Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: CHEPLAPHARM Arzneimittel GmbH, Ziegelhof 24, 17489, Greifswald, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Visudyne is also contraindicated in patients with porphyria and in patients with severe hepatic impairment (see “Hepatic impairment” under section 4.2).
Patients who receive Visudyne will become photosensitive for 48 hours after the infusion. During that period, patients should avoid exposure of unprotected skin, eyes or other body organs to direct sunlight or bright indoor light such as tanning salons, bright halogen lighting, or high power lighting in surgery operating rooms or dental surgeries. Prolonged exposure to light from light-emitting medical devices such as pulse oximeters should also be avoided for 48 hours following Visudyne administration.
If patients have to go outdoors in daylight during the first 48 hours after treatment, they must protect their skin and eyes by wearing protective clothing and dark sunglasses. UV sunscreens are not effective in protecting against photosensitivity reactions.
Ambient indoor light is safe. Patients should not stay in the dark and should be encouraged to expose their skin to ambient indoor light, as it will help eliminate the medicinal product quickly through the skin by a process called photobleaching.
Visudyne therapy should be considered carefully in patients with moderate hepatic impairment or biliary obstruction since no experience has been gained in these patients. Since verteporfin is excreted primarily via the biliary (hepatic) route, increased verteporfin exposure is possible.
Patients who experience a severe decrease of vision (equivalent to 4 lines or more) within one week after treatment should not be re-treated, at least until their vision has completely recovered to pre- treatment level and the potential benefits and risks of subsequent treatment have been carefully considered by the treating physician.
Extravasation of Visudyne, especially if the affected area is exposed to light, can cause severe pain, inflammation, swelling, blistering or discoloration at the injection site. The relief of pain may require analgesic treatment. Localised (skin) necrosis at the injection site following extravasation has also been reported. If extravasation occurs, infusion should be stopped immediately. Protect the affected area thoroughly from bright direct light until swelling and discoloration have disappeared, and put cold compresses on the injection site. To avoid extravasation, a free-flowing intravenous line should be established before starting Visudyne infusion and the line should be monitored. The largest possible arm vein, preferably the antecubital, should be used for the infusion and small veins in the back of the hand should be avoided.
Chest pain, vasovagal reactions and hypersensitivity reactions related to Visudyne infusion have been reported. Both vasovagal and hypersensitivity reactions are associated with general symptoms such as syncope, sweating, dizziness, rash, dyspnoea, flushing, and changes in blood pressure and heart rate. On rare occasions these reactions may be severe and potentially include convulsions. Patients should be under close medical supervision during the Visudyne infusion.
Cases of anaphylactic reactions have been observed in patients receiving Visudyne. If an anaphylactic or other serious allergic reaction occurs during or following infusion, administration of Visudyne should be discontinued immediately and appropriate therapy initiated.
There are no clinical data on the use of Visudyne in anaesthetised patients. In sedated or anaesthetised pigs, a Visudyne dose significantly higher than the recommended dose in patients given as a bolus injection caused severe haemodynamic effects including death, probably as a result of complement activation. Pre-dosing with diphenhydramine diminished these effects, suggesting that histamine may play a role in this process. This effect was not observed in conscious non-sedated pigs, or in any other species, including man. Verteporfin at more than 5 times the expected maximum plasma concentration in treated patients, caused a low level of complement activation in human blood in vitro. No clinically relevant complement activation was reported in clinical trials but anaphylactic reactions have been reported during post-marketing surveillance. Patients should be under close medical supervision during the Visudyne infusion and caution should be exercised when Visudyne treatment under general anaesthesia is considered.
Visudyne contains small amounts of butylated hydroxytoluene (E321), which may be irritant to eyes, skin and mucous membranes. Therefore it must be washed off extensively with water in the event of direct contact.
No interaction studies have been performed in humans.
It is possible that concomitant use of other photosensitising medicinal products (e.g. tetracyclines, sulphonamides, phenothiazines, sulfonylurea, hypoglycaemic medicinal products, thiazide diuretics, and griseofulvin) could increase the potential for photosensitivity reactions. Caution should therefore be exercised when using Visudyne concomitantly with other photosensitising medicinal products (see “Photosensitivity and exposure to light” under section 4.4).
Agents such as calcium channel blockers, polymixin B, and radiation therapy are known to alter the vascular endothelium. Based on theoretical data and despite the lack of clinical evidence these agents might result in enhanced verteporfin tissue-uptake when used concurrently.
Although there is no clinical evidence, theoretical data suggest that antioxidants (e.g. beta-carotene) or medicinal products which scavenge free radicals (e.g. dimethylsulfoxide (DMSO), formate, mannitol or alcohol) might quench the activated oxygen species generated by verteporfin, resulting in decreased verteporfin activity.
