Background for Advisory Committee
Meeting to Discuss Oral Tazarotene for the Treatment of Moderate to Severe Psoriasis
I. Introduction to
Psoriasis
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
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 α2-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
Psoriasis occurs in 2% of the
world's population. Depending on the
source, the prevalence in the
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
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
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
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 D3
Analogues
The prototype of this group of drug
products is calcipotriene, approved in the
Side effects are cutaneous and include
burning, stinging, itching, skin irritation, and tingling of the skin.
Topical Retinoids
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
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/ cm2 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/cm2 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
Methotrexate (Aminopterin)
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)
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)
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
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)
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
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 TazoracÒ 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
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
General toxicology: 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: Tazarotene
was non-mutagenic in
Carcinogenicity: 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 (AUCde)
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: 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:
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 |
Tazarotene |
Acitretin) a (Soriatane) |
Etretinate b,c |
Tretinoin b |
Isotretinoin b (Accutane) |
|
Human |
|
|
0.2 |
N.D. |
0.4 |
|
Primates |
|
|
5 |
7.5 |
5 |
|
Hamsters |
|
|
2.8 |
1.25 |
25 |
|
Rabbits |
0.2 |
0.6 |
2 |
2 - 10 |
10 |
|
Rats |
0.25 – 1 |
15 |
2 – 8 |
0.4 - 2 |
150 |
|
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
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 2nd 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
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 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)
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
Success1 |
||
|
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
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
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
· 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:
- 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
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 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
Distribution of OLA score at Week 12
|
Study 048 |
Study 049 |
||
|
Tazarotene (n = 166) |
Placebo (n = 171) |
Tazarotene (n = 182) |
Placebo (n = 187) |
|
|
0 – None 1 – Minimal 2 – Mild 3 – Moderate 4 – Severe 5 – Very Severe |
4 (2.4%) 22 (13.3%) 61 (36.7%) 64 (38.6%) 14 (8.4%) 1 (0.6%) |
2 (1.2%) 4 (2.3%) 20 (11.7%) 94 (55.0%) 49 (28.7%) 2 (1.2%) |
7 (3.8%) 27 (14.8%) 65 (35.7%) 61 (33.5%) 22 (12.1%) 0 |
2 (1.1%) 7 (3.7%) 21 (11.2%) 102 (54.5%) 51 (27.3%) 4 (2.1%) |
Percentage of patients
with OLA score of 0 or 1
|
26/166 (15.7%) |
6/171 (3.5%) |
34/182 (18.7%) |
9/187 (4.8%) |
Comparison1
|
< 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
|
Study |
Study Site |
Tazarotene |
Placebo |
Comparison1 |
|
048 |
|
16/99 (16.2%) |
2/102 (2.0%) |
< 0.001 |
|
Non-U.S. |
10/67 (14.9%) |
4/69 (5.8%) |
0.078 |
|
|
049 |
|
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 Endpoint1
(ITT) Study 048
|
Subgroup |
Tazarotene (n = 166) |
Placebo (n = 171) |
Comparison2 |
|
Total |
26/166
(15.7%) |
6/171
(3.5%) |
<
