UVADEX Solution for injection Ref.[11072] Active ingredients: Methoxsalen

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.

Photosensitivity

Severe photosensitivity can occur in patients treated with UVADEX. Advise patients to wear UVA absorbing, wrap-around sunglasses and cover exposed skin or use a sunblock (SP 15 or higher), and avoid all exposure to sunlight for twenty-four (24) hours following photopheresis treatment. See Precautions section for additional information.

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.

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.

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.

Venous and arterial thromboembolism

Thromboembolic events, such as pulmonary embolism and deep vein thrombosis, have been reported with UVADEX administration through photopheresis systems for treatment of patients with graft-versus-host disease, a disease for which UVADEX is not approved.

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.

See Warnings Section.

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.

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.