PITTSBURGH, April 29 /PRNewswire/ -- More than 50 million recurrent cold
sore sufferers in the United States now have a medication that's proven to
speed the healing of cold sores.  Denavir, the first and only topical
antiviral cream to be cleared by the U.S. Food and Drug Administration for the
treatment of recurrent cold sores in healthy adults, is available from
SmithKline Beecham Consumer Healthcare.
    Available by prescription only, Denavir (penciclovir cream) 1%, which is
active against the herpes simplex virus type 1, blocks the virus that causes
cold sores.  Denavir is a non-greasy cream specially formulated for the lips
and face.
    Healing Time Reduced
    In the two largest clinical trials ever conducted among patients with cold
sores, Denavir was shown to significantly reduce the duration of pain and
speed healing.  Denavir heals cold sores on average in 4.5 days.  In clinical
trials, Denavir was generally well tolerated.  The most frequently reported
side effects for both Denavir and placebo were headaches (5.3% Denavir vs.
5.8% placebo) and reactions at the site where the product was applied (1.3%
Denavir vs. 1.8% placebo).  Currently, products marketed for cold sores in the
United States are nonprescription preparations, which moisturize and/or
relieve pain.
    "The clinical studies showed that Denavir was significantly better than
placebo in treating cold sores," said Virginia Sulica, M.D., chief, Division
of Dermatology, Georgetown University Medical Center, and a key member of the
Denavir Investigative Team.  "Denavir should be used at the first sign of a
cold sore, at the first sign of swelling or tingling, which is why it's
important for recurrent cold sore sufferers to keep the product on hand, so
they're prepared for their next outbreak."
    A Sore Subject
    Cold sores are unsightly and can be embarrassing.  To try to understand
the feelings and experiences of recurrent cold sore sufferers, SmithKline
Beecham surveyed more than 1,000 U.S. adults and found some interesting
results.
    The survey sample projected that nearly 16 million cold sore sufferers
incorrectly believe their outbreaks are caused by an airborne virus.
Recurrent cold sores are actually caused by the herpes simplex virus type 1,
and most people are infected with the virus before they are 4 years of age.
The virus that causes cold sores is NOT the same virus that generally causes
genital herpes, herpes simplex virus type 2.
    Once one is infected with the virus, it stays in the body forever.  The
most common factors that trigger cold sores are:


    --Fever          --Dental work             --Common cold
    --Stress         --Excessive heat or cold  --Sun exposure
    --Exhaustion     --Shaving                 --Menstruation
    --Pregnancy      --General ill health

    Cold sores also can have many social implications.  According to the
survey, 30 percent of women would like to stay home from work during a cold
sore outbreak.  And one of three respondents wish they could miss or
reschedule a business meeting when they have a cold sore.  Additionally, 24
percent of adult sufferers wish they could cancel a date when they have a cold
sore outbreak.  As the survey revealed, many people want to miss work or
cancel appointments, but today's hectic lifestyles don't allow people to do
so.  Only 8 percent of cold sore sufferers actually do stay home from work
during a cold sore outbreak.
    The Word of Mouth
    To clear up cold sore misconceptions and answer questions about the causes
and treatments of cold sores, cold sore sufferers can call 1-888-HEALS-FAST to
receive a free brochure.
    SmithKline Beecham, one of the world's leading healthcare companies,
discovers, develops, manufactures and markets pharmaceuticals, vaccines, over-
the-counter medicines and health-related consumer products, and provides
healthcare services, including clinical laboratory testing, disease management
and pharmaceutical benefit management.

    * See attached Denavir prescribing information.

