Summary of medicine characteristics - Foscan
1. NAME OF THE MEDICINAL PRODUCT
Foscan 1 mg/ml solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 1 mg of temoporfin.
Excipients with known effect
Each ml contains 376 mg of ethanol anhydrous and 560 mg of propylene glycol.
For the full list of excipients, see section 6.1
3. PHARMACEUTICAL FORM
Solution for injection
Dark purple solution
4. CLINICAL PARTICULARS4.1 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.
Posology
The dose is 0.15 mg/kg body weight.
Paediatric population
There is no relevant use of Foscan in the paediatric population.
Method of administration
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. Foscan shall not be diluted nor flushed with sodium chloride or any other aqueous solution.
The required dose of Foscan is administered by slow intravenous injection, over not less than 6 minutes. 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 0.5 cm.
Light must be administered not less than 90 hours and not more than 110 hours after Foscan injection.
The incident light dose is 20 J/cm2, delivered at an irradiance of 100 mW/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.
4.3 Contraindications
- • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- • Porphyria or other diseases exacerbated by light.
- • Hypersensitivity 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.
- • Co-existing ophthalmic disease likely to require slit-lamp examination within the next 30 days.
- • Existing therapy with a photosensitizing agent.
4.4 Special warnings and precautions for use
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 (see the light protection guidelines for patients at the end of this section).
For 6 months following Foscan treatment prolonged direct sunlight exposure of the injection site arm shall be avoided. As a precautionary measure, if prolonged outdoor activity is planned, the injection arm should be protected by wearing a long sleeved, coloured shirt.
Clinicians should be aware that most of the toxicities associated with photodynamic therapy are local effects seen as consequence of photoactivation. Photoactivation induces local tissue damage resulting in acute inflammatory response. This response is commonly associated with oedema and pain, followed by necrosis. The photodynamic effect may also lead to damage of the surrounding tissue that may cause fistula, perforation, or vascular rupture as well as infection and subsequent sepsis. It is therefore important that during photoactivation by laser illumination care should be taken to protect normal tissue surrounding the tumour from photoactivation by proper illumination and shielding techniques. Proactively managing the local effects and diminishing photoactivation in non-tumour areas is important to manage the risks.
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.
Adverse reactions, including cholangitis, cholecystitis, liver abscess and oesophageal perforation have been reported after unapproved use in the treatment of malignant biliary strictures and mesothelioma. There is a risk of damage of the surrounding area following photoactivation.
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. The use of headlamps is recommended instead.
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.
Pain, other than injection site pain, listed in section 4.8 may require the use of NSAIDs or opiate analgesics for a short time following treatment. Pain occurs the day after illumination and usually lasts 2 to 4 weeks.
Illumination of airways may lead to local inflammation and oedema. The resulting complications (i.e. dyspnoea or even airway obstruction leading to, for instance, intubation or tracheotomy) should be anticipated. Prophylactic treatment with corticosteroids should be considered.
Clinicians must counsel patients to observe the following precautions that are provided in the Package Leaflet.
| Time after Foscan Injection | What should I do to prevent burns? |
| Day 1 (0–24 hours) | Stay indoors in a darkened room. Keep the curtains drawn and use light bulbs of 60 W or less. Avoid exposure to direct sunlight. |
| Days 2–7 | You can gradually return to normal indoor lighting. Remember to avoid direct sunlight coming through the window or direct light from household appliances such as reading lamps. You may watch television. You can go outdoors after dusk. If it is absolutely necessary to go outdoors during the hours of daylight, you must be careful to cover up all your skin including your face and hands and wear dark glasses. The type of clothes you must wear are:
strong light. Wear dark, closely woven clothing.
burning feeling on the skin. You must get out of the light immediately. Your eyes may be very sensitive to bright lights during this week. You may get eye pain or headache when lights are switched on. If you have this problem, wear dark glasses. |
| Days 8–14 | You can now begin to go outside during daylight hours. Stay in shaded areas or go out when it is cloudy. Continue to wear dark, closely woven clothing. Start on Day 8 with 10–15 minutes outdoors. If you do not see any skin redness in the next 24 hours, you can gradually increase your time outdoors during the week. Avoid direct sunlight or strong indoor lighting. Stay in the shade. |
| Day 15 onward | Your sensitivity to light is gradually getting back to normal. You must test this carefully by exposing the back of your hand to the sun for 5 minutes. Wait 24 hours to see if there is any redness. If there is redness, you should avoid direct sunlight for another 24 hours. You can then repeat the test. If there is no redness, you can gradually increase your exposure to sunlight day by day. Do not stay in the sunlight for more than 15 minutes the first time. Most people will be able to go back to their normal routine by Day 22. On the first day after the skin test, you can stay in direct sunlight for 15 minutes. You can increase your exposure by another 15 minutes each day i.e. second day 30 minutes, third day 45 minutes, fourth day 60 minutes and so on. If at any time you notice a prickly or burning feeling or see skin reddening after exposure to sun, wait until this disappears before exposing your skin to light for this length of time again. For 30 days following Foscan treatment, avoid eye tests that use bright lights. |
| For 3 months following Foscan treatment, avoid UV tanning beds. Do not sunbathe. For 6 months following Foscan treatment, care should be taken to avoid direct prolonged sunlight exposure of the arm used for Foscan injection. As a precautionary measure, if prolonged outdoor activity is planned, the injection arm should be protected by wearing long sleeved, coloured clothing. |
This medicinal product contains 48 vol % ethanol (alcohol), i.e up to 4.2 g per dose, equivalent to 84 ml of beer, 35 ml wine per dose. Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease or epilepsy.The amount of alcohol in this medicinal product may alter the effects of other medicines.The amount of alcohol in this medicinal product may impair the ability to drive or use machines.
