4.1. Therapeutic indications

UVADEX is used in conjunction with the THERAKOS CELLEX Photopheresis System in the palliative treatment of the skin manifestations (patch plaque, extensive plaque, erythroderma) of advanced stage (T2 - T4) cutaneous T-cell lymphoma (CTCL), only in patients who have not been responsive to other forms of treatment, (e.g. puvatherapy, systemic cortocosteroids, caryolysin, interferon alpha).

4.2. Posology and method of administration

Posology

Adults

During each photopheresis treatment with UVADEX, the dosage of UVADEX is calculated according to the treatment volume (which is displayed on the display panel of the instrument) using the formula:

For example:

Treatment volume x 0.017 ml of UVADEX for each treatment

Treatment volume = 240 ml x 0.017 = 4.1 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. (see 4.4.)

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.

Skin score determination:

The severity of skin lesions should be determined for each of 29 body sections (similar to these used in the estimation of burn damage) from 0 to 4, according to the following scale:

0 = normal skin

0.5 = 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. All regional scores should be added together to obtain an overall lesion score.

A 25% improvement is a clinically significant change that is typically associated with the extent of overall disease burden (degree of blood and lymph node involvement with malignant T-lymphocytes), an improvement in the skin manifestations of the disease being accompanied by a parallel improvement in systemic disease. To avoid short-lived, modest waxing and waning of skin lesions being confused with an improvement that is real, any positive changes in skin lesions must be maintained for at least four weeks to be considered clinically significant.

The number of photopheresis sessions administered should not exceed 20 in six months.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. History of idiosyncratic or hypersensitivity reaction to methoxsalen, psoralen compounds or any of the excipients.

Use by sexually active men and women of childbearing potential unless adequate contraception is used during treatment (see section 4.6).

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.

4.4. Special warnings and precautions for use

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. If there is any possibility of unscheduled damage to the blood during the procedure (e.g. > 43°C 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.

Adverse effects on the skin

Oral doses of psoralen compounds (e.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.

Extracorporeal use of UVADEX is associated with considerably lower systemic exposure to methoxsalen. However, the amount of phototoxicity from low levels of methoxsalen has not been investigated systematically. Therefore, as a precaution, patients should avoid exposure to sunlight during the 24-hours following photopheresis treatment.

PUVA therapy has been associated with dose dependent development of squamous cell carcinoma, basal cell carcinoma and possibly malignant melanoma. There is no evidence that there is an increased risk of these skin cancers with the extracorporeal use of UVADEX, nevertheless, patients with co-existing basal cell carcinoma, squamous cell carcinoma or malignant melanoma should be monitored for any changes of their skin cancer.

Renal impairment

Although several 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 renally-impaired patients. No extra precautions, such as reduction of dose or prolongation of protection from UV light, were taken in the few renal transplant recipients who have undergone photopheresis treatment and the procedures were well tolerated and effective.

Hepatic diseases

No specific information is available on the use of photopheresis using UVADEX in patients with hepatic impairment. Since hepatic biotransformation is necessary for urinary excretion, it is possible that hepatic impairment may result in an extended half life of methoxsalen. This may lead to prolonged photosensitivity and thus require continued precautions against exposure to sunlight beyond 24 hours following photopheresis treatment. The potential benefits of photopheresis treatment should be weighed against any possible risk before embarking on the procedure.

Paediatric population

UVADEX has not been clinically evaluated in children.

Alcohol content

This medicinal product contains small amounts of 5% (v/v) of ethanol and each dose (maximum volume 5.6 ml) contains up to 217 mg of alcohol (ethanol), which is equivalent to 3.1 mg/kg per 5.6 ml dose. The amount in one 5.6 ml dose of this medicine is equivalent to less than 6 ml beer or 3 ml wine.

With extracorporeal administration systemic exposure is expected to be low and a clinical effect has not been evident, however Prescriber's should be aware of the potential effects of other medicines and caution is advised in liver disease, alcoholism, epilepsy, brain injury or disease.

Sodium content

UVADEX contains less than 1 mmol sodium (23 mg) per dose administered (maximum volume 5.6 ml).

4.5. Interaction with other medicinal products and other forms of interaction

Although methoxsalen has been shown to be capable of both induction and inhibition of hepatic enzymes, in man it appears to act primarily as a potent inhibitor of hepatic microsomal oxidative metabolic processes, including, but not limited to, CYP1A2, 2A6 and 2B1. Thus, it is to be expected that interactions will occur between methoxsalen and other medicinal products whose metabolism involves the hepatic cytochrome P450 system. The clearance of caffeine and antipyrine have been shown to be markedly reduced after methoxsalen treatment. Therefore, consumption of other P450 substrates may result in an extended half life of methoxsalen, and consequently lead to prolonged photosensitivity and thus requiring continued precautions against exposure to sunlight beyond 24 hours following photopheresis treatment.

