targretin
Generic Name: (
bexarotene)
Dosage Type: gel Organization: Ligand Pharmaceuticals Inc.
DESCRIPTION
Targretin® (bexarotene) gel 1% contains
bexarotene and is intended for topical application only. Bexarotene is a
member of a subclass of retinoids that selectively activate retinoid X
receptors (RXRs). These retinoid receptors have biologic activity
distinct from that of retinoic acid receptors (RARs).
The chemical name is
4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]
benzoic acid, and the structural formula is as follows:
Bexarotene is an off-white to white powder with a molecular
weight of 348.48 and a molecular formula of
C24H28O2. It is insoluble in water
and slightly soluble in vegetable oils and ethanol, USP.
Targretin® gel is a clear gelled solution
containing 1.0% (w/w) bexarotene in a base of dehydrated alcohol, USP,
polyethylene glycol 400, NF, hydroxypropyl cellulose, NF, and butylated
hydroxytoluene, NF.
CLINICAL PHARMACOLOGY
Mechanism of Action
Bexarotene selectively binds and activates retinoid X
receptor subtypes (RXRa, RXRß, RXR?).
RXRs can form heterodimers with various receptor partners such
as retinoic acid receptors (RARs), vitamin D receptor, thyroid
receptor, and peroxisome proliferator activator receptors
(PPARs). Once activated, these receptors function as
transcription factors that regulate the expression of genes that
control cellular differentiation and proliferation. Bexarotene
inhibits the growth in
vitro of some tumor cell lines of hematopoietic and
squamous cell origin. It also induces tumor regression in vivo in some animal models.
The exact mechanism of action of bexarotene in the treatment of
cutaneous T-cell lymphoma (CTCL) is unknown.
Pharmacokinetics
General
Plasma concentrations of bexarotene were
determined during clinical studies in patients with CTCL
or following repeated single or multiple-daily dose
applications of Targretin® gel 1%
for up to 132 weeks. Plasma bexarotene concentrations
were generally less than 5 ng/mL and did not exceed 55
ng/mL. However, only two patients with very intense
dosing regimens (> 40% BSA lesions and QID
dosing) were sampled. Plasma bexarotene concentrations and the frequency of detecting quantifiable plasma
bexarotene concentrations increased with increasing
percent body surface area treated and increasing
quantity of Targretin® gel applied.
The sporadically-observed and generally low plasma
bexarotene concentrations indicated that, in patients
receiving doses of low to moderate intensity, there is a
low potential for significant plasma concentrations
following repeated application of
Targretin® gel. Bexarotene is
highly bound (>99%) to plasma proteins. The
plasma proteins to which bexarotene binds have not been
elucidated, and the ability of bexarotene to displace
drugs bound to plasma proteins and the ability of drugs
to displace bexarotene binding have not been studied
(see PRECAUTIONS: Protein Binding). The uptake of bexarotene by organs or
tissues has not been evaluated.
Metabolism
Four bexarotene metabolites have been identified
in plasma following oral administration of bexarotene:
6- and 7-hydroxy-bexarotene and 6- and
7-oxo-bexarotene. In
vitro studies suggest that cytochrome P450 3A4
is the major cytochrome P450 responsible for formation
of the oxidative metabolites and that the oxidative
metabolites may be glucuronidated. The oxidative
metabolites are active in in vitro assays of retinoid receptor
activation, but the relative contribution of the parent
and any metabolites to the efficacy and safety of
Targretin® gel is
unknown.
Elimination
The renal elimination of bexarotene and its
metabolites was examined in patients with Type 2
diabetes mellitus following oral administration of
bexarotene. Neither bexarotene nor its metabolites were
excreted in urine in appreciable amounts.
Special Populations
Elderly, Gender, Race: Because of a large number
of immeasurable plasma concentrations (< 1ng/mL),
any potential pharmacokinetic differences between
Special Populations could not be assessed.
Pediatric: Studies to evaluate bexarotene
pharmacokinetics in the pediatric population have not
been conducted (see PRECAUTIONS: Pediatric Use).
Renal Insufficiency: No formal studies have been
conducted with Targretin® gel in
patients with renal insufficiency. Urinary elimination
of bexarotene and its known metabolites is a minor
excretory pathway (<1% of an orally administered
dose), but because renal insufficiency can result in
significant protein binding changes, pharmacokinetics
may be altered in patients with renal insufficiency (see PRECAUTIONS: Renal Insufficiency).
