**Background for Advisory Committee Meeting to Discuss Oral Tazarotene
for the Treatment of Moderate to Severe Psoriasis**

**[I. Introduction to Psoriasis]{.underline}**

Psoriasis is a polygenic disease and various triggering factors, e.g.
trauma, infections, or medications, may elicit a psoriatic phenotype in
predisposed individuals. There is some evidence that various cytokines
and immunologic function may be involved in the pathogenesis of the
disease. It is a chronic, relapsing disease with variable clinical
features. Psoriasis occurs in all races and all age groups. There are
many therapeutic modalities that are currently available for psoriasis.
None of them is perfect and none of them induces a permanent remission.

[Genetics and Pathogenesis]{.underline}

There is some evidence that the immune system is involved in the
pathogenesis of psoriasis. The strongest evidence is the association of
psoriasis with the major histocompatibility complex (MHC) situated on
the short arm of chromosome 6 and its association with several
histocompatibility antigens (HLA): HLA-B13, HLA-B17, HLA-B37, and
HLA-Bw16. The strongest risk of developing psoriasis is associated with
HLA-Cw6.

Some observations have suggested that psoriasis may be driven in part by
a T-lymphocyte-mediated mechanism and that psoriasis is actually a
systemic disease with skin manifestations being only one component. This
is reflected in other clinical manifestations of the disease: Koebner
phenomenon, elevated uric acid levels, which may lead to gouty
arthritis, mild anemia, increased ESR, increased α~2~-macroglobulin,
immunoglobulin aberrations, including increased IgA levels and increased
quantities of immune complexes, psoriatic arthropathy, the aggravation
of psoriasis by systemic factors such as stress, medication and focal
infections, and the life-threatening forms of psoriasis.

[Prevalence]{.underline}

Psoriasis occurs in 2% of the world\'s population. Depending on the
source, the prevalence in the U.S. and Canada may be as high as 4.6% and
4.7%, respectively. The prevalence in ethnic groups other than
Caucasians is much lower. The frequency in Africans, African Americans,
and Asians is between 0.4% and 0.7%. Psoriasis occurs with equal
frequency is males and females. Psoriasis may occur at any age, from
infancy to the 10^th^ decade of life. First signs of psoriasis occur in
females at a mean age of 27 and in males at a mean age of 29. Two peaks
of occurrence are generally accepted, one at 20-30 years of age and one
at 50-60 years of age. However, approximately 75% of patients have an
onset of disease prior to the age of 40. The prevalence of psoriasis in
children is much lower, somewhere between 0.5% and 1.1% in children 16
years old and younger with an estimated mean age of onset in children
between 8 and 12.5 years of age.

Two-thirds of patients with psoriasis have mild disease, while one-third
of patients have moderate to severe disease. Early onset of disease
(prior to age 15) has been associated with more severe disease in terms
of body surface area (BSA) involvement and response to therapy. Patients
with early onset of psoriasis are also more likely to have a family
history of the disease.

Once the disease occurs, it persists throughout life, manifesting itself
at unpredictable intervals. There may be spontaneous remissions which
have been reported to occur, and remission times of 5 years or more have
been reported in approximately 5% of patients.

[Clinical Variants of Psoriasis]{.underline}

The characteristic lesion of psoriasis is a sharply demarcated
erythematous plaque with micaceous silvery white scale. The scaly red
plaque is a clinical reflection of the histopathology which includes
hyperkeratosis, parakeratosis, acanthosis of the epidermis, tortuous and
dilated vessels and an inflammatory infiltrate composed mostly of
lymphocytes. The severity of the disease is associated, in part, with
the degree of plaque elevation, erythema, and scale present on lesional
skin. The evaluation of the severity of the disease is complex, as
patients may have localized severe disease or widespread mild disease.
It depends in part on the intensity of the 3 cardinal signs of the
individual lesions: erythema, plaque elevation, and scale.

The most common variant of psoriasis is chronic plaque psoriasis. This
is characterized by psoriatic plaques that may be as large as 20 cm in
diameter. Sites of predilection include symmetrical lesions on the
elbows, knees, presacrum, scalp, as well as the hands and feet. However,
the lesions may be widespread and cover up to 90% of the BSA. The
genitalia are involved in up to 30% of patients. The face is usually
spared in psoriasis, except for areas that are contiguous with the
scalp. Most patients with psoriasis have varying degrees of nail
changes. These may range from nail pitting, to \"oil spots\", to
involvement of the entire nail bed with onychodystrophy, to loss of the
nail plate. Patients often complain of the unsightliness of the lesions,
low self-esteem, feelings of being socially outcast, pruritus, and pain,
especially when the hands, feet, or intertriginous areas are involved.
Patients with more generalized psoriasis complain of excessive scale and
heat loss.

Guttate psoriasis is characterized by numerous 0.5 to 1.5 cm papules and
plaques over the upper trunk and proximal extremities. This form of
psoriasis is characteristic of early age of onset and is the most common
form in children. Streptococcal throat infection often is a trigger
factor. Spontaneous remissions are the rule in children but in adults it
can become chronic.

There are two variants of psoriasis associated with high morbidity and
that can be fatal, generalized pustular psoriasis and erythrodermic
psoriasis. Generalized pustular psoriasis is an unusual manifestation of
psoriasis which may be gradual or acute in onset. It is characterized by
waves of pustules on erythematous skin. Short episodes of fever, 39˚to
40˚, are followed by a new wave of pustules. Patients also experience
weight loss, muscle weakness, hypocalcemia, leukocytosis, and increased
ESR. Although the cause of this illness is obscure, there are known
triggering factors which include infection, pregnancy, lithium,
hypocalcemia secondary to hypoalbuminemia, irritant contact dermatitis,
and withdrawal from glucocorticosteroids.

In erythrodermic psoriasis, the classic lesion is lost and the entire
skin surface becomes markedly erythematous with desquamative scaling.
Clues that the erythroderma is secondary to psoriasis are the presence
of the classic nail changes and usually, but not always, facial sparing.
This disease can be fatal, and triggering factors include systemic
infection, withdrawal of high potency topical or oral steroids,
phototoxicity, and irritant contact dermatitis (e.g. tar).

[State of the Armamentarium]{.underline}

The focus of this advisory committee meeting is the treatment of
moderate to severe psoriasis, thus treatments for less severe forms of
the disease will not be discussed. As a background, there does not exist
any perfect treatment for psoriasis. Treatments to date do not induce a
permanent remission and most often must be given in cyclical or
continuous fashion in an effort to circumvent unwanted adverse events in
a disease that has to be treated over an individual\'s lifetime.

[Topical Corticosteroids]{.underline}

Topical corticosteroids have been the mainstay of treatment of psoriasis
since their introduction in 1952. They are often first-line treatment
for mild to moderate psoriasis as well as in sites such as the flexures
and genitalia. The developments of high potency and super potent topical
steroids have opened the door for successful treatment of severe
psoriasis, as well. The high potency topical steroids include the
fluocinonide family (cream, ointment, gel) as well as betamethasone
dipropionate cream. The super potent topical steroids include the
clobetasol propionate family (cream, ointment, gel, foam, lotion) as
well as diflorasone diacetate ointment and betamethasone dipropionate
ointment.

The efficacy of these drug products is well established in the treatment
of chronic plaque psoriasis. A recent study of clobetasol propionate
lotion in the treatment of moderate to severe psoriasis demonstrated
efficacy after 4 weeks of twice daily treatment in 36.6% of patients
compared to 0% in placebo. Treatment success was achieved in patients
who obtained a score of clear or almost clear on the Investigator\'s
Global Assessment Scale.

Side effects associated with the use of topical corticosteroids include
skin atrophy, burning and stinging, and suppression of the
hypothalamic-pituitary-adrenal (HPA) axis. This may occur after two
weeks of use with certain topical corticosteroids.

[Topical Vitamin D~3~ Analogues]{.underline}

The prototype of this group of drug products is calcipotriene, approved
in the United States. It comes in 3 formulations, cream, ointment, and
scalp solution. The former two are approved for plaque psoriasis and the
scalp solution is approved for moderately severe psoriasis of the scalp.
In clinical trials, the proportion of patients with at least marked
improvement after 8 weeks of twice daily therapy was 50% and 49.6% for
the cream and ointment formulations, respectively. Thirty-one percent of
patients after 8 weeks of twice daily treatment with scalp solution were
clear or almost clear.

Side effects are cutaneous and include burning, stinging, itching, skin
irritation, and tingling of the skin.

[Topical Retinoids]{.underline}

Topical tazarotene gel is approved in two strengths, 0.05% and 0.1%, for
the treatment of stable plaque psoriasis of up to 20% BSA involvement.
In clinical trials, patients with at least moderate psoriasis were
treated for 12 weeks once daily. The percentage of patient with at least
a 75% improvement from baseline was 28% and 18% for the 0.05%
concentration in two placebo controlled studies and 38% and 25% for the
0.1% formulation in two placebo controlled studies. The vehicle effect
was 12% and 10%.