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 active substances. Such a reaction has been reported with topical 5-fluorouracil.
No other 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 Fertility, pregnancy and lactation
Pregnancy
There are no data from the use of temoporfin in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Foscan should not be used during pregnancy unless the clinical condition of the woman requires treatment with temoporfin.
Women of childbearing potential have to use effective contraception during and up 3 months after treatment.
Breast-feeding
It is unknown whether temoporfin/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued for at least one month following injection of Foscan.
Fertility
The effects of Foscan on fertility in humans have not been studied.
4.7 Effects on ability to drive and use machines
The amount of alcohol in this medicinal product may impair the ability to drive or use machines.
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 (see 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
Summary of the safety profile
All patients who receive Foscan will become temporarily photosensitive and must be instructed to observe precautions to avoid sunlight and bright indoor light. Regarding the tabulated adverse reactions gastrointestinal disorders, adverse skin reactions and general disorders and administration site conditions are the most frequently observed adverse reactions.
Most of the toxicities associated with photodynamic 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 and commonly include oedema and pain followed by necrosis (see section 4.4).
Photosensitivity reactions may occur, however, complying with the light protection guidelines (see above section 4.4) and avoiding unnecessary indoor light during illumination reduces this risk.
The low number of treated patients did not allow identification of adverse reactions, which may be categorised as uncommon and rare. Injection site pain is transient and can be reduced by slowing the injection rate. For treatment of other types of pain listed in this section, please see section 4.4.
Tabulated summary of adverse reactions
Frequencies are defined as: 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 (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| System Organ Class |
Infections and infestations
Common:
Localised infection in the area of photoactivation, e.g. pharyngitis, stomatitis Unknown:
Sepsis1
Blood and lymphatic system disorders
Common:
Anaemia
Nervous system disorders
Common:
Dizziness, burning sensation
Vascular disorders
Very common: Haemorrhage Unknown:
Vascular rupture: see section 4.3
Respiratory, thoracic and mediastinal disorders
Unknown:
Airway obstruction3
Gastrointestinal disorders
Very common:
Constipation, stomatitis necrotising, dysphagia
Common:
Vomiting, nausea, mouth ulceration
Skin and subcutaneous tissue disorders
Common:
Blister, erythema, skin hyperpigmentations, photosensitivity reaction, skin necrosis2
Musculoskeletal, connective tissue and bone disorders
Common:
Trismus3 Unknown:
Fistula2
| General disorders and administration site conditions | Very common: Pain in the photoactivated area, e.g. facial pain, headache, injection site pain, oedema in the photoactivated area, e.g. face oedema, tongue oedema Common: Pyrexia, injection site reaction, oedema |
| Injury, poisoning and procedural complications | Very common: Scar2 Common: Thermal burn, sunburn2 |
1 As a consequence of local infection
2 In the photoactivated area
3 As a consequence of local oedema
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 national reporting system listed in Appendix V.
4.9 Overdose
In the event of an overdose, 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 overdose and re-administration of Foscan must be allowed.
The adverse reactions associated with overdose 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 PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XD05.
Temoporfin is a photosensitising agent used in the photodynamic therapy of tumours.
The pharmacological activity is initiated by photoactivation of temoporfin with non-thermal light at 652 nm 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 squamous cell carcinoma, 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 10 mm 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 substance with a terminal plasma half-life of 65 hours in patients. Peak plasma levels occur at 2–4 hours post-injection 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 undesirable 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, however, in dogs treated with the recommended therapeutic dose, systemic exposure exceeded that of humans.
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 PARTICULARS6.1 List of excipients
Ethanol, anhydrous (E1510)
Propylene glycol (E1520)
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Foscan must not be diluted with aqueous solutions.
6.3 Shelf life
5 years
Once opened, the solution must be used immediately.
6.4 Special precautions for storage
Do not store above 25 oC.
Store in the original package in order to protect from light.
6.5 Nature and contents of container
Type I amber glass vials with a bromobutyl elastomer stopper and aluminium seal containing either
-
1 ml or 3 ml or 6 ml of solution for injection.
6.6 Special precautions for disposal and other handling
Appropriate precaution must be taken when handling this medicinal product. Studies have shown that Foscan is non-irritant. Each vial represents a single dose and any unused solution must be discarded.
Foscan is photosensitive. Once removed from its packaging it must be administered immediately. Where delay is unavoidable, the solution must be protected from light.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
biolitec Pharma Ltd.
Otto-Schott-Str. 15
07745 Jena
Germany
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/01/197/003
EU/1/01/197/004
EU/1/01/197/005
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 24 October 2001
Date of latest renewal: 22 September 2011