PhotoBarr - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 15 mg porfimer sodium. After reconstitution, each ml solution contains 2.5 mg porfimer sodium.

For a full list of excipients, see

3. PHARMACEUTICAL FORM

4.2 Posology and method of administration

Only a solution without particles should be used and without visible signs of deterioration.

Photodynamic therapy with PhotoBarr is a two-stage process requiring administration of both medicinal product and light. One course of PDT consists of one injection plus one or two light applications.

In case of persistence of HGD, further treatment courses (upo a maximumhree courses) may be given (separated by a minimum of 90 days) to increase the ronse rate. Ts to be balanced against the increased rate of stricture formation (see section 4.8 and section 5.1).

Progression to cancer was related to the number of PDT courses administered. Patients who received one course of PDT had a greater risk of progression to cancer than patients who received two or three courses of PDT (50% vs. 39% and 11% respectively)

Method of administration

For instructions on reconstitution prior to administration, see section 6.6.

Physicians should be trained in the use of PDT. The first stage of PDT is the slow intravenous injection of PhotoBarr. The second stage of therapy is illumination with laser light 40–50 hours following injection with PhotoBarr. Patients may receive a second laser light application 96–120 hours after administration.

PhotoBarr should be administered as a single slow intravenous injection over 3 to 5 minutes. If accidentally injected paravenously there may be damage to paravenous tissue. Therefore, care should be taken to prevent extravasation at the injection site. If extravasation does occur, the area should be protected from light for a minimum of 90 days. There is no known benefit from injecting the extravasation site with another substance.

Approximately 40–50 hours after PhotoBarr administration, light should be delivered by a fibre optic diffuser passed through the central channel of a centring balloon. The choice of fibre optic/balloon diffuser combination will depend on the length of oesophagus to be treated (Table 1).

Table 1 Fibre optic diffuser/balloon combination“

a Whenever possible, the BO segment selected for treatment should include normal tissue margins of a few millimetres at the proximal and distal ends.

Light doses

Photoactivation is controlled by the total lig

areas of HGD and the entire length of diffuser length using a centring balloon. balloon/diffuser combination rang

To calculate the light dose, the following specific light dosimetry equation applies for all fibre optic diffusers:

The light dose (J/cm) = power output from diffuser (W) x treatment time (sec) xP Diffuser length (cm)

Table 2 provides the settings that would be used to deliver the dose within the shortest time (light intensity of 270 mW/cm). A second option (light intensity of 200 mW/cm) has also been included where necessary to accommodate lasers with a total capacity that does not exceed 2.5 W.

Table 2. Fibre optic power outputs and treatment times required to deliver 130 J/cm of diffuser length using the centring balloon

a As measured by immersing the diffuser into the cuvette in the power meter and slowly increasing the laser power. Note: No more than 1.5 times the required diffuser power output should be needed from the laser. If more than this is required, the system should be checked.

Short fibre optic diffusers (< 2.5 cm) are to be used to pretreat nodules with 50 J/cm diffuser length prior to regular balloon treatment in the first laser light session or for the retreatment of „skip“ areas after the first light session. For this treatment, the fibre optic diffuser is used without a balloon, and a light intensity of 400 mW/cm should be used. Table 3 lists appropriate fibre optic power outputs and treatment times using a light intensity of 400 mW/cm.

Table 3. Short fibre optic diffusers to be used without a centering balloon to deliver 50 J/cm of

diffus er length at a light intensity of400 mW/cm

aAs measured by immersing the diffuser into the cuvette in the power meter and slowly increasing the laser power. Note: No more than 1.5 times the required diffuser power output should be needed from the laser. If more than this is required, the system should be checked.