The most frequent adverse reactions were limited to the skin. These
included pruritus, burning/stinging, erythema, worsening of psoriasis,
irritation, and skin pain.

It should be noted that topical tazarotene has other indications.
Tazarotene gel, 0.1%, is also approved for the treatment of facial acne
vulgaris of mild to moderate severity, and tazarotene cream, 0.1%, is
approved as an adjunctive agent for use in the mitigation of facial fine
wrinkling, facial mottled hyper- and hypopigmentation, and benign facial
lentigines in patients who use comprehensive skincare and sunlight
avoidance programs.

Tazarotene gel and cream are pregnancy category X drug products and as
such are contraindicated in women who are or may become pregnant. A
negative pregnancy test should be obtained 2 weeks prior to initiation
of therapy, and therapy should be initiated during a normal menses.
Women of childbearing potential should use adequate birth control.

[Photo(chemo)therapy]{.underline}

Phototherapy is usually reserved for moderate to severe psoriasis.
Phototherapy involves treatment with UVB alone. Broadband UVB
phototherapy has been an effective approach to treatment of moderate to
severe psoriasis. In recent years, a shift to narrow band UVB (311-313
nm) has become more optimal.

Treatment with UVB is time consuming, requiring 2-3 visits/week for
treatment for several months and the possibility of experiencing an
acute sunburn reaction.

Photochemotherapy consists of ingestion of or topical treatment with a
psoralen followed by UVA. Photochemotherapy with a psoralen followed by
UVA has been very successful in the treatment of severe, recalcitrant,
disabling psoriasis, not responsive to other therapies. Patients must be
protected from further ultraviolet light for 24 hours after exposure to
the psoralen + UVA. In the case of oral ingestion, wrap around
UV-blocking eyeglasses are worn for 24 hours post treatment. In most
patients clearing of the disease is achieved after 19-25 treatments,
approximately 100 - 245 J/ cm^2^ of UVA.

Treatment with PUVA is time consuming, requiring visits 2-3 times per
week for treatment. Side effects of oral psoralen can include nausea,
dizziness, and headache. A major early side effect of PUVA is pruritus.
Long term side effects include skin damage and an increased risk for
skin cancer, particularly squamous cell carcinoma. For squamous
carcinoma, the risk increases after 2000 J/cm^2^ of UVA.

Contraindications to the use of psoralen include patients under 12 years
of age, patients possessing a history of light sensitive disease states,
patients with, or with a history of, melanoma, patients with invasive
squamous cell carcinoma, and patients with aphakia because of increased
risk of retinal damage due to the absence of lenses.

[Systemic Therapies - Oral]{.underline}

[Methotrexate (Aminopterin)]{.underline}

Methotrexate (MTX) is a folic acid antagonist approved for the treatment
of severe, recalcitrant, disabling psoriasis that is not adequately
responsive to other forms of therapy. Maximum improvement from MTX can
be expected after 8-12 weeks of therapy. There are no recent placebo
controlled trials in patients with psoriasis. However, in one series by
A. Nyfors in the Danish Medical Bulletin, \>75% improvement was observed
in 90% of 248 patients. Of 141 patients with nail psoriasis, complete
resolution was observed in 63 patients (44.7%).

Contraindications to the use of methotrexate include nursing mothers,
patients with alcoholism, alcoholic liver disease, or other chronic
liver disease, patients with overt or laboratory evidence of
immunodeficiency syndromes, and patients who have preexisting blood
dyscrasias, such as bone marrow hypoplasia, leukopenia,
thrombocytopenia, or significant anemia.

Methotrexate is a pregnancy category X drug product, as it is a human
teratogen which can cause cranial defects and absence of digits. It is
contraindicated in pregnant women with psoriasis. Women of childbearing
potential should not be started on methotrexate until pregnancy is
excluded and should be fully counseled on the serious risk to the fetus
should they become pregnant while undergoing treatment. Pregnancy should
be avoided if either partner is receiving methotrexate; during and for a
minimum of three months after therapy for male patients, and during and
for at least one ovulatory cycle after therapy for female patients.

The most serious side effects of methotrexate in psoriasis patients
include acute or chronic hepatotoxicity, hepatic cirrhosis, leukopenia,
thrombocytopenia, anemia, including aplastic anemia, and rarely
interstitial pneumonitis. Erythrodermic psoriasis has occurred upon
withdrawal of methotrexate. Other side effects include stomatitis,
nausea/vomiting, alopecia, photosensitivity, and \"burning of skin
lesions.\"

Multiple prescreening tests must be performed before the use of MTX in
the treatment of psoriasis including a liver biopsy in patients with
risk factors for hepatic disease. All patients that receive a cumulative
dose of MTX of 1.5 grams, which may occur after 2 years of continuous
use, must have a liver biopsy.

[Neoral (Cyclosporine)]{.underline}

Neoral is a potent immunosuppressive agent approved for adult,
nonimmunocompromised patients with severe, recalcitrant plaque psoriasis
who have failed at least one systemic therapy. Although approved for a
more severe form of psoriasis, many patients in an active controlled
trial comparing Neoral to Sandimmune (cyclosporine) had moderate to
severe disease. The percentage of patients that obtained a clear or
almost clear on Neoral and Sandimmune was 58.8% and 50.0%, respectively,
after 16 weeks of twice daily therapy.

Contraindications to the use of Neoral in psoriasis patients include
concomitant PUVA or UVB therapy, methotrexate or other immunosuppressive
agents, coal tar or radiation therapy. It is also contraindicated in
psoriasis patients with abnormal renal function, uncontrolled
hypertension, or malignancies. Cyclosporine should also not be given to
psoriasis patients who are breast-feeding.

The most serious risk with cyclosporine therapy is the possibility of
irreversible renal damage. The other serious risk is the development of
new onset hypertension or worsening of existing hypertension. Other
principal side effects associated with cyclosporine use include
headache, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or
hyperesthesia, influenza-like symptoms, nausea/vomiting, diarrhea,
lethargy, and arthralgia.

Multiple prescreening tests must be performed and monitored throughout
the use of cyclosporine in patients with psoriasis to prevent end-organ
damage.

[Soriatane (acitretin)]{.underline}

Soriatane is an oral retinoid approved for the treatment of severe
psoriasis in adults.

Soriatane is contraindicated in patients with severely impaired liver or
kidney function and in patients with chronic abnormally elevated blood
lipid values. The combined use of methotrexate and Soriatane is also
contraindicated.

Soriatane is a human teratogen and therefore is a pregnancy category X
drug product. It is contraindicated in pregnant females or in those who
intend to become pregnant during therapy or at any time for at least 3
years following discontinuation of therapy. Ethanol is also
contraindicated when on therapy and for 2 months following therapy with
Soriatane in female patients.

Side effects associated with Soriatane are those that are associated
with retinoid therapy. Those include primarily cheilitis, alopecia, skin
peeling, dry skin, pruritus, rhinitis, xeropthalmia, arthralgia,
hypertriglyceridemia (66%), decreased HDL (40%), hypercholesterolemia
(33%), elevated liver function tests (33%), elevated alkaline
phosphatase (10-25%), hyperglycemia (10-25%), and elevated CPK (10-25%).
Hepatitis and jaundice occurred in less than 1% of patients in clinical
trials on Soriatane.

Multiple prescreening and continued monitoring with possible dose
adjustment is necessary throughout therapy with Soriatane to prevent
end-organ damage.

[Parenteral Therapy]{.underline}

There are 3 biologics that have recently been approved for the treatment
of moderate to severe chronic plaque psoriasis in adults, Amevive
(alefacept), Raptiva (efalizimab), and Enbrel (etanercept). Amevive will
be discussed as a prototype for this class of drug products.

[Amevive (alefecept)]{.underline}

Amevive is an immunosuppressive dimeric fusion protein that consists of
the extracellular CD2-binding portion of the human leukocyte function
antigen-3 (LFA-3) linked to the Fc portion of human IgG1. It is
indicated for the treatment of adult patients with moderate to severe
chronic plaque psoriasis who are candidates for systemic therapy or
phototherapy.

In clinical trials, patients received either 7.5 mg IV of Amevive or 15
mg IM of Amevive once weekly for 12 weeks. The percentage of patients
who achieved a disease state of clear or almost clear was 11% and 14%,
respectively.

The major side effect of amevive is a dose-dependent reduction in
circulating CD4+ and CD8+ T lymphocytes. CD4+ T lymphocytes must be
monitored before and throughout therapy with Amevive.

