5-Fluorouracil 0.5% Cream for Multiple Actinic or Solar Keratoses of the Face and Anterior Scalp
A.K. Gupta, MD, FRCPC,a J.S. Weiss, MD,b J.L. Jorizzo, MDc
1Division of Dermatology, Department of Medicine, Sunnybrook and Womens' College Health Sciences Center (Sunnybrook site), and the University of Toronto, Toronto
2Gwinnett Dermatology, Snellville, Georgia
3Wake Forest University School of Medicine, Winston-Salem, North Carolina
Carac® (5-fluorouracil 0.5% cream, Aventis Pharma) was approved by the US FDA in October 2000, for the treatment of
multiple actinic or solar keratoses involving the face and anterior scalp. The cream should be applied in a thin film once
daily to the skin where actinic keratoses (AKs) are present. When it is applied for 1, 2 or 4 weeks, it is significantly more
effective than a vehicle in the management of patients with five or more AKs at pretherapy. Pooled data from the two
pivotal trials (n=384) indicate that following 4 weeks of therapy the number of subjects with total AK clearance in the
Carac® and vehicle groups was 52.9% and 1.6%, respectively (p<0.001). Furthermore, the corresponding reduction of AK
lesion counts in the Carac® and vehicle groups was 82.5% and 19.3%, respectively (p<0.001). Treatment should be
continued for up to 4 weeks as tolerated by the patient. The most common adverse-effect is facial irritation.
actinic keratosis, actinic keratoses, solar keratosis, 5-fluorouracil
Actinic keratoses (AKs) can be described as cutaneous neoplasms
that display chromosomal abnormalities and occur primarily on
sun-exposed skin surfaces.1 They may develop as a result of
long-term exposure to the sun’s ultraviolet light in susceptible
individuals.2–4 Other risk factors include increasing age, male
gender and increased susceptibility to ultraviolet radiation.5 We
may be in the midst of an ongoing skin cancer epidemic since the
development of AKs, and basal cell and squamous cell carcinomas
is a growing health issue especially for individuals who have a
fair-skinned complexion.2,6 In a survey of outpatient visits to
dermatologists in the US between 1990–1994, the most common
reasons given for office visits were acne, dermatitis, actinic
dermatoses and skin cancer.7
AKs may be a sensitive indicator of an individual’s exposure to
sunlight over the years, and a predictive factor of that person’s
potential for the development of both basal cell and squamous cell
carcinomas.10 The average number of AKs per individual is
reported to be 6–8.8,9 The natural history of AKs in the community
may be one of high turnover with a small percentage of susceptible
individuals carrying the major burden. Marks, et al10 estimated that
the risk of malignant transformation of an average AK into a
squamous cell carcinoma (SCC) in one year is 0.0075%. Dodson,
et al11 demonstrated that over a 10-year period, a person with an
average of 7.7 AKs has a 6.1–10.2% chance of developing an SCC.
Therefore, a low yearly rate of transformation of a single AK lesion
into an SCC can translate into an increased risk in patients with
multiple AKs, especially when considered over a long period
The treatment modalities approved by the US FDA for the
treatment of AKs include topical 5-fluorouracil (5-FU) (Carac®,
Efudex®, Fluoroplex®) and photodynamic therapy (Levulan®
Kerastick™, Solaraze®).12,15,16 Another option is local excision or
destruction of the lesion, including liquid nitrogen cryotherapy.15
Mechanism of Action
Pyrimidine analogs can be subdivided into fluoropyrimidine and
cytidine analogs, with 5-FU being an example of the former.13
Biochemically, 5-FU may mimic uracil, interact with enzymes of
pyrimidine metabolism, and interfere with other aspects of
pyrimidine action. Fluorouracil may prevent DNA synthesis by
inhibiting thymidylate synthetase. It may be incorporated into RNA
resulting in an aberrant form of one or more types of RNA, and
interfere with the incorporation of uracil into RNA.14 It is possible
that the inhibition of thymidylate synthetase and the consequent
interruption of DNA synthesis may distort the metabolism of the
DNA-synthesizing cell to the extent that they are unable to reproduce
normally, thereby leading to cell death.14 The effects of DNA
and RNA deprivation may be most marked in those cells that grow
more rapidly and take up fluorouracil at a relatively faster rate.
