Source: European Medicines Agency (EU) Revision Year: 2012 Publisher: Pinnacle Biologics B.V., p/a Trust Company Amsterdam B.V., Crystal Tower 21st Floor, Orlyplein 10, 1043 DP Amsterdam, The Netherlands
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.
Patients older than 75 years may be at a higher risk of respiratory related adverse events such as pleural effusion and dyspnoea.
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, dyspnoea, cough, pleural effusion, pharyngitis, atelectasis and events like dehydration (see also section 4.8).
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 indoor light is, however, beneficial because the remaining medicinal product will be inactivated gradually through a photobleaching reaction. Therefore, patients should not stay in a darkened room during this period and should be encouraged to expose their skin to ambient indoor light. The level of photosensitivity will 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 indoor light, the patient should test it for residual photosensitivity. A small area of skin should be exposed to sunlight for 10 minutes. The tissue around the eyes may be more sensitive, and therefore, it is not recommended that the face be used for testing. If no photosensitivity reaction (erythema, oedema, blistering) occurs within 24 hours, the patient can gradually resume normal outdoor activities, initially continuing to exercise caution and 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.
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 impairment. Patients with mild to moderate hepatic impairment should be clearly instructed that the period requiring the precautionary measures described below may be longer than 90 days.
Patients should be advised to consult their ophthalmologist if they notice any vision changes after treatment with PhotoBarr PDT.
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.
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.
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.
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.
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.
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.
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 every six months after four consecutive biopsy results had shown no more high-grade dysplasia (see section 5.1). Available treatment and surveillance guidelines should be considered.
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 fluoroquinolones) could 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.
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.
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.
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 sedated for the procedure.
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 exposure. Other less common skin manifestations were reported in areas where photosensitivity reactions had occurred, such as increased hair growth, skin discolouration, skin nodules, skin wrinkling and skin fragility. These manifestations may be attributable to a pseudoporphyria state (temporary medicinal product-induced cutaneous porphyria). The frequency and nature of the photosensitivity reactions experienced in this study are unlike the documented incidence seen in previous 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.
PhotoBarr PDT 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.
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:
Uncommon: Bronchitis, nail fungal infection, sinusitis, skin infection
Not known: Pneumonia
Uncommon: Basal cell carcinoma, lentigo
Uncommon: Leukocytosis
Not known: Anaemia
Not known: Hypersensitivity
Very common: Dehydration*
Common: Appetite decreased, electrolyte imbalance
Uncommon: Hypokalaemia
Common: Anxiety, insomnia
Uncommon: Restlessness
Common: Headache, paraesthesia, dysgeusia
Uncommon: Dizziness, hypoaesthesia, tremor
Uncommon: Eye irritation, eye oedema
Not known: Cataract
Uncommon: Deafness, tinnitus, tinnitus aggravated
Common: Tachycardia, chest pain
Uncommon: Angina pectoris, atrial fibrillation, atrial flutter, chest discomfort
Uncommon: Hypertension, haemorrhage, hot flushes, hypotension, orthostatic hypotension
Not known: Embolism, Deep vein thrombosis, Phlebitis
Common: Pleural effusion, pharyngitis, atelectasis, dyspnoea
Uncommon: Choking, dyspnoea exertional, haemoptysis, hypoxia, nasal congestion, pneumonia aspiration, productive cough, respiratory depression, respiratory tract congestion, wheezing
Very common: Oesophageal stenosis acquired*, vomiting*, dysphagia, constipation, nausea*
Common: Hiccups, odynophagia, diarrhoea, dyspepsia, oesophageal ulcer, abdominal pain upper*, abdominal pain, haematemesis, oesophageal pain, eructation, melaena (haematocheznia), oesophageal disorder, regurgitation of food, abdominal rigidity, oesophageal spasm, oesophagitis.
Uncommon: Loose stools, oesophagitis ulcerative, abdominal discomfort, abdominal distension, abdominal pain lower, acquired pylori stenosis, chapped lips, colitis, flatulence, gastritis, gastrointestinal haemorrhage, halitosis, oesophageal haemorrhage, oesophageal perforation.
Not known: Tracheo-oesophageal fistula, Gastrointestinal necrosis
Very common: Photosensitivity reaction
Common: Pruritus, rash, skin fragility, skin discolouration, skin ulcer, dermatitis exfoliative, dry skin, milia, rash maculo-papular, rash papular, scar, skin hyperpigmentation, skin lesion, skin nodule, urticaria
Uncommon: Cold sweat, dermatitis, hair growth abnormal, increased tendency to bruise, keloid scar, night sweats, photosensitive rash, rash macular, rash scaly, scab, scar pain, vitiligo.
Common: Back pain, pain in the limb
Uncommon: Joint contracture, joint range of motion decreased, musculoskeletal chest pain, plantar fascitis
Uncommon: Urinary retention
Uncommon: Gynaecomastia
Uncommon: Pigmented naevus
Very common: Pyrexia
Common: Rigors, fatigue
Uncommon: Feeling hot, injection site erythema, lethargy, malaise, oedema peripheral, pain, pitting oedema, temperature intolerance, weakness
Common: Weight decreased, body temperature increased
Uncommon: Blood albumin decreased, blood chloride increased, blood urea increased, haematocrit decreased, haemoglobin decreased, oxygen saturation decreased, protein total decreased
Common: Post procedural pain, abrasion
Uncommon: Blister, post procedural haemorrhage
Of the serious adverse events (SAEs) in the PhotoBarr PDT + OM group, 44 (23.1%) were considered associated with the treatment. The most frequently reported treatment-associated serious adverse reaction (SAR) was dehydration (4%), experienced by 5 patients. The majority of the SARs were gastrointestinal disorders (8% - 11 patients), specifically nausea (3% - 4 patients), vomiting (3% - 4 patients) and upper 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.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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