It may also increase the risk of malignancies, infection, and reactivate
latent, chronic infections, as reflected in the clinical trials. The
most serious adverse reactions were lymphopenia, malignancies, serious
infections requiring hospitalization, and hypersensitivity reactions.
Malignancies accounted for 1.3% of amevive treated patients compared to
0.5% in the placebo group. The majority of malignancies were cutaneous
malignancies, squamous cell and basal cell. There were, however, 3 cases
of lymphoma diagnosed.

Since alefacept was approved only recently, the safety experience is
substantially less than for methotrexate and other drug products that
have been used for many years.

**[II. Summary of NDA 21-701]{.underline}**

Tazarotene capsule is an oral retinoid, a probable human teratogen,
submitted under NDA 21-701 with a proposed indication of "the treatment
of moderate to very severe psoriasis\". The drug is intended to be taken
at a dose of 4.5 mg once a day, with or without food. The Sponsor
proposes to market two dosage strengths, a 4.5 mg capsule and a 1.5 mg
capsule, with the claim that there may be a compliance problem with the
4.5 mg capsule. It is proposed that the safety and efficacy of
tazarotene capsules beyond 52 weeks of treatment has not been
established. Tazarotene is currently marketed as a gel formulation under
the trade name Tazorac^^ in two strengths, 0.05% and 0.1%, for the
treatment of stable plaque psoriasis. Tazorac gel, 0.1% is also approved
for the treatment of facial acne vulgaris of mild to moderate severity.

The terminal elimination half-lives of tazarotene and its metabolite are
much shorter than that of the other systemic retinoids, isotretinoin
(Accutane) and acitretin (Soriatane). The effective half-life range is
from 6.68 to 11.8 hours for tazarotene. It is 17-50 hours (mean 25) for
4-oxo-isotretinoin, the major metabolite of isotretinoin, and 8-157
hours (mean 63) for cis-acitretin, the major metabolite of acitretin
(see Appendix).

Semen analysis revealed that tazarotenic acid could be found in the
semen in a 1:1 ratio with that of the plasma. In a few cases, the semen
to plasma tazarotenic acid concentration ratio was 2.8:1 (see Appendix).

In toxicology animal studies, tazarotene appears to be a more potent
teratogen when compared to other retinoids.

[Non-Clinical]{.underline}

[General toxicology]{.underline}: Oral administration of tazarotene in
rats (3 to 6 months), dogs (4 to 9 months), and monkeys (1month to 1
year) produced effects that were characteristic of retinoid toxicity.
Maximum systemic exposure (AUC) to tazarotenic acid in these studies was
generally similar or greater than (dogs), or less than (rats and
monkeys) systemic exposure in humans at the recommended daily oral dose
(4.5 mg). Primary target organs/systems included bone, liver (including
serum lipids), kidney, heart, thymus, testis, and skin.

[Genetic toxicology]{.underline}: Tazarotene was non-mutagenic in Ames
assays using *Salmonella* and *E. coli* and did not produce structural
chromosomal aberrations in a human lymphocyte assay*.* Tazarotene was
also non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation
assay and was non-clastogenic in the in vivo mouse micronucleus test.

[Carcinogenicity]{.underline}: A long-term study of tazarotene following
oral administration of 0.025, 0.050, and 0.125 mg/kg/day to rats showed
no indications of increased carcinogenic risks. Based on pharmacokinetic
data from a shorter-term study in rats, the highest dose of 0.125
mg/kg/day was anticipated to give systemic exposure
[(AUC~de~)]{.underline} in the rat less than 0.1 times that seen in
humans given a single dose of 4.5 mg tazarotene (AUC = 478 ng⋅hr/mL).

A long term topical application study of up to 0.1% tazarotene in a gel
formulation in mice terminated at 88 weeks showed that dose levels of
0.05, 0.125, 0.25, and 1.0 mg/kg/day (reduced to 0.5 mg/kg/day for males
after 41 weeks due to severe dermal irritation) revealed no carcinogenic
effects when compared to vehicle control animals; untreated control
animals were not completely evaluated. Systemic exposure at the highest
dose was below (0.7 times) the systemic exposure in humans given a
single oral dose of 4.5 mg tazarotene.

[Reproductive toxicology]{.underline}: No impairment of mating
performance or fertility was observed in male rats treated for 70 days
prior to mating with oral doses of up to 1 mg/kg/day of tazarotene. That
dose produced systemic exposure that was 0.3 times that observed in
humans given the maximum recommended oral dose of 4.5 mg tazarotene.
However, there was a significantly reduced sperm count and density in
male rats treated orally with 3 mg/kg/day tazarotene, in which the
systemic exposure was approximately 0.7 times the systemic exposure in
humans given a single oral dose of 4.5 mg tazarotene.

No effect on parameters of mating performance or fertility was observed
in female rats treated for 15 days prior to mating and continuing
through day 7 of gestation with oral doses of tazarotene up to 2
mg/kg/day. However, there was a significant decrease in the number of
estrus stages and an increase in developmental effects at this dose.
This dose produced systemic exposure that was 0.6 times the systemic
exposure in humans given a single oral dose of 4.5 mg tazarotene.

Teratogenic effects, including cleft palate and skull anomalies,
developmental and behavior delays, and post-implantation loss were seen
when parent rats were dosed orally with 0.25 mg/kg/day of tazarotene
during gestation day 6 through 17. This dose produced systemic exposure
that was 0.2 times the systemic exposure in humans given a single oral
dose of 4.5 mg of tazarotene. Teratogenic effects, including pinnae
anomalies, cleft palate, spina bifida, heart anomalies, skull anomalies,
hyoid anomalies, and tympanic ring anomalies and post-implantation loss
were seen when parent rabbits were dosed orally with 0.20 mg/kg/day of
tazarotene during gestation day 6 through 18. This dose produced
systemic exposure that was 4.7 times the systemic exposure in humans
given a single oral dose of 4.5 mg of tazarotene. Tazarotene 0.05% gel
administered topically during gestation day 6 through 17 at 0.25
mg/kg/day in rats resulted in reduced fetal body weights and reduced
skeletal ossification. Rabbits dosed topically with 0.25 mg/kg/day of
tazarotene gel during gestation day 6 through 18 were noted with single
incidences of known retinoid malformations, including spina bifida,
hydrocephaly, and heart anomalies.

Stillbirths, decreased F1 survival and body weights, retinoid
malformations, developmental delays and decreased reproductive
capabilities of F1 females (reduced number of corpora lutea,
implantations, and live litter size) were observed following an oral
dose of 1 mg/kg/day of tazarotene in female F0 parental rats from
gestation day 7 through lactation day 20. This dose produced systemic
exposure that was 0.4 times the systemic exposure in humans given a
single oral dose of 4.5 mg of tazarotene. The maternal and
reproductive/developmental NOAEL for oral tazarotene in rats was 0.1
mg/kg/day.

[Conclusion:]{.underline} Tazarotene was a teratogen in rats and
rabbits. The maximum recommended human dose is 0.075 mg/kg/day for
tazarotene, 0.83 mg/kg/day for Soriatane, and 2.0 mg/kg/day for
Accutane. Based on the following information, tazarotene is more potent
than the other retinoids based on a mg/kg/day basis in rats and rabbits,
and tazarotene is a probable human teratogen.

Lowest Teratogenic Dose (mg/kg/day)

+---------+----------+-----------+----------+----------+-------------+
| Species | Ta       | A         | Et       | T        | I           |
|         | zarotene | citretin) | retinate | retinoin | sotretinoin |
|         |          | ^a^       | ^b,c^    | ^b^      | ^b^         |
|         |          |           |          |          |             |
|         |          | (S        |          |          | (Accutane)  |
|         |          | oriatane) |          |          |             |
+---------+----------+-----------+----------+----------+-------------+
| Human   |          |           | 0.2      | N.D.     | 0.4         |
+---------+----------+-----------+----------+----------+-------------+
| P       |          |           | 5        | 7.5      | 5           |
| rimates |          |           |          |          |             |
+---------+----------+-----------+----------+----------+-------------+
| H       |          |           | 2.8      | 1.25     | 25          |
| amsters |          |           |          |          |             |
+---------+----------+-----------+----------+----------+-------------+
| Rabbits | 0.2      | 0.6       | 2        | 2 - 10   | 10          |
+---------+----------+-----------+----------+----------+-------------+
| Rats    | 0.25 --  | 15        | 2 -- 8   | 0.4 - 2  | 150         |
|         | 1        |           |          |          |             |
+---------+----------+-----------+----------+----------+-------------+
| Mice    |          | 3         | 4        | 4        | 100         |
+---------+----------+-----------+----------+----------+-------------+

> ^a^ Pharmac. Ther. 40:29-43, 1989
>
> ^b^ Toxicology 57:117-161, 1989
>
> ^c^ J. Am. Acad. Dermatol. 6:652-659, 1982

[Clinical Safety]{.underline}

There have been a total of 987 patients treated with tazarotene and 383
patients treated with placebo. Of the patients treated with tazarotene
831 subjects were treated with 4.5 mg once daily. The 831 patient safety
data base is derived from the two pivotal phase 2 trials, and 2
open-label trials. The pivotal phase 3 trials consisted of 12 weeks of
treatment with 12-week post-follow-up. Study 052P, an open label phase 3
trial, enrolled patients in the placebo arm of the pivotal trials and
those in the tazarotene arm with no response to treatment. These
patients received 12 weeks of tazarotene

followed by a 12-week post-treatment follow-up. Study 050P, an open
label phase 3 trial, consisted of patients treated once daily with 4.5
mg of tazarotene over the course of 52 weeks, with a 12-week
post-treatment follow-up.