In a multiple-dose, randomized, open-label, parallel study, patients
with AKs were treated with Carac® (0.5% cream) in a once daily
1gm application, or with Efudex® (5% cream) 1gm in two divided
daily doses, for a maximum of 28 days. Data from plasma and
urine samples were available from 20 patients. Only 3 of 10
patients applying the 0.5% cream had measurable 5-FU plasma
concentrations, with only one patient having enough data points to
determine systemic pharmacokinetics. Five of 10 patients applying
the 0.5% cream had measurable urine concentrations. The data
showed that both formulations demonstrated low plasma
concentrations of fluorouracil when administered under steady-state
concentrations. Cumulative urinary excretion was low for both the
0.5% and 5% cream formulations: 0.055% and 0.24% of the
applied doses, respectively.
Three concentrations of Carac®, 0.5%, 2.5% and 5%, as well as 5%
Efudex®, and a vehicle (placebo) cream were evaluated for the
treatment of AKs in a double-blinded, parallel group, multicenter
study.17 All patients were randomly assigned a treatment cream to
be applied twice daily for 4 weeks. Although there were no
statistically significant differences between the three concentrations
of the Carac® and the 5% Efudex®, patients in the 0.5% and 2.5%
groups demonstrated a greater reduction in AK lesions. There was
a greater proportion of patients with 100% improvement in the
evaluations of overall AK severity when compared to the two 5%
creams. Furthermore, the 0.5% cream had the best irritation/
tolerability profile of all the concentrations tested. As a result, the
5-FU 0.5% cream was chosen for further studies in a Phase III
Two phase III multicenter, vehicle-controlled, double-blinded,
parallel group trials were performed with three different treatment
arms and three matching vehicle arms.17 The treatment arms
consisted of 0.5% 5-FU cream and vehicle being applied in a 1:1:1
ratio for 1, 2 and 4 weeks. All patients had five or more AKs on the
face or anterior bald scalp, and were randomly allocated to active
or vehicle treatment in a 2:1 ratio. Each treatment was applied once
daily to the affected area. The clinical response was evaluated 4
weeks after the last scheduled application of the study cream. The
clinical efficacy outcome from the use of the vehicle cream for 1, 2
and 4 weeks was pooled because duration of treatment with vehicle
had no substantive effect on clearance of AKs. The clinical efficacy
of the 0.5% 5-FU cream in the treatment of AKs on the ears and
other sun exposed areas was not evaluated in these studies. The
0.5% 5-FU cream, when applied once daily for 1, 2 or 4 weeks was
significantly more effective than the vehicle control group, both in
the reduction and in the number of AKs, and in the proportion of
patients experiencing total clearance.
The perception of many physicians is that the clinical efficacy of
5-FU is associated with the severity of skin irritation induced
following its application. In fact, the data indicate that there was a
statistically significant correlation between a reduction in the
severity of AK lesions and the severity of facial irritation, or the
presence of symptoms/signs of facial irritation (e.g., erythema,
dryness, edema, erosion, pain and burning) evaluated at the final
visit in the treatment phase, or at 1-week posttreatment.
In general, patients with a greater number of lesions, or more
severe actinic damage at pretherapy, were observed to have a
greater absolute reduction in the number of lesions from pretherapy
to the final evaluation, when compared to those with less actinic
damage at pretherapy.
Improved efficacy was observed with increased treatment duration.
The course of treatment should be continued for as long as
possible, up to a maximum of 4 weeks, depending upon the
tolerance of the patient to treatment.
There were no significant differences in efficacy and safety
parameters in patients aged 65 years and older when compared to
all other patients.
The data show that the 0.5% 5-FU cream in a Microsponge®
formulation applied once daily for 1, 2 or 4 weeks is effective in
the treatment of patients with five or more AKs.
Table 1: Efficacy of 0.5% 5-Fluorouracil cream in the two Phase III studies
Number of subjects with total AK clearance
Proportional reduction of AK lesion counts
US 1 study
Age (mean ± SD): 65.0 ± 10.1 years
Skin Type (1/ II/ III/ IV): 80:99:27:1
Active 4 week: 26/45 (57.8%)
Vehicle: 0/69 (0%)
Active 4 week: 15.4 ± 8.0 (baseline) to 2.2 ± 4.2 (91.7% reduction)
Vehicle: 15.6 ± 12.0 (baseline) to 12.4 ± 12.5 (21.6% reduction)
US II Study
Age (mean ± SD): 63.2 ± 11.1 years
Male/ Female: 152/ 25
Skin Type (1/ II/ III/ IV): 69:81:27:0
Active 4 week: 19/40 (47.5%)
Vehicle: 2/58 (3.4%)
Active 4 week: 14.1 ± 8.2 (baseline) to 3.0 ± 5.7 (88.7% reduction)
Vehicle: 16.4 ± 11.1 (baseline) to 13.7 ± 12.3 (34.4% reduction)
Age (mean ± SD): 64.2 ± 10.6 years
Male/ Female: 318/66
Skin Type (1/ II/ III/ IV): 149:180:54:1
Active 4 week: 45/85 (52.9%)
Vehicle: 2/127 (1.6%)
Active 4 week: 14.8 ± 8.1 (baseline) to 2.5 ± 5.0 ( 82.5 % reduction)
Vehicle: 5.9 ± 11.6 (baseline) to 13.0 ± 12.4 (19.3 % reduction)
In the phase III studies, the adverse-effects that occurred in at least
1% of all patients were application site reaction (facial irritation),
eye irritation, headache, common cold, sinusitis, allergy, and skin
There was no evidence of a duration response effect for the
incidence of any adverse event, including application site reaction.
