Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of action: The exact mechanism of action of methoxsalen is not known. The best-known biochemical reaction of methoxsalen is with DNA. Methoxsalen, upon photoactivation, conjugates and forms covalent bonds with DNA which leads to the formation of both monofunctional (addition to a single strand of DNA) and bifunctional adducts (crosslinking of psoralen to both strands of DNA). Reactions with proteins have also been described. The formation of photoadducts results in inhibition of DNA synthesis, cell division and epidermal turnover. For the palliative treatment of Cutaneous T-Cell Lymphoma, Photopheresis consists of removing a portion of the patient's blood and separating the red blood cells from the white cell layer (buffy coat) by centrifugation. The red cells are returned to the patient and the UVADEX® Sterile Solution is then injected into the instrument and mixed with the buffy coat. The instrument then irradiates this drug-cell mixture with ultraviolet light (UVA light, 320–400 nm) and returns the treated cells to the patient. See the appropriate Operator's Manual for details of this process. Although extracorporeal phototherapy exposes less than 10% of the total body burden of malignant cells to methoxsalen plus light, some patients achieve a complete response. Animal studies suggest that the photopheresis may activate an immune-mediated response against the malignant T-cells. Use of the UVAR and UVAR XTS® Systems after oral administration of methoxsalen were previously approved for the treatment of Cutaneous T-Cell Lymphoma. Interpatient variability in peak plasma concentration after an oral dose of methoxsalen ranges from 6 to 15 fold. UVADEX® is injected directly into the separated buffy coat in the instrument in an attempt to diminish this interpatient variability and to improve the exposure of the cells to the drug. Methoxsalen is reversibly bound to serum albumin and is also preferentially taken up by epidermal cells. Methoxsalen is rapidly metabolized in humans, with approximately 95% of the drug excreted as metabolites in the urine within 24 hours. Systemic administration of methoxsalen followed by UVA exposure leads to cell injury. The most obvious manifestation of this injury after skin exposure is delayed erythema, which may not begin for several hours and peaks at 48–72 hours. The inflammation is followed over several days to weeks, by repair which is manifested by increased melanization of the epidermis and thickening of the stratum corneum. The total dose of methoxsalen delivered in UVADEX® is substantially lower (approximately 200 times) than that used with oral administration. More than 80% of blood samples collected 30 minutes after reinfusion of the photoactivated buffy coat had methoxsalen levels below detection limits of the assay ( < 10 ng/ml), and the mean plasma methoxsalen concentration was approximately 25 ng/ml. Clinical Studies Three single-arm studies were performed to evaluate the effectiveness of photopheresis in the treatment of the skin manifestations of Cutaneous T-Cell Lymphoma (CTCL). In the first study (CTCL 1), 39 patients were treated with the oral formulation of methoxsalen in conjunction with the UVAR Photopheresis System. The second study (CTCL 2) was a 5-year post approval follow-up of 57 CTCL patients that was conducted to evaluate long-term safety. This study also used the oral dosage formulation of methoxsalen. In the third study (CTCL 3), 51 patients were treated with the UVADEX® formulation of methoxsalen in conjunction with the UVAR Photopheresis System. In study CTCL 3, 86% of the patients were Caucasian, the median age was 62 years, and the average number of prior therapies was 4.3. In study CTCL 1, prednisone up to 10 mg/day was permitted in addition to topical steroids. In CTCL 2, there was no concomitant medication restriction. In CTCL 3, topical steroids were permitted only for the treatment of fissures on the soles of the feet and the palms of hands. All other steroids, topical or systemic, were prohibited. In all three studies, patients were initially treated on two consecutive days every four to five weeks. If the patient did not respond after four cycles, treatment was accelerated to two consecutive days every other week. If the patient did not respond after four cycles at the accelerated schedule, the patient was treated on two consecutive days every week. If the patient still did not respond after four cycles of weekly treatments, the schedule was increased to three consecutive days every week for three cycles. In study CTCL 3, 15 of the 17 responses were seen within six months of treatment. Only two patients responded to treatment after six months. Clinical experience does not extend beyond this treatment frequency and there is no evidence to show that treatment with UVADEX® beyond six months or using a different schedule provided additional benefit. Overall skin scores were used in the clinical studies of photopheresis to assess the patient's response to treatment. The patient's baseline skin score was used for comparison with subsequent scores. A 25% reduction in skin score maintained for four consecutive weeks was considered a successful response to photopheresis therapy. Table 1 indicates the percent of successful responses within six months of beginning therapy for all patients who received at least one course of photopheresis. Only patients with patch plaque, extensive plaque and erythrodermic disease were enrolled in these studies. No patients with disease in the tumor phase were treated. There are no data available regarding the efficacy of UVADEX® in patients with disease in the tumor phase. Table 1: Percentage of Successful Responses Within Six Months of Beginning Therapy Study Response % Within Six Months CTCL 3 (UVADEX®) 17/51 (33) CTCL 2 (oral methoxsalen) 16/57 (28) CTCL 1 (oral methoxsalen) 21/39 (54) Although the response rate with UVADEX® in CTCL 3 was similar to with oral methoxsalen in CTCL 2, the possibility that UVADEX® is inferior in efficacy to oral methoxsalen cannot be excluded due to the design and size of the clinical trials. The higher response rate with oral methoxsalen in CTCL 1 may be partly due to patients receiving more treatments (mean of 64 in CTCL 1, 31 in CTCL 2, and 20 in CTCL 3), and to the administration of systemic steroids in CTCL 1. Retrospective analyses of three clinical benefit parameters from the Body Area Severity Scores in CTCL 3 suggested a correlation between skin score response and improvement in edema, scaling and resolution of fissures.