In these studies, the majority of patients who did not complete the
treatment period discontinued for treatment related reasons. Treatment
related reasons (lack of efficacy and adverse events) accounted for 54%
(93/173) discontinuations during the treatment period among patients
treated with tazarotene 4.5 mg.

In the placebo-controlled studies, 3.4% (12/348) patients on tazarotene
discontinued because of adverse events compared to 2.5% (9/358) in the
placebo group. There were more adverse events that occurred in the
tazarotene group vs. the placebo group, 90.2% and 74.6%, respectively
(p\<0.001). Tazarotene treated subjects had significantly more headache
(18.7% vs. 12.0%), back pain (6.6% vs. 2.8%), foot pain (2.9% vs. 0.8%),
cheilitis (65.5% vs. 16.8%), arthralgia (17.5% vs. 7.3%), myalgia (14.7%
vs. 8.4%), joint disorder (4.0% vs. 1.1%), nasal dryness (3.7% vs.
1.1%), dry skin (23.6% vs.14.8%), rash (2.9% vs. 0.6%), and dermatitis
(1.4% vs. 0%) than did subjects treated with placebo. In the
post-treatment period, many of these adverse events improved. Only
cheilitis remained a statistically significant event.

Overall decreases in bone mineral density (BMD) were seen in up to 17%
of patients in the controlled studies. In study 048, at week 24 there
were 4 patients treated with tazarotene and one with placebo who had
decreases in BMD of \>5%. All were men in the age range of 40-69 years.
In addition, there was one patient who had a decrease of 50%. This is
significant because men lose bone density at a rate of only 0.5 - 0.75%
per year and women lose bone density at a rate of 1.5-2% per year. Thus,
a loss of even 1-3% over 36 weeks implies a greater than normal bone
loss over a year. Over a period of 5-10 years of treatment, this could
be significant.

Laboratory evaluations to assess for risk for end-organ damage revealed
significant elevations in plasma triglycerides as compared to placebo by
the reviewer and hyperglycemia as compared to placebo by the Applicant.
Other laboratory evaluations were not significant when compared to
placebo. There were 4 cases of hypothyroidism, 3 in the short term
trials and 1 in the long term trial. All patients were taking oral
tazarotene. At the present time, there have not been any signals
detected in the short term studies for psychiatric events. Full
evaluation of ophthalmology and audiology data is still pending.

Discontinuation rate was slightly higher for those patients previously
treated with tazarotene vs. those not (6.5% vs. 3.2%). It was found that
patients treated with a 2^nd^ course of tazarotene had significantly
more back pain (17.4% vs. 7.7%), arthralgias (33.7% vs. 14.1%), and
alopecia (5.4% vs. 0.9%) than patients who received only one course of
tazarotene. There was also a significant increase in hyperostosis scores
in the previously treated group than in the placebo group at weeks 12
and 24. The Sponsor found modest increases in triglyceride and alkaline
phosphatase levels in both groups. However, the increases in alkaline
phosphatase were higher in the group that received a second course and
remained elevated in the post-treatment period.

The long term safety study was conducted for 64 weeks, 52 weeks of
treatment and a 12 week post-treatment follow-up. Patients were
instructed to take oral tazarotene, a 4.5 mg capsule once daily for 52
weeks. If the patient\'s OLA score was reduced to 0 (clear) at any
visit, the patient was instructed to stop medication and subsequent
visits would evaluate the need to resume medication. During the 52-week
treatment period, the mean duration of exposure to tazarotene was 271.8
days (range 6 to 388 days, median, 359 days). Treatment exposure was at
least 24 weeks for 76.8% (202/263) of patients, was at least 48 weeks
for 58.2% (153/263), and was at least 52 weeks for 38.4% (101/253) of
patients. Treatment exposure for 50 and 51 weeks was 55.1% (145/263) and
53.6% (141/263), respectively.

During the 52-week treatment period, 1 or more adverse events were
reported for 98.9% (260/263) of patients. Adverse events that occurred
in more than 5% of patients were cheilitis (64.3%), arthralgia (36.1%),
myalgia (28.9%), infection (primarily upper respiratory tract; 28.5%),
dry skin (22.8%), back pain (22.1%), headache (20.9%), asthenia (11.4%),
and pruritus (11.4%), foot pain (9.9%), alopecia (7.6%), leg pain
(7.2%), arthritis (6.8%), paresthesia (6.5%), flu syndrome (6.5%),
nausea (6.1%), joint disorder (6.1%), insomnia (6.1%), rhinitis (5.7%),
and bronchitis (5.7%). Most of the adverse events were reported as mild
in severity.

In the long-term study, 14.4% (38/263) patients discontinued because of
adverse events. The adverse events that led to discontinuation of
treatment for more than 1 patient were arthralgia (10), myalgia (7),
arthritis (4), back pain (4), alopecia (4), dermatitis (3), joint
disorder (3), abnormal liver function tests (3), cheilitis (2), asthenia
(2), depression (2), and emotional liability (2).

Laboratory adverse events were evaluated by including those patients who
had normal values at screening but subsequently had elevated values on
at least 2 monthly visits and those patients who had abnormal values at
baseline and subsequently became worse at some point during the 52-week
treatment period.

Abnormal laboratory tests included hypertriglyceridemia (41.1%),
abnormal liver function tests (22.9%), elevated CPK (16.3%), elevated
alkaline phosphatase (13.7%), elevated TSH (5.3%), elevated SGOT (6.5%),
elevated SGPT (9.1%), abnormalities in hemic and lymphatic system
(5.7%).

Compared to the placebo controlled trials, only the elevation in
alkaline phosphatase is higher, 3.4% in the placebo controlled trials
vs. 13.7% in the long term safety study. This elevation in alkaline
phosphatase is may be related to an effect on bone synthesis. Alkaline
phosphatase levels remained elevated at the end of the post-treatment
period for 69.4% (25/36) of patients who had increases during treatment.
Based on the review of the current data, there is a trend toward a dose-
and follow-up time-related effect on osteosynthesis reactions to the
drug, manifest in exacerbation of musculoskeletal symptoms, increased
bone turnover, decreased bone mineral density and some mild increases in
ligament calcifications.

There were 6 moderate fractures without known cause reported in the
trials. Whether this is correlated to a decrease in bone mineral density
(BMD) is still being evaluated. The mean BMD decreased over time for the
entire set of patients tested in the trials, with some having decreases
close to 30%. Over 10% had significant decreases greater than 5%. In the
long term study, over 52 weeks of treatment, 5.3% (12/226) patients had
significant changes in calcification and/or osteophyte formation scores
of the cervical spine. Twenty-six percent of patients had worsening
changes in hyperostosis and ligament calcification with each vertebrae
of the cervical spine being involved. There was also a statistically
significant increase in ankle ligament osteophyte formation at weeks 52
and 64.

Musculoskeletal complaints also accounted for the majority of adverse
events that continued into the 12 week post-treatment period. Arthralgia
continued for 19.7% of patients, back pain for 17.8%, myalgia for 15.8%,
and arthritis for 6.6%. Other adverse events that continued for more
than 3% of patients included cheilitis (38.2%), dry skin (17.1%),
asthenia (7.9%), pruritus (6.6%), alopecia (4.6%), insomnia (3.9%),
joint disorder (3.9%), bronchitis (3.3%), oral dryness (3.3%), and hemic
and lymphatic (3.3%).

There have been 4 pregnancies that have occurred in trials with oral
tazarotene, one in a psoriasis trial (study 050P) and 3 in acne trials.
The pregnancy that occurred in the psoriasis trial was a result of
nonconsensual sex. The pregnancy was electively terminated. In the acne
trials, there was one elective termination, one spontaneous abortion 18
days after discontinuing tazarotene (fetal exposure of \~17 days), and
one term delivery, 38 weeks gestation. The term baby was exposed to
tazarotene 15 days after presumed date of conception. At 16.5 months,
the child had no evidence of complications.