The 0.5% 5-FU cream demonstrated excellent systemic tolerance
with few reported non-facial irritation adverse effects. No serious
adverse events were thought to be related to the study medication.
In the Phase III studies, application of the 0.5% 5-FU cream in
each of the 1, 2, 4 week and vehicle groups resulted in facial
irritation, probably due to the study drug, in 87.1%, 95.4%, 95.3%
and 48.0%, of patients respectively. The most common symptoms
and signs of facial irritation were dryness, burning and erythema.
Only facial irritation demonstrated a dose-response and doseduration
relationship. Patients with the greatest amount of actinic
damage, and those with the highest number of AKs at pretherapy
were more likely to experience moderate or severe facial irritation.
The median day of onset of facial irritation for all groups was 4
days after therapy began. Severity increased with treatment
duration, generally increasing during the first 2 weeks of treatment
using a once daily application. There was little increase in severity
beyond the second week of therapy. The number of patients who
discontinued treatment due to facial irritation also increased as
the treatment duration became longer: 1-week active therapy
(0 patients), 2-week group (7 patients, 8.0%), 4-week group (20
patients, 23.5%), and vehicle group (1 patient, 0.8%). The median
duration of facial irritation following completion of 0.5% 5-FU
cream therapy was 16 days and this was similar for the three active
treatment groups (compared to 4 days for the placebo group).
Following the completion of therapy, facial irritation decreased
rapidly and the incidence of each symptom and sign was below
pretherapy levels by 2 weeks after treatment was stopped.
In phase I dermal safety tests the 0.5% 5-FU cream demonstrated
no phototoxicity, photoallergy, little irritation potential and no
No formal drug-drug or drug-food interaction studies have been
conducted with the 0.5% 5-FU cream. However, pharmacokinetic
studies confirm that there is very limited systemic absorption,
making it unlikely that there would be any important interactions
with oral or systemic products, which could have an effect on
Dosage and cost
Carac® is indicated for once daily application for up to 4 weeks by
adults to treat AKs on the face and the anterior portion of the scalp.
Enough cream should be used to cover the entire area with a thin
film 10 minutes after thoroughly washing, rinsing, and drying the
sites where the cream is to be applied. It should not be applied
under occlusion or in close proximity to certain anatomic sites such
as the eyes, nostrils or mouth. The patient should be counseled that
in many instances skin reaction may develop at the application site,
including redness, dryness, burning, pain, erosion, and edema. The
user should also be informed that the treated area may become
somewhat unsightly during therapy and for >2 weeks following the
end of therapy. The once daily application and relatively short
duration of application may help with compliance.
While using the 5-FU the patient should be encouraged to avoid
sunlight or other ultraviolet light sources (e.g., tanning beds). When
out in the sun during a treatment course, sun protection measures
The 0.5% 5-FU cream is contraindicated in women who are or may
become pregnant (US FDA category X), in patients with
dihydropyrimidine dehydrogenase (DPD) enzyme deficiency, and
in those with known hypersensitivity to any of the components of
the cream. This product is not recommended for use when patients
are breast-feeding, or in individuals under 18 years of age. Carac®
is available in a 30gm tube in the US; it is currently unavailable in
Canada. The average wholesale price in the US is $95.00 USD
(January 2001 price).
The US FDA recently approved 0.5% 5-FU cream (Carac®) for the
topical treatment of multiple actinic or solar keratoses on the face
and anterior scalp. The cream should be applied once daily to the
actinic keratoses for up to 4 weeks as tolerated by the patient. The
most common adverse-effect is facial irritation.
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In this issue:
- 5-Fluorouracil 0.5% Cream for Multiple Actinic or Solar Keratoses of the Face and Anterior Scalp
- Update on Drugs and Drug News - Number 9 2000