    PRESCRIBING INFORMAT10N
    DENAVIR(TM)
    brand of
    penciclovir cream, 1%
    For Dermatologic Use Only

    DESCRIPTION
    Denavir contains penciclovir, an antiviral agent active against herpes
viruses.  Denavir is available for topical administration as a 1% white cream.
Each gram of Denavir contains 10 mg of penciclovir and the following inactive
ingredients: cetomacrogol 1000 BP, cetostearyl alcohol, mineral oil, propylene
glycol, purified water and white petrolatum.
    Chemically, penciclovir is known as 9-[4-hydroxy-3-(hydroxymehyl)
butyl]guanine.  Its molecular formula is C10H15N503; its molecular weight is
253.26.  It is a synthetic acyclic guanine derivative and has the following
structure:

    penciclovir

    Penciclovir is a white to pale yellow solid.  At 20 degrees C it has a
solubility of 0.2 mg/mL in methanol, 1.3 mg/mL in propylene glycol, and 1.7
mg/mL in water.  In aqueous buffer (pH 2) the solubility is 10.0 mg/mL.
Penciclovir is not hygroscopic.  Its partition coefficient in n-octanol/water
at pH 7.5 is 0.024 (1ogP= -1.62).

    CLINICAL PHARMACOLOGY
    Microbiology
    Mechanism of Antiviral Activity: The antiviral compound penciclovir has in
vitro inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2
(HSV-2).  In cells infected with HSV-1 or HSV-2, viral thymidine kinase
phosphorylates penciclovir to a monophosphate form which, in turn, is
converted to penciclovir triphosphate by cellular kinases.  In vitro studies
demonstrate that penciclovir triphosphate inhibits HSV polymerase
competitively with deoxyguanosine triphosphate.  Consequently, herpes viral
DNA synthesis and, therefore, replication are selectively inhibited.
    Antiviral Activity In Vitro and In Vivo: In cell culture studies,
penciclovir has antiviral activity against HSV-1 and HSV-2.  Sensitivity test
results, expressed as the concentration of the drug required to inhibit growth
of the virus by 50% (IC50) or 99% (IC99) in cell culture, vary depending upon
a number of factors, including the assay protocols.  See Table 1.

    Table 1
                                   Table 1
    Method of Assay         Virus Type     Cell Type IC50 (mcg/mL)     IC99
                                                                     (mcg/mL)
    Plaque Reduction        HSV-1 (c.i.)     MRC-5     0.2-0.6
                            HSV-1 (c.i.)      WISH    0.04-0.5
                            HSV-2 (c.i.)     MRC-5     0.9-2.1
                            HSV-2 (c.i.)      WISH     0.1-0.8
    Virus Yield Reduction   HSV-1 (c.i.)     MRC-5                   0.4-0.5
                            HSV-2 (c.i.)     MRC-5                   0.6-0.7
    DNA Synthesis InhibitionHSV-1 (SC16)     MRC-5        0.04
                               HSV-2(MS)     MRC-5        0.05

    (c.i.) - clinical isolates.  The latent state of any herpes virus is not
known to respond to any antiviral therapy.

    Drug Resistance: Penciclovir-resistant mutants of HSV can result from
qualitative changes in viral thymidine kinase or DNA polymerase.  The most
commonly encountered acyclovir-resistant mutants that are deficient in viral
thymidine kinase are also resistant to penciclovir.
    Pharmacokinetics
    Measurable penciclovir concentrations were not detected in plasma or urine
of healthy male volunteers (n=12) following single or repeat application of
the 1% cream at a dose of 180 mg penciclovir daily (approximately 67 times the
estimated usual clinical dose).
    Pediatric Patients: The systemic absorption of penciclovir following
topical administration has not been evaluated in patients <18 years of age.

    CLINICAL TRIALS
    Denavir was studied in two double-blind, placebo (vehicle)-controlled
trials for the treatment of recurrent herpes labialis in which otherwise
healthy adults were randomized to either Denavir or placebo.  Therapy was to
be initiated by the subjects within 1 hour of noticing signs or symptoms and
continued for 4 days, with application of study medication every 2 hours while
awake.  In both studies, the mean duration of lesions was approximately
one-half-day shorter in the subjects treated with Denavir (N=1,516) as
compared to subjects treated with placebo (N=1,541) (approximately 4.5 days
versus 5 days, respectively).  The mean duration of lesion pain was also
approximately one-half-day shorter in the Denavir group compared to the
placebo group.

