Summary of product characteristics

1. NAME OF THE MEDICINAL PRODUCT

Foscan 4mg/ml Solution for Injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active Substance

Temoporfin 4mg/ml

For excipients see section 6.1

3. PHARMACEUTICAL FORM

Solution for injection

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Foscan is indicated for the palliative treatment of patients with advanced head and neck squamous cell carcinoma failing prior therapies and unsuitable for radiotherapy, surgery or systemic chemotherapy.

4.2 Posology and method of administration

Foscan photodynamic therapy must only be administered in specialist oncology centres in which a multidisciplinary team assesses patient treatment and under the supervision of physicians experienced in photodynamic therapy.

Adults (including the elderly):
Foscan is administered via an in-dwelling intravenous cannula in a large proximal limb vein, preferably in the antecubital fossa, as a single slow intravenous injection over not less than 6 minutes. The patency of the in-dwelling cannula should be tested before injection and every precaution taken against extravasation (see section 4.4).

The dark purple colour of the solution, together with the amber vials makes a visual check for particulates impossible. Thus, an in-line filter must be used as a precautionary measure and is provided in the package. Do not flush with sodium chloride or any other aqueous solution.

The dose is 0.15mg/kg body weight. Do not dilute Foscan.

96 hours after the administration of Foscan, the treatment site is to be illuminated with light at 652 nm from an approved laser source. Light must be delivered to the entire surface of the tumour using an approved microlens fibre-optic. Wherever possible, the illuminated area must extend beyond the tumour margin by a distance of 0.5cm.

Patients must not be treated with a drug/light interval of less than 90 hours or more than 110 hours.

The incident light dose is 20J/cm2, delivered at an irradiance of 100mW/cm2 to the tumour surface, implying an illumination time of approximately 200 seconds.

Each field is to be illuminated once only at each treatment. Multiple non-overlapping fields may be illuminated. Care must be taken to ensure that no area of tissue receives more than the specified light dose. Tissue outside the target area must be shielded completely to avoid photoactivation by scattered or reflected light.

A second course of treatment may be given at the discretion of the treating physician in patients where additional tumour necrosis and removal is deemed appropriate, with a recommended minimum interval of 4 weeks between treatments.

Children and neonates:
Safety and efficacy in children and neonates has not been established.

 4.3 Contraindications

• porphyria or other diseases exacerbated by light
• hypersensitivity to temoporfin or to any of the excipients
• known allergies to porphyrins
• tumours known to be eroding into a major blood vessel in or adjacent to the illumination site
• a planned surgical procedure within the next 30 days
• coexisting ophthalmic disease likely to require slit-lamp examination within the next 30 days
• existing therapy with a photosensitising agent

4.4 Special warnings and special precautions for use

Special care must be taken to prevent extravasation at the injection site. If extravasation occurs, protect the area from light for at least 3 months. There is no known benefit from injecting the extravasation site with another substance.

Some pulse oximeters may produce light of a wavelength close to that used for the photoactivation of Foscan. Oximeters must be repositioned at least every 10-15 minutes to avoid the risk of local skin burns.

Unplanned or emergency surgical procedures where Foscan has been administered within the previous 30 days must be undertaken only if absolutely necessary and the potential benefits outweigh the risk to the patient. All precautions must be taken to avoid direct illumination of the patient with surgical lamps during these procedures.

All patients who receive Foscan will become temporarily photosensitive. Precautions must be taken to avoid exposure of skin and eyes to direct sunlight or bright indoor light during the first 15 days after injection. Skin photosensitivity reactions are caused by visible light, therefore ultraviolet sunscreens provide no protection. It is important that patients are re-introduced to normal light gradually.

Clinicians must counsel patients to observe the following precautions that are provided in the Patient Information Leaflet:

4.5 Interaction with other medicinal products and other forms of interaction

There is potential for exacerbation of skin photosensitivity if Temoporfin is used with other photosensitising drugs. Such a reaction has been reported with topical 5-fluorouracil.