CLINICAL PHARMACOLOGY The combination treatment regimen of psoralen (P) and ultraviolet radiation of 320–400 nm wavelength commonly referred to as UVA is known by the acronym, PUVA. Skin reactivity to UVA (320–400 nm) radiation is markedly enhanced by the ingestion of methoxsalen. The drug reaches its maximum bioavailability 1 1/2–3 hours after oral administration and may last for up to 8 hours (Pathak et al. 1974)1. Methoxsalen is reversibly bound to serum albumin and is also preferentially taken up by epidermal cells (Artuc et al. 1979)2. At a dose which is six times larger than that used in humans, it induces mixed function oxidases in the liver of mice (Mandula et al. 1978)3. In both mice and man, methoxsalen is rapidly metabolized. Approximately 95% of the drug is excreted as a series of metabolites in the urine within 24 hours (Pathak et al. 1977)4. The exact mechanism of action of methoxsalen with the epidermal melanocytes and keratinocytes is not known. The best known biochemical reaction of methoxsalen is with DNA. Methoxsalen, upon photoactivation, conjugates and forms covalent bonds with DNA which leads to the formation of both monofunctional (addition to a single strand of DNA) and bifunctional adducts (crosslinking of psoralen to both strands of DNA) (Dall'Acqua et al., 19715; Cole, 19706; Musajo et al., 19747; Dall'Acqua et al., 19798). Reactions with proteins have also been described (Yoshikawa, et al., 19799). Methoxsalen acts as a photosensitizer. Administration of the drug and subsequent exposure to UVA can lead to cell injury. Orally administered methoxsalen reaches the skin via the blood and UVA penetrates well into the skin. If sufficient cell injury occurs in the skin, an inflammatory reaction occurs. The most obvious manifestation of this reaction is delayed erythema, which may not begin for several hours and peaks at 48–72 hours. The inflammation is followed, over several days to weeks, by repair which is manifested by increased melanization of the epidermis and thickening of the stratum corneum. The mechanisms of therapy are not known. In the treatment of vitiligo, it has been suggested that melanocytes in the hair follicle are stimulated to move up the follicle and to repopulate the epidermis (Ortonne et al, 197910). In the treatment of psoriasis, the mechanism is most often assumed to be DNA photodamage and resulting decrease in cell proliferation but other vascular, leukocyte, or cell regulatory mechanisms may also be playing some role. Psoriasis is a hyperproliferative disorder and other agents known to be therapeutic for psoriasis are known to inhibit DNA synthesis. REFERENCES 1. Pathak, M. A., Kramer, D. M., Fitzpatrick, T. B.: Photobiology and Photochemistry of Furocoumarins (Psoralens), SUNLIGHT AND MAN: Normal and Abnormal Photobiologic Responses. Edited by M. A. Pathak, L. C. Harbor, M. Seiji et al. University of Tokyo Press. 1974, pp. 335-368. 2. Artuc, M., Stuettgen, G., Schalla, W., Schaefer, H., and Gazith, J.: Reversible binding of 5- and 8-methoxypsoralen to human serum proteins (albumin) and to epidermisin vitro:Brit. J. Dermat. 101, pp. 669-677 (1979). 3. Mandula, B. B., Pathak, M. A., Nakayama, Y., and Davidson, S. J.: Induction of mixed-function oxidases in mouse liver by psoralens, Ibid, 99, pp. 687-692 (1978). 4. Pathak, M. A., Fitzpatrick, T. B., Parrish, J. A.: PSORIASIS, Proceedings of the Second International Symposium. Edited by E. M. Farber, A. J. Cox, Yorke Medical Books, pp. 262–265 (1977). 5. Dall'Acqua, F., Marciani, S., Ciavatta, L., Rodighiero, G.: Formation of interstrand cross-linkings in the photoreactions between furocoumarins and DNA; Z Naturforsch (B), 26, pp. 561–569 (1971). 6. Cole, R. S.: Light-induced cross-linkings of DNA in the presence of a furocoumarin (psoralen), Biochem. Biophys. Acta. 217, pp. 30–39 (1970). 7. Musajo, L., Rodighiero, G., Carporale, G., Dall'Acqua, F., Marciani, S., Bordin, F., Baccichetti, F., Bevilacqua, R.: Photoreactions between Skin-Photosensitizing Furocoumarins and Nucleic Acids, SUNLIGHT AND MAN; Normal and Abnormal Photobiologic Responses. Edited by M. A. Pathak, L. C. Harber, M. Seiji et al., University of Tokyo Press, pp. 369–387 (1974). 8. Dall'Acqua, F., Vedaldi, D., Bordin, F., and Rodighiero, G.: New studies in the interaction between 8-methoxypsoralen and DNA in vitro; J. Investigative Dermat., 73, pp. 191–197 (1979). 9. Yoshikawa, K., Mori, N., Sakakibara, S., Mizuno, N., Song, P.: Photo-Conjugation of 8-methoxypsoralen with Proteins,Photochem & Photobiol. 29, pp. 1127–1133 (1979). 10. Ortonne, J. P., MacDonald, D. M., Micoud, A., Thivolet, J.: PUVA-induced repigmentation of vitiligo: a histochemical (split-DOPA) and ultra-structural study: Brit. J. of Dermat., 101, pp. 1–12 (1979).