Off-label use of oral tazarotene is a concern. There is already
widespread recognition among physicians who treat acne that there is a
topically delivered form of tazarotene approved for acne. Additional
enthusiasm for off-label use in acne may follow the Roster exhibits at
the Annual Meeting of the American Academy of Dermatology in February
2004. The following posters were presented:

P65 Photographic Documentation of the Efficacy of Oral Tazarotene in
Nodulocystic Acne

P67 Safety of Oral Tazarotene in Nodulocystic Acne

P69 Effects of Oral Tazarotene on Health-Related Quality of Life in
Patients with Severe Nodulocystic Acne: Results from a Phase II
Dose-Ranging Study

P78 Oral Tazarotene Reduces Comedones

Further, in the April 2004 issue of [Dermatology Times]{.underline} was
an article by Cheryl Guttman,"Phase II Study Shows Oral Tazarotene
Treatment Yields QOL Benefits For Suffering of Severe Acne," citing a
statistically significant superiority of 3.0 mg and 6.0 mg per day over
placebo.

[Efficacy Short Term Studies (Placebo Control & Open Label)]{.underline}

Study 048P & 049P

Two phase 3 pivotal trials were conducted to demonstrate efficacy and
safety of tazarotene oral capsules: 190168-048P and 19068-049P. These
two trials were exactly alike in design. Subjects 21 years of age and
older with a diagnosis of chronic plaque psoriasis with a severity score
of at least 3 on the Overall Lesional Assessment Scale and a minimum
body surface area involvement of at least 10% could be enrolled into the
studies. The majority of patients in the studies were male, 75% and 70%
for studies 048P and 049P, respectively. The studies were multicentered,
randomized, double-blind, placebo controlled trials in which patients
took either tazarotene 4.5 mg once a day or placebo for 12 weeks with a
12-week post-treatment follow-up. An important exclusion criterion to
note was the exclusion of any male who was not willing to use a condom
when having sexual intercourse with a female of childbearing potential.

The primary efficacy variable was the Overall Lesional Assessment (OLA),
which has severity grades from 0-5. Secondary efficacy variables
included plaque elevation, scaling, and erythema, with severity scales
ranging from 0-4. Treatment success, as defined by the Division, is the
proportion of subjects who achieve a score of 0 or 1 on the OLA at week
12.

**Table 1**

**Treatment Success**

+-----------------+---------------------+--------------------+---------+
| **Trial**       | **Treatment         |                    |         |
|                 | Success^1^**        |                    |         |
+-----------------+---------------------+--------------------+---------+
|                 | Tazarotene Capsules | Placebo            | p-value |
+-----------------+---------------------+--------------------+---------+
| 190168-048P     | 24/158 (15.2%)      | 2/163 (1.2%)       | \<0.001 |
+-----------------+---------------------+--------------------+---------+
| 190168-049P     | 34/182 (18.7%)      | 9/187 (4.8%)       | \<0.001 |
+-----------------+---------------------+--------------------+---------+
| 1Overall        |                     |                    |         |
| Lesional        |                     |                    |         |
| Assessment -    |                     |                    |         |
| success = score |                     |                    |         |
| of 0 or 1 at    |                     |                    |         |
| week 12         |                     |                    |         |
|                 |                     |                    |         |
| Source:         |                     |                    |         |
| Sponsor\'s NDA  |                     |                    |         |
| submission,     |                     |                    |         |
| module 5,       |                     |                    |         |
| Volume 45, page |                     |                    |         |
| 99 and Volume   |                     |                    |         |
| 73, page 94     |                     |                    |         |
+-----------------+---------------------+--------------------+---------+

Although the majority of patients in the studies were male, a larger
percentage of females achieved success. Approximately two-thirds of the
patients who entered the tazarotene arms of the studies had moderate
psoriasis and it was the patients with moderate disease that
consistently achieved success over placebo across both studies. For
severe disease, this was true in only one of the two studies.

Oral tazarotene did not provide efficacy in the treatment of nail
psoriasis but a subgroup analysis did demonstrate efficacy in scalp
psoriasis. (See Biostatistics analysis below for details).

Study 052P

Patients entered this study from the pivotal studies, tazarotene and
placebo arm, if they did not have a response, had no change or an
increase in severity per the OLA.

Although an open-label study, after 12 weeks of treatment for the group
being treated for the first time, the percentage of patients with
success was 38/196 (19.4%). This analysis lends support to the
placebo-controlled trials in that the point estimate for success is the
same.

[Biostatistics]{.underline}

Two multinational placebo-controlled trials (denoted as studies 048 and
049) were conducted to support the efficacy claim of tazarotene 4.5 mg
capsule. Study 048 was conducted in the U.S., Canada, Panama and
Guatemala during September 2001 and October 2002. Study 049 was
conducted in the U.S., Canada, Ecuador and Costa Rica during November
2001 and November 2002. Totals of 337 and 369 patients were enrolled
from 28 and 29 sites in studies 048 and 049, respectively. Among the
study sites, 8 and 7 sites in studies 048 and 049, respectively, were
located in foreign countries. The patient enrollment at foreign sites
accounted for about 40% of study enrollment. The enrolled patients were
randomized in a 1:1 treatment allocation ratio to receive either
tazarotene or placebo. The randomization resulted in 166 and 171
patients in tazarotene and placebo, respectively, for study 048; while
182 and 187 patients in the respective group for study 049.

The primary efficacy endpoint is the percentage of patients with Overall
Lesional Assessment (OLA) score of 0 or 1 at week 12. No significant
statistical issue that affects efficacy results in the pivotal trials is
noted.

The following tables present efficacy results of studies 048 and 049:

-   Table 1: distribution of OLA scores and number (%) of patients with
    OLA score of 0 or 1 at week 12.

-   Table 2: number (%) of patients with OLA score of 0 or 1 at week 12
    for U.S. sites vs. non-U.S. sites. As the trials are multinational,
    patients recruited from non-U.S. sites accounted for about 40% of
    study enrollment. One may ask if tazarotene is better than placebo
    for patient population in the U.S.

-   Table 3: Subgroup results of the primary efficacy endpoint for study
    048.

-   Table 4: Subgroup results of the primary efficacy endpoint for study
    049.

[Summary of the results in Tables]{.underline}:

1.  Efficacy results are generally robust. The overall efficacy findings
    are:

    a.  The superiority of tazarotene to placebo is established with
        respect to the Division's recommended primary efficacy endpoint
        for each of studies 048 and 049 (p-value \< 0.001, Table 1). The
        overall success rates are 15.7% vs. 3.5% for tazarotene vs.
        placebo in study 048; and 18.7% vs. 4.8% in study 049.

    b.  For patient population in the U.S., the superiority of
        tazarotene to placebo is established for each of studies 048 and
        049 (p-value \< 0.001 and = 0.003, Table 2). The success rates
        are 16.2% vs. 2.0% for tazarotene vs. placebo in study 048; and
        21.3% vs. 7.3% in study 049.

> The findings in subgroups are:

c.  There is a gender effect in the efficacy results. Even though a
    higher rate of patients in the studies are males (about 75% and 70%
    in studies 048 and 049, respectively), the response rates of male
    patients are lower than those of female patients regardless of
    treatments for each study. Moreover, female subjects in placebo
    group for study 049 had an exceptionally high success rate (14.6%).
    Female subjects with success responses are examined in terms of
    compliance. No outstanding compliance issue that resulted in higher
    response rates for female patients is noted.

d.  More than 70% of subjects are Caucasian, the response rates for
    Caucasian are similar to those based on the whole intent-to-treat
    (ITT) population. For Hispanic subjects, tazarotene group is better
    than placebo in study 049 with a significant magnitude (20.5% vs.
    2.2%), and numerically better than placebo in study 048 (21.9% vs.
    14.8%). For other races, it is difficult to make statistical
    comparisons, as the sample sizes are small.

e.  Age was divided into three groups, \< 45 years, 45 -- 65 years, and
    \> 65 years. Generally, efficacy results over age group do not show
    outstanding differences except a high response rate for geriatric
    patients in tazarotene group for study 049. Tazarotene is better
    than placebo for subjects in age groups of \< 45 years and 45 -- 65
    years for each study in a significant manner. The geriatric patients
    in tazarotene group showed a high response rate (41.2%) in study 049
    as compared to other age groups. Following examining the subjects,
    geriatric patients were generally compliant regardless of achieving
    success and treatment groups. No significant compliance issues are
    noted.

f.  The response rate of the primary efficacy endpoint generally
    decreases as the baseline OLA severity score increases. Tazarotene
    is better than placebo for patients with moderate or severe disease
    status at baseline. There were 5 (1.5%) and 10 (2.7%) patients
    having OLA score of "*very severe*" at baseline in studies 048 and
    049, respectively. Only one patient in placebo group (study 048)
    achieved success at week 12 (i.e., OLA score of 0 or 1). The
    efficacy claim of tazarotene capsules in the labeling for the
    treatment of "*very severe plaque psoriasis*" is
    ***[not]{.underline}*** supported.