Hepatic Insufficiency: No specific studies have
been conducted with Targretin® gel
in patients with hepatic insufficiency. Because less
than 1% of the dose of oral bexarotene is excreted in
the urine unchanged and there is in vitro evidence of extensive hepatic contribution to bexarotene
elimination, hepatic impairment would be expected to
lead to greatly decreased clearance (see PRECAUTIONS: Hepatic
Insufficiency).
Drug-Drug Interactions
No formal studies to evaluate drug interactions
with bexarotene or Targretin® gel
have been conducted. Bexarotene oxidative metabolites
appear to be formed through cytochrome P450 3A4. Drugs
that affect levels or activity of cytochrome P450 3A4
may potentially affect the disposition of bexarotene.
Concomitant gemfibrozil was associated with increased
bexarotene concentrations following oral administration
of bexarotene.
Clinical Studies
Targretin® gel was evaluated for the
treatment of patients with early stage (Stage IA-IIA) CTCL in
one multicenter, open-label, clinical trial as well as in a
Phase I-II program (dose-seeking trials with different response
criteria than the multicenter trial). These clinical studies
enrolled a total of 117 patients.
In the multicenter, open-label clinical trial,
Targretin® gel was evaluated for the
treatment of patients with early stage CTCL who were refractory
to, intolerant to, or reached a response plateau for at least
six months on at least two prior therapies. The study was
conducted in the U.S., Canada, Europe, and Australia and
enrolled a total of 50 patients; 46% of these patients were
male, 80% were Caucasian, and the median age was 64 years (range
13 to 85).
Targretin® gel was also evaluated for
the treatment of patients with CTCL in a U.S. Phase I-II program
involving patients with early stage CTCL. This program enrolled
a total of 67 patients; 55% of these patients were male, 85%
were Caucasian, and the median age was 61 years (range 30 to
87).
In the multicenter, open-label clinical trial,
considering prior systemic, irradiation, and topical treatments,
patients had been exposed to a median of 3 prior therapies
(range 2-7). All patients failed at least two treatments; the
majority (68%) of patients were either refractory to two or more
therapies, or were refractory to one therapy and intolerant to
at least one therapy.
Patients were treated with Targretin®
gel 1% for a planned 16-week period with an option to continue
provided that no unacceptable toxicity was occurring.
Tumor response was assessed in the multicenter study by
observation of up to five baseline-defined index lesions using a
Composite Assessment of Index Lesion Disease Severity (CA). This
endpoint was based on a summation of the grades, for all index
lesions, of erythema, scaling, plaque elevation,
hypopigmentation or hyperpigmentation, and area of involvement.
New cutaneous lesions or tumors and extracutaneous disease
manifestations were not considered in response or disease
progression assessments.
All tumor responses required confirmation over at least
two assessments separated by at least four weeks. A partial
response was defined as an improvement of at least 50% in the
index lesions. A complete clinical response required complete
disappearance of the index lesions, but did not require
confirmation by biopsy.
Targretin® gel produced an overall
response rate of 26% (13/50) with a corresponding exact 95%
confidence interval from 14.6% to 40.3% by the Composite
Assessment of Index Lesion Severity. For the Stage IA and IB
patients, the response rate was 28% (13/47) with a corresponding
exact 95% confidence interval from 15.6% to 42.6%. For the Stage
II patients the response rate was 0% (0/3). Two percent of
patients (1/50) had a clinical complete response. The median
time to best response on the Composite Assessment of Index
Lesion Severity (n=13) was 85 days (range: 36-154).
The rate of relapse in responding patients by the
Composite Assessment of Index Lesion Severity was 23% (3/13) over a median observation period of 149 days (range 56-342).
Fourteen patients developed new lesions in untreated areas
(14/50; 28%). Four patients developed clinically abnormal lymph
nodes (= 1cm diam) (4/50; 8%). One patient developed a
cutaneous tumor (1/50; 2%).
The Phase I-II program (dose-seeking trials with
different response criteria than the multicenter trial) was
supportive of the multicenter study results.
