Methoxsalen

III. INDICATIONS AND USAGE Photochemotherapy (Methoxsalen with long wave UVA radiation) is indicated for the symptomatic control of severe, recalcitrant, disabling psoriasis not adequately responsive to other forms of therapy and when the diagnosis has been supported by biopsy. Methoxsalen is intended to be administered only in conjunction with a schedule of controlled doses of long wave ultraviolet radiation.

IX. DRUG DOSAGE & ADMINISTRATION CAUTION: Methoxsalen Capsules, USP represents a new dose form of methoxsalen. This new dosage form of methoxsalen exhibits significantly greater bioavailability and earlier photosensitization onset time than previous methoxsalen dosage forms. Each patient should be evaluated by determining the minimum phototoxic dose (MPD) and phototoxic peak time after drug administration prior to onset of photochemotherapy with this dosage form. Human bioavailability studies have indicated the following drug dosage and administration directions are to be used as a guideline only. PSORIASIS THERAPY 1. DRUG DOSAGE -INITIAL THERAPY: Methoxsalen capsules should be taken 1-1/2 to 2 hours before UVA exposure with some low-fat food or milk according to the following table: Patient's Weight Dose (kg) (lbs) (mg) <30 <66 10 30-50 66-110 20 51-65 112-143 30 66-80 146-176 40 81-90 179-198 50 91-115 201-254 60 >115 >254 70 Geriatric patients should generally be started at the low end of the dose recommended according to body weight and closely monitored during PUVA therapy. Although clinical experience has not identified differences in response between elderly and younger patients, the use of methoxsalen in older individuals may be affected by the presence of pre-existing medical conditions. 2. INITIAL EXPOSURE: The initial UVA exposure energy level and corresponding time of exposure is determined by the patient's skin characteristics for sun burning and tanning as follows: *Patients with natural pigmentation of these types should be classified into a lower skin type category if the sunburning history so indicates. Skin Type History Recommended J/cm 2 I Always burn, never tan (patients with erythrodermic psoriasis are to be classed as Type I for determination of UVA dosage.) 0.5 J/cm 2 II Always burn, but sometimes tan 1.0 J/cm 2 III Sometimes burn, but always tan 1.5 J/cm 2 IV Never burn, always tan 2.0 J/cm 2 Skin Type Physician Examination J/cm 2 V* Moderately pigmented 2.5 J/cm 2 VI* Blacks 3.0 J/cm 2 If the MPD is done, start at 1/2 MPD. Additional drug dosage directions are as follows: Weight Change: In the event that the weight of a patient changes during treatment such that he/she falls into an adjacent weight range/dose category, no change in the dose of methoxsalen is usually required. If, in the physician's opinion, however, a weight change is sufficiently great to modify the drug dose, then an adjustment in the time of exposure to UVA should be made. Dose/Week: The number of doses per week of methoxsalen capsules will be determined by the patient's schedule of UVA exposures. In no case should treatments be given more often than once every other day because the full extent of phototoxic reactions may not be evident until 48 hours after each exposure. Dosage Increase: Dosage may be increased by 10 mg. after the 15th treatment under the conditions outlined in section XI.B.4.b. X. UVA RADIATION SOURCE SPECIFICATIONS AND INFORMATION A. IRRADIANCE UNIFORMITY The following specifications should be met with the window of the detector held in a vertical plane: Vertical Variation: For readings taken at any point along the vertical center axis of the chamber (to within 15 cm from the top and bottom), the lowest reading should not be less than 70 % of the highest reading. Horizontal Variation: Throughout any specific horizontal plane, the lowest reading must be at least 80 % of the highest reading, excluding the peripheral 3 cm of the patient treatment space. B. PATIENT SAFETY FEATURES: The following safety features should be present: (1) Protection from electrical hazard: All units should be grounded and conform to applicable electrical codes. The patient or operator should not be able to touch any live electrical parts. There should be ground fault protection. (2) Protective shielding of lamps: The patient should not be able to come in contact with the bare lamps. In the event of lamp breakage, the patient should not be…

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 exceeded. B. CARCINOGENICITY: ANIMAL STUDIES: Topical or intraperitoneal methoxsalen has been reported to be a potent photocarcinogen in albino mice and hairless mice (Hakim et al., 1960 10 ). 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., 1957 11 ). 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., 1979 12 , Stern et al., 1980 13 , and Stern et al., 1984 14 ). 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., 1984 14 . 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., 1980 15 , 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., 1997 16 ) has shown that these patients have 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, 1980 17 ). Clinically, the keratoses were keratotic papules, actinic keratosis-like macules, nonscaling dome-shaped papules, and lichenoid porokeratotic-like papules. C. CATARACTOGENICITY: 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 ). 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 (Lerman et al., 1980 21 ). 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., 1979 12 ). Thirty-five of 1380 patients have developed cataracts in the 5 years since their fi…

IV. 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 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.

D. DRUG INTERACTIONS: See WARNINGS – GENERAL.

F. PREGNANCY: 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.

G. NURSING MOTHERS: 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.

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 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. B. COMBINED METHOXSALEN/UVA THERAPY: 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. 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. IMPORTANT DIFFERENCES BETWEEN PUVA ERYTHEMA AND SUNBURN: PUVA-induced inflammation differs from sunburn or UVB phototherapy in several ways. The % 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 % through the skin. (Diffey, 1982 22 ). 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. 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. To report SUSPECTED ADVERSE REACTION, contact Strides Pharma Inc. at 1-877-244-9825 or go to www.strides.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.