Find Lowest Prices on UVADEX® (methoxsalen) Sterile Solution, 20 mcg/mL CAUTION: READ THE THERAKOS® UVAR XTS® or THERAKOS® CELLEX® PHOTOPHERESIS SYSTEM OPERATOR'S MANUAL PRIOR TO PRESCRIBING OR DISPENSING THIS MEDICATION. UVADEX® (methoxsalen) Sterile Solution should be used only by physicians who have special competence in the diagnosis and treatment of cutaneous T-cell lymphoma and who have special training and experience in the THERAKOS® UVAR XTS® or THERAKOS® CELLEX® Photopheresis System. Please consult the appropriate Operator's Manual before using this product. DESCRIPTION Methoxsalen is a naturallyx occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant. It belongs to a group of compounds known as psoralens or furocoumarins. The chemical name of methoxsalen is 9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one; it has the following structure: Each mL of UVADEX® (methoxsalen, 8-methoxypsoralen) Sterile Solution contains methoxsalen 20 mcg, propylene glycol 50 mg, sodium chloride 8 mg, sodium acetate 1.75 mg, ethanol 40.550 mg, glacial acetic acid 1.260 mg, and Water for Injection q.s. to 1.0 mL. Glacial acetic acid and sodium hydroxide are used to adjust the pH of the solution if necessary. UVADEX® is a clear, colorless to pale yellow liquid. UVADEX® is used in combination with the THERAKOS® UVAR XTS® and THERAKOS® CELLEX® Photopheresis Systems to extracorporeally treat leukocyte enriched buffy coat.

Find Lowest Prices on 8-MOP® CAPSULES (methoxsalen) Capsules, USP, 10 mg CAUTION: METHOXSALEN IS A POTENT DRUG. READ ENTIRE BROCHURE PRIOR TO PRESCRIBING OR DISPENSING THIS MEDICATION. 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 photo chemotherapy. Psoralen and ultraviolet radiation therapy should be under constant supervision of such a physician. For the treatment of patients with psoriasis, photo chemotherapy 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. DESCRIPTION 8-MOP (Methoxsalen, 8-Methoxypsoralen) Capsules, 10 mg. Methoxsalen is a naturally occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant and in the roots of Heraclem Candicans. It belongs to a group of compounds known as psoralens, or furocoumarins. The chemical name of methoxsalen is 9-methoxy-7 H-furo[3, 2-g][1]-benzopyran-7-one; it has the following structure:

INDICATIONS UVADEX® (methoxsalen) Sterile Solution is indicated for extracorporeal administration with the THERAKOS® UVAR XTS® or THERAKOS® CELLEX® Photopheresis System in the palliative treatment of the skin manifestations of Cutaneous T-Cell Lymphoma (CTCL) that is unresponsive to other forms of treatment. DOSAGE AND ADMINISTRATION Drug Dosage And Administration Each UVADEX® treatment involves collection of leukocytes, photoactivation, and reinfusion of photoactivated cells. UVADEX® (methoxsalen) Sterile Solution is supplied in 10 mL vials containing 200 mcg of methoxsalen (concentration of 20 mcg/mL). The THERAKOS® UVAR XTS® or THERAKOS® CELLEX® Photopheresis System Operator's Manual should be consulted before using this product. UVADEX® should not be diluted. The contents of the vial should be injected into the THERAKOS® UVAR XTS® or THERAKOS® CELLEX® Photopheresis System immediately after being drawn up into a syringe. Do not inject directly into patients. The UVADEX® vial is for single use only. Any UVADEX® that is not used during a procedure should be immediately discarded. UVADEX® can adsorb onto PVC and plastics, therefore only THERAKOS® UVAR XTS® or THERAKOS® CELLEX® photopheresis procedural kits supplied for use with the instrument should be used to administer this medicinal product. Once UVADEX® is drawn into a plastic syringe it should be immediately injected into the photoactivation bag. UVADEX® exposed to a plastic syringe for more than one hour should be discarded. During treatment with the THERAKOS® UVAR XTS® or THERAKOS® CELLEX® Photopheresis System, the dosage of UVADEX® for each treatment will be calculated according to the treatment volume. The prescribed amount of UVADEX® should be injected into the recirculation bag prior to the Photactivation Phase using the formula: TREATMENT VOLUME X 0.017 = mL of UVADEX® for each treatment Example: Treatment volume of 240 mL X 0.017 = 4.1 mL of UVADEX® Frequency/Schedule Of Treatment Normal Treatment Schedule: Treatment is given on two consecutive days every four weeks for a minimum of seven treatment cycles (six months). Accelerated Treatment Schedule: If the assessment of the patient during the fourth treatment cycle (approximately three months) reveals an increased skin score from the baseline score, the frequency of treatment may be increased to two consecutive treatments every two weeks. If a 25% improvement in the skin score is attained after four consecutive weeks, the regular treatment schedule may resume. Patients who are maintained in the accelerated treatment schedule may receive a maximum of 20 cycles. There is no clinical evidence to show that treatment with UVADEX® beyond six months or using a different schedule provides additional benefit. In study CTCL 3, 15 of the 17 responses were seen within six months of treatment and only two patients responded to treatment after six months. HOW SUPPLIED UVADEX® (methoxsalen) Sterile Solution 20 mcg/mL in 10 mL amber glass vials (NDC 64067-216-01), and cartons of 12 vials (NDC 64067-216-01). One vial of 10 mL contains 200 micrograms methoxsalen. The drug product must be stored between 59°F (15°C) and 86°F (30°C) REFERENCES 1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402. 