Verteporfin

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 and does not require any dose adjustment.

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.

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.

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 verteporfin concomitantly with other photosensitising medicinal products.

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.

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.

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

Chest pain, vasovagal reactions and hypersensitivity reactions related to 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 verteporfin infusion.

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

Patients who receive 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 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.

No clinical data on exposed pregnancies are available for verteporfin. Studies in animals have shown teratogenic effects in one species (rat). The potential risk for humans is unknown. Verteporfin 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.

Fertility

There are no human fertility data for verteporfin. In non-clinical studies, no impairment of fertility and no genotoxicity have been observed. The clinical relevance is unknown. Patients of reproductive age should be made aware of the lack of fertility data, and verteporfin should only be given after consideration of individual risks and benefits.

Following 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.

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 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 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 pain^5,6.

¹ Vasovagal reactions and hypersensitivity reactions related to 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 verteporfin courses) occurred in the form of sunburn following exposure to sunlight, usually within 24 hours from verteporfin treatment. Such reactions should be avoided by compliance with the photosensitivity protection instructions.
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 verteporfin group was not associated with any evidence of haemolysis or allergic reaction and usually resolved by the end of the infusion.