No other drug interactions have been observed. An in-vitro study with human liver tissue has shown no potential for drug interaction through inhibition of cytochrome P-450 enzymes by temoporfin.

4.6 Pregnancy and lactation

Pregnancy
There are no data from the use of temoporfin in pregnant women. Animal studies are insufficient with respect to effects on embryonal/foetal development (see section 5.3). The potential risk for humans is unknown. Temoporfin should not be used during pregnancy unless clearly necessary.

Women of child bearing potential
Animal studies suggest a toxic effect in early pregnancy (see section 5.3). The potential risk for humans is unknown. Therefore, pregnancy must be avoided for 3 months after treatment with Temoporfin.

Lactation
It is not known if temoporfin is excreted in human milk. Women receiving Foscan must not breast feed for at least one month following injection.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

On the basis of the pharmacodynamic profile, Temoporfin is presumed to be safe or unlikely to produce an effect. To avoid photosensitivity problems, it is advised not to drive during the first
15 days after injection, and to use machines only if it is practical to do so under subdued lighting conditions according to the recommended lighting precautions (Section 4.4). Driving and use of machines may resume under normal lighting or daylight conditions once photosensitivity has been shown to have subsided.

4.8 Undesirable effects

All patients who receive Foscan will become temporarily photosensitive and must be instructed to observe precautions to avoid sunlight and bright indoor light.
Most toxicities associated with this therapy are local effects seen in the region of illumination and occasionally in surrounding tissues. The local adverse reactions are characteristic of an acute tissue inflammatory response induced by photoactivation.

Injection site reaction
Very common effects: Injection site pain (12%). This pain is transient and can be reduced by slowing the injection rate.
Common effects: injection site reaction (3%), burning sensation (3%).

Tumour/local tissue reaction
Very common effects: pain (15%), haemorrhage (15%), pain in face (13%), scar (12%), mouth necrosis (12%), dysphagia (11%), face oedema (11%). The pain may require the use of NSAIDs or opiate analgesics for a short time following treatment.
Common effects:, oedema (8%),  trismus (8%), difficulty in swallowing (5%), localised infection (8%), fever (8%),  mouth ulceration (6%), skin necrosis (2%).

Phototoxicity
Common effects: burn (3%), blisters (5%), erythema (5%), hyperpigmentation (3%), photosensitivity reaction (3%), sunburn (3%)

Other clinical events
Very common effects: constipation (11%),
Common effects: vomiting (9%), anaemia (8%), nausea (6%), giddiness (2%), 

 4.9 Overdose

In the event of an overdosage, laser treatment would result in deeper tumour necrosis than would be expected with the recommended dose. Illumination of the tumour should only be carried out if the potential benefit justifies the potential risk of excessive necrosis.  If the tumour is not illuminated, a period of at least 4 weeks between overdosage and re-administration of Foscan must be allowed.

The adverse effects associated with overdosage would be expected to be limited to photosensitivity reactions. Exposure to ambient light after overdose carries an increased risk of photosensitivity reactions. Published clinical research has shown that the duration and intensity of photosensitivity at the recommended dose of 0.15 mg/kg were reduced by one third relative to a dose of 0.3 mg/kg. Animal studies have shown some haematological and blood chemistry changes (decreased platelets, erythrocytes and haemoglobin, increased neutrophils, fibrinogen, bilirubin, triglyceride and cholesterol).

Strict observance of the reduced light regime is required. A skin photosensitivity test must be carried out before the patient returns to normal light conditions.

No specific systemic symptoms are known to be associated with overdose. Treatment should be supportive.

Limited information is available on the effects of overexposure to laser light during treatment. Increased damage to tissue was noted.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Temoporfin is a photosensitising agent used in the photodynamic therapy of tumours. The ATC code is L01XX.