INDICATIONS AND USAGE
Targretin® (bexarotene) gel 1% is indicated
for the topical treatment of cutaneous lesions in patients with CTCL
(Stage IA and IB) who have refractory or persistent disease after other
therapies or who have not tolerated other therapies.
CONTRAINDICATIONS
Targretin® gel 1% is contraindicated in
patients with a known hypersensitivity to bexarotene or other components
of the product.
Pregnancy: Category X
Targretin® gel 1% may cause fetal
harm when administered to a pregnant woman.
Targretin® gel must not be given to a
pregnant woman or a woman who intends to become pregnant. If a
woman becomes pregnant while taking
Targretin® gel,
Targretin® gel must be stopped immediately
and the woman given appropriate counseling.
Bexarotene caused malformations when administered orally
to pregnant rats during days 7-17 of gestation. Developmental
abnormalities included incomplete ossification at 4 mg/kg/day
and cleft palate, depressed eye bulge/microphthalmia, and small ears at 16 mg/kg/day. At doses greater than 10 mg/kg/day,
bexarotene caused developmental mortality. The no-effect oral
dose in rats was 1 mg/kg/day. Plasma bexarotene concentrations
in patients with CTCL applying Targretin®
gel 1% were generally less than one hundredth the Cmax
associated with dysmorphogenesis in rats, although some patients
had Cmax levels that were approximately one eighth the
concentration associated with dysmorphogenesis in rats.
Women of child-bearing potential should be advised to
avoid becoming pregnant when Targretin® gel
is used. The possibility that a woman of child-bearing potential
is pregnant at the time therapy is instituted should be
considered. A negative pregnancy test (e.g., serum beta-human
chorionic gonadotropin, beta-HCG) with a sensitivity of at least
50 mIU/L should be obtained within one week prior to
Targretin® gel therapy, and the
pregnancy test must be repeated at monthly intervals while the
patient remains on Targretin® gel. Effective
contraception must be used for one month prior to the initiation
of therapy, during therapy and for at least one month following
discontinuation of therapy; it is recommended that two reliable forms of contraception be used simultaneously unless abstinence
is the chosen method. Male patients with sexual partners who are
pregnant, possibly pregnant, or who could become pregnant must
use condoms during sexual intercourse while applying
Targretin® gel and for at least one
month after the last dose of drug.
Targretin® gel therapy should be initiated
on the second or third day of a normal menstrual period. No more
than a one month supply of Targretin® gel
should be given to the patient so that the results of pregnancy
testing can be assessed and counseling regarding avoidance of
pregnancy and birth defects can be reinforced.
PRECAUTIONS
Pregnancy: Category X. See CONTRAINDICATIONS
General:
Targretin® gel should be used with
caution in patients with a known hypersensitivity to other
retinoids. No clinical instances of cross-reactivity have been
noted.
Vitamin A Supplementation: In clinical studies,
patients were advised to limit vitamin A intake to=15,000 IU/day. Because of the relationship of
bexarotene to vitamin A, patients should be advised to limit vitamin A supplements to avoid potential additive
toxic effects.
Photosensitivity: Retinoids as a class have
been associated with photosensitivity. In vitro assays
indicate that bexarotene is a potential photosensitizing
agent. There were no reports of photosensitivity in
patients in the clinical studies. Patients should be
advised to minimize exposure to sunlight and artificial
ultraviolet light during the use of
Targretin® gel.
Drug-Drug Interactions
Patients who are applying Targretin®
gel should not concurrently use products that contain DEET
(N,N-diethyl-m-toluamide), a common
component of insect repellent products. An animal toxicology
study showed increased DEET toxicity when DEET was included as
part of the formulation.
No formal studies to evaluate drug interactions with
bexarotene have been conducted. Bexarotene oxidative metabolites
appear to be formed through cytochrome P450 3A4.
On the basis of the metabolism of bexarotene by
cytochrome P450 3A4, concomitant ketoconazole, itraconazole,
erythromycin and grapefruit juice could increase bexarotene
plasma concentrations. Similarly, based on data that gemfibrozil increases bexarotene concentrations following oral bexarotene
administration, concomitant gemfibrozil could increase
bexarotene plasma concentrations. However, due to the low
systemic exposure to bexarotene after low to moderately intense
gel regimens (see Clinical Pharmacology), increases that occur
are unlikely to be of sufficient magnitude to result in adverse
effects.
