VISUDYNE 15mg powder infusion solution medication leaflet

Visudyne 15 mg powder for solution for infusion

Each vial contains 15 mg of verteporfin.

After reconstitution, 1 ml contains 2 mg of verteporfin. 7.5 ml of reconstituted solution contains 15 mgof verteporfin.

For the full list of excipients, see section 6.1.

Powder for solution for infusion

Dark green to black powder.

Visudyne is indicated for the treatment of

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

- adults with subfoveal choroidal neovascularisation secondary to pathological myopia.

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

Adults, including the elderly (≥65 years old)

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

The first step is a 10-minute intravenous infusion of Visudyne 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 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, Visudynetherapy may be given up to 4 times per year.

Treatment of the second eye with Visudyne

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

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

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

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

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

This medicinal product is intended for intravenous infusion only.

For the light activation of Visudyne, a diode laser generating non-thermal red light (wavelength689 nm ± 3 nm) is used via a slit lamp mounted fibre optic device and a suitable contact lens. At therecommended light intensity of 600 mW/cm2, it takes 83 seconds to deliver the required light dose of50 J/cm2.

The greatest linear dimension of the choroidal neovascular lesion is estimated using fluoresceinangiography and fundus photography. Fundus cameras with a magnification within the range of2.4 - 2.6X are recommended. The treatment spot should cover all neovasculature, blood and/orblocked fluorescence. To ensure treatment of poorly demarcated lesion borders, an additional marginof 500 µm should be added around the visible lesion. The nasal edge of the treatment spot must be atleast 200 µm from the temporal edge of the optic disc. The maximum spot size used for the firsttreatment in the clinical studies was 6,400 µm. For treatment of lesions that are larger than themaximum 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.

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 hepaticimpairment (see “Hepatic impairment” under section 4.2).

Photosensitivity and exposure to light

Patients who receive Visudyne will become photosensitive for 48 hours after the infusion. During thatperiod, patients should avoid exposure of unprotected skin, eyes or other body organs to directsunlight or bright indoor light such as tanning salons, bright halogen lighting, or high power lighting insurgery operating rooms or dental surgeries. Prolonged exposure to light from light-emitting medicaldevices such as pulse oximeters should also be avoided for 48 hours following Visudyneadministration.

If patients have to go outdoors in daylight during the first 48 hours after treatment, they must protecttheir skin and eyes by wearing protective clothing and dark sunglasses. UV sunscreens are noteffective in protecting against photosensitivity reactions.

Ambient indoor light is safe. Patients should not stay in the dark and should be encouraged to exposetheir skin to ambient indoor light, as it will help eliminate the medicinal product quickly through theskin by a process called photobleaching.

Use in patients with moderate hepatic impairment or biliary obstruction

Visudyne therapy should be considered carefully in patients with moderate hepatic impairment orbiliary obstruction since no experience has been gained in these patients. Since verteporfin is excretedprimarily 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 weekafter 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 carefullyconsidered by the treating physician.

Extravasation of the solution for infusion

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 requireanalgesic treatment. Localised (skin) necrosis at the injection site following extravasation has alsobeen reported. If extravasation occurs, infusion should be stopped immediately. Protect the affectedarea thoroughly from bright direct light until swelling and discoloration have disappeared, and putcold compresses on the injection site. To avoid extravasation, a free-flowing intravenous line shouldbe established before starting Visudyne infusion and the line should be monitored. The largest possiblearm vein, preferably the antecubital, should be used for the infusion and small veins in the back of thehand should be avoided.

Chest pain, vasovagal reactions and hypersensitivity reactions related to Visudyne infusion have beenreported. Both vasovagal and hypersensitivity reactions are associated with general symptoms such assyncope, 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 shouldbe under close medical supervision during the Visudyne infusion.

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

Anaesthesia

There are no clinical data on the use of Visudyne in anaesthetised patients. In sedated or anaesthetisedpigs, a Visudyne dose significantly higher than the recommended dose in patients given as a bolusinjection caused severe haemodynamic effects including death, probably as a result of complementactivation. Pre-dosing with diphenhydramine diminished these effects, suggesting that histamine mayplay a role in this process. This effect was not observed in conscious non-sedated pigs, or in any otherspecies, including man. Verteporfin at more than 5 times the expected maximum plasma concentrationin treated patients, caused a low level of complement activation in human blood in vitro. No clinicallyrelevant complement activation was reported in clinical trials but anaphylactic reactions have beenreported during post-marketing surveillance. Patients should be under close medical supervisionduring the Visudyne infusion and caution should be exercised when Visudyne treatment under generalanaesthesia 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 ofdirect contact.

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 thereforebe exercised when using Visudyne 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 thevascular endothelium. Based on theoretical data and despite the lack of clinical evidence these agentsmight 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) ormedicinal products which scavenge free radicals (e.g. dimethylsulfoxide (DMSO), formate, mannitolor alcohol) might quench the activated oxygen species generated by verteporfin, resulting in decreasedverteporfin activity.

Medicinal products which antagonise blood vessel occlusion

Since blood vessel occlusion is the major mechanism of verteporfin action, there is a theoreticalpossibility 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 shownteratogenic 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 justifiesthe potential risk to the foetus).

Verteporfin and its diacid metabolic are excreted in human milk in low amounts. It should thereforenot be administered to nursing mothers, or breastfeeding should be interrupted for 48 hours afteradministration.

There are no human fertility data for verteporfin. In non-clinical studies, no impairment of fertility andno genotoxicity have been observed (see section 5.3). The clinical relevance is unknown. Patients ofreproductive age should be made aware of the lack of fertility data, and Visudyne should only be givenafter consideration of individual risks and benefits.