2. AMA Council Report, Guidelines for Handling of Parenteral Antineoplastics. JAMA, 1985; 2.53 (11): 1590–1592. 3. National Study Commission on Cytotoxic Exposure- Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115. 4. Clinical Oncological Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426–428. 5. Jones, RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from The Mount Sinai Medical Center. CA- A Cancer Journal for Clinicians, 1983;(Sept/Oct) 258–263. 6. American Society of Hospital Pharmacists Technical Assistance Bulletin of Handling Cytotoxic and Hazardous Drugs. Am J. Hosp Pharm, 1990;47:1033–1049. 7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines), AM J. Health-Syst Pharm, 1996; 53: 1669–1685. Manufactured by Patheon Manufacturing Services LLC, Greenville, NC 27834, For Therakos, Inc., 10 North High Street, Suite 300, West Chester, PA 19380-3014 USA. August 2014

INDICATIONS 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. Photochemotherapy is intended to be administered only in conjunction with a schedule of controlled doses of long wave ultraviolet radiation. Photochemotherapy (methoxsalen with long wave ultraviolet radiation) is indicated for the repigmentation of idiopathic vitiligo. Photopheresis (methoxsalen with long wave ultraviolet radiation of white blood cells) is indicated for use with the UVAR* System in the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL) in persons who have not been responsive to other forms of treatment. While this dosage form of methoxsalen has been approved for use in combination with photopheresis, Oxsoralen Ultra_ Capsules have not been approved for that use. DOSAGE AND ADMINISTRATION Vitiligo Therapy Drug Dosage: Two capsules (10 mg each) in one dose taken with milk or in food two to four hours before ultraviolet light exposure. Light Exposure: The exposure time to sunlight should comply with the following guide: Basic Light Skin Color Medium Dark Initial Exposure 15min 20min 25min Second Exposure 20min 25min 30min Third Exposure 25min 30min 35min Fourth Exposure 30min 35min 40min Subsequent Exposure: Gradually increase exposure based on erythema and tenderness of the amelanotic skin. Therapy should be on alternate days and never two consecutive days. Psoriasis Therapy Drug Dosage – Initial Therapy: The methoxsalen capsules should be taken 2 hours before UVA exposure with some food or milk, according to the following table: Patient's(kg) Weight(lbs) Dose(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 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 fifteenth treatment under the conditions outlined in Section XI.B.4.b. Uva Radiation Source Specifications & Information Irradiance Uniformity: (For photopheresis, refer to the UVAR* System Operator's Manual.) 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 percent of the highest reading. Horizontal variation: Throughout any specific horizontal plane, the lowest reading must be at least 80 percent of the highest reading, excluding the peripheral 3 cm of the patient treatment space. 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 exposed to broken lamp components. (3) Hand rails and hand holds: Appropriate supports should be available to the patient. (4) Patient viewing window: A window which blocks UV should be provided for viewing the patient during treatment. (5) Door and latches: Patients should be able to open the door from the inside with only slight pressure to the door. (6) Non-skid floor: The floor should be of a non-skid nature. (7) Thermoregulation: Sufficient air flow should be provided for patient safety and comfort, limiting temperature within the UVA radiator cabinet to approximately less than 100° F. (8) Timer: The irradiator should be equipped with an automatic timer which terminates the exposure at the conclusion of a pre-set time interval. (9) Patient alarm device: An alarm device within the UVA irradiator chamber should be accessible to the patient for emergency activation. (10) Danger label: The unit should have a label prominently displayed which reads as follows: DANGER – Ultraviolet radiation – Follow your physician's instructions – Failure to use protective eyewear may result in eye injury. UVA Exposure Dosimetry Measurements The maximum radiant exposure or irradiance (within ±15 percent) of UVA (320–400 nm) delivered to the patient should be determined by using an appropriate radiometer calibrated to be read in Joules/cm² or mW/cm². In the absence of a standard measuring technique approved by the National Bureau of Standards, the system should use a detector corrected to a cosine spatial response. The use and recalibration frequency of such a radiometer for a specific UVA irradiator chamber should be specified by the manufacturer because the UVA dose (exposure) is determined by