4.1. Therapeutic indications

Methoxsalen G.L. Pharma 20 micrograms/ml solution is indicated in adults for extracorporeal use in the palliative treatment of advanced stage cutaneous T-cell lymphoma in patients who have not been responsive to other forms of treatment.

4.2. Posology and method of administration

Posology

Adults

During each photopheresis treatment with methoxsalen, the dosage is calculated according to the treatment volume, using the formula below:

Treatment volume x 0.017 ml of Methoxsalen G.L. Pharma for each treatment

For example: Treatment volume = 240 ml x 0.017 = 4.1 ml of Methoxsalen G.L. Pharma

Paediatric population (under 18 years of age)

The safety and efficacy of Methoxsalen G.L. Pharma in children and adolescents have not been established for this indication.

Hepatic or renal impairment

Methoxsalen G.L. Pharma 20 micrograms/ml solution has not been clinically tested in patients with renal or hepatic impairment.

Liver enzymes should be monitored regularly before and during therapy (see section 4.4).

Method of administration

Extracorporeal use.

Note:

Extracorporeal photochemotherapy is to be carried out only by persons with special training and in institutions disposing of the suitable equipment for this treatment.

Psoralen and UV irradiation therapy should take place under constant supervision by a physician with the appropriate training.

The working instructions for the procedure (according to the company manufacturing the equipment in use and/or to recent guidelines) must be followed strictly.

The content of the ampoule must not be injected directly into the patient as there are no studies with direct injection of Methoxsalen G.L. Pharma in humans.

In the photopheresis process the components of the whole-blood are separated. The erythrocytes and excess plasma are returned to the patient immediately, while the buffy coat (leucocyte-enriched blood) and some plasma are collected, Methoxsalen G.L. Pharma is added, radiated wih UV light and then reinfused into the patient.

The following basic rules should be observed:

- The haematocrit of the separated blood fraction should not exceed 5%, in order not to block exposure to the UVA radiation and thus lower the efficacy of treatment.

- Before radiation with UVA light (in the radiation bag) heparin, isotonic saline solution and the prescribed amount of Methoxsalen G.L. Pharma are added to the leucocytes.

- The quantities collected for therapy may vary (from 120 to 540 ml) depending on body weight, blood volume and therapy method used (on-line or off-line method).

- During photoactivation the leucocyte-enriched blood is radiated with UVA light (1 to 2 J/cm2).

- At the end of the photoactivation cycle, the photoactivated cells are reinfused via intravenous drip. The recommended duration of reinfusion is 15 to 20 minutes.

- The buffy coat collection cycle is repeated up to six times, and the complete photopheresis procedure lasts approximately 3 to 4 hours.

- During therapy blood pressure, heart rate and body temperature should be monitored.

Duration of treatment

During the first three months it is recommended to carry out treatment on two successive days every 2 to 4 weeks. After that, two-day treatment cycles every 3 to 4 weeks are recommended.

It has been shown that higher treatment frequencies do not lead to better treatment results.

As soon as maximum treatment response is achieved, intervals should be gradually extended to 4 to 8 weeks, and then continued as a maintenance therapy every 8 weeks.

The duration of photopheresis therapy should be at least 6 months. In patients who respond well to treatment or whose disease can be stabilised offering them good quality of life, photopheresis may be carried out for 2 years or more.

The above recommendations are a general guideline. Therapy cycles may be adapted individually to the specific clinical picture and the patient's response.

4.3. Contraindications

- Hypersensitivity to the active substance, other psoralen compounds or to any of the excipients listed in section 6.1

- Co-existing malignant skin tumour (e.g. melanoma, basalioma)

- Photosensitive disease (e.g. porphyria, systemic lupus erythematosus or albinism)

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

- Aphakia

- Pregnancy and lactation.

Contraindications to the photopheresis procedure:

- Inability to tolerate the transitory volume loss (e.g. because of severe cardiac disease, severe anaemia etc.)