The pharmacological activity is initiated by photoactivation of temoporfin with non-thermal light at 652nm following intravenous administration. The therapeutic effect is mediated through the generation of highly reactive oxygen species, a process dependent on the intracellular interaction of temoporfin with light and oxygen.

In a clinical trial of 147 patients with advanced head and neck cancer, tumour response, defined as a reduction of a minimum of 50% of the tumour mass for a minimum of four weeks, was observed in 25% after a single treatment. A WHO local complete response was observed in 14% of patients. Tumour responses are enhanced in patients with fully illuminated lesions of 10mm or less in depth.

The median observed duration of tumour response for all patients was 57 days for overall response and 84 days for complete response.

Thirty-seven patients received at least 2 treatments with Foscan. Ten patients achieved a tumour response due to re-treatment. Of these, 6 had a complete local response according to WHO criteria.

5.2 Pharmacokinetic properties

Temoporfin is a low clearance drug with a terminal plasma half-life of 65 hours in patients. Peak plasma levels occur at 2-4 hours post-infusion, thereafter plasma levels decline in a bi-exponential manner. An extensive volume of distribution is observed that is intermediate between total and extracellular body water. Temoporfin does not concentrate in the tissues. Plasma protein binding is at 85-87%. Temoporfin is bound to plasma lipoproteins and high density proteins such as albumin in the blood. By 15 days post-infusion, temoporfin plasma concentration has declined to background such that patients are generally able to begin a gradual return to normal outdoor lighting conditions.

Limited data are available on the elimination of temoporfin in humans. Animal data show temoporfin is exclusively eliminated by the liver into the bile and excreted in the faeces. Two major metabolites of temoporfin are eliminated into the bile. There is no enterohepatic recirculation of these metabolites. Both these metabolites show conjugated character.  No metabolites are seen in the systemic circulation.

5.3 Preclinical safety data

In repeated dose toxicity studies in rats and dogs, the main adverse effects of temoporfin were phototoxicity and adverse injection site reactions. Local irritancy of Foscan solution for injection after intravenous administration occurred with all doses. High rates of administration caused death in dogs and rabbits. No other signs of toxicity were found, but only in dogs systemic exposure exceeded that of humans at the recommended therapeutic dose.

The genotoxicity of temoporfin has been investigated to a limited extent. Due to the generation of reactive oxygen species, temoporfin poses a minor risk of mutagenicity. This risk can be controlled in the clinical situation by minimising direct exposure to light (see section 4.4).

In developmental toxicity studies in rabbits, temoporfin, at systemic exposures equal to those obtained in humans with the recommended therapeutic dose, caused an increase in early post-implantation loss. Although no other developmental effects were observed, the applied doses were not sufficiently in excess of the human therapeutic dose to provide an adequate margin of safety.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ethanol, anhydrous
Propylene glycol

6.2 Incompatibilities

In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products. Do not dilute with aqueous solutions

6.3 Shelf life

4 years
The opened solution must be used immediately

6.4 Special precautions for storage

Do not store above 25°C.
Store in the original container.
Keep the container in the outer package

6.5 Nature and contents of container

Foscan is supplied as a dark purple solution for injection in vials containing a nominal 3.5ml
(14mg temoporfin) or nominal 5ml (20mg temoporfin). A filter with Luer lock connections for syringe and cannula is provided.

6.6 Instructions for use and handling

Appropriate precaution must be taken when handling. Studies have shown that Foscan is non-irritant. Each vial represents a single dose and any unused solution must be discarded.

Administer the required dose of Foscan by slow intravenous injection, over not less than 6 minutes.
Foscan is photosensitive. Once removed from its packaging it must be administered immediately. Where delay is unavoidable, the solution must be protected from light.

7. MARKETING AUTHORISATION HOLDER

biolitec pharma ltd.
United Drug House
Magna Drive
Dublin 24,
Irland.

8. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

EU/1/01/197/001
EU/1/01/197/002

9. OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24-10-01

10. DATE OF REVISION OF THE TEXT

05-08-05

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