    INDICATIONS AND USAGE

    Denavir (penciclovir cream) is indicated for the treatment of recurrent
herpes labialis (cold sores) in adults.

    CONTRAINDICATIONS
    Denavir is contraindicated in patients with known hypersensitivity to the
product or any of its components.

    PRECAUTIONS
    General
    Denavir should only be used on herpes labialis on the lips and face.
Because no data are available, application to human mucous membranes is not
recommended.  Particular care should be taken to avoid application in or near
the eyes since it may cause irritation.  The effect of Denavir has not been
established in immunocompromised patients.
    Carcinogenesis, Mutagenesis, Impairment of Fertility
    In clinical trials, systemic drug exposure following the topical
administration of penciclovir cream was negligible, as the penciclovir content
of all plasma and urine samples was below the limit of assay detection (0.1
mcg/mL and 10 mcg/mL, respectively).  However, for the purpose of
inter-species dose comparisons presented in the following sections, an
assumption of 100% absorption of penciclovir from the topically applied
product has been used.  Based on use of the maximal recommended topical dose
of penciclovir of 0.05 mg/kg/day and an assumption of 100% absorption, the
maximum theoretical plasma AUC0-24 hrs for penciclovir is approximately 0.129
mcg.hr/mL.
    Carcinogenesis: Two-year carcinogenicity studies were conducted with
famciclovir (the oral prodrug of penciclovir) in rats and mice.  An increase
in the incidence of mammary adenocarcinoma (a common tumor in female rats of
the strain used) was seen in female rats receiving 600 mg/kg/day
(approximately 395x the maximum theoretical human exposure to penciclovir
following application of the topical product, based on area under the plasma
concentration curve comparisons [24 hr. AUC]).  No increases in tumor
incidence were seen among male rats treated at doses up to 240 mg/kg/day
(approximately 190x the maximum theoretical human AUC for penciclovir), or in
male and female mice at doses up to 600 mg/kg/day (appromimately 100x the
maximum theoretical human AUC for penciclovir).
    Mutagenesis: When tested in vitro, penciclovir did not cause an increase
in gene mutation in the Ames assay using multiple strains of S. typhimurium or
E. coli (at up to 20,000 mcg/plate), nor did it cause an increase in
unscheduled DNA repair in mammalian HeLa S3 Cells (at up to 5,000 mcg/mL).
However, an increase in clastogenic responses was seen with penciclovir in the
L5178Y mouse lymphoma cell assay (at doses > or = 1000 mcg/mL) and, in human
lymphocytes incubated in vitro at doses > or = 250 mcg/mL.  When tested in
vivo, penciclovir caused an increase in micronuclei in mouse bone marrow
following the intravenous administration of doses > or = 500 mg/kg (> or =
810x the maximum human dose, based on body surface area conversion).
    Impairment of Fertility: Testicular toxicity was observed in multiple
animal species (rats and dogs) following repeated intravenous administration
of penciclovir (160 mg/kg/day and 100 mg/kg/day, respectively, approximately
1155 and 3255x the maximum theoretical human AUC).  Testicular changes seen in
both species included atrophy of the seminiferous tubules and reductions in
epididymal sperm counts and/or an increased incidence of sperm with abnormal
morphology or reduced motility.  Adverse testicular effects were related to an
increasing dose or duration of exposure to penciclovir.  No adverse testicular
or reproductive effects (fertility and reproductive function) were observed in
rats after 10 to 13 weeks dosing at 80 mg/kg/day, or testicular effects in
dogs after 13 weeks dosing at 30 mg/kg/day (575 and 845x the maximum
theoretical human AUC, respectively).  Intravenously administered penciclovir
had no effect on fertility or reproductive performance in female rats at doses
of up to 80 mg/kg/day (26Ox the maximum human dose [BSA]).
    There was no evidence of any clinically significant effects on sperm
count, motility or morphology in 2 placebo-controlled clinical trials of
Famvir(R) (famciclovir [the oral prodrug of penciclovir], 250 mg b.i.d; n=66)
in immunocompetent men with recurrent genital herpes, when dosing and
follow-up were maintained for 18 and 8 weeks, respectively (approximately 2
and 1 spermatogenic cycles in the human).

