FDA label 81bd9e44-4367-4982-855b-f9ced06acb05

Methoxsalen with UV radiation should be used only by physicians who have special competence in the diagnosis and treatment of psoriasis and vitiligo and who have special training and experience in photochemotherapy. Psoralen and ultraviolet radiation therapy should be under constant supervision of such a physician. For the treatment of patients with psoriasis, photochemotherapy should be restricted to patients with severe, recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, and only when the diagnosis is certain. Because of the possibilities of ocular damage, aging of the skin, and skin cancer (including melanoma), the patient should be fully informed by the physician of the risks inherent in this therapy. When methoxsalen is used in combination with photopheresis, refer to the UVAR* System Operator's Manual for specific warnings, cautions, indications, and instructions related to photopheresis.

CAUTION: 8-MOP ® Capsules (Methoxsalen Hard Gelatin Capsules) may not be interchanged with Oxsoralen-Ultra ® Capsules (Methoxsalen Soft Gelatin Capsules) without retitration of the patient.

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. B. 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 albino mice or by any route in pigmented mice is considerably less phototoxic or carcinogenic (Hakim et at. 1960 11 ; Pathak et al. 1959 12 ). 2. HUMAN STUDIES: 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. 1979 13 and Stern et al. 1980 14 ). 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. 1980 15 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., 1997 16 ) 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, 1980 17 ). Clinically, the keratoses were keratotic papules, actinic keratosis-like macules, nonscaling dome-shaped papules, and lichenoid porokeratotic-like papules. C. CATARACTOGENICITY: 1. ANIMAL STUDIES: Exposure to large doses of UVA causes cataracts in animals, and this effect is enhanced by the administration of methoxsalen (Cloud et al. 1960 18 ; Cloud et al. 1961 19 ; Freeman et al. 1969 20 ). 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 (Lerman et al. 1980 21 ). However, if the lens is shielded from UVA, the methoxsalen will diffuse out of the lens in a 24 hour period 21 . 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 methyl orange.

VII. ADVERSE REACTIONS A. METHOXSALEN: The most commonly reported side effect of methoxsalen alone is nausea, which occurs with approximately 10% of all patients. This effect may be minimized or avoided by instructing the patient to take methoxsalen with milk or food, or to divide the dose into two portions, taken approximately one-half hour apart. Other effects include nervousness, insomnia, and psychological depression. B. COMBINED METHOXSALEN/UVA THERAPY: 1. PRURITUS: This adverse reaction occurs with approximately 10% of all patients. In most cases, pruritus can be alleviated with frequent application of bland emollients or other topical agents; severe pruritus may require systemic treatment. If pruritus is unresponsive to these measures, shield pruritic areas from further UVA exposure until the condition resolves. If intractable pruritus is generalized, UVA treatment should be discontinued until the pruritus disappears. 2. ERYTHEMA: Mild, transient erythema at 24-48 hours after PUVA therapy is an expected reaction and indicates that a therapeutic interaction between methoxsalen and UVA occurred. Any area showing moderate erythema (greater than Grade 2 – See Table 1 for grades of erythema) should be shielded during subsequent UVA exposures until the erythema has resolved. Erythema greater than Grade 2 which appears within 24 hours after UVA treatment may signal a potentially severe burn. Erythema may become progressively worse over the next 24 hours, since the peak erythemal reaction characteristically occurs 48 hours or later after methoxsalen ingestion. The patient should be protected from further UVA exposures and sunlight, and should be monitored closely. 3. IMPORTANT DIFFERENCES BETWEEN PUVA ERYTHEMA AND SUNBURN: PUVA-induced inflammation differs from sunburn or UVB phototherapy in several ways. The in situ depth of photochemistry is deeper within the tissue because UVA is transmitted further into the skin. The DNA lesions induced by PUVA are very different from UV-induced thymine dimers and may lead to a DNA crosslink. This DNA lesion may be more problematic to the cell because crosslinks are more lethal and psoralen-DNA photoproducts may be "new" or unfamiliar substrates for DNA repair enzymes. DNA synthesis is also suppressed longer after PUVA. The time course of delayed erythema is different with PUVA and may not involve the usual mediators seen in sunburn. PUVA-induced redness may be just beginning at 24 hours, when UVB erythema has already passed its peak. The erythema dose-response curve is also steeper for PUVA. Compared to equally erythemogenic doses of UVB, the histologic alterations induced by PUVA show more dermal vessel damage and longer duration of epidermal and dermal abnormalities. 4. OTHER ADVERSE REACTIONS: Those reported include edema, dizziness, headache, malaise, depression, hypopigmentation, vesiculation and bullae formation, non-specific rash, herpes simplex, miliaria, urticaria, folliculitis, gastrointestinal disturbances, cutaneous tenderness, leg cramps, hypotension, and extension of psoriasis.