Another finding of note is that the data from pivotal trials showed some
effectiveness of oral tazarotene in treating scalp psoriasis, but not
nail psoriasis. It should be noted that 2 and 1 patients in placebo arm
achieved fingernail and toenail psoriasis severity score of 0 at week
12, respectively. However, none of the patients in oral tazarotene group
achieved severity score of 0. Furthermore, treatment success in
tazarotene group is not permanent. A relatively high percentage of
patients had a relapse on or prior to week 24.

**Table 1: Percentage of Patients with OLA Score of 0 or 1 at Week 12**

+------------------+------------+----------+-------------+-----------+
| # Dist           | **Study    |          | **Study     |           |
| ribution of OLA  | 048**      |          | 049**       |           |
| score at Week 12 |            |          |             |           |
+------------------+------------+----------+-------------+-----------+
|                  | **Ta       | **P      | **T         | **        |
|                  | zarotene** | lacebo** | azarotene** | Placebo** |
|                  |            |          |             |           |
|                  | **(n =     | **(n =   | **(n =      | **(n =    |
|                  | 166)**     | 171)**   | 182)**      | 187)**    |
+------------------+------------+----------+-------------+-----------+
| 0 -- None        | 4 (2.4%)   | 2 (1.2%) | 7 (3.8%)    | 2 (1.1%)  |
|                  |            |          |             |           |
| 1 -- Minimal     | 22 (13.3%) | 4 (2.3%) | 27 (14.8%)  | 7 (3.7%)  |
|                  |            |          |             |           |
| 2 -- Mild        | 61 (36.7%) | 20       | 65 (35.7%)  | 21        |
|                  |            | (11.7%)  |             | (11.2%)   |
| 3 -- Moderate    | 64 (38.6%) |          | 61 (33.5%)  |           |
|                  |            | 94       |             | 102       |
| 4 -- Severe      | 14 (8.4%)  | (55.0%)  | 22 (12.1%)  | (54.5%)   |
|                  |            |          |             |           |
| 5 -- Very Severe | 1 (0.6%)   | 49       | 0           | 51        |
|                  |            | (28.7%)  |             | (27.3%)   |
|                  |            |          |             |           |
|                  |            | 2 (1.2%) |             | 4 (2.1%)  |
+------------------+------------+----------+-------------+-----------+
| #                | 26/166     | 6/171    | 34/182      | 9/187     |
|  Percentage of p | (15.7%)    | (3.5%)   | (18.7%)     | (4.8%)    |
| atients with OLA |            |          |             |           |
|  score of 0 or 1 |            |          |             |           |
+------------------+------------+----------+-------------+-----------+
| # Comparison^1^  | \< 0.001   |          | \< 0.001    |           |
+------------------+------------+----------+-------------+-----------+
| ^1^ p-value in   |            |          |             |           |
| comparison is    |            |          |             |           |
| based on         |            |          |             |           |
| Cochran          |            |          |             |           |
| -Mantel-Haenszel |            |          |             |           |
| test controlling |            |          |             |           |
| for analysis     |            |          |             |           |
| center.          |            |          |             |           |
+------------------+------------+----------+-------------+-----------+

**Table 2: Percentage of Patients with OLA Score of 0 or 1 at Week 12**

for U.S. vs. Non-U.S. Sites (ITT) -- Studies 048 and 049

  ------------------------- ---------- ---------------- ------------- -------------------
  **Study**                 **Study    **Tazarotene**   **Placebo**   **Comparison^1^**
                            Site**                                    

  **048**                   U.S.       16/99 (16.2%)    2/102 (2.0%)  \< 0.001

                            Non-U.S.   10/67 (14.9%)    4/69 (5.8%)   0.078

  **049**                   U.S.       23/108 (21.3%)   8/110 (7.3%)  0.003

                            Non-U.S.   11/74 (14.9%)    1/77 (1.3%)   0.002

  ^1^ p-value is based on                                             
  Cochran-Mantel-Haenszel                                             
  test controlling for                                                
  analysis center.                                                    
  ------------------------- ---------- ---------------- ------------- -------------------

**Table 3: Subgroup Results of the Primary Efficacy Endpoint^1^**

(ITT) Study 048

+-------------------+-----------------+-----------------+--------------+
| **Subgroup**      | **Tazarotene**  | **Placebo**     | **Com        |
|                   |                 |                 | parison^2^** |
|                   | **(n = 166)**   | **(n = 171)**   |              |
+-------------------+-----------------+-----------------+--------------+
| **Total**         | 26/166 (15.7%)  | 6/171 (3.5%)    | \< 0.001     |
+-------------------+-----------------+-----------------+--------------+
| **Age**           | 13/76 (17.1%)   | 3/84 (3.6%)     | 0.004        |
|                   |                 |                 |              |
| \< 45 years       | 11/76 (14.5%)   | 3/73 (4.1%)     | 0.030        |
|                   |                 |                 |              |
| 45 -- 65          | 2/14 (14.3%)    | 0/14 (0.0%)     | 0.481        |
|                   |                 |                 |              |
| \> 65 years       |                 |                 |              |
+-------------------+-----------------+-----------------+--------------+
| **Gender**        | 9/34 (26.5%)    | 3/48 (6.3%)     | 0.011        |
|                   |                 |                 |              |
| Female            | 17/132 (12.9%)  | 3/123 (2.4%)    | 0.002        |
|                   |                 |                 |              |
| Male              |                 |                 |              |
+-------------------+-----------------+-----------------+--------------+
| **Race**          | 16/126 (12.7%)  | 2/134 (1.5%)    | \< 0.001     |
|                   |                 |                 |              |
| Caucasian         | 2/5 (40.0%)     | 0/5 (0.0%)      | 0.444        |
|                   |                 |                 |              |
| Black             | 1/1 (100.0%)    | 0/2 (0.0%)      | 0.333        |
|                   |                 |                 |              |
| Asian             | 7/32 (21.9%)    | 4/27 (14.8%)    | 0.488        |
|                   |                 |                 |              |
| Hispanic          | 0/2 (0.0%)      | 0/3 (0.0%)      | NA           |
|                   |                 |                 |              |
| Others            |                 |                 |              |
+-------------------+-----------------+-----------------+--------------+
| **Baseline OLA    | 19/100 (19.0%)  | 3/105 (2.9%)    | \< 0.001     |
| Score**           |                 |                 |              |
|                   | 7/64 (10.9%)    | 2/63 (3.2%)     | 0.164        |
| Moderate          |                 |                 |              |
|                   | 0/2 (0.0%)      | 1/3 (33.3%)     | 1.000        |
| Severe            |                 |                 |              |
|                   |                 |                 |              |
| Very severe       |                 |                 |              |
+-------------------+-----------------+-----------------+--------------+
| **^1^**Primary    |                 |                 |              |
| efficacy endpoint |                 |                 |              |
| is per the        |                 |                 |              |
| Division's        |                 |                 |              |
| definition,       |                 |                 |              |
| percentage of     |                 |                 |              |
| patients with OLA |                 |                 |              |
| score of 0 or 1   |                 |                 |              |
| at week 12.       |                 |                 |              |
|                   |                 |                 |              |
| **^2^** p-values  |                 |                 |              |
| listed are for    |                 |                 |              |
| reference         |                 |                 |              |
| purpose, as the   |                 |                 |              |
| study was not     |                 |                 |              |
| designed to show  |                 |                 |              |
| significance over |                 |                 |              |
| subgroups.        |                 |                 |              |
+-------------------+-----------------+-----------------+--------------+