First light application

A maximum of 7 cm of Barrett's mucosa is treated at the first light session using an appropriate size of centering balloon and fibre optic diffuser (Table 1). Whenever possible, the segment selected for the first light application should include all the areas of HGD. Also, whenever possible, the BO segment selected for the first light applications should include normal tissue margin of a few millimetre at the proximal and distal ends. Nodules are to be pre-treated at a light doses of 50 J/cm of diffuser length with a short (< 2.5 cm) fibre optic diffuser placed directly against the nodules followed by standard balloon application as described above.

Repeat light application

A second laser light application may be given to a previously treated segment that shows a ‚skip‘ area, (i.e., an area that does not show sufficient mucosal response) using a short < 2.5 cm fibre optic diffuser at the light dose of 50 J/cm of diffuser length (see Table 3). The treatment regimen is summarized in Table 4. Patients with BO > 7 cm, should have the remaining untreated length of Barrett's epit­helium treated with a second PDT course at least 90 days later.

Table 4. High-grade dysplasia in Barrett's oesop­hagus of < 7 cm

aDiscrete nodules will receive an initial light application of 50 J/cm (using short diffuser)

before the balloon light application.

Patients may receive a second course of PDT a minimum of 90 days after the initial therapy; up to three courses of PDT (each injection separated by a minimum of 90 days) should be given to a previously treated segment which still shows HGD or to a new segment if the initial Barrett's segment was >7 cm in length. Both residual and additional segments may be treated in the same light session(s) if the total length of the segments treated with the balloon/diffuser combination is not greater than 7 cm. In the case of a previously treated oesophageal segment, if it has not sufficiently healed and/or histological assessment of biopsies is not clear, the subsequent course of PDT may be delayed for an additional 1–2 months.

Special care to ensure accurate PhotoBarr dosing and/or light dose is crucial, since miscalculation of either medicinal product or light dose may lead to a less effective treatment or cause detrimental effect to the patient. Photodynamic therapy with PhotoBarr should be applied by physicians trained in endoscopic use of PDT and only in those facilities properly equipped for the procedure.

Special populations

Paediatric patients

PhotoBarr is not recommended for use in children below age 18 years due to a and efficacy.

Elderly patients (> 65 years old)

Dose modification based upon age is not required.

Renal impairment

The influence of renal impairment on exposure to porfimer sodium has not been evaluated (see section 4.3).

Hepatic impairment

The influence of hepatic impairment on exposure t section 4.3 and 4.4).

4.3 Contraindications

Hypersensitivity to the active substance,

Porphyria.

Oesophageal or gastric varices or patients with oesophageal ulcers >1 cm in diameter.

broncho-oesophageal fistula.

of major blood vessels due to risk of massive, potentially fatal haemorrhage.

4.4 Special warnings and precautions for use

Efficacy and especially safety of PDT with PhotoBarr have not been established in patients with contraindications to, or not being eligible for, oesophagectomy. Photodynamic therapy with PhotoBarr has exclusively been studied in patients not suffering from severe medical conditions, such as congestive heart failure of advanced stage or serious pulmonary conditions that might impair the eligibility of patients for surgical procedures.

In clinical trials, PhotoBarr PDT has only been tested in patients being treatment naive concerning mucosal ablative therapy. Safety and efficacy in patients with treatment failure of other local mucosal ablative therapy has not been evaluated.

Elderly

Patients older than 75 years may be at a higher risk of respiratory related adverse events such as pleural effusion and dyspnoea.

Pulmonary or cardiac disorders

Patients with pulmonary or cardiac medical illness or a history of such illness should be treated with caution. These patients may be at higher risk for the development of cardiac and pulmonary related adverse events such as heart rhythm disorders, angina pectoris, dysp cough, pleural effusion, pharyngitis, atelectasis and events like dehydration (see also section 4.8).

