terbinafine. BMJ
1998;316:441.
7
© 3M Pharmaceuticals 2004. Printed in U.S.A. 4/04 AL-8695
HMP Communications
83 General Warren Blvd., Suite 100
Malvern, PA 19355
PRSRT STD
US POSTAGE
PAID
BENSALEM, PA
PERMIT #182