**Table 4: Subgroup Results of the Primary Efficacy Endpoint^1^**

(ITT) Study 049

+-------------------+-----------------+-----------------+--------------+
| **Subgroup**      | **Tazarotene**  | **Placebo**     | **Com        |
|                   |                 |                 | parison^2^** |
|                   | **(n = 182)**   | **(n = 187)**   |              |
+-------------------+-----------------+-----------------+--------------+
| **Total**         | 34/182 (18.7%)  | 9/187 (4.8%)    | \< 0.001     |
+-------------------+-----------------+-----------------+--------------+
| **Age**           | 11/71 (15.5%)   | 3/77 (3.9%)     | 0.016        |
|                   |                 |                 |              |
| \< 45 years       | 16/94 (17.0%)   | 6/96 (6.3%)     | 0.020        |
|                   |                 |                 |              |
| 45 -- 65          | 7/17 (41.2%)    | 0/14 (0.0%)     | 0.009        |
|                   |                 |                 |              |
| \> 65 years       |                 |                 |              |
+-------------------+-----------------+-----------------+--------------+
| **Gender**        | 15/63 (23.8%)   | 7/48 (14.6%)    | 0.227        |
|                   |                 |                 |              |
| Female            | 19/119 (16.0%)  | 2/139 (1.4%)    | \< 0.001     |
|                   |                 |                 |              |
| Male              |                 |                 |              |
+-------------------+-----------------+-----------------+--------------+
| **Race**          | 25/134 (18.7%)  | 7/131 (5.3%)    | \< 0.001     |
|                   |                 |                 |              |
| Caucasian         | 1/4 (25.0%)     | 1/6 (16.7%)     | 1.000        |
|                   |                 |                 |              |
| Black             | 0/3 (0.0%)      | 0/1 (0.0%)      | NA           |
|                   |                 |                 |              |
| Asian             | 8/39 (20.5%)    | 1/46 (2.2%)     | 0.010        |
|                   |                 |                 |              |
| Hispanic          | 0/2 (0.0%)      | 0/3 (0.0)       | NA           |
|                   |                 |                 |              |
| Others            |                 |                 |              |
+-------------------+-----------------+-----------------+--------------+
| **Baseline OLA    | 24/121 (19.8%)  | 7/125 (5.6%)    | \< 0.001     |
| Score**           |                 |                 |              |
|                   | 10/57 (17.5%)   | 2/56 (3.6%)     | 0.016        |
| Moderate          |                 |                 |              |
|                   | 0/4 (0.0%)      | 0/6 (0.0%)      | NA           |
| Severe            |                 |                 |              |
|                   |                 |                 |              |
| Very severe       |                 |                 |              |
+-------------------+-----------------+-----------------+--------------+
| **^1^**Primary    |                 |                 |              |
| efficacy endpoint |                 |                 |              |
| is per the        |                 |                 |              |
| Division's        |                 |                 |              |
| definition,       |                 |                 |              |
| percentage of     |                 |                 |              |
| patients with OLA |                 |                 |              |
| score of 0 or 1   |                 |                 |              |
| at week 12.       |                 |                 |              |
|                   |                 |                 |              |
| **^2^** p-values  |                 |                 |              |
| listed are for    |                 |                 |              |
| reference         |                 |                 |              |
| purpose, as the   |                 |                 |              |
| study was not     |                 |                 |              |
| designed to show  |                 |                 |              |
| significance over |                 |                 |              |
| subgroups.        |                 |                 |              |
+-------------------+-----------------+-----------------+--------------+

**[III. Evolution of Risk Management for Systemic
Retinoids]{.underline}**

This section describes the evolution of FDA thinking and actions
concerning fetal exposure prevention risk management programs for
systemic retinoids. This information is intended to provide the Advisory
Committee (AC) with some historical and scientific context for potential
risk management discussions concerning oral tazarotene.

The FDA has granted marketing approval for four systemic retinoids for
cutaneous conditions: isotretinoin (Accutane, Amnesteem, Claravis,
Sotret), etretinate (Tegison), acitretin (Soriatane) and bexarotene
(Targretin). Etretinate (Tegison) has been voluntarily withdrawn from
the market by the sponsor, but the other three remain in use.
Additionally, other systemic retinoids are in development for a variety
of conditions. Isotretinoin is indicated for the treatment of severe
recalcitrant nodular acne, etretinate and acitretin for severe
psoriasis, and bexarotene for refractory cutaneous T-cell lymphoma.

The first FDA approved systemic retinoid and the one that is most widely
used by women of reproductive potential is isotretinoin. Evaluations
conducted over the 20 years encompassing isotretinoin's three successive
risk management efforts as described below, have provided FDA the best
quality and greatest amount of evidence about the effectiveness of
different interventions to reduce fetal exposure to systemic retinoids.
As such, the history and development of the three successive fetal
exposure prevention risk management programs (RMP) for isotretinoin are
described first, as a prototype and benchmark of Agency thought. The
risk management programs of the other three systemic retinoids are
outlined secondarily.

Isotretinoin, the first systemic retinoid marketed in the US, was
approved on May 7, 1982, for the treatment of severe recalcitrant
nodular acne. Accutane was introduced with a Category X pregnancy
designation base on the identification of fetal abnormalities in animal
studies and the determination that the risk of use in pregnant women
clearly exceeded any possible benefit. Risk management at the time of
approval was limiting to labeling, which described the risk of
teratogenicity in the Contraindications, Warnings and Precautions
sections of the package insert.

The first case of human malformation associated with Accutane exposure
was reported in June 1983, and additional cases were reported in the
ensuing months. In response, multiple Dear Doctor and Dear Pharmacist
letters were issued to inform health care providers of these
malformations and to reinforce the information in the package insert,
and pharmacists were provided with red warning stickers for application
to prescriptions. The package insert was updated to emphasize the
information about potential teratogenicity, first by highlighting that
information in boldface type within the Contraindications, Warnings and
Precautions sections (Aug 1983), and then by adding a boxed warning at
the front of the package insert (Feb 1984).

Despite these actions, fetal exposures to isotretinoin continued to
occur. In response, a pregnancy prevention risk management plan, which
the Sponsor entitled the Accutane Pregnancy Prevention Program (APPP),
was presented to the AC, approved, and implemented in October 1988. For
purposes of discussion and simplicity, we consider the APPP to be the
second isotretinoin risk management plan for pregnancy prevention, with
product labeling being the first effort. The APPP was designed to
provide patients and prescribers information about the teratogenicity of
Accutane and preventive strategies for maintenance of a non-pregnant
state for one month before, during, and for one month following Accutane
treatment. The components of the APPP included blister packaging with
the "Avoid Pregnancy" icon and boxed warning printed directly on the
package label, informed consent for female patients, educational
materials, referral and reimbursement for contraceptive counseling, and
modifications of the package insert. Modifications to the package insert
recommended a negative pregnancy test within one week before starting
Accutane, monthly pregnancy testing and contraceptive counseling, and
use of two forms of effective contraception simultaneously for one month
before, during, and one month following Accutane therapy. The Accutane
Survey, a voluntary patient survey, and the Accutane Prescriber Tracking
Survey, a telephonic survey of prescribers, were introduced to monitor
program effectiveness.

In the first year following implementation of the Accutane PPP, the
total number of reported exposed pregnancies increased significantly,
likely due to the introduction of a new reporting instrument, the
Accutane Survey, while the number of spontaneously reported exposed
pregnancies was relatively unchanged. In the subsequent ten years, the
number of reported exposed pregnancies remained relatively constant.
However, over this time period, the number of patients who received
isotretinoin prescriptions each year more than doubled. Because of the
increasing size of the population exposed to isotretinoin, as well as
the fact that the total public health burden of isotretinoin-exposed
pregnancies was not decreasing, an AC was convened in September, 2000.
At that time, FDA had already seen preliminary data on the performance
of another risk management program to prevent fetal exposure (for
thalidomide), that had been approved by FDA in 1998. The AC that met in
2000 recommended augmentation of the isotretinoin risk management plan
to incorporate some of the features of the thalidomide fetal protection
program, in particular the closed linkage of pregnancy testing to
product dispensing.

On October 30, 2001, following extensive negotiations with the
manufacturer, the FDA approved the System to Manage Accutane Related
Teratogenicity (S.M.A.R.T.™) Program, the Sponsor's response to the
requested changes in the Accutane risk management program. The
S.M.A.R.T. ™ program as described below did not incorporate all the
features of the thalidomide pregnancy prevention risk management
program. In its October 2001 approval letter of S.M.A.R.T. ™, FDA
required a report and the public meeting on the forthcoming program's
overall effectiveness after one year and stated the possibility that
changes might be required at that time including a mandatory patient
registry (such as was in use for thalidomide). The S.M.A.R.T. ™ program
linked prescriber qualification of patients to dispensing of Accutane
through use of yellow stickers placed on prescriptions, and uses
voluntary patient and pharmacy surveys to assess compliance. Components
of the S.M.A.R.T. ™ program included patient informed consent forms, a
prescriber checklist, Letter of Understanding for prescribers, yellow
qualification stickers, Medication Guide dispensed with each
prescription, instruction guide for prescribers, instruction guide for
pharmacists, FDA Letter to Pharmacy boards, Dear Accutane Prescriber
Letter, Dear Pharmacist Letter, separate patient brochures for women and
men, carton dispensing instructions, and updated package insert, patient
package insert, container and carton labels. One-year performance
benchmarks were set at achievement of an Accutane survey enrollment rate
of 60%, and qualification sticker use approaching 100%.

On February 26, 2004, the AC was again convened to comment on the
metrics from the one-year evaluation of the S.M.A.R.T. ™ program.
Although sticker use was high, exceeding 90%, it proved an
unsatisfactory surrogate endpoint for compliance with the RMP since the
number of exposed pregnancies was unchanged within the first year of
S.M.A.R.T.'s implementation. Accutane survey enrollment failed to reach
60%. Most significantly, the AC advised implementation of a more
rigorous pregnancy prevention RMP to include mandatory registration of
all prescribers, pharmacies, and patients (male and female). The Agency
is currently working with the Sponsors of the innovator and generic
isotretinoin products to implement these recommendations. Contributing
to FDA and sponsor thinking and risk management program development has
been well-documented and complete exposure-based evidence collected to
date about pregnancy exposures under the thalidomide pregnancy
prevention risk management program (called S.T.E.P.S.) Under this
program there has been only one pregnancy exposure, albeit in a small
population of females of childbearing potential.