No drug interaction data are available on concomitant
administration of Targretin® gel and other
CTCL therapies.
Renal Insufficiency
No formal studies have been conducted with
Targretin® gel in patients with renal
insufficiency. Urinary elimination of bexarotene and its known
metabolites is a minor excretory pathway for bexarotene
(<1% of an orally administered dose), but because renal
insufficiency can result in significant protein binding changes, and bexarotene is >99% protein bound, pharmacokinetics
may be altered in patients with renal insufficiency.
Hepatic Insufficiency
No specific studies have been conducted with
Targretin® gel in patients with hepatic
insufficiency. Because less than 1% of the dose of oral
bexarotene is excreted in the urine unchanged and there isin vitro evidence of
extensive hepatic contribution to bexarotene elimination,
hepatic impairment would be expected to lead to greatly
decreased clearance.
Protein Binding
Bexarotene is highly bound (>99%) to plasma
proteins. The plasma proteins to which bexarotene binds have not
been elucidated, and the ability of bexarotene to displace drugs
bound to plasma proteins and the ability of drugs to displace
bexarotene binding have not been studied.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to assess the carcinogenic
potential of bexarotene have not been conducted. Bexarotene was
not mutagenic to bacteria (Ames assay) or mammalian cells (mouse
lymphoma assay). Bexarotene was not clastogenic in vivo (micronucleus test in
mice). No formal fertility studies were conducted with
bexarotene. Bexarotene caused testicular degeneration when oral
doses of 1.5 mg/kg/day were given to dogs for 91
days.
Use in Nursing Mothers
It is not known whether bexarotene is excreted in human
milk. Because many drugs are excreted in human milk and because
of the potential for serious adverse reactions in nursing
infants from bexarotene, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not
been established.
Geriatric Use
Of the total patients with CTCL in clinical studies of
Targretin® gel, 62% were under 65 years
and 38% were 65 years or older. No overall differences in safety
were observed between patients 65 years of age or older and
younger patients, but greater sensitivity of some older
individuals to Targretin® gel cannot be
ruled out. Responses to Targretin® gel were
observed across all age group decades, without preference for
any individual age group decade.
ADVERSE REACTIONS
The safety of Targretin® gel has been
assessed in clinical studies of 117 patients with CTCL who received
Targretin® gel for up to 172 weeks. In the
multicenter open label study, 50 patients with CTCL received
Targretin® gel for up to 98 weeks. The mean
duration of therapy for these 50 patients was 199 days. The most common
adverse events reported with an incidence at the application site of at
least 10% in patients with CTCL were rash, pruritus, skin disorder, and
pain.
Adverse events leading to dose reduction or study drug
discontinuation in at least two patients were rash, contact dermatitis,
and pruritus.
Of the 49 patients (98%) who experienced any adverse event, most
experienced events categorized as mild (9 patients, 18%) or moderate (27
patients, 54%). There were 12 patients (24%) who experienced at least
one moderately severe adverse event. The most common moderately severe
events were rash (7 patients, 14%) and pruritus (3 patients, 6%). Only
one patient (2%) experienced a severe adverse event (rash).
In the patients with CTCL receiving
Targretin® gel, adverse events reported regardless
of relationship to study drug at an incidence of =5% are
presented in Table 1.
A similar safety profile for Targretin® gel
was demonstrated in the Phase I-II program. For the 67 patients enrolled
in the Phase I-II program, the mean duration of treatment was 436 days (range 12-1203 days). As in the multicenter study, the most common
adverse events regardless of relationship to study drug in the Phase
I-II program were rash (78%), pain (40%), and pruritus (40%).