the design of the irradiator, the number of lamps, and the age of the lamps. If irradiance is measured, the radiometer reading in mW/cm² is used to calculate the exposure time in minutes to deliver the required UVA dose in Joules/cm² to a patient in the UVA irradiator cabinet. The equation is: Exposure Time in minutes = Desired UVA Dose (J/cm²)/0.06 x Irradiance (mW/cm²) Overexposure due to human error should be minimized by using an accurate automatic timing device, which is set by the operator and controlled by energizing and de-energizing the UVA irradiator lamp. The timing device calibration interval should be specified by the manufacturer. Safety systems should be included to minimize the possibility of delivering a UVA exposure which exceeds the prescribed dose, in the event the timer or radiometer should malfunction. Uva spectral output distribution The spectral distributions of the lamps should meet the following specifications: Wavelength Band (Nanometers) Output1 < 310 < 1 310 to 320 1 to 3 320 to 330 4 to 8 330 to 340 11 to 17 340 to 350 18 to 25 350 to 360 19 to 28 360 to 370 15 to 23 370 to 380 8 to 12 380 to 390 3 to 7 390 to 400 1 to 3 1As a percentage of total irradiance between 320 and 400 nanometers. Puva Treatment Protocol Initial Exposure: The initial UVA exposure should be conducted according to the guidelines presented previously under IX.B.1 and 2, Psoriasis therapy, Drug dosage-initial Therapy and Exposure. Skin Type History Recommended Joules/cm² I Always burn, never tan (Patients with Erythrodermic psoriasis are to be classed as Type I for determination of UVA dosage.) 0.5 J/cm² II Always burn, but sometimes tan 1.0 J/cm² III Sometimes burn, but always tan 1.5 J/cm² IV Never burn, always tan 2.0 J/cm² Physician Examination V* Moderately pigmented 2.5 J/cm² VI* Blacks 3.0 J/cm² [*Patients with natural pigmentation of these types should be classified into a lower skin type category if the sunburning history so indicates.] Clearing Phase: Specific recommendations for patient treatment are as follows: Skin Types I, II & III. Patients with skin types I, II and III may be treated 2 or 3 times per week. UVA exposure may be held constant or increased by up to 1.0 Joule/cm² at each treatment, according to the patient's response. If erythema occurs, however, do not increase exposure time until erythema resolves. The severity and extent of the patient's erythema may be used to determine whether the next exposure should be shortened, omitted, or maintained at the previous dosage. See ADVERSE REACTIONS section for additional information. Skin Types IV, V & VI. Patients with skin types IV, V and VI may be treated 2 or 3 times per week. UVA exposure may be held constant or increased by up to 1.5 Joules/cm² at each treatment unless erythema occurs. If erythema occurs, follow instructions outlined above in the procedures for patients with skin types I, II and III. Erythrodermic Psoriasis Patients with erythrodermic psoriasis should be treated with special attention because pre-existing erythema may obscure observations of possible treatment-related phototoxic erythema. These patients may be treated 2 or 3 times per week, as a Type I patient. Miscellaneous situations If there is no response after a total of 10 treatments, the exposure of UVA energy may be increased by an additional 0.5–1.0 Joules/cm² above the prior incremental increases for each treatment. (Example: a patient whose exposure dosage is being increased by 1.0 Joule/cm² may now have all subsequent doses increased by 1.5–2.0 Joules/cm².) If there is no response, or only minimal response, after 15 treatments, the dosage of methoxsalen may be increased by 10 mg. (a one-time increase in dosage). This increased dosage may be continued for the remainder of the course of treatment but should not be exceeded. If a patient misses a treatment, the UVA exposure time of the next treatment should not be increased. If more than one treatment is missed, reduce the exposure by 0.5 Joules/cm² for each treatment missed. If the lower extremities are not responding as well as the rest of the body and do not show erythema, cover all other body area and give 25 percent of the present exposure dose as an additional exposure to the lower extremities. This additional exposure to the lower extremities should be terminated if erythema develops on these areas. Non-responsive psoriasis: If a patient's generalized psoriasis is not responding, or if the condition appears to be worsening during treatment, the possibility of a generalized phototoxic reaction should be considered. This may be confirmed by the improvement of the condition following temporary discontinuance of this therapy for two weeks. If no improvement occurs during the interruption of treatment, this patient may be considered a treatment failure. Alternative exposure schedule As an alternative to increasing the UVA exposure at each treatment, the following schedule may be followed; this schedule may reduce the total number of Joules/cm² received by the patient over the entire course of therapy. Incremental increases in UVA exposure for all patients may range from 0.5 to 1.5 Joules/cm², according