Methoxsalen is a naturally 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 UVAOEX® (methoxsalen, 8-methoxypsoralen) Sterile Solution contains methoxsalen 20 mcg, propylene glycol 50 mg, sodium chloride 8 mg, sodium acetate 1.75 mg, ethanol 0.05 mL, glacial acetic acid 0.0012 mL, and Water for Injection q.s.to 1.0 mL

UVAOEX® is used in combination with the UVAR® or UVAR® XTS™ Photopheresis System to extracorporeally treat leukocyte enriched buffy coat.

Last updated on RxList: 12/2/2008

UVAOEX® (methoxsalen) Sterile Solution is indicated for extracorporeal administration with the UVAR® or UVAR® XTS™ Photopheresis Systemin the palliative treatment of the skin manifestations of Cutaneous T-Cell Lymphoma (CTCL) that is unresponsive to other forms of treatment.

Each UVADEX® treatment involves collection of leukocytes, photoactivation, and reinfusion of photo activated cells. UVADEX® (methoxsalen) Sterile Solution is supplied in 10 ml vials containing 200 mcg of methoxsalen (concentration of 20 mcg/ml), During each photopheresis treatment performed with the UVAR® Photopheresis System,10 ml (200mcg) of UVADEX® is injected directly into the photoactivation bag during the first buffy coat collection cycle, At the end of six cycles, a total of 740 ml (240 ml of buffy coat, 300 ml of plasma, and 200 ml of normal saline priming fluid) will be collected and mixed with the 200 mcg of UVADEX® present in the photoactivation bag. The UVAR® Photopheresis System Operator's Manual should be consulted before using this product.

During treatment with the UVAR® XTS™ System, the dosage of UVADEX® for each treatment will be calculated according to the treatment volume (displayed on the XTS display panel).

• The prescribed amount of UVADEX® will 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 treatment severy 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 CTCL3, 15 of the 17 responses were seen within six months of treatment and only two patients responded to treatment after six months.

UVAOEX® (methoxsalen) Sterile Solution 20 mcg/mL in 10 mL vials (NDC 64067-216-01), and cartons of 12 vials (NDC 64067-216-01). 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. MedJ Australia,1983; 1:426-428.

5. Jones, RB, etal. Safe Handling of Chemotherapeutic Agents: A Report from TheMount Sinai Medical Center.CA-A Cancer Journalfor 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: 1669-16B5.

Manufactured by: Ben Venue Laboratories, Bedford, OH44146-0568. For Therakos, A Johnson & Johnson Company, Exton, PA19341. FDA Rev date: 2/25/1999

Last updated on RxList: 12/2/2008

Side effects of photopheresis (UVADEX® used with the UVAR® Photopheresis System) were primarily related to hypotension secondary to changes in extra corporeal volume ( > 1%), In study CTCL3 (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 Hick man 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.

See WARNINGS Section.

Last updated on RxList: 12/2/2008

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 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.

Mettioxsalen 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 extra corporeal 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). Mothoxsalen 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 child bearing potential should be advised to avoid becoming pregnant.

General: ACTINIC DEGENERATlON:

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 mothoxsalen 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. 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 out doors 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 rnethoxsalen 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,

Last updated on RxList: 12/2/2008

There are no known reports of overdosage with extracorporeal administration of methoxsalen. However, in the event of overdosage, the patients hould be kept in a darkened room for atleast 24 hours.

PHOTOSENSITIVITY: UVADEX® (methoxsalen) Sterile Solution is contraindicated in patients exhibiting idiosyncratic reactions to psoralen compounds. 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.

Last updated on RxList: 12/2/2008

Mechanism of action: The exact mechanism of action of methoxsalen is not known.The best-known bio-chemical reaction of methoxsalen is wrth DNA. Methoxsalen,upon photoactivation,conjugates and forms covalent bonds with DNA which leads to the formation of both mono functional (addition to a single strand of DNA) and bifunctional adducts (cross linking of psoralen to both strands of DNA). Reactions with proteins have also been described.

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 cell from the white cell layer (buffy coat) by centrifugation. The red cells are returned to the patient and the UVADEX® Sterile Solutionis then injected into the instrument and mixed with the buffy coat. The instrument then irradiates this drug-cell mixture with ultra violet 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 extra corporeal 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.

Clinical Studies

Three single-arm studies were pertormed to evaluate the effectiveness of photopheresis in the treatment of the skin manifestations of Cutaneous T-Cell Lymphoma (CTCL). In the first study (CTCL1), 39 patients were treated with the oral formulation of methoxsalen in conjunction with the UVAR® Photopheresis System. The second study (CTCL2) 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 (CTCL3), 51 patients were treated with the UVADEX® formulation of methoxsalen in conjunction with the UVAR® Photopheresis System. In study CTCL3, 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 CTCL3, 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 CTCL3, 15 of the17 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 comparis on 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.

