UVADEX

1 ml of UVADEX Paediatric population The safety and efficacy of UVADEX in children has not been clinically evaluated for this indication. Hepatic or renal impairment UVADEX has not been clinically evaluated in patients with renal or hepatic impairment.

) Method of administration Extracorporeal use. Do not inject directly into patients. In the photopheresis process, the patient is connected to the THERAKOS CELLEX instrument via a catheter interface. Red blood cells are separated from the white blood cells and plasma in the centrifuge bowl.

The red blood cells and excess plasma are returned to the patient while the buffy coat (leukocyte-enriched blood) and some plasma are collected into the photoactivation bag located on the side of the instrument. The buffy coat collection cycle is repeated three or six times, depending on the size of centrifuge bowl used in the instrument.

The prescribed amount of UVADEX is injected into the recirculation bag prior to the photoactivation phase. During photoactivation the leukocyte-enriched blood is continually circulated through the photoactivation chamber (photoceptor) for a maximum of 90 minutes whilst being exposed to UVA light (1-2 J/cm2) from a single bank of UVA lamps.

At the end of the photoactivation cycle, the photoactivated cells are then reinfused into the patient by gravity; the recommended reinfusion time is 15-20 minutes. The complete photopheresis procedure is up to 3 hours in duration. The patient should receive treatment on two successive days each month for six months.

Patients who fail to show an adequate response to treatment after eight treatment sessions may have their treatment schedule increased to two successive days every two weeks for the next three months. An ‘adequate response’ is considered to be a 25% improvement in the skin score (see below) maintained for at least 4 weeks.

5 = background normal, with scattered erythematous papules 1 = minimal erythema and edema; no scaling or fissuring 2 = substantial erythema and edema; no scaling or fissuring 3 = submaximal erythema, scaling, and edema; no fissuring or ectropion 4 = most severe; universal involvement with maximal erythema, edema and scaling; any fissuring or ectropion Each severity score should be multiplied by the percentage surface area to obtain a regional score.

In the clinical study of photopheresis/UVADEX (CTCL 3), adverse events were usually mild and transient and in most cases related to underlying pathology. 9% in the study. 2) Adverse events associated with the photopheresis procedure from clinical experience (clinical trials) with UVADEX in other indications are presented below.

Event Other Clinical Trial Experience with UVADEX By Patients By N umber of Treatments Hypotension < 2/100 <8/10,000 Transient fever 6-8 hrs after reinfusion of photoactivated cells < 1/100 <2 /10,000 Vascular access complication < 5/100* <4/1000** Infection/ Catheter related infection/sepsis < 4/100 <2/1000 * Two thirds of patients had progressive systemic sclerosis ** Two thirds of events occurred in progressive systemic sclerosis patients Small, but statistically significant, changes occurred in several biochemical and haematological parameters during treatment of CTCL with UVADEX.

These are not considered to be of clinical relevance and are summarised below. 2 Tabulated list of adverse reactions The following list of adverse reactions is based on experience from clinical trials and on post marketing experience and are displayed by system organ class and frequency in table below: very common (1/10); common (1/100 to < 1/10); uncommon (1/1,000 to< 1/100); rare (1/10,000 to < 1/1,000); and not known (cannot be estimated from the available data).

System organ class Adverse reaction(s) Frequency Infections and infestations Infections Common Immune system disorders Allergic reaction Not known Nervous system disorders Dysgeusia Common Cardiac disorders Hypotension Common Gastrointestinal disorders Nausea and vomiting Common Skin and subcutaneous tissue disorders Photosensitivity reaction Uncommon Injury, poisoning and procedural complications Transient fever & Vascular access complication Common Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

Only physicians who have special competence in the diagnosis and treatment of cutaneous T- cell lymphoma and who have special training and experience with the THERAKOS CELLEX Photopheresis System should use UVADEX. Psoralen and ultraviolet radiation therapy should be under constant supervision of such a physician.

Because of the possibilities of ocular damage, the patient should be fully informed by the physician of the risks inherent in this therapy. UVADEX should only be used ex vivo administered directly into the photoactivation bag. g. > 43ºC alarm sounding), the blood should only be reinfused into the patient if hemolysis has not occurred.

Contraceptive precautions Both men and women who are being treated with UVADEX should take adequate contraceptive precautions both during and after completion of photopheresis therapy. Cataractogenicity Exposure to large doses of UVA causes cataracts in animals, an effect enhanced by the administration of oral methoxsalen.

As the concentration of methoxsalen in the human lens is proportional to the serum level, the concentration will be substantially lower following ex vivo methoxsalen treatment (with UVADEX) compared to that seen following oral administration.

Nonetheless, if the lens is exposed to UVA during the time methoxsalen is present in the lens, photochemical action may lead to an irreversible binding of methoxsalen to protein and DNA components of the lens. For this reason the patient’s eyes should be protected from UVA light by wearing wrap-around, UVA-opaque sunglasses during the treatment cycle and during the following 24 hours.

g. methoxsalen) followed by exposure to UVA irradiation are used in PUVA therapy. Serum concentrations of psoralen may exceed 200 ng/ml in PUVA therapy and exposure to sunlight or ultraviolet radiation (even through window panes) may result in serious burns and, in the long-term, "premature aging" of the skin.

1. History of idiosyncratic or hypersensitivity reaction to methoxsalen, psoralen compounds or any of the excipients. 6). During pregnancy and lactation Aphakia Contraindications to the photopheresis procedure: Photosensitive disease (eg porphyria,systemic lupus erythematosus, or albinism).

Inability to tolerate extracorporeal volume loss (eg due to severe cardiac disease, severe anaemia etc). White blood cells count greater than 25,000 per mm³. Previous splenectomy. Coagulation disorders.