CONTRAINDICATIONS
A. Patients exhibiting idiosyncratic reactions to psoralen compounds.
B. Patients possessing a specific history of light sensitive disease states should not initiate
methoxsalen therapy except under special circumstances. Diseases associated with
photosensitivity include lupus erythematosus, porphyria cutanea tarda, erythropoietic
protoporphyria, variegate porphyria, xeroderma pigmentosum, and albinism.
C. Patients with melanoma or possessing a history of melanoma.
D. Patients with invasive squamous cell carcinomas
E. Patients with aphakia, because of the significantly increased risk of retinal damage due to
the absence of lenses.
Topical
A. Patients exhibiting idiosyncratic reactions to psoralen compounds or a history of sensitivity
reactions to them.
B. Patients exhibiting melanoma or with a history of melanoma.
C. Patients exhibiting invasive skin carcinoma generally.
D. Patients with photosensitivity diseases such as porphyria, acute lupus erythematosus,
xeroderma, pigmentosum, etc.
E. Children under 12 since clinical studies to determine the efficacy and safety of treatment
in this age group have not been done.
WARNINGS
Oral
Skin Burning: Serious burns from either UVA or sunlight (even through window glass) can result
if the recommended dosage of the drug and/or exposure schedules are not maintained.
Carcinogenicity
1. Animal Studies: Topical or intraperitoneal methoxsalen has been reported to be a potent
photocarcinogen in albino mice and hairless mice. However, methoxsalen given by the oral
route to Swiss albino mice suggests this agent exerts a protective effect against ultraviolet
carcinogenesis; mice given 8-methoxypsoralen in their diet showed 38% ear tumors 180 days
after the start of ultraviolet therapy compared to 62% for controls.
2. Human Studies: A 5.7 year prospective study of 1380 psoriasis patients treated with oral
methoxsalen and ultraviolet. A photochemotherapy (PUVA) demonstrated that the risk of
cutaneous squamous-cell carcinoma developing at least 22 months following the first PUVA
exposure was approximately 12.8 times higher in the high dose patients than in the low dose
patients. The substantial dose-dependent increase was observed in patients with neither a
prior history of skin cancer nor significant exposure to cutaneous carcinogens. Reduction in
PUVA dosage significantly reduces the risk. No substantial dose related increase was noted
for basal cell carcinoma according to Stern et al., 198414. Increases appear greatest in
patients who have pre-PUVA exposure to 1) prolonged tar and UVB treatment, 2) ionizing
radiation, or 3) arsenic.
Roenigk et al., 198015, studied 690 patients for up to 4 years and found no increase in the risk of
non-melanoma skin cancer, although patients in this cohort has significantly less exposure to PUVA
than in the Stern et al. study. After 5 years, two of the 1380 patients in the Stern et al. PUVA study
have developed malignant melanoma. In addition, more than 1/5 of the patients in this cohort have
developed macular pigmented lesions on the buttocks. While there is no evidence that an increased
risk of melanoma exists in PUVA treated patients, these observations indicated the need for
continued evaluation of melanoma risk of PUVA treated patients.
In a study in Indian patients treated for 4 years for vitiligo, 12 percent developed keratoses, but not
cancer, in the depigmented, vitiliginous areas. Clinically, the keratoses were keratotic papules,
actinic keratosis-like macules, nonscaling dome shaped papules, and lichenoid porokeratotic-like
papules.
Cataractogenicity
1. Animal Studies: Exposure to large doses of UVA causes cataracts in animals, and this
effect is enhanced by the administration of methoxsalen.
2. Human Studies: It has been found that the concentration of methoxsalen in the lens is
proportional to the serum level. If the lens is exposed to UVA during the time methoxsalen is
present in the lens, photochemical action may lead to irreversible binding of methoxsalen to
proteins and the DNA components of the lens. However, if the lens is shielded from UVA,
the methoxsalen will diffuse out the lens in a 24 hour period. Patients should be told
emphatically to wear UVA absorbing, wrap-around sunglasses for the twenty-four (24) hour
period following ingestion of methoxsalen whether exposed to direct or indirect sunlight in the
open or through a window glass.