Table 1. Incidence of All Adverse Events* and Application Site
Adverse Events with Incidence =5% for All Application
Frequencies of Targretin® Gel in the Multicenter
CTCL Study
|
|
All Adverse Events |
Application Site Adverse
Events |
|---|
COSTART 5
Body System/Preferred Term |
N = 50
n (%) |
N = 50
n (%) |
|---|
|
* Regardless of association with treatment
Includes Investigator terms such as:
1 Contact dermatitis, irritant contact
dermatitis, irritant dermatitis
2 Pruritus, itching, itching of lesion
3 Erythema, scaling, irritation, redness, rash,
dermatitis
4 Skin inflammation, excoriation, sticky or
tacky sensation of skin; NOS = Not Otherwise
Specified
|
|
Skin and Appendages
|
|
|
|
Contact
Dermatitis1
|
7 (14)
|
4 (8)
|
|
Exfoliative
Dermatitis
|
3 (6)
|
0
|
|
Pruritus2
|
18 (36)
|
9 (18)
|
|
Rash3
|
36 (72)
|
28 (56)
|
|
Maculopapular
Rash
|
3 (6)
|
0
|
|
Skin
Disorder (NOS)4
|
13 (26)
|
9 (18)
|
|
Sweating
|
3 (6)
|
0
|
|
Body as a Whole
|
|
|
|
Asthenia
|
3 (6)
|
0
|
|
Headache
|
7 (14)
|
0
|
|
Infection
|
9 (18)
|
0
|
|
Pain
|
15 (30)
|
9 (18)
|
|
Cardiovascular
|
|
|
|
Edema
|
5 (10)
|
0
|
|
Peripheral
Edema
|
3 (6)
|
0
|
|
Hemic and Lymphatic
|
|
|
|
Leukopenia
|
3 (6)
|
0
|
|
Lymphadenopathy
|
3 (6)
|
0
|
|
WBC
Abnormal
|
3 (6)
|
0
|
|
Metabolic and Nutritional
|
|
|
|
Hyperlipemia
|
5 (10)
|
0
|
|
Nervous
|
|
|
|
Paresthesia
|
3 (6)
|
3 (6)
|
|
Respiratory
|
|
|
|
Cough
Increased
|
3 (6)
|
0
|
|
Pharyngitis
|
3 (6)
|
0
|
OVERDOSAGE
Systemic toxicity following acute overdosage with topical
application of Targretin® gel is unlikely because of
low systemic plasma levels observed with normal therapeutic doses. There
is no specific antidote for overdosage.
There has been no experience with acute overdose of
Targretin® gel in humans. Any overdose with
Targretin® gel should be treated with supportive
care for the signs and symptoms exhibited by the patient.
DOSAGE AND ADMINISTRATION
Targretin® gel should be initially applied
once every other day for the first week. The application frequency
should be increased at weekly intervals to once daily, then twice daily,
then three times daily and finally four times daily according to
individual lesion tolerance. Generally, patients were able to maintain a
dosing frequency of two to four times per day. Most responses were seen
at dosing frequencies of two times per day and higher. If application
site toxicity occurs, the application frequency can be reduced. Should
severe irritation occur, application of drug can be temporarily
discontinued for a few days until the symptoms subside. See CONTRAINDICATIONS:
Pregnancy: Category X.
Sufficient gel should be applied to cover the lesion with a
generous coating. The gel should be allowed to dry before covering with
clothing. Because unaffected skin may become irritated, application of
the gel to normal skin surrounding the lesions should be avoided. In
addition, do not apply the gel near mucosal surfaces of the body.
A response may be seen as soon as 4 weeks after initiation of
therapy but most patients require longer application. With continued
application, further benefit may be attained. The longest onset time for
the first response among the responders was 392 days based on the
Composite Assessment of Index Lesion Severity in the multicenter
study. In clinical trials,
Targretin® gel was applied for up to 172 weeks.
Targretin® gel should be continued as long as
the patient is deriving benefit.
Occlusive dressings should not be used with
Targretin® gel.
Targretin® gel is a topical therapy and is
not intended for systemic use. Targretin® gel has
not been studied in combination with other CTCL therapies.
HOW SUPPLIED
Targretin® gel is supplied in tubes
containing 60 g (600 mg active bexarotene).
60 g tube
.............................................................................................
NDC 64365-504-01
Store at 25°C (77°F); with excursions permitted
to 15°-30°C (59°-86°F) [see USP].
Avoid exposing to high temperatures and humidity after the tube is
opened. Protect from light.
Manufactured for: Ligand Pharmaceuticals Incorporated
San
Diego, CA 92121
by: Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
Ligand Part #3000204 (Rev. 0101)
Revised: 03/2006Ligand Pharmaceuticals Inc.