Temoporfin

Temoporfin is a photosensitising agent used in the photodynamic therapy (PDT) of tumours. Its pharmacological activity is started by light: after intravenous injection the drug is photoactivated with non-thermal light at 652 nm, and the therapeutic effect depends on the interaction of temoporfin with light and oxygen inside the cells.

Mechanism of Action

• Photoactivation: light at 652 nm lifts temoporfin to an excited state. It is thought to pass to a longer-lived triplet state that can react with surrounding molecules or with oxygen, in the type I and type II reactions typical of photodynamic agents.
• Reactive oxygen species: the reactions generate highly reactive oxygen species and radicals. They cause oxidative damage to tumour cells, which leads to cell death and, in the illuminated field, acute inflammation, oedema and necrosis.
• Immune cells: in studies, PDT with temoporfin activated macrophages and increased phagocytosis and the release of tumour necrosis factor-α and nitric oxide, which may add to tumour cell kill.
• Clinical effect: in a trial of 147 patients with advanced head and neck squamous cell carcinoma, a tumour response (reduction of the tumour mass by at least 50% for at least four weeks) was seen in 25% after a single treatment and a WHO local complete response in 14%. Responses were better in fully illuminated lesions 10 mm or less in depth. The median duration of response was 57 days overall and 84 days for complete responses. Of 37 patients who had at least two treatments, 10 responded to re-treatment, 6 of them with a complete local response.

Pharmacokinetics

• Absorption and distribution: after injection, plasma levels fall rapidly and then rise slowly to a peak 2–4 hours after the injection, and decline thereafter in two phases. The volume of distribution is large, intermediate between total and extracellular body water (0.34–0.46 L/kg), and temoporfin does not concentrate in the tissues. Plasma protein binding is 85–87%, to lipoproteins and to high-density proteins such as albumin.
• Metabolism: two major conjugated metabolites are formed and eliminated into the bile; none is seen in the systemic circulation.
• Elimination: temoporfin is a low-clearance substance (3.9–4.1 mL/h/kg) with a terminal plasma half-life of 65 hours in patients. Human data on elimination are limited; in animals the drug is eliminated only by the liver into the bile and faeces, with no enterohepatic recirculation of its metabolites.
• Time course: by 15 days after injection, the plasma concentration has fallen to background, which is why patients can generally begin a gradual return to normal outdoor lighting.

• Advanced head and neck squamous cell carcinoma: palliative treatment of patients whose disease has failed prior therapies and who are unsuitable for radiotherapy, surgery or systemic chemotherapy.

• Hypersensitivity to the active substance or to any of the excipients.
• 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 photosensitising agent.

Most toxicities of photodynamic therapy are local effects in the illuminated region and sometimes the surrounding tissue: an acute inflammatory response that commonly brings oedema and pain, followed by necrosis. All patients become temporarily photosensitive. Gastrointestinal disorders, skin reactions and general or administration-site disorders were the most frequent reactions. Few patients were treated, so uncommon and rare reactions could not be identified. Injection-site pain is transient and can be reduced by injecting more slowly.

Very common (≥1/10): haemorrhage; constipation, necrotising stomatitis, dysphagia; pain in the photoactivated area (for example facial pain, headache, injection-site pain); oedema in the photoactivated area (for example face or tongue oedema); scarring in the photoactivated area.

Common (≥1/100 to <1/10): localised infection in the photoactivated area (for example pharyngitis, stomatitis); anaemia; dizziness, burning sensation; nausea, vomiting, mouth ulceration; blistering, erythema, skin hyperpigmentation, photosensitivity reaction, skin necrosis (in the photoactivated area); trismus (a consequence of local oedema); pyrexia, injection-site reaction, oedema; thermal burn, sunburn (in the photoactivated area).

Not known: sepsis (as a consequence of local infection); vascular rupture; airway obstruction (as a consequence of local oedema); fistula (in the photoactivated area).

The photodynamic effect can also damage the tissue around the tumour, leading to fistula, perforation or vascular rupture, and to infection and sepsis. Injury to the surrounding area is the main serious risk, which is why illumination and shielding technique matter.

• Other photosensitising substances: the skin photosensitivity can be made worse, and such a reaction has been reported with topical 5-fluorouracil. Existing therapy with a photosensitising agent is a contraindication.
• Cytochrome P-450 enzymes: an in vitro study with human liver tissue showed no potential for interaction through inhibition of these enzymes. No other interactions have been observed.
• Alcohol content: the ethanol in the medicine may alter the effects of other medicines.

Foscan photodynamic therapy must only be given in specialist oncology centres where a multidisciplinary team assesses the patient’s treatment, under the supervision of physicians experienced in photodynamic therapy.

Dose and Injection

• Dose: 0.15 mg/kg body weight, as a single slow intravenous injection over not less than 6 minutes.
• Access: through an in-dwelling intravenous cannula in a large proximal limb vein, preferably in the antecubital fossa. The cannula is tested for patency before the injection, and every precaution is taken against extravasation.
• Filter: the dark purple solution in amber vials makes a visual check for particles impossible, so the in-line filter supplied in the pack must be used.
• No dilution: Foscan must not be diluted or flushed with sodium chloride or any other aqueous solution.