Table1: 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 CTCL3 was similar to with oral methoxsalen in CTCL 2, the possibility that UVADEX®.is inferior in efficacy to oral mothoxsalen cannot be excluded due to the design and size of the clinical trials. The higher response rate with oral methoxsalen in CTCL1 may bepartly 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 at fissures.

Last updated on RxList: 12/2/2008

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.

Last updated on RxList: 12/2/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

METHOXSALEN SOLUTION - INJECTION

(meh-THOX-sal-en)

COMMON BRAND NAME(S): Uvadex

USES: This medication is used to treat cutaneous T-cell lymphoma (CTCL), a type of cancer that affects the skin and blood and sometimes the lymph nodes and other organs. CTCL is caused by the uncontrolled growth of abnormal white blood cells in the skin. This drug is used in a procedure called photopheresis. Some of your blood is removed from your body through a vein and goes into a special machine that separates the white blood cells. The machine adds methoxsalen to these white blood cells, then shines ultraviolet (UV) light on them. Then the machine returns the treated cells (and the rest of your blood) to your body through the same vein. Your immune system is thought to react to the treated cells and other similar untreated T-cells that are not working properly. This effect helps to restore your immune balance and lessens the skin problems (e.g., rash, plaques, tumors) of CTCL. Methoxsalen is known as a psoralen photosensitizer. It works by making the treated white blood cells more sensitive to UV light.

HOW TO USE: See Uses section.

This medication is injected into your collected white blood cells during photopheresis by a health care professional. Health care professionals must follow all the manufacturer's instructions for properly using this drug. If you have any questions about using this medication properly, consult your doctor or pharmacist. This medication is usually used once a day for 2 days in a row or as directed by your doctor. Photopheresis is usually repeated every 4 weeks depending on your response to treatment.

Dosage is based on your medical condition, the amount of white blood cells collected, and response to treatment.

Learn how to store and discard needles and medical supplies safely. Consult your pharmacist.

SIDE EFFECTS: Dizziness, headache, weakness, leg cramps, or bitter/sour taste in the mouth may occur. Skin freckling, dry skin, and skin aging may also occur. If these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication will make your eyes and skin more sensitive to the sun. (See also Precautions section.) Tell your doctor immediately if any of these signs of sun sensitivity occur: swollen/red/blistering/peeling skin, vision changes.

Tell your doctor immediately if any of these unlikely but serious side effects occur: depression, swollen ankles/feet.

Tell your doctor immediately if any of these rare but very serious side effects occur: new/unusual skin sores, irregular heartbeat.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using methoxsalen, tell your doctor or pharmacist if you are allergic to it; or to sunlight; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: unusual or bad reaction to other psoralen products in the past, conditions that make you sensitive to light (e.g., lupus, certain porphyrias, xeroderma pigmentosum, albinism), no natural lens in the eye.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: coal tar/UVA treatment, radiation treatment, arsenic treatments, other skin cancer (melanoma, basal cell or squamous cell carcinomas), cataracts, liver problems, kidney problems, heart problems.

For 24 hours after treatment with this medication, your eyes and skin will be more sensitive to the sun, including sunlight through a glass window. Avoid direct sun exposure, tanning booths, and sunlamps. To protect your skin when outdoors during this time, wear protective clothing and use a sunscreen (SPF 15 or higher). To protect your eyes, wear dark wrap-around UV-absorbing sunglasses. Consult your doctor or pharmacist for more details.

This drug may make you dizzy. Use caution while driving, using machinery, or taking part in any other activity that requires alertness. Limit alcoholic beverages.

This medication is not recommended for use during pregnancy. Consult your doctor for more details and to discuss using at least 2 reliable forms of birth control (e.g., condoms, birth control pills) while using this medication. If you become pregnant or think you may be pregnant, tell your doctor immediately.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anthralin, bacteriostatic soaps, coal tar, certain dyes (methylene blue, toluidine blue, rose bengal, methyl orange), griseofulvin, nalidixic acid, phenothiazines (e.g., promethazine, thiothixene), sulfa antibiotics (e.g., sulfamethoxazole, sulfisoxazole), tetracycline antibiotics (e.g., doxycycline, tetracycline), certain "water pills" (thiazide diuretics such as hydrochlorothiazide).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: serious burning/blistering of skin.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood counts) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled treatment with this medication as directed. If you miss a treatment, contact your doctor to establish a new treatment schedule.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.