to the patient's response to therapy. Once Grade 2 clearing (see Table 2) has been reached and the patient is progressing adequately, UVA dosage is held constant. This dosage is maintained until Grade 4 clearing is reached. If the rate of clearing significantly decreases, exposure dosage may be increased at each treatment (0.1–1.5 Joules/cm²) until Grade 3 clearing and a satisfactory progress rate is attained. The UVA exposure will be held constant again until Grade 4 clearing is attained. These increases may be used also if the rate of clearing significantly decreases between Grade 3 and Grade 4 response. However, the possibility of a phototoxic reaction should be considered; see Non-responsive Psoriasis, above. In summary, this schedule raises slightly the increments (Joules/cm²) of UVA dosage, but limits these increases to those periods when the patient is not responding adequately. Otherwise, the UVA exposure is held at the lowest effective dose. Maintenance Phase The goal of maintenance treatment is to keep the patient as symptom-free as possible with the least amount of UVA exposure. Schedule Of Exposures: When patients have achieved 95 percent clearing, or Grade 4 response (Table 2), they may be placed on the following maintenance schedules (M1 – M4), in sequence. It is recommended that each maintenance schedule be adhered to for at least 2 treatments (unless erythema or psoriatic flare occurs, in which case see (2a) and (2b) below). Maintenance Schedules M1 – once/week M2 – once/2 weeks M3 – once/3 weeks M4 - p.r.n. (i.e., for flares) Length Of Exposure: The UVA exposure for the first maintenance treatment of any schedule (except M4 as noted below) is the same as that of the patient's last treatment under the previous schedule. For skin types I-IV, however, it is recommended that the maximum UVA dosage during maintenance treatments not exceed the following: SKIN TYPES JOULES/CM²/TRE ATMENT I 12 II 14 III 18 IV 22 If the patient develops erythema or new lesions of psoriasis, proceed as follows: Erythema: During maintenance therapy, the patient's tan and threshold dose for erythema may gradually decrease. If maintenance treatments produce significant erythema, the exposure to UVA should be decreased by 25 percent until further treatments no longer produce erythema. Psoriasis: If the patient develops new areas of psoriasis during maintenance therapy (but still is classified as having a Grade 4 response), the exposure to UVA may be increased by 0.5–1.5 Joules/cm² at each treatment; this is appropriate for all types of patients. These increases are continued until the psoriasis is brought under control and the patient is again clear. The exposure being administered when this clearing is reached should be used for further maintenance treatment. Flares During Maintenance: If the patient flares during maintenance treatment (i.e., develops psoriasis on more than 5 percent of the originally involved areas of the body) his maintenance treatment schedule may be changed to the preceding maintenance or clearing schedule. The patient may be kept on his schedule until again 95 percent clear. If the original maintenance treatment schedule is unable to control the psoriasis, the schedule may be changed to a more frequent regimen. If a flare occurs less than 6 weeks after the last treatment, 25 percent of the maximum exposure received during the clearing phase, may be used and then proceed with the clearing schedule previously followed for this patient. (At 95 percent clearing follow regular maintenance until the optimum maintenance schedule is determined for the patient.) If more than 6 weeks have elapsed since the last treatment was given, treat patients as if they were beginning therapy insofar as exposure dosages are concerned, since their threshold for erythema may have decreased. Table 1. Grades of Erythema GRADE ERYTHEMA LEVEL 0 No erythema 1 Minimally perceptible erythema—faint pink 2 Marked erythema but with no edema 3 Fiery erythema with edema 4 Fiery erythema with edema and blistering Table 2. Response to Therapy GRADE CRITERIA PERCENT IMPROVEMENT (COMPARED TO ORIGINAL EXTENT OF DISEASE) -1 Psoriasis worse 0 0 No change 0 1 Minimal improvement—slightly less scale and/or erythema 5-20 2 Definite improvement—partial flattening of all plaques—less scaling and less erythema 20-50 3 Considerable improvement—nearly complete flattening of all plaques but borders of plaques still palpable 50-95 4 Clearing; complete flattening of plaques including borders; plaques may be outlined by pigmentation 95 HOW SUPPLIED 8-MOP Capsules, each containing 10 mg. of methoxsalen (8-methoxypsoralen) packaged in amber glass bottles of 50 (NDC 0187-0651-42). Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F). ICN Pharmaceuticals, Inc. 3300 Hyland Ave. Costa Mesa, CA 92626. Rev. 8-98. FDA rev date: 3/26/2003

PATIENT INFORMATION Patients should be told emphatically to wear UVA-absorbing, wrap-around sunglasses and cover exposed skin or use a sunblock (SP 15 or higher) for the twenty-four (24) hour period following treatment with methoxsalen, whether exposed to direct or indirect sunlight in the open or through a window glass.