- Previous splenectomy

- Coagulation disorder

- Leucocyte count above 25,000/mm³.

4.4. Special warnings and precautions for use

Extracorporeal photochemotherapy is to be carried out only by persons with special training and in institutions disposing of the suitable equipment for this treatment.

Psoralen and UV irradiation therapy should take place under constant supervision by a physician with the appropriate training.

Because of the possibility of irreversible eye damage occurring as a side effect, the patient should be fully informed about the risks of this type of therapy.

Methoxsalen G.L. Pharma should only be used ex vivo and is to be added directly to the separated leucocytes. If there is a possibility that the blood has been damaged during the procedure, it should only be reinfused into the patient if haemolysis has not occurred.

Hypotension

Transient hypotension may occur in some patients during therapy. In most patients it stays asymptomatic and disappears after reinfusion of the blood. Occasionally, normal saline solution must be infused during photopheresis to stabilise blood pressure. Patients regularly taking anti-hypertensives should wait with the intake until the end of the photopheresis procedure (see section 4.8).

Hypertriglyceridemia

In patients with increased blood triglyceride levels the efficacy of the procedure might be limited because the photopheresis instruments cannot separate white blood cells from fat-rich blood. Therefore patients about to get a photopheresis treatment should fast before the therapy – their triglyceride level should be lower than 300 mg/dl at the start of treatment.

Formation of cataracts

Exposure to large doses of UVA light 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 Methoxsalen G.L. Pharma) compared to the concentration seen after oral administration. Nevertheless, if the lens is exposed to UVA light during the time methoxsalen is present in the lens, photochemical action may lead to irreversible binding of methoxsalen to protein and DNA components of the lens. For this reason, the patients' eyes should be protected from UVA light by wrap-around UVA-opaque sunglasses during the treatment cycle and during the following 24 hours (see section 4.8).

Adverse effects on the skin

Following oral administration of psoralen (where serum concentrations may exceed 200 ng/ml), exposure to sunlight or UV radiation (even through window glass) may result in serious burns and, over the long term, 'premature aging' of the skin.

Extracorporeal use of Methoxsalen G.L. Pharma 20 micrograms/ml solution is associated with a much lower systemic exposure to methoxsalen (more than 80 % of the blood samples taken 30 minutes after reinfusion of the photoactivated buffy coat exhibited methoxsalen levels < 10 ng/ml and the average methoxsalen concentration in plasma was about 25 ng/ml). However, the amount of phototoxicity of these levels has not been investigated systematically. Therefore, as a precaution, patients should avoid exposure to sunlight during the 24 hours following photopheresis treatment.

Hepatic impairment

As hepatic biotransformation is necessary for urinary excretion, it is possible that hepatic impairment may result in an extended half-life of methoxsalen. This may result in prolonged photosensitivity. In patients with hepatic diseases precautions against exposure to sunlight should therefore be prolonged where required.

No specific information is available on the use of photopheresis with Methoxsalen G.L. Pharma in patients with hepatic impairment.

Renal impairment

Although several renal transplant recipients with poor renal function have been treated with photopheresis, little additional information is available on the use of methoxsalen in renally-impaired patients. No extra precautions, such as dose reduction 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.

Information about certain excipients

This medicinal product contains small amounts of ethanol (alcohol): At an assumed treatment volume of 240 ml the patient is exposed to 4.1 ml of Methoxsalen G.L. Pharma and therefore to 8.528 mg alcohol (2.08 mg alcohol/ml).

With extracorporeal administration systemic exposure is expected to be low, and clinical effects have not been observed yet. However, the prescribing physician should bear in mind possible interactions with other medicinal products. Special caution is advised in hepatic disease, alcoholism, epilepsy, brain injury or brain disease.

This medicinal product contains less than 1 mmol sodium (23 mg) per millilitre, that is to say essentially 'sodium-free'.