    Pregnancy
    Teratogenic Effects-Pregnancy Category B.  No adverse effects on the
course and outcome of pregnancy or on fetal development were noted in rats and
rabbits following the intravenous administration of penciclovir at doses of
80 and 60 mg/kg/day, respectively (estimated human equivalent doses of 13 and
18 mg/kg/day for the rat and rabbit, respectively, based on body surface area
conversion; the body surface area doses being 260 and 355x the maximum
recommended dose following topical application of the penciclovir cream).
There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human
response, penciclovir should be used during pregnancy only if clearly needed.
    Nursing Mothers
    There is no information on whether penciclovir is excreted in human milk
after topical administration.  However, following oral administration of
famciclovir (the oral prodrug of penciclovir) to lactating rats, penciclovir
was excreted in breast milk at concentrations higher than those seen in the
plasma.  Therefore, a decision should be made whether to discontinue the drug,
taking into account the importance of the drug to the mother.  There is no
data on the safety of penciclovir in newborns.
    Pediatric Use
    Safety and effectiveness in pediatric patients have not been established.
    Geriatric Use
    In 74 patients > or = 65 years of age, the adverse events profile was
comparable to that observed in younger patients.

    ADVERSE REACTIONS
    In two double-blind, placebo-controlled trials, 1,516 patients were
treated with Denavir (penciclovir cream) and 1,541 with placebo.  The most
frequently reported adverse event was headache, which occurred in 5.3% of the
patients treated with Denavir and 5.8% of the placebo-treated patients.  The
rates of reported local adverse reactions are shown in Table 2 below.  One or
more local adverse reactions were reported by 2.7% of the patients treated
with Denavir and 3.9% of placebo-treated patients.

    Table 2 -- Local Adverse Reactions Reported in Phase III Trials

                                                Penciclovir      Placebo
                                                  n=1,516        n=1,541
                                                     %              %
    Application site reactions                      1.3            1.8
    Hyperthesa/Local anesthesia                     0.9            1.4
    Taste perversion                                0.2            0.3
    Pruritus                                        0.0            0.3
    Pain                                            0.0            0.1
    Rash (erythematous)                             0.1            0.1
    Allergic reaction                               0.0            0.1

    Two studies, enrolling 108 healthy subjects, were conducted to evaluate
the dermal tolerance of 5% penciclovir cream (a 5-fold higher concentration
then the commercial formulation) compared to vehicle using repeated occluded
patch testing methodology.  The 5% penciclovir cream induced mild erythema in
approximately one-half of the subjects exposed, an irritancy profile similar
to the vehicle control in terms of severity and proportion of subjects with a
response.  No evidence of sensitization was observed.

    OVERDOSAGE
    Since penciclovir is poorly absorbed following oral administration,
adverse reactions related to penciclovir ingestion are unlikely.  There is no
information on overdose.

    DOSAGE AND ADMINISTRATION
    Denavir should be applied every 2 hours during waking hours for a period
of 4 days.  Treatment should be started as early as possible (i.e., during the
prodrome or when lesions appear).

    HOW SUPPLIED
    Denavir is supplied in a 2 gram tube containing 10 mg of penciclovir per
gram.
    NDC 00135-315-51
    Store at or below 30 degrees C (86 degrees F).  Do not freeze.
    CAUTION: Federal law prohibits dispensing without prescription.

    DATE OF ISSUANCE JANUARY 1997 * SmithKline Beecham, 1997

    Comments or questions?  Call toll-free 1-800-320-6022.

    Manufactured in Crawley, UK by SmithKline Beecham Pharmaceuticals, for
SmithKline Beecham Consumer Healthcare, L.P., Pittsburgh, PA 15230

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