OVERDOSE There are no known reports of overdosage with extracorporeal administration of methoxsalen. However, in the event of overdosage, the patient should be kept in a darkened room for at least 24 hours. CONTRAINDICATIONS Photosensitivity UVADEX® (methoxsalen) Sterile Solution is contraindicated in patients exhibiting idiosyncratic or hypersensitivity reactions to methoxsalen, other psoralen compounds or any of the excipients. Patients possessing a specific history of a light sensitive disease state should not initiate methoxsalen therapy. Diseases associated with photosensitivity include lupus erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, variegate porphyria, xeroderma pigmentosum and albinism. UVADEX® Sterile Solution is contraindicated in patients with aphakia, because of the significantly increased risk of retinal damage due to the absence of lenses. Patients should not receive UVADEX® if they have any contraindications to the photopheresis procedure.

SIDE EFFECTS Side effects of photopheresis (UVADEX® used with the THERAKOS® Photopheresis System) were primarily related to hypotension secondary to changes in extracorporeal volume ( > 1%). In study CTCL 3 (UVADEX®), six serious cardiovascular adverse experiences were reported in five patients (5/51, 10%). Five of these six events were not related to photopheresis and did not interfere with the scheduled photopheresis treatments. One patient (1/51, 2%) with ischemic heart disease had an arrhythmia after the first day of photopheresis that was resolved the next day. Six infections were also reported in five patients. Two of the six events were Hickman catheter infections in one patient, which did not interrupt the scheduled photopheresis. The other four infections were not related to photopheresis and did not interfere with scheduled treatments. Postmarketing An analysis of postmarketing data shows the following events occurred with an incidence of < 0.01%: rash, allergic reaction, pyrexia, nausea, dysgeusia. DRUG INTERACTIONS See WARNINGS Section.

SIDE EFFECTS 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. 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 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. 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. DRUG INTERACTIONS See WARNINGS Section.

WARNINGS Concomitant Therapy 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 may be at greater risk for photosensitivity reactions with UVADEX®. Carcinogenicity, Mutagenesis, Impairment Of Fertility Oral administration of methoxsalen followed by cutaneous UVA exposure (PUVA therapy) is carcinogenic. In a prospective study of 1380 patients given PUVA therapy for psoriasis, 237 patients developed 1422 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® 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® 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 1900 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 4000 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. PRECAUTIONS General Actinic Degeneration After methoxsalen administration, exposure to sunlight and/or ultraviolet radiation may result in “premature aging” of the skin. Basal Cell Carcinomas Since oral psoralens may increase the risk of skin cancers, monitor closely those patients who exhibit multiple basal cell carcinomas or who have a history of basal cell carcinomas. Serious Skin Burns Serious burns from either UVA or sunlight (even through window glass) can result if the recommended dosage of methoxsalen is exceeded or precautions are not followed. Advise patients to avoid all exposure to sunlight during the 24 hours following photopheresis treatment. Cataract Formation 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® 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. Instruct patients 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. Carcinogenesis, Mutagenesis, And Impairment Of Fertility See WARNINGS Section. Pregnancy Pregnancy Category D. See WARNINGS Section. 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 Section as well as the probability of actinic degeneration which is also described in the Warnings Section. Patients With Renal Or Hepatic Impairment UVADEX® has not been evaluated in patients with renal or hepatic impairment Renal impairment Although renal transplant recipients with poor renal function have been treated with photopheresis using UVADEX®, little additional information is available on the use of UVADEX® in patients with varying degree of renal impairment. No reduction of dose or prolongation of UV light protection were reported in the renal transplant recipients who have undergone photopheresis treatment. Hepatic impairment No specific information is available on the use of photopheresis with UVADEX® in patients with hepatic impairment. In view of the very low systemic exposure to methoxsalen, it is unlikely that patients with severe hepatic impairment will be at greater risk than patients with normal hepatic function. However, the potential benefits of photopheresis treatment should be weighed against any possible risk before embarking on the procedure.