Photosensitivity

All patients who receive PhotoBarr will be photosensitive and must observe precautions to avoid exposure of skin and eyes to direct sunlight or bright indoor light (from examination lamps, including dental lamps, operating room lamps, unshaded light bulbs at close proximity, neon lights, etc.) for at least 90 days after treatment, as some patients may remain photosensitive for up to 90 days or more. During this period, patients should wear dark sunglasses, which have an average white light transmittance of < 4% when outdoors. The photosensitivity is due to residual photoactive substances, which will be present in all parts of the skin. Exposure of the skin to ambient in

beneficial because the remaining medicinal product will be inactivated gra bleaching reaction. Therefore, patients should not stay in a darkened room should be encouraged to expose their skin to ambient indoor light. The lev vary for different areas of the body, depending on the extent of previous exposure to light.

Before exposing any area of skin to direct sunlight or bright indo r light, the patient should test it for residual photosensitivity. A small area of skin should be expo

around the eyes may be more sensitive, and therefore, it is testing. If no photosensitivity reaction (erythema, oedema, patient can gradually resume normal outdoor activities, ini gradually allowing increased exposure. If some photosensitivity reaction occurs with the limited skin test, the patient should continue exercising precautions for another 2 weeks before retesting.

If patients travel to a different geographical area with greater sunshine, they should retest their level of photosensitivity. Conventional UV (ultraviolet) sunscreens are of no value in protecting against photosensitivity reactions because photoactivation is caused by visible light.

Hepatic impairment

No pharmacokinetic and safety data in patients with hepatic impairment are available. Based on evidence for a primarily hepatic/biliary elimination of photoactive substances, severity of phototoxic reactions and duration of the period of photosensitivity in patients with any grade of hepatic impairment may be increased. PhotoBarr is contraindicated in patients with severe hepatic

with mild to moderate hepatic impairment should be clearly instructed that the recautionary measures described below may be longer than 90 days.

Ocular s

Patients should be advised to consult their ophthalmologist if they notice any vision changes after treatment with PhotoBarr PDT.

Hypersensitivity

Acute hypersensitivity reactions including anaphylaxis have been reported. In case of an allergic reaction, appropriate measures (standard of care) should be taken and the PDT treatment should not be repeated. The medicinal product should only be administered when material and personnel experienced in evaluating and treating anaphylaxis are immediately available.

Non Cardiac Chest Pain

As a result of PDT treatment, patients may complain of substernal chest pain because of inflammatory responses within the area of treatment. Such pain may be of sufficient intensity to warrant the shortterm prescription of opiate analgesics.

Oesophageal Stenosis

Prophylactic use of corticosteroids to reduce stricture formation should be avoided during PDT as its use has shown not to reduce, and may worsen, stricture formation.

Nutrition in Patients

PhotoBarr PDT regularly causes dysphagia, odynophagia, nausea and vomiting. Therefore, patients should be advised to receive liquid food during the first days (up to 4 weeks) after the laser light application. If intake of food and/or drink becomes impossible or repeated vomiting occurs, patients should be advised to return to the clinic for evaluation and to receive intravenous fluids if needed.

Use Before or After Radiotherapy

If PDT is to be used before or after radiotherapy, sufficient time should be allowed between the therapies to ensure that the inflammatory reaction produced by the first treatment has subsided prior to commencement of the second treatment.

Thrombo-embolism

There may be an increase in the risk of thrombo-embolic events especially in patients with prolonged immobilization, post major surgery and other thromboembolic risk factors.

Follow-up procedure

Data on the long-term effect of PhotoBarr (beyond two years) are not available at the moment. Also, treating physicians should be aware of the possibility of squamous overgrowth and the risk of overlooking cancer. Therefore, adequate and rigorous surveillance should be continued despite possible endoscopic partial or complete restitution of the normal squamous mucosa. In the clinical studies with PhotoBarr, follow-up surveillance was done every three months, or everonths after four consecutive biopsy results had shown no more high-grade dysplasia (see section 5.1). Available treatment and surveillance guidelines should be considered.

4.5 Interaction with other medicinal products and other forms of interaction

No formal interaction studies have been performed with PhotoBarr investigating pharmacokinetic interactions with other medicinal products.