Since blood vessel occlusion is the major mechanism of verteporfin action, there is a theoretical possibility that agents such as vasodilators and those which diminish clotting and platelet aggregation (e.g. thromboxane A2 inhibitors) can antagonise the action of verteporfin.
No clinical data on exposed pregnancies are available for verteporfin. Studies in animals have shown teratogenic effects in one species (rat) (see section 5.3). The potential risk for humans is unknown. Visudyne should not be used during pregnancy unless clearly necessary (only if the benefit justifies the potential risk to the foetus).
Verteporfin and its diacid metabolic are excreted in human milk in low amounts. It should therefore not be administered to nursing mothers, or breastfeeding should be interrupted for 48 hours after administration.
There are no human fertility data for verteporfin. In non-clinical studies, no impairment of fertility and no genotoxicity have been observed (see section 5.3). The clinical relevance is unknown. Patients of reproductive age should be made aware of the lack of fertility data, and Visudyne should only be given after consideration of individual risks and benefits.
Following Visudyne treatment, patients may develop transient visual disturbances such as abnormal vision, vision decrease, or visual field defects that may interfere with their ability to drive or use machines. Patients should not drive or use machines as long as these symptoms persist.
Most adverse reactions were mild to moderate and transient in nature. Undesirable effects reported in patients with pathological myopia were similar to those reported in patients with AMD.
The most frequently reported adverse reactions to Visudyne (verteporfin for infusion) are injection site reactions (including pain, oedema, inflammation, extravasation, rashes, haemorrhage, discolouration) and visual impairment (including blurred, fuzzy vision, photopsia, reduced visual acuity and visual field defects, including scotoma and black spots).
The following adverse reactions were considered potentially related to Visudyne therapy. The adverse reactions are listed by system organ class and frequency using the following convention: 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, adverse reactions are presented in order of decreasing seriousness.
Common: Hypersensitivity1.
Not known: Anaphylactic reaction.
Common: Hypercholesteraemia.
Common: Syncope, headache, dizziness1.
Uncommon: Hyperesthesia.
Not known: Vasovagal reactions1.
Common: Severe reduced visual acuity2, visual impairment such as reduced visual acuity, blurred, fuzzy vision, or photopsia, visual field defect such as scotoma, grey or dark haloes and black spots.
Uncommon: Retinal detachment, retinal haemorrhage, vitreous haemorrhage, retinal oedema.
Rare: Retinal ischaemia (retinal or choroidal vessel non-perfusion).
Not known: Retinal pigment epithelial tear, macular oedema.
Not known: Myocardial infarction3.
Uncommon: Hypertension.
Common: Dyspnoea1.
Common: Nausea.
Common: Photosensitivity reaction4.
Uncommon: Rash, urticaria, pruritus1.
Common: Injection site pain, injection site oedema, injection site inflammation, injection site extravasation, asthenia.
Uncommon: Injection site hypersensitivity, injection site haemorrhage, injection site discoloration, pyrexia, pain.
Rare: Malaise1.
Not known: Injection site vesicles, injection site necrosis.
Common: Infusion-related chest pain5, infusion-related reaction primarily presented as back pain5,6.
1 Vasovagal reactions and hypersensitivity reactions related to Visudyne infusion have been reported. General symptoms can include headache, malaise, syncope, hyperhydrosis, dizziness, rash, urticaria, pruritus, dyspnoea, flushing, and changes in blood pressure and heart rate. On rare occasions these reactions may be severe and potentially include convulsions.
2 Severely reduced visual acuity, equivalent to 4 lines or more, within seven days after treatment was reported in 2.1% of the verteporfin-treated patients in the placebo-controlled ocular Phase III clinical studies and in less than 1% of patients in uncontrolled clinical studies. The reaction occurred mainly in patients with occult only (4.9%) or minimally classic CNV lesions in patients with AMD and was not reported for placebo-treated patients. Partial recovery of vision was observed in some patients.
3 Myocardial infarction has been reported, particularly in patients with previous cardiovascular history, sometimes within 48 hours after the infusion.
4 Photosensitivity reactions (in 2.2% of patients and <1% of Visudyne courses) occurred in the form of sunburn following exposure to sunlight, usually within 24 hours from Visudyne treatment. Such reactions should be avoided by compliance with the photosensitivity protection instructions given in section 4.4.
5 Infusion-related back and chest pain, which may radiate to other areas, including, but not limited to, the pelvis, shoulder girdle or rib cage.
6 The higher incidence of back pain during infusion in the Visudyne group was not associated with any evidence of haemolysis or allergic reaction and usually resolved by the end of the infusion.
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.
Visudyne precipitates in sodium chloride solution. Do not use normal sodium chloride solutions or other parenteral solutions.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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