0.001 |
|
Age < 45 years 45 – 65 > 65 years |
13/76 (17.1%) 11/76 (14.5%) 2/14 (14.3%) |
3/84 (3.6%) 3/73 (4.1%) 0/14 (0.0%) |
0.004 0.030 0.481 |
|
Gender Female Male |
9/34 (26.5%) 17/132 (12.9%) |
3/48 (6.3%) 3/123 (2.4%) |
0.011 0.002 |
|
Race Caucasian Black Asian Hispanic Others |
16/126 (12.7%) 2/5 (40.0%) 1/1 (100.0%) 7/32 (21.9%) 0/2 (0.0%) |
2/134 (1.5%) 0/5 (0.0%) 0/2 (0.0%) 4/27 (14.8%) 0/3 (0.0%) |
< 0.001 0.444 0.333 0.488 NA |
|
Baseline OLA Score
Moderate Severe Very severe |
19/100 (19.0%) 7/64 (10.9%) 0/2 (0.0%) |
3/105 (2.9%) 2/63 (3.2%) 1/3 (33.3%) |
< 0.001 0.164 1.000 |
|
1Primary 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 Endpoint1
(ITT) Study 049
|
Subgroup |
Tazarotene (n = 182) |
Placebo (n = 187) |
Comparison2 |
|
Total |
34/182
(18.7%) |
9/187
(4.8%) |
<
0.001 |
|
Age < 45 years 45 – 65 > 65 years |
11/71 (15.5%) 16/94 (17.0%) 7/17 (41.2%) |
3/77 (3.9%) 6/96 (6.3%) 0/14 (0.0%) |
0.016 0.020 0.009 |
|
Gender Female Male |
15/63 (23.8%) 19/119 (16.0%) |
7/48 (14.6%) 2/139 (1.4%) |
0.227 < 0.001 |
|
Race Caucasian Black Asian Hispanic Others |
25/134 (18.7%) 1/4 (25.0%) 0/3 (0.0%) 8/39 (20.5%) 0/2 (0.0%) |
7/131 (5.3%) 1/6 (16.7%) 0/1 (0.0%) 1/46 (2.2%) 0/3 (0.0) |
< 0.001 1.000 NA 0.010 NA |
|
Baseline OLA Score Moderate Severe Very severe |
24/121 (19.8%) 10/57 (17.5%) 0/4 (0.0%) |
7/125 (5.6%) 2/56 (3.6%) 0/6 (0.0%) |
< 0.001 0.016 NA |
|
1Primary 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
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
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
On
On
On
On
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
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.
•
The absolute bioavailability of TA was estimated to be approximately 83% when systemic drug
exposure from an intravenous study (15 mg/kg) was compared to
those from an oral study at a similar dose (1.5 mg).
•
TA
exposure is proportional to oral dose
from 3 mg to 6.3 mg.
•
Following intravenous administration, tazarotene
was measurable in the plasma and was eliminated from the body rapidly with a
terminal half-life of 6.2 hours.
•
Following intravenous administration , plasma TA concentration rose rapidly and declined bi-exponentially
with a terminal half-life of 13.8 hours.
•
When tazarotene was administered once-daily orally, plasma TA
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
Mean TA Plasma
Concentration-Time profiles on Study Days 13 to 15
•
Steady state is expected to reach by day 7 following
oral administration.
•
Accumulation ratio was approximately 1. (i.e. there
was essentially no accumulation) following oral administration.
•
TA
is highly bound to plasma proteins, with an unbound fraction of less than 1%.
•
Fecal elimination of TA is the predominant pathway, since 63.0% of an oral dose
was eliminated in the feces, mostly as the active
metabolite.
•
In the urine, tazarotene was excreted, primarily as the
inactive sulfoxide metabolite of TA.
•
The following describes a comparison of systemic
exposure of TA from various topical and oral formulations:
|
Formulation |
Indication |
BSA |
Parameters |
|
|
|
|
|
Cmax (ng/mL) |
AUC0-24h (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:
•
The highest individual semen to plasma TA concentration ratio was found
to be 2.8.
•
The highest individual TA concentration observed in semen was 83.1 ng/ml. (vs 161.0
ng/mL peak plasma level).
• Mean semen to
plasma TA concentration ratio from samples pooled together over the
entire study period is approximately 1 (one) indicating that there is no
preferential uptake of TA.
•
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.
•
The no-effect
limit for teratogenicity for tazarotene/TA is unknown.
•
Fertilized egg may remain exposed to TA in the semen following
continuous sexual encounters.
• Risk
to a fetus, if any, while a male patient is taking the drug
or after it is discontinued can not be ruled out.