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.

Carcinogenicity, Mutagenesis, Impairment of Fertility

Oral administration of methoxsalen followed by cutaneous UVA exposure (PUVA therapy) is carcinogenic. In a prospective study of 1,380 patients given PUVA therapy for psoriasis, 237 patients developed 1,422 cutaneous squamous cell cancers. This observed incidence of cutaneous carcinoma is 17.6 times that expected for the general population. Previous cutaneous exposure to tar and UVB treatment, ionizing radiation or arsenic increased the risk of developing skin carcinomas after PUVA therapy. Because the dose of methoxsalen with Uvadex^Ò therapy is about 200 times less than with PUVA and the skin is not exposed to high cumulative doses of UVA light, the risk of developing skin cancer following Uvadex^Ò therapy may be lower.

Methoxsalen was carcinogenic in male rats that were given the drug by oral gavage five days per week for 103 weeks at doses of 37.5 and 75 mg/kg. The 37.5 mg/kg dose is about 1,900 times greater than a single human methoxsalen dose during extracorporeal photopheresis treatment on a body surface area basis. The neoplastic lesions in rats included adenomas and adenocarcinomas of the tubular epithelium of the kidneys, carcinoma or squamous cell carcinoma of the Zymbal gland and alveolar or bronchiolar adenomas. Topical or intraperitoneal methoxsalen is a potent photo-carcinogen in albino mice and hairless mice.

With S9 activation, methoxsalen is mutagenic in the Ames test. In the absence of S9 activation and UV light, methoxsalen is clastogenic in vitro (sister chromatid exchange and chromosome aberrations in Chinese hamster ovary cells). Methoxsalen also causes DNA damage, interstrand cross-links and errors in DNA repair.

Pregnancy

Methoxsalen may cause fetal harm when given to a pregnant woman. Doses of 80 to 160 mg/kg/day given during organogenesis caused significant fetal toxicity in rats. The lowest of these doses, 80 mg/kg/day, is over 4,000 times greater than a single dose of UVADEX on a mg/m² basis. Fetal toxicity was associated with significant maternal weight loss, anorexia and increased relative liver weight. Signs of fetal toxicity included increased fetal mortality, increased resorptions, late fetal death, fewer fetuses per litter, and decreased fetal weight. Methoxsalen caused an increase in skeletal malformation and variations at doses of 80 mg/kg/day and above. There are no adequate and well-controlled studies of methoxsalen in pregnant women. If UVADEX is used during pregnancy, or if the patient becomes pregnant while receiving UVADEX , the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

General

Actinic Degeneration: After methoxsalen administration, 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.

Skin Burning: Serious burns from either UVA or sunlight (even through window glass) can result if the recommended dosage of methoxsalen is exceeded or precautions not followed.

The Formation Of Cataracts: Exposure to large doses of UVA light causes cataracts in animals. Oral methoxsalen exacerbates this toxicity. The concentration of methoxsalen in the human lens is proportional to the concentration in serum. Serum methoxsalen concentrations are substantially lower after extracorporeal UVADEX^Ò treatment than after oral methoxsalen treatment. Nevertheless, if the lens is exposed to UVA light while methoxsalen is present, photoactivation of the drug may cause adducts to bind to biomolecules within the lens. If the lens is shielded from UVA light, the methoxsalen will diffuse out of the lens in about 24 hours.

Patients who use proper eye protection after PUVA therapy (oral methoxsalen) appear to have no increased risk of developing cataracts. The incidence of cataracts in these patients five years after their first treatment is about the same as that in the general population. Patients should be told emphatically to wear UVA absorbing, wrap-around sunglasses for twenty-four (24) hours after UVADEX treatment. They should wear these glasses any time they are exposed to direct or indirect sunlight, whether they are outdoors or exposed through a window.

Information for Patients: See PATIENT INFORMATION section.

Drug Interactions: See

WARNINGS

Carcinogenesis, Mutagenesis, and Impairment of Fertility: See

WARNINGS

Pregnancy: Pregnancy Category D. See

WARNINGS

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.

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

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