A study investigating pharmacodynamic interactions has demonstrated that corticosteroids given before or concomitant with PDT to decrease formation of strictures may decrease the safety of treatment.

It is possible that concomitant use of other photosensitising agents (e.g., tetracyclines, sulphonamides,

phenothiazines, sulphonylurea hypoglycaemic agents, thiazide diuretics, griseofulvin and

increase the photosensitivity reaction.

PhotoBarr PDT causes direct intracellular damage by initiating radical chain reactions that damage intracellular membranes and mitochondria. Tissue damage also results from ischaemia secondary to vasoconstriction, platelet activation and aggregation and clotting. Research in animals and in cell culture has suggested that many active substances could influence the effects of PDT, possible examples of which are described below. There are no human data available to support or rebut these possibilities. Compounds that quench active oxygen species or scavenge radicals, such as dimethyl sulphoxide, b-carotene, ethanol, formate and mannitol would be expected to decrease PDT activity. Preclinical data also suggest that tissue ischaemia, allopurinol, calcium channel blockers and some prostaglandin synthesis inhibitors could interfere with PhotoBarr PDT. Medicinal products that decrease clotting, vasoconstriction or platelet aggregation, e.g., thromboxane A2 inhibitors, could decrease the efficacy of PDT.

• 4.6 Fertility, Pregnanc and lactation

Pregnancy

There are no clinical data on exposed pregnancies available for porfimer sodium. Animal studies are insufficient with respect to effects on pregnancy, embryo/foetal development, parturition and postnatal development (see section 5.3). The potential risk for humans is unknown. Porfimer sodium should not be used during pregnancy, unless clearly necessary. Women of child-bearing potential should use effective contraception before, during and for at least 90 days after treatment.

Lactation

It is not known whether porfimer sodium is excreted into human breast milk. In rats, porfimer sodium passed into breast milk. Breast-feeding should be terminated prior to treatment.

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.

For the PDT procedure, sedation may be required, and consequently caution should be taken. Patients should not drive or use machines after the light treatment if they have been d for the procedure.

4.8 Undesirable effects

• a. Summary of the safety profile

All patients who receive PhotoBarr will be photosensitive and must observe precautions to avoid sunlight and bright indoor light (see section 4.4). In an open label pharmacokinetic study, all 24 healthy subjects experienced photosensitivity reactions, which were characteristically represented by erythematous rash and oedema and were mild to moderate in intensity. The photosensitivity reactions occurred primarily on the face, hands, and neck regions, which are the areas of the skin that are most susceptible to accidental sunlight e e. Other less common skin manifestations were

ions had occurred, such as increased hair growth, skin and skin fragility. These manifestations may be mporary medicinal product-induced cutaneous porphyria). ensitivity reactions experienced in this study are unlike the ous clinical studies in cancer patients (approx. 20%) or the spontaneously reported incidence from commercial use of PhotoBarr (< 20%). It is possible that prolonged exposure to light at the clinical research unit or accidental sunlight exposure after discharge may be responsible for the high frequency of photosensitivity reactions. The more active lifestyle of the healthy and relatively younger subjects compared with cancer patients may have been a contributing factor to these photosensitivity reactions.

plus omeprazole (PDT + OM) treatment was compared to a group treated with omeprazole alone (OM only), in the BO with HGD controlled clinical trial. In the PDT + OM group, 133 patients were treated. The most frequently reported adverse reactions were photosensitivity reactions (69%), oesophageal stenosis (40%), vomiting (32%), chest pain of non-cardiac origin (20%), pyrexia (20%), dysphagia (19%), constipation (13%), dehydration (12%) and nausea (11%). The majority of these reported adverse reactions were mild to moderate in intensity.

b.Tabulated summary of adverse reactions

Adverse reactions reported are listed below in Table 5 by organ class and frequency. Frequencies are defined as: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 5. Summary of adverse reactions with porfimer sodium ___________

