Source: FDA, National Drug Code (US) Revision Year: 2017
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 with 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.
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 exceeded.
Animal studies:
Topical or intraperitoneal methoxsalen has been reported to be a potent photocarcinogen in albino mice and hairless mice (Hakim et al., 196010). 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 (O’Neal et al., 195711).
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 (Stern et al., 197912, Stern et al., 198013, and Stern et al., 198414). 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 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% 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% 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.
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., 196018; Cloud et al., 196119; Freeman et al., 196920).
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., 198021). However, if the lens is shielded from UVA, the methoxsalen will diffuse out of the lens in a 24-hour period (Lerman et al., 198021). Patients should be told emphatically to wear UVA-absorbing, wrap-around sunglasses for the 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 (Stern et al., 197912). Thirty-five of 1380 patients have developed cataracts in the 5 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.
Exposure to sunlight and/or ultraviolet radiation may result in “premature aging” of the skin.
Patients exhibiting multiple basal cell carcinomas or having a history of basal cell carcinomas should be diligently observed and treated.
Patients having a history of previous x-ray therapy or grenz ray therapy should be diligently observed for signs of carcinoma.
Patients having a history of previous arsenic therapy should be diligently observed for signs of carcinoma.
Patients with hepatic insufficiency should be treated with caution since hepatic biotransformation is necessary for drug urinary excretion.
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.
Caution should be used in elderly patients, especially those with a pre-existing history of cataracts, cardiovascular conditions, kidney and/or liver dysfunction, or skin cancer.
The total cumulative dose of UVA that can be given over long periods of time with safety has not as yet been established.
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.
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 in milk or food, or to divide the dose into two portions, taken approximately one-half hour apart. Other effects include nervousness, insomnia, and depression.
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.
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.
PUVA-induced inflammation differs from sunburn or UVB phototherapy in several ways. The percent transmission of UVB varies between 0% to 34% through skin whereas UVA varies between 1% to 80% transmission; thus, UVA is transmitted to a larger percent through the skin. (Diffey, 198222). 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.
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.
To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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:
During puva therapy:
After combined methoxsalen/UVA therapy:
See accompanying Patient Package Insert.
See WARNINGS – GENERAL.
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 with reproductive capacity only if clearly needed.
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.
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 – GENERAL section as well as the probability of actinic degeneration which is also described in the WARNINGS – GENERAL section.
Clinical studies with Oxsoralen-Ultra capsules did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects responded differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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