V. WARNINGS - GENERAL
A. 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.
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 albino mice or by any route in pigmented mice is considerably less phototoxic or carcinogenic (Hakim et at. 196011; Pathak et al. 195912).
A prospective study of 1380 patients over 5 years revealed an approximately nine-fold increase in risks of squamous cell carcinoma among PUVA treated patients (Stern et al. 197913 and Stern et al. 198014). This increase in risk appears greatest among patients who are fair skinned or had pre-PUVA exposure to 1) prolonged tar and UVB treatment, 2) ionizing radiation, or 3) arsenic.
In addition, an approximately two-fold increase in the risk of basal cell carcinoma was noted in this study. Roenigk et al. 198015 studied 690 patients for up to 4 years and found no increase in the risk of non-melanoma skin cancer. However, patients in this cohort had significantly less exposure to PUVA than in the Stern et al study. Recent analysis of new data in the Stern et al cohort (Stern et al., 199716) has shown that these patients had an elevated relative risk of contracting melanoma. The relative risk for melanoma in these patients was 2.3 (95 percent confidence interval 1.1 to 4.1). The risk is particularly higher in those patients who have received more than 250 PUVA treatments and in those whose treatment has spanned greater than 15 years earlier. Some patients developing melanoma did so even after having ceased PUVA therapy over 5 years earlier. These observations indicate the need for monitoring of PUVA patients for skin tumors throughout their lives.
In a study in Indian patients treated for 4 years for vitiligo, 12 percent developed keratoses, but not cancer, in the depigmented, vitiliginous areas (Mosher, 198017). Clinically, the keratoses were keratotic papules, actinic keratosis-like macules, nonscaling dome-shaped papules, and lichenoid porokeratotic-like papules.
Exposure to large doses of UVA causes cataracts in animals, and this effect is enhanced by the administration of methoxsalen (Cloud et al. 196018; Cloud et al. 196119; Freeman et al. 196920).
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 (Lerman et al. 198021). However, if the lens is shielded from UVA, the methoxsalen will diffuse out of the lens in a 24 hour period21. Patients should be told emphatically to wear UVA-absorbing, wraparound 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.13 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.
D. ACTINIC DEGENERATION
Exposure to sunlight and/or ultraviolet radiation may result in "premature aging" of the skin.
E. BASAL CELL CARCINOMAS
Patients exhibiting multiple basal cell carcinomas or having a history of basal cell carcinomas should be diligently observed and treated.
F. RADIATION THERAPY
Patients having a history of previous x-ray therapy or grenz ray therapy should be diligently observed for signs of carcinoma.
G. ARSENIC THERAPY
Patients having a history of previous arsenic therapy should be diligently observed for signs of carcinoma.
H. HEPATIC DISEASES
Patients with hepatic insufficiency should be treated with caution since hepatic biotransformation is necessary for drug urinary excretion.
I. 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.
J. TOTAL DOSAGE
The total cumulative dose of UVA that can be given over long periods of time with safety has not as yet been established.
K. 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, fluoroquinolone antibiotics, halogenated salicylanilides (bacteriostatic soaps), sulfonamides, tetracyclines, thiazides, and certain organic staining dyes such as methylene blue, toluidine blue, rose bengal, and mythyl orange.
A. GENERAL - APPLICABLE TO BOTH VITILIGO AND PSORIASIS TREATMENT:
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 patient's response to photochemotherapy.
AFTER METHOXSALEN INGESTION
a. 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 a 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.
DURING PUVA THERAPY
a. 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.
AFTER COMBINED METHOXSALEN/UVA THERAPY
a. 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.
a. The dosage of methoxsalen should not be increased above 0.6 mg/kg since overdosage may result in serious burning of the skin.
b. Eye and skin sun protection as described in the Precautions - General section should be observed.
B. INFORMATION FOR PATIENTS:
See accompanying Patient Package Insert.
C. LABORATORY TESTS:
1. Patients should have an ophthalmologic examination prior to the start of therapy, and thence yearly.
2. Patients should have the following tests prior to the start of therapy and should be retested 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).
D. DRUG INTERACTIONS:
See Warnings Section.
See Warnings Section.
Pregnancy Category C.
Animal reproduction studies have not been conducted with 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.
G. NURSING MOTHERS:
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when methoxsalen is administered to a nursing woman.
H. PEDIATRIC USE:
Safety in children has not been established. Potential hazards of long-term therapy include the possibilities of carcinogenicity and cataractogenicity as described in the Warnings Section as well as the probability of actinic degeneration which is also described in the Warnings Section.