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

Phenytoin

Phenytoin may induce the metabolism of psoralens. Failure of methoxsalen therapy may be attributed to this interaction if they are administered concomitantly.

Tolbutamide

Methoxsalen is highly bound to serum albumin but can also be displaced, particularly by tolbutamide. Concomitant use of methoxsalen and tolbutamide may lead to enhanced photosensitivity.

Cytochrome P450

Methoxsalen is metabolised via cytochrome P450 (CYP1A2). Therefore, caution is required if medicinal products that are metabolised predominantly by CYP1A2 (melatonin, xanthines such as caffeine, theophylline) are administered concomitantly. Co-administration may prolong the half-life of methoxsalen and result in prolonged photosensitivity.

Although methoxsalen has been shown to be capable of both induction and inhibition of hepatic enzymes, in humans it seems to act primarily as a potent inhibitor of microsomal oxidative metabolic processes. It is therefore to be expected that interactions will occur between methoxsalen and other medicinal products whose metabolism involves the cytochrome P450 system (particularly CYP1A2). The clearance rates of caffeine were markedly reduced after methoxsalen treatment. Both conjugated and unconjugated metabolites have been identified, but neither of them showed pharmacologically relevant activity.

Photosensitising agents

Caution is also required in patients taking cytotoxic or other photosensitising agents concomitantly:

Fluoroquinolones, furosemide, retinoids, sulfonylureas, anthralin, coal tar, griseofulvin, nalidixic acid, sulfonamides, tetracyclines, halogenated salicyl aniline derivatives, thiazides, phenothiazines, methylene blue, tolonium chloride, rose Bengal, methyl orange, oral coumarin anticoagulants.

4.6. Fertility, pregnancy and lactation

Both, men and women treated with Methoxsalen G.L. Pharma have to use suitable methods of contraception, both during and after completion of photopheresis therapy.

Pregnancy

To date, there are no or a limited amount of data from the use of methoxsalen in pregnant women. Therefore, methoxsalen is contraindicated during pregnancy.

Preclinical data indicate that methoxsalen may possibly damage the foetus when it is used in pregnant animals.

Breast-feeding

It is not known whether methoxsalen is excreted in human milk, therefore it is contraindicated during breast-feeding.

Fertility

No clinical fertility data are available.

Preclinical data indicate that long-term exposure to high-dosed oral psoralens may have negative effects on male and female fertility.

4.7. Effects on ability to drive and use machines

As a result of the special mode of administration (extracorporeal use), transient cardiovascular instability may occur. In addition, patients should wear sunglasses following photopheresis treatment (see section 4.4). Therefore, patients should not drive or use machines immediately following photopheresis treatment.

4.8. Undesirable effects

The most commonly reported side effects with extracorporea use of methoxsalen were phototoxic reactions, nausea, vomiting, congestive heart failure and hypotension. During the course of therapy, the severity and frequency of undesirable effects may decline and generally do not require discontinuation of the therapy.

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

Very rare:

<1/10,000

Not known:

Frequency cannot be estimated from the available data

Common

(≥ 1/100 to < 1/10)

Not known

(Frequency cannot be estimated from the available data)

Infections and infestations

Infections

Eye disorders

Phototoxic reactions, e.g. cataract formation, chorioretinitis (see section 4.4)

Vascular disorders

Hypotension

Dizziness

Gastrointestinal disorders

Nausea

Vomiting

Skin and subcutaneous tissue disorders

Phototoxic reactions, e.g. pruritus or erythema (see section 4.4)

General disorders and administration site conditions

Fever (2 to 12 hours after therapy low grade fever may occur)

Injury, poisoning and procedural complications

Venous access complication after repeated venipuncture

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 : Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

4.9. Overdose

Dangerous overdosage of extracorporeal methoxsalen is highly unlikely – to date, there are no known cases.

With oral intoxication, the symptoms most likely to occur are nausea, intense vomiting and dizziness.

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