4.1. Therapeutic indications

Visudyne/Verteporfin is indicated for the treatment of

- adults with exudative (wet) age-related macular degeneration (AMD) with predominantly classic subfoveal choroidal neovascularisation (CNV) or

- adults with subfoveal choroidal neovascularisation secondary to pathological myopia.

4.2. Posology and method of administration

Visudyne/Verteporfin should be administered only by ophthalmologists experienced in the management of patients with age-related macular degeneration or with pathological myopia.

Posology

Adults, including the elderly ( ≥ 65 years old)

Visudyne/Verteporfin photodynamic therapy (PDT) is a two-step process:

The first step is a 10-minute intravenous infusion of Visudyne/Verteporfin at a dose of 6 mg/m2 body surface area, diluted in 30 ml infusion solution (see section 6.6).

The second step is the light activation of Visudyne/Verteporfin at 15 minutes after the start of the infusion (see “Method of administration”).

Patients should be re-evaluated every 3 months. In the event of recurrent CNV leakage, Visudyne/Verteporfin therapy may be given up to 4 times per year.

Treatment of the second eye with Visudyne/Verteporfin

There are no clinical data to support concomitant treatment of the second eye. However, if treatment of the second eye is deemed necessary, light should be applied to the second eye immediately after light application in the first eye but no later than 20 minutes from the start of the infusion.

Special populations

Hepatic impairment

Visudyne/Verteporfin therapy should be considered carefully in patients with moderate hepatic dysfunction or biliary obstruction. No experience is available in these patients. Since verteporfin is excreted primarily via the biliary (hepatic) route, increased verteporfin exposure is possible. Verteporfin exposure is not significantly increased in patients with mild hepatic impairment (see “Biotransformation” and “Elimination” under section 5.2) and does not require any dose adjustment.

Visudyne/Verteporfin is contraindicated in patients with severe hepatic impairment (see section 4.3).

Renal impairment

Visudyne/Verteporfin has not been studied in patients with renal impairment. However the pharmacological characteristics do not indicate any need to adjust the dose (see “Biotransformation” and “Elimination” under section 5.2).

Paediatric population

The safety and efficacy of Visudyne/Verteporfin in the paediatric population have not been established. Visudyne/Verteporfin is not indicated in this population.

Method of administration

This medicinal product is intended for intravenous infusion only.

For the light activation of Visudyne/Verteporfin, a diode laser generating non-thermal red light (wavelength 689 nm ± 3 nm) is used via a slit lamp mounted fibre optic device and a suitable contact lens. At the recommended light intensity of 600 mW/cm2, it takes 83 seconds to deliver the required light dose of 50 J/cm2.

The greatest linear dimension of the choroidal neovascular lesion is estimated using fluorescein angiography and fundus photography. Fundus cameras with a magnification within the range of 2.4 - 2.6X are recommended. The treatment spot should cover all neovasculature, blood and/or blocked fluorescence. To ensure treatment of poorly demarcated lesion borders, an additional margin of 500 µm should be added around the visible lesion. The nasal edge of the treatment spot must be at least 200 μm from the temporal edge of the optic disc. The maximum spot size used for the first treatment in the clinical studies was 6,400 μm. For treatment of lesions that are larger than the maximum treatment spot size, apply the light to the greatest possible area of active lesion.

It is important to follow the above recommendations to achieve the optimal treatment effect.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Visudyne/Verteporfin is also contraindicated in patients with porphyria and in patients with severe hepatic impairment (see “Hepatic impairment” under section 4.2).

4.4. Special warnings and precautions for use

Photosensitivity and exposure to light

Patients who receive Visudyne/Verteporfin 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/Verteporfin 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.

Use in patients with moderate hepatic impairment or biliary obstruction

Visudyne/Verteporfin 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.

Risk of severe decrease of vision

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 the solution for infusion

Extravasation of Visudyne/Verteporfin, 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/Verteporfin 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.

Hypersensitivity reactions

Chest pain, vasovagal reactions and hypersensitivity reactions related to Visudyne/Verteporfin 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/Verteporfin infusion.

Cases of anaphylactic reactions have been observed in patients receiving Visudyne/Verteporfin. If an anaphylactic or other serious allergic reaction occurs during or following infusion, administration of Visudyne/Verteporfin should be discontinued immediately and appropriate therapy initiated.

Anaesthesia

There are no clinical data on the use of Visudyne/Verteporfin in anaesthetised patients. In sedated or anaesthetised pigs, a Visudyne/Verteporfin 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/Verteporfin infusion and caution should be exercised when Visudyne/Verteporfin treatment under general anaesthesia is considered.

Other

Visudyne/Verteporfin 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.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed in humans.

Other photosensitising agents

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/Verteporfin concomitantly with other photosensitising medicinal products (see “Photosensitivity and exposure to light” under section 4.4).

Agents which increase verteporfin uptake in the vascular endothelium

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.

Free radical scavengers

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.

Medicinal products which antagonise blood vessel occlusion

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

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/Verteporfin should not be used during pregnancy unless clearly necessary (only if the benefit justifies the potential risk to the foetus).

Breast-feeding

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.

Fertility

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/Verteporfin should only be given after consideration of individual risks and benefits.

4.7. Effects on ability to drive and use machines

Following Visudyne/Verteporfin 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.

4.8. Undesirable effects

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 (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/Verteporfin 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.

Immune system disorders

Common

Hypersensitivity1.

Not known

Anaphylactic reaction.

Metabolism and nutrition disorders

Common

Hypercholesteraemia.

Nervous system disorders

Common

Syncope, headache, dizziness1.

Uncommon

Hyperesthesia.

Not known

Vasovagal reactions1.

Eye disorders

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.

Cardiac disorders

Not known

Myocardial infarction3.

Vascular disorders

Uncommon

Hypertension.

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea1.

Gastrointestinal disorders

Common

Nausea.

Skin and subcutaneous tissue disorders

Common

Photosensitivity reaction4.

Uncommon

Rash, urticaria, pruritus1.

General disorders and administration site conditions

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.

Injury, poisoning and procedural complications

Common

Infusion-related chest pain5, infusion-related reaction primarily presented as back pain5, 6.

1 Vasovagal reactions and hypersensitivity reactions related to Visudyne/Verteporfin 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/Verteporfin courses) occurred in the form of sunburn following exposure to sunlight, usually within 24 hours from Visudyne/Verteporfin 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/Verteporfin group was not associated with any evidence of haemolysis or allergic reaction and usually resolved by the end of the infusion.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdose of the medicinal product and/or light in the treated eye may result in non-selective non-perfusion of normal retinal vessels, with the possibility of severe vision decrease.

Overdose of the medicinal product may result in the prolongation of the period during which the patient remains photosensitive. In such cases, the patient should prolong skin and eye protection from direct sunlight or bright indoor light for a period proportionate with the overdose given.