Methoxsalen

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 THERAKOS ® UVAR and UVAR XTS ® Photopheresis 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.

INDICATIONS AND USAGE UVADEX ® (methoxsalen) Sterile Solution is indicated for extracorporeal administration with the 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.

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 ® 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 ® 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 ® 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 ® 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 Photoactivation Phase using the formula: TREATMENT VOLUME × 0.017 = mL of UVADEX ® for each treatment Example: Treatment volume of 240 mL × 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.

ADVERSE REACTIONS Side effects of photopheresis (UVADEX ® used with THERAKOS ® Photopheresis Systems) 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 Adverse reactions reported from postmarketing experience include nausea, dysgeusia, photosensitivity reaction, pyrexia and hypersensitivity reactions including anaphylaxis and rash.

Drug Interactions See Warnings Section.