Illumination (Photoactivation)

• Timing: the treatment site is illuminated 96 hours after the injection, and not less than 90 hours or more than 110 hours after it.
• Light: laser light at 652 nm from an approved laser source, delivered through an approved microlens fibre-optic to the entire tumour surface. Wherever possible, the illuminated area extends 0.5 cm beyond the tumour margin.
• Light dose: 20 J/cm² delivered at an irradiance of 100 mW/cm² to the tumour surface, which means an illumination time of about 200 seconds.
• Fields: each field is illuminated once at each treatment, and several non-overlapping fields may be illuminated. No area of tissue may receive more than the specified light dose, and tissue outside the target area must be shielded completely to avoid photoactivation by scattered or reflected light.

Repeat Treatment

A second course may be given at the treating physician’s discretion when additional tumour necrosis and removal is judged appropriate, with a recommended minimum interval of 4 weeks between treatments.

Special Populations

There is no relevant use of Foscan in the paediatric population.

Photosensitivity and Light Protection

All patients become temporarily photosensitive. Skin and eyes must be protected from direct sunlight and bright indoor light during the first 15 days after the injection. Skin photosensitivity reactions are caused by visible light, so ultraviolet sunscreens give no protection. Patients must be brought back to normal light gradually, and clinicians must counsel them on the following precautions (given in the package leaflet):

• Day 1 (0–24 hours): stay indoors in a darkened room with the curtains drawn and light bulbs of 60 W or less; avoid direct sunlight.
• Days 2–7: return gradually to normal indoor lighting, avoiding direct sunlight through windows and direct light from household appliances such as reading lamps; television is allowed. Go outdoors only after dusk. If it is absolutely necessary to go out in daylight, cover all skin, including face and hands, with dark, closely woven clothing and wear dark glasses. Accidental exposure may cause a prickly or burning feeling, and the patient must then get out of the light at once. The eyes may be very sensitive to bright light during this week.
• Days 8–14: patients can go outside in daylight, staying in the shade or going out when it is cloudy, and continuing to wear dark, closely woven clothing. Start with 10–15 minutes outdoors on day 8 and, if no skin redness appears within 24 hours, increase the time gradually. Avoid direct sunlight and strong indoor lighting.
• From day 15: light sensitivity gradually returns to normal. Test it by exposing the back of the hand to the sun for 5 minutes and waiting 24 hours; if there is redness, avoid direct sunlight for another 24 hours and repeat the test. If there is none, increase sun exposure gradually, no more than 15 minutes on the first day and then 15 minutes more each day. Most people can return to their normal routine by day 22.
• Longer term: for 30 days avoid eye tests that use bright lights; for 3 months avoid UV tanning beds and sunbathing; for 6 months avoid prolonged direct sunlight on the arm used for the injection, and if prolonged outdoor activity is planned, protect that arm with long-sleeved, coloured clothing.

Extravasation

Special care must be taken to prevent the drug leaking out of the vein at the injection site. If this happens, the area must be protected from light for at least 3 months. Injecting another substance into the site has no known benefit.

Local Tissue Effects and Shielding

Normal tissue around the tumour must be protected from photoactivation by proper illumination and shielding. Local effects should be managed proactively. Serious reactions including cholangitis, cholecystitis, liver abscess and oesophageal perforation have been reported after unapproved use in malignant biliary strictures and mesothelioma.

Airways

Illumination of the airways may cause local inflammation and oedema, with dyspnoea or even airway obstruction needing intubation or tracheotomy. These complications should be anticipated, and prophylactic treatment with corticosteroids should be considered.

Pain

Pain other than injection-site pain begins the day after illumination and usually lasts 2 to 4 weeks. NSAIDs or opiate analgesics may be needed for a short time.

Surgery, Eye Examinations and Monitoring Equipment

• Unplanned or emergency surgery within 30 days of an injection should be done only if absolutely necessary and if the benefit outweighs the risk. Direct illumination with surgical lamps must be avoided; headlamps are recommended instead.
• Some pulse oximeters emit light close to the wavelength used for photoactivation. The probe must be repositioned at least every 10–15 minutes to avoid local skin burns.

Alcohol Content

The medicine contains 48 vol % ethanol, up to 4.2 g per dose (equal to 84 mL of beer or 35 mL of wine). This is harmful for people with alcoholism and should be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease or epilepsy. It may alter the effects of other medicines and may impair the ability to drive or use machines.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data in pregnant women, and animal studies showed reproductive toxicity. Foscan should not be used in pregnancy unless the woman’s clinical condition requires it.
• Contraception: women of childbearing potential must use effective contraception during treatment and for up to 3 months afterwards.
• Breastfeeding: it is unknown whether temoporfin or its metabolites pass into milk and a risk to the infant cannot be excluded; breast-feeding should be stopped for at least one month after the injection.
• Fertility: the effects on human fertility have not been studied.

Effect on Driving

To avoid photosensitivity problems, patients should not drive during the first 15 days after the injection and should use machines only if it is practical to do so under subdued lighting, following the recommended lighting precautions. The alcohol in the medicine may also impair the ability to drive or use machines. Driving and the use of machines may resume under normal lighting or daylight conditions once photosensitivity has been shown to have subsided.

Do not store above 25 °C. Keep the vial in the original package to protect it from light; no cold chain is needed. Each pack holds one amber glass vial (1 mL, 3 mL or 6 mL) and a filter with Luer lock connections; not all pack sizes may be marketed. Once opened, the solution must be used immediately.

5 years. Once opened, the solution must be used immediately.

Prescription only (Rx), subject to restricted medical prescription (Annex II B). Photodynamic therapy is given only in specialist oncology centres by physicians experienced in it, so Foscan is supplied to the hospital or clinic that administers it.