Infections and infestations

Uncommon:     Bronchitis, nail fungal infection, sinusitis, skin infection

Not known:     Pneumonia

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Uncommon:     Basal cell carcinoma, lentigo

Blood and lymphatic system disorders

Uncommon:    Leukocytosis

Not known:     Anaemia

Immune system disorders

Not known:     Hypersensi­tivity

Metabolism and nutrition disorders

Dehydration*

Appetite decreased, electrolyte imbalance

Hypokalaemia

Psychiatric disorders

Common:       Anxiety, insomnia

Uncommon:     Restlessness

Nervous system disorders

Common:       Headache, paraesthesia, dysgeusia

Uncommon:     Dizziness, hypoaesthesia, tremor

Eye irritation, eye oedema Cataract

Ear and labyrinth disorders Uncommon:     Deafness, tinnitus, tinnitus aggravated

Cardiac disorders

Common:       Tachycardia, chest pain

Uncommon:     Angina pectoris, atrial fibrillation, atrial flutter, chest discomfort

Respiratory, thoraci

Common:             al effusion, pharyngitis, atelectasis, dyspnoea

Uncommon:     Choking, dyspnoea exertional, haemoptysis, hypoxia, nasal congestion,

pneumonia aspiration, productive cough, respiratory depression, respiratory tract congestion, wheezing

Gastrointestinal disorders

Skin and subcutaneous tissue disorders

e events (SAEs) in the PhotoBarr PDT + OM group, 44 (23.1%) were considered eatment. The most frequently reported treatment-associated serious adverse ehydration (4%), experienced by 5 patients. The majority of the SARs were l disorders (8% – 11 patients), specifically nausea (3% – 4 patients), vomiting (3% – 4 pper abdominal pain (2% – 2 patients).

The majority of treatment-associated oesophageal stenosis (which includes oesophageal narrowing and oesophageal strictures) reported in the PhotoBarr PDT + OM group were of mild or moderate intensity (92%). All incidences of strictures were considered associated with treatment of which 1% was considered serious.

An occurrence rate of 12% for oesophageal strictures was observed during the first course of treatment. The occurrence rate rose to 32% when a second course of therapy was given, especially in the areas where second treatment overlaps the first and amounted to 10% for those who received a third treatment course. The majority of these was mild to moderate in intensity and could be managed through 1–2 dilatations. Eight percent were severe, requiring multiple (6 – >10) dilatations. The formation of oesophageal stenosis cannot be reduced or eliminated by the use of steroids.

4.9 Overdose

PhotoBarr

There is no information on overdose of PhotoBarr. The recommended 2 mg/kg dose, instead of the recommended single administration, was given twice two days apart (10 patients) and three times within two weeks (1 patient), withoutnotable adverse reactions being reported. The effects of an overdose on the duration of photosensitivity are unknown. Laser treatment should not be given if an overdose of PhotoBarr is administered. In the event of an overdose, patients should protect their eyes and skin from direct sunlight or bright indoor lights for 90 days. At this time, patients should test for residual photosensitivity (see section 4.4).

Porfimer sodium is not dialyzable.

Laser light

Light doses of two to three times the recommended dose have been administered to a few patients with superficial endobronchial tumours. One patient experienced life-threatening dyspnoea and the others had no notable complications. Increased symptoms and damage to normal tissue might be expected following an overdose of light.

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5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Sensitizers used in photodynamic/ra­diation therapy, ATC code: L01XD01