Studies have shown that methoxsalen also decreases the metabolic activation of paracetamol in animals and humans, probably as a consequence of methoxsalen-associated inhibition of hepatic cytochrome P450 oxidative transformation of paracetamol.

One report describes a psoriatic and epileptic patient in whom phenytoin administration induced increased metabolism of methoxsalen leading to low levels of methoxsalen and failure of PUVA therapy. Substitution of valproate for phenytoin resulted in a three to four-fold increase in methoxsalen levels to within the putative therapeutic range.

In the blood methoxsalen is normally highly bound to albumin but can be displaced by a number of medicinal products such as dicoumarol, promethazine and tolbutamide. As a coumarin derivative, it is conceivable that methoxsalen binds to the warfarin site of albumin, which could be of clinical significance when the two medicinal products are co-administered. However, of the medicinal products studied, only tolbutamide at therapeutic concentrations displaces methoxsalen from its binding site to a clinically relevant extent. Concomitant use of methoxsalen and tolbutamide may therefore lead to enhanced photosensitivity.

Special care should be exercised in treating patients who are receiving concomitant therapy (either topically or systemically) with known photosensitising agents. Such agents include fluoroquinolones, furosemide, nalidixic acid, phenothiazines, retinoids, sulfonamides, sulfonylureas, tetracyclines, and thiazides.

4.6. Fertility, pregnancy and lactation

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.

Pregnancy

Although there is no human experience of the use of UVADEX during pregnancy, animal data suggest that methoxsalen may cause foetal harm when administered to a pregnant woman. Therefore, UVADEX is contraindicated in women who are or may become pregnant (see section 4.3)

Breast-feeding

It is not known whether methoxsalen is excreted in human milk. Thus and because of the pharmacodynamic properties of UVADEX, lactation is a contraindication.

Fertility

Fertility studies to assess the reproductive toxicity of UVADEX have not been conducted.

4.7. Effects on ability to drive and use machines

Because of the possibility of transient cardiovascular instability and the recommendation that following photopheresis patients wear sunglasses, photopheresis treatment using UVADEX is likely to produce minor or moderate undesirable effects and patients should not drive or operate machinery immediately following photopheresis.

4.8. Undesirable effects

In the clinical study of photopheresis/UVADEX (CTCL 3), adverse events were usually mild and transient and in most cases related to underlying pathology. Nausea and vomiting (commonly associated with methoxsalen when administered orally) were reported only once in each of two patients, representing an incidence of 3.9% in the study.

Adverse events associated with the photopheresis procedure used in the treatment of CTCL were as follows:

Event

CTCL 3

UVADEX

CTCL 1 & 2

Oral Methoxsalen

No of Patients (%)

N=51

Total No by Treatments

No of Treatments = 1032

No of Patients (%)

N=96

Total No by Treatments

No of Treatments = 4319

Hypotension

0

0

7 (7.3)

7 (< 0.2)

Transient fever 6-8 hrs after reinfusion of photoactivated cells

0

0

8 (8.3)

17 (< 0.4)

Vascular access complication

9 (17.6)

10 (< 0.1)

0

0

Infection

1 (2.0)

1 (< 0.1)

5 (5.2)

5 (< 0.2)

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.

Statistically Significant Laboratory Value Changes Mean ± SD

Parameter

N

Baseline

Final

Delta

Albumin (g/l)

51

13.8 ± 16.8

12.8 ± 15.6

-1.0

Calcium (mg/dl)

51

7.8 ± 3.2

7.5 ± 3.1

-0.3

Haematocrit (%)

51

41.1 ± 4.3

38.0 ± 4.7

-3.1

Haemoglobin (g/dl)

51

13.8 ± 1.4

12.7 ± 1.6

-1.1

Potassium (mEq/l)

48

4.4 ± 0.5

4.1 ± 0.4

-0.3

RBC (x1012/l)

51

4.6 ± 0.5

4.4 ± 0.6

-0.2

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. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Acute animal experience suggests a large margin of safety and dangerous overdose is extremely unlikely to occur.

Whilst there is no human experience of overdose with UVADEX, there is one case of overdosage with oral methoxsalen recorded in the medical literature. A 25-year-old woman ingested a dose equivalent to about 85 mg/kg body weight (ie approximately 140 times the therapeutic dose of oral methoxsalen). The major symptoms of intoxication were nausea, vomiting and dizziness. The patient was kept in a darkened room and her cardiovascular function was monitored. She recovered without sequelae and was released from hospital 36 hours after admission.

In the event of methoxsalen overdose, the patient should be kept in a darkened room for at least 24 hours.

The THERAKOS CELLEX instrument has been engineered to deliver the optimum level of UVA energy to the leukocyte enriched blood fraction when the UVA exposure time is set to 1.5 hours at the end of collection. In the event of UVA energy overexposure of the leukocyte enriched blood fraction beyond 30 additional minutes the photoactivated cells should not be returned to the patient.