WARNINGS General 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. Carcinogenicity 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 al. 196011, Pathak et al. 195912). 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. 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 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. 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. 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. 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 period20. 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. Actinic Degeneration: Exposure to sunlight and/or ultraviolet radiation may result in “prematureaging” 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. Radiation Therapy: Patients having a history of previous x-ray therapy or grenz ray therapy should be diligently observed for signs of carcinoma. Arsenic Therapy: Patients having a history of previous arsenic therapy should be diligently observed for signs of carcinoma. Hepatic Diseases: Patients with hepatic insufficiency should be treated with caution since hepatic biotransformation is necessary for drug urinary excretion. 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. 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. 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. 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 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. 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 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. Abdominal skin, breasts, genitalia, and other sensitive areas should be protected for approximately 1/3 of the initial exposure time until tanning occurs. Unless affected by disease, male genitalia should be shielded. After Combined Methoxsalen/Uva Therapy UVA-absorbing wrap-around sunglasses should be worn during the daylight for 24 hours after combined methoxsalen/ UVA therapy. Patients should not sunbathe for 48 hours after therapy. Erythema and/or burning due to photochemotherapy and sunburn due to sun exposure are additive. Vitiligo Therapy The dosage of methoxsalen should not be increased above 0.6 mg/kg since overdosage may result in serious burning of the skin. Eye and skin sun protection as described in the PRECAUTIONS — General section should be observed. Information for Patients See accompanying Patient Package Insert. Laboratory tests Patients should have an ophthalmologic examination prior to start of therapy, and thence yearly. 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. Complete Blood Count (Hemoglobin or Hematocrit; White Blood Count—if abnormal, a differential count). Anti-nuclear Antibodies. Liver Function Tests. Renal Function Tests (Creatinine or Blood Urea Nitrogen). Carcinogenesis See WARNINGS Section. Pregnancy 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. 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 Section as well as the probability of actinic degeneration which is also described in the WARNINGS Section. REFERENCES 11. Hakim, R. E., Griffin, A. C., Knox, J. M.: Erythema and tumor formation in methoxsalen treated mice exposed to fluorescent light; Arch. Dermatol. 82, pp.572–-577 (1960). 12. Pathak, M. A., Daniels, F., Hopkins, C. E., Fitzpatrick, T. B.: Ultraviolet carcinogenesis in albino and pigmented mice receiving furocoumarins: psoralens and 8-methoxypsoralen,Nature 183, pp. 728–730 (1959). 13. Stern, R. S., Thibodeau, L. A., Kleinerman, R. A., Parrish, J. A., Fitzpatrick, T. B., and 22 Participating Investigators: Risk of Cutaneous Carcinoma in Patients Treated with Oral Methoxsalen Photochemotherapy for Psoriasis, NEJM, 300 No. 15, pp. 809–813 (1979). 14. Stern, R. S., Parrish, J. A., Zierler, S.: Skin Carcinoma in Patients with Psoriasis Treated with Topical Tar and Artificial Ultraviolet Radiation. Lancet, 1, pp. 732–735 (1980). 15. Roenigk, Jr., H. H., and 12 Cooperating Investigators: Skin Cancer in the PUVA-48 Cooperative Study of Psoriasis. Program for Forty-First Annual Meeting for The Society of Investigative Dermatology, Inc., Sheraton Washington Hotel, Washington, D.C., May 12, 13, and 14, 1980. AbstractJID, 74 No. 4, p. 250 (April, 1980). 16. Stern et al, Malignant melanoma in patients treated for psoriasis with methoxalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. New England Journal of Medicine, 336:104-1045, (April 10,1997) 17. Mosher, D. B., Pathak, M. A., Harris, T. J., Fitzpatrick, T. B.: Development of Cutaneous Lesions in Vitiligo During Long-Term PUVA Therapy. Program for Forty-First Annual Meeting for The Society for Investigative Dermatology, Inc., Sheraton Washington Hotel, Washington, D.C., May 12, 13, and 14, 1980, Abstracts JID, 74 No. 4, p. 259 (April, 1980). 18 Cloud, T. M., Hakim, R., Griffin, A. C.: Photosensitization of the eye with methoxsalen. I. Acute effects; Arch. Ophthalmol. 64, pp. 346–352 (1960). 19 Cloud, T. M., Hakim, R., Griffin, A. C.: Photosensitization of the eye with methoxsalen. II. Chronic effects, Ibid, 66, pp.689–694 (1961). 20 Freeman, R. G., Troll, D.: Photosensitization of the eye by 8-methoxypsoralen, JID, 53:, pp. 449–453 (1969). 21. Lerman, S., Megaw, J., Willis, I.: Potential ocular complications from PUVA therapy and their prevention; J. Invest. Dermat., 74, pp. 197–199 (1980). PRECAUTIONS Included as part of the WARNINGS section.