Mechanism of action                   ­T“^

Porfimer sodium is a mixture of porphyrin units, which are linked together in chains of two to eight units The cytotoxic actions of porfimer sodium are light and oxygen-dependent. Photodynamic therapy with PhotoBarr is a 2-stage process. The first stage is the intravenous injection of PhotoBarr. Clearance from a variety of tissues occurs over 40–72 hours, but tumours, skin, and organs of the reticuloendothelial system (including liver and spleen) retain porfimer sodium for a longer period. Illumination of the target area with 630 nm wavelength laser light constitutes the second stage of therapy. Tumour and dysplastic tissue selectivity in treatment may occur partly through selective retention of porfimer sodium but mainly through a selective delivery of light. Cellular damage caused by porfimer sodium PDT is a consequence of the propagation of free radical reactions. Radical initiation may occur after porfimer sodium absorbs light to form a porphyrin excited state. Spin transfer from porfimer sodium to molecular oxygen may then generate singlet oxygen. Subsequent free radical reactions can form superoxide and hydroxyl radicals. Tumour cell death also occurs through ischaemic necrosis secondary to vascular occlusion that appears to be partly mediated by thromboxane A2 release. The laser treatment induces a photochemical, not a thermal, effect. The necrotic reaction and associated inflammatory response evolve over several days.

Clinical efficacy

In a controlled clinical trial, a PhotoBarr PDT + OM (omeprazole) patient group (n=183)was compared to a group of patients receiving OM only (n=70). Eligible patients for this study were to have biopsy-proven HGD in Barrett's oesop­hagus (BO). Patients were excluded from the study if there was a presence of invasive oesophageal cancer, if they had a history of cancer other than nonmelanoma skin cancer or if they had received prior PDT to the oesophagus. Other exclusion criteria were patients in whom omeprazole therapy was contraindicated.

Patients randomised to treatment with PDT received PhotoBarr at a dose of 2 mg/kg body weight through slow intravenous injection over 3 to 5 minutes. One or 2 laser light treatments were administered following PhotoBarr injection. The first laser light session occurred 40–50 hours after injection and a second session, if indicated, occurred 96–120 hours after injection. Co-administration of omeprazole (20 mg BID) began at least 2 days before PhotoBarr injection. Patients randomised to the OM only group received orally omeprazole 20 mg BID for the duration of the study.

Patients were followed every 3 months until 4 consecutive, quarterly follow-up endoscopic biopsy results were negative for HGD, and then biannually until the last enrolled patient had completed a minimum of 24 months of follow-up evaluations after randomisation.

PhotoBarr PDT + OM was effective in eliminating HGD in patients with BO. At final analysis, performed at a minimum of 24 months follow-up, a statistically significant percentage of patients (77%) in the PhotoBarr PDT + OM group demonstrated complete HGD ablation compared to 39% of

patients in the OM alone group (p<0.0001). Fifty-two percent of patients in the PDT + O showed normal squamous cell epithelium while 59% had absence of dysplasia compared

14% in the OM alone group, respectively (p<0.0001). These results confirm those minimum of 6 months follow-up which showed HGD ablation in 72% of patien PDT + OM group compared to 31% in the OM only group. Forty-one perc normal squamous cell epithelium and 49% had absence of dysplasia.

By the end of the minimum follow-up of two years, 13% in the PhotoBarr PDT + OM group had

progressed to cancer compared to 28% in the OM only group in The proportion of patients who progressed to cancer in the Ph

statistically lower than in the OM only group (p=0.0060). end of the entire follow-up period, patients in the PhotoB being cancer-free as compared to a 53% chance for patients in the OM only group. Comparison between the survival curves of the two treatment arms using the log rank test showed a statistically significant difference between the curves of the two groups in the ITT population (p=0.0014), indicating a significant delay in the progression to cancer.

5.2 Pharmacokinetic properties

The pharmacokinetics of porfimer sodium have been studied in 12 patients with endobronchial cancer and 23 healthy subjects (11 men and 12 women), given 2 mg/kg porfimer sodium through slow intravenous injection. Plasma samples were obtained out to 56 days (patients) or 36 days (volunteers) post-injection.

In patients, the mean peak plasma concentration (Cmax) was 79.6 gg/ml (CV 61%, range 39–222), whereas in volunteers Cmax was 40 gg/ml and AUCinf was 2400 gg/h/ml.