On September 30, 1986, a second systemic retinoid, Tegison (etretinate),
was approved for marketing in the US, indicated for the treatment of
severe recalcitrant psoriasis. Because of malformations seen in animal
studies as well as human experience with isotretinoin, Tegison received
a Category X pregnancy designation. The pregnancy prevention risk
management program for Tegison was similar to that current for
isotretinoin at that time: a boxed warning at the beginning of the
package insert and additional warnings in the Contraindications,
Warnings and Precautions sections of labeling. Tegison was withdrawn
from the market by the Sponsor on December 20, 2002, and is no longer
available in the US.

On October 28, 1996, Soriatane (acitretin) became the third systemic
retinoid approved for marketing in the US. Soriatane is indicated in
adults for the treatment of severe psoriasis. In women of childbearing
potential, acitretin use "should be reserved for patients who are
unresponsive to other therapies or in whom such treatments are
contraindicated." Soriatane received a Category X pregnancy designation
based on fetal malformations in exposed animals and human teratogenicity
with other retinoids. Although possessing an indication and a
risk-benefit calculus distinct from Accutane, the Soriatane sponsor was
required to implement a risk management program analogous to the best
known practice at the time in 1996 (the current for isotretinoin APPP)
because of the potential that Soriatane would be used in women of
childbearing potential. The risk management program for Soriatane,
entitled the Soriatane Pregnancy Prevention Program (SPPP) included the
essential elements of the APPP, such as the boxed warning about
teratogenicity, recommendations in women of childbearing potential for a
negative pregnancy test within one week before starting treatment and
regularly during treatment, use of two forms of contraception during and
for three years after completion of therapy, and signed informed
consent. The SPPP differed from the Accutane PPP in that the SPPP did
not include a patient or prescriber survey to assess program
effectiveness, did not use blister packaging, and required pregnancy
prevention for a longer duration following completion of therapy. A
Medication Guide was added to the SPPP on April 18, 2003.

On December 29, 1999, Targretin (bexarotene), indicated for the
treatment of the cutaneous manifestations of cutaneous T-cell lymphoma
in patients refractory to at least one prior systemic therapy, became
the fourth systemic retinoid approved in the US. Like the other systemic
retinoids, Targretin received a Category X pregnancy designation based
on fetal malformations in exposed animals and human teratogenicity with
other retinoids. Fetal exposure prevention risk management for Targretin
is composed of elements similar to those of the APPP and SPPP, including
a boxed warning about teratogenicity, information in the
Contraindications and Precautions sections of labeling, recommendations
for a negative pregnancy test within one week of treatment initiation
and monthly thereafter and for use of two forms of contraception for one
month before, during and one month after therapy, and limitation of
amount dispensed to 30 days supply. A Medication Guide was added on
April 21, 2003.

In summary, fetal exposure prevention risk management of systemic
retinoids has evolved and been informed through three programs
(labeling, APPP, and S.M.A.R.T.™) implemented for the first FDA-approved
product in this category, isotretinoin. Subsequent product approvals for
systemic retinoids have employed analogous risk management programs to
the APPP that was in place for isotretinoin at the time they were
approved. Now that the one year implementation and evaluation of the
isotretinoin S.M.A.R.T.™ program has been completed, discussed publicly,
and found to be insufficiently effective in fetal exposure prevention
for isotretinoin, FDA anticipates further discussion and exploration of
fetal exposure prevention risk management programs that are similarly
effective to what has been documented for thalidomide.

> **[IV. Discussion Topics]{.underline}**

The Joint Advisory Committee will be asked to consider and discuss the
following topics:

-   the evidence for the effectiveness of oral tazarotene in moderate to
    severe plaque psoriasis

-   the safety profile for oral tazarotene, including teratogenicity,
    presence of tazarotenic acid in the semen, bone and liver
    abnormalities, and hyperlipidemia, especially for repeated,
    intermittent, long-term use

-   the risk-benefit calculus for oral tazarotene for the proposed
    population with moderate to severe psoriasis

-   the appropriate teratogenic risk management plan to prevent fetal
    exposure

-   the need for additional studies, and whether this information is
    needed before or can be obtained after marketing approval

**Appendix**

**Clinical Pharmacology and Biopharmaceutics Section**

**Background:**

-   Once in the body, tazarotene is hydrolyzed quickly and extensively
    to tazarotenic acid (TA), the primary active entity and the only
    species present in the systemic circulation.

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-   The absolute bioavailability of TA was estimated to be approximately
    83% when systemic drug exposure from an intravenous study (15 μg/kg)
    was compared to those from an oral study at a similar dose (1.5 mg).

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-   TA exposure is proportional to oral dose from 3 mg to 6.3 mg.

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-   Following intravenous administration, [tazarotene]{.underline} was
    measurable in the plasma and was eliminated from the body rapidly
    with a terminal half-life of 6.2 hours.

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-   Following intravenous administration , plasma [TA]{.underline}
    concentration rose rapidly and declined bi-exponentially with a
    terminal half-life of 13.8 hours.

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-   When tazarotene was administered once-daily orally, plasma
    [TA]{.underline} concentration dropped approximately 42 times from
    its peak level within 24 hours with a mean terminal half-life of
    12.5 hours (range 7.1 to 41.1 hours) at proposed dose of 4.5 mg/day.

**Mean TA Plasma Concentration-Time profiles on Study Days 7 and 13**

![](media/image1.png){width="5.558333333333334in"
height="3.2708333333333335in"}

**Mean TA Plasma Concentration-Time profiles on Study Days 13 to 15**

![](media/image2.png){width="5.416666666666667in"
height="3.3020833333333335in"}

-   Steady state is expected to reach by day 7 following oral
    administration.

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-   Accumulation ratio was approximately 1. (i.e. there was essentially
    no accumulation) following oral administration.

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-   [TA]{.underline} is highly bound to plasma proteins, with an unbound
    fraction of less than 1%.

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-   Fecal elimination of [TA]{.underline} is the predominant pathway,
    since 63.0% of an oral dose was eliminated in the feces, mostly as
    the *active* metabolite.

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-   In the urine, tazarotene was excreted, primarily as the *inactive*
    sulfoxide metabolite of [TA]{.underline}.

-   The following describes a comparison of systemic exposure of TA from
    various topical and oral formulations:

  ------------- ------------- -------------- --------------- --------------
  Formulation   Indication    BSA            Parameters      

                                             C~max~ (ng/mL)  AUC~0-24h~
                                                             (ng.h/mL)

  0.1% Cream    Acne          15%            1.20±0.41       17.0±6.1

  0.1% Gel      Acne          15%            4.84±6.05       44.6±38.9

  0.1% Cream    Psoriasis     14±11%         2.31±2.78       31.2±35.2

  0.1% Gel      Psoriasis     13±5%          12±7.6          105±55

  4.5 mg Tablet Psoriasis     NA             95.2±27.1       427±105
  ------------- ------------- -------------- --------------- --------------

-   Following Once-Daily oral dosing of tazarotene 4.5 mg capsules for
    two weeks in healthy male subjects, TA concentrations in \> 79%
    semen samples were above the LLOQ (0.1 ng/mL).

-   Semen to Plasma Tazarotenic Acid Concentration Ratio -Time Profiles
    from Samples Pooled together within and between Subjects over the
    Entire Study Period are presented using boxplot in the following
    figure:

> ![](media/image3.png){width="5.058333333333334in"
> height="3.020138888888889in"}

-   The highest individual semen to plasma [TA]{.underline}
    concentration ratio was found to be 2.8.

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-   The highest individual [TA]{.underline} concentration observed in
    semen was 83.1 ng/ml. (vs 161.0 ng/mL peak plasma level).

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-   Mean semen to plasma [TA]{.underline} concentration ratio from
    samples pooled together over the entire study period is
    approximately 1 (one) indicating that there is no preferential
    uptake of [TA]{.underline}.

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-   Assuming an ejaculate volume of 10 mL, the amount of drug
    transferred in semen would be 831 ng which is about 1/ 5,000th of a
    single 4.5 mg capsule.

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-   The no-effect limit for teratogenicity for
    tazarotene/[TA]{.underline} is unknown.

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-   Fertilized egg may remain exposed to [TA]{.underline} in the semen
    following continuous sexual encounters.

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-   Risk to a fetus, if any, while a male patient is taking the drug or
    after it is discontinued can not be ruled out.