Among patients using proper eye protection, there is no evidence for a significantly increased risk of
cataracts in association with PUVA therapy. Thirty-five of 1380 patients have developed cataracts
in the five years since their first PUVA treatment. This incidence is comparable to that expected in
a population of this size and age distribution. No relationship between PUVA dose and cataract risk
in this group has been noted.
Actinic Degeneration: Exposure to sunlight and/or ultraviolet radiation may result in
"premature aging" of the skin.
Basal Cell Carcinomas: Patients exhibiting multiple basal cell carcinomas or having a
history of basal cell carcinomas should be diligently observed and treated.
Radiation Therapy: Patients having a history of previous x-ray therapy or grenz ray therapy
should be diligently observed for signs of carcinoma.
Arsenic Therapy: Patients having a history of previous arsenic therapy should be diligently
observed for signs of carcinoma.
Hepatic Diseases: Patients with hepatic insufficiency should be treated with caution since
hepatic biotransformation is necessary for drug urinary excretion.
Cardiac Diseases: Patients with cardiac diseases or others who may be unable to tolerate
prolonged standing or exposure to heat stress should not be treated in a vertical UVA
chamber.
Total Dosage: The total cumulative dose of UVA that can be given over long periods of
time with safety has not yet been established.
Concomitant Therapy: Special care should be exercised in treating patients who are
receiving concomitant therapy (either topically or systemically) with known photosensitizing
agents such as anthralin, coal tar or coal tar derivatives, griseofulvin, phenothiazines, nalidixic
acid, halogenated salicylanilides (bacteriostatic soaps), sulfonamides, tetracyclines, thiazides,
and certain organic staining dyes such as methylene blue, toluidine blue, rose bengal, and
methyl orange.
Topical
Skin Burns: Serious skin burns either UVA or sunlight (even through window glass) can result if
recommended exposure schedule is exceeded and/or protective covering or sunscreens are not
used. The blistering of the skin sometimes encountered after UV exposure generally heals without
complications or scarring. Suitable covering of the area of application or a topical sunblock should
follow the therapeutic UVA exposure.
Carcinogenicity
1. Animal Studies: Topical methoxsalen has been reported to be a potent photocarcinogen
in certain strains of mice.
2. Human Studies: None of our clinical investigators reported skin cancer as a complication
of topical treatment for vitiligo. However, it is recommended that caution be exercised when
the patient is fair-skinned, has a history of prior coal tar UV treatment, or has had ionizing
radiation or taken arsenical compounds. Such patients who subsequently have oral psoralen -
UVA treatment (PUVA) are at increased risk for developing skin cancer.
Concomitant Therapy: Special care should be exercised in treating patients who are
receiving concomitant therapy (either topically or systemically) with known photosensitizing
agents such as anthralin, coal tar or coal tar derivatives, griseofulvin, phenothiazines, nalidixic
acid, halogenated salicylanilides (bacteriostatic soaps), sulfonamides, tetracyclines, thiazides,
and certain organic staining dyes such a methylene blue, toluidine blue, rose bengal, and
methyl orange.
PRECAUTIONS
General
Oral: Applicable To And Psoriasis Treatment:
1. Before Methoxsalen ingestion, patients must not sunbathe during the 24 hours prior to
methoxsalen ingestion and UV exposure. The presence of a sunburn may prevent an
accurate evaluation of the patients's response to photochemotherapy.
2.
a. After Methoxsalen ingestion UVA-absorbing wrap-around sunglasses should be
worn during daylight for 24 hours after methoxsalen ingestion. The protective
eyewear must be designed to prevent entry of stray radiation to the eyes, including
that which may enter from the sides of the eyewear. The protective eyewear is used
to prevent the irreversible binding of methoxsalen to the proteins and DNA
components of the lens. Cataracts form when enough of the binding occurs. Visual
discrimination should be permitted by the eyewear for patient well-being and comfort.
b. Patients must avoid sun exposure, even through window glass or cloud cover, for at
least 8 hours after methoxsalen ingestion. If sun exposure cannot be avoided, the
patient should wear protective devices such as hat and gloves, and/or apply
sunscreens which contain ingredients that filter out UVA radiation (e.g., sunscreens
containing benzophenone and/or PABA esters which exhibit a sun protective factor
equal to or greater than 15). These chemical sunscreens should be applied to all areas
that might be exposed to the sun (including lips). Sunscreens should not be applied to
areas affected by psoriasis until after the patient has been treated in the UVA
chamber.
3.
a. During PUVA therapy, total UVA-absorbing/blocking goggles mechanically
designed to give maximal ocular protection must be worn. Failure to do so may
increase the risk of cataract formation. A reliable radiometer can be used to verify
elimination of UVA transmission through the goggles.
b. Abdominal skin, breasts, genitalia, and other sensitive areas should be protected for
approximately 1/3 of the initial exposure time until tanning occurs.
c. Unless affected by disease, male genitalia should be shielded.
4.
a. After combined Methoxsalen/UVA therapy, UVA-absorbing wrap-around
sunglasses should be worn during the daylight for 24 hours after combined
methoxsalen/UVA therapy.
b. Patients should not sunbathe for 48 hours after therapy. Erythema and/or burning
due to photochemotherapy and sunburn due to sun exposure are additive.
Topical: This product should be applied only in small well-defined lesions and preferably on lesions
which can be protected by clothing or a sunscreen from subsequent exposure to radiant UVA. If
this product is used to treat vitiligo of face or hands, be very emphatic when instructing the patient
to keep the treated areas protected from light by the use of protective clothing or sunscreening
agents. The area of application may be highly photosensitive for several days and may result in
severe burn injury if exposed to additional UV or sunlight.
Laboratory Tests
Oral Forms: Patients should have an ophthalmologic examination prior to start of therapy, and
thence yearly.
Oxsoralen-Ultra Capsules: Patients should have the following tests prior to the start of therapy
and at regular periods thereafter if patients are on extended treatments.
8-MOP Capsules: Patients should have the following tests prior to the start of therapy and should
be retested in 6-12 months subsequently. Additional tests at more extended time periods should be
conducted as clinically indicated.
a. Complete Blood Count (Hemoglobin or Hematocrit; White Blood Count - if abnormal, a
differential count).
b. Anti-nuclear Antibodies.
c. Liver Function Tests
d. Renal Function Tests (Creatinine or Blood Urea Nitrogen).
Carcinogenesis
See WARNINGS.
Pregnancy Category C
Animal reproduction studies have not been conducted with oral or topical methoxsalen. It is also not
known whether methoxsalen can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. Methoxsalen should be given to a woman only if clearly needed.
Nursing Mothers
8-MOP Capsules: It is not known whether this drug is excreted in human milk. Because many
drugs are excreted in human milk, either methoxsalen ingestion or nursing should be discontinued.
Topical: It is not known whether topical methoxsalen is absorbed or excreted in human milk.
Caution is advised when topical methoxsalen is used in a nursing mother.
Pediatric Use
Oral: Safety in children has not been established. Potential hazards of long-term therapy include the
possibilities of carcinogenicity and cataractogenicity as described in WARNINGS as well as the
probability of actinic degeneration which is also described in WARNINGS.
8-MOP Capsules: Safety in children has not been established. Potential hazards of long-term
therapy include the possibilities of carcinogenicity and cataractogenicity as described in
WARNINGS as well as the probability of actinic degeneration which is also described in
WARNINGS.
Topical: Safety and effectiveness in children below the age of 12 years have not been established.