Distribution

In vitro binding of porfimer sodium to human serum protein is around 90% and independent of concentration between 20 and 100 gg/ml.

Elimination

Porfimer sodium is cleared slowly from the body, with a mean CLT of 0.859 ml/h/kg (CV 53%) in patients. The serum decay was bi-exponential, with a slow distribution phase and a very long elimination phase that started approximately 24 hours after injection. The mean elimination half-life (t1/2) was 21.V range 264–672) in patients and 17 days in volunteers.

Special populations

The influence of renal and hepatic impairment on exposure to porfimer sodium has not been evaluated (see sections 4.2, 4.3 and 4.4).

Gender had no effect on pharmacokinetic parameters except for tmax, which was approximately

1.5 hours in women and 0.17 hours in men. At the time of intended photoactivation 40–50 hours after injection, the pharmacokinetic profiles of porfimer sodium in men and women were very similar.

5.3 Preclinical safety data

Porfimer sodium was not mutagenic in standard genotoxicity tests in the absence of light. With light activation, porfimer sodium was mutagenic in some in-vitro tests.

Reproductive toxicology studies were insufficient to support the safety of porfimer sodium during pregnancy, as no light activation had been used. In these studies foetotoxicity, but not teratogenicity, occurred in rats and rabbits only at evaluated intravenous doses (greater than of equal to 4 mg/kg) and at greater frequency (daily) compared in the clinical use.

Preclinical studies indicate that the excretion of porfimer sodium components occurs faecal route.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Hydrochloric acid (for pH-adjustment) Sodium hydroxide (for pH-adjustment)

6.2 Incompatibilities

6.3 Shelf lifePowder: 3 years.After it has been reconstifrom light. Chemica microbiological in-use storageAfter reconstitution: use imwithin 3 hours).6.4 Special precautions for storage, PhotoBarrshould be used immediately (within 3 hours) and protected hysical in-use stability has been demonstrated for 3 hours at 23°C. From a view, the product should be used immediately. If not used immediately,d conditions prior to use are the responsibility of the user.

6.5 Nature and contents of container 15 mg powder in a vial (glass type I, 7 ml capacity) with a grey butyl stopper.

6.6 Special precautions for disposal and other handling

Instructions for reconstitution

PhotoBarr 15 mg vial should be reconstituted with 6.6 ml of 5% glucose solution for injection resulting in a final porfimer sodium concentration of 2.5 mg/ml in the solution for injection.

Do not use other diluents. Do not mix PhotoBarr with other medicinal products in the same solution.

Sufficient vials of PhotoBarr should be reconstituted to provide the patient with a dose of 2 mg/kg.

For most patients (up to 75 kg) two vials of PhotoBarr 75 mg will suffice. A PhotoBarr 15 mg vial will be needed for every additional 7.5 kg body weight.

Spills and disposal

Spills of PhotoBarr should be wiped up with a damp cloth. Skin and eye contact should be avoided due to the potential for photosensitivity reactions upon exposure to light; use of rubber gloves and eye protection is recommended.

PhotoBarr is for single use only and any unused solution should be discarded.

Any unused product or waste material should be disposed of in accordance with local requirements.

Accidental exposure

PhotoBarr is neither a primary ocular irritant nor a primary dermal irritant. However, because of its potential to induce photosensitivity, PhotoBarr might be an eye and/or skin irritant in the presence of bright light. It is important to avoid contact with the eyes and skin during preparation and/or administration. As with therapeutic overdose, any accidentally overexposed person must be protected from bright light.’

Pinnacle Biologics B.V.

p/a Trust Company Amsterdam B.V Crystal Tower 21st Floor,

Orlyplein 10, 1043 DP Amsterdam The Netherlands

NG AUTHORISATION NUMBER(S)

EU/1/04/272/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 March 2004

Date of latest renewal: 4 March 2009

10. DATE OF REVISION OF THE TEXTDetailed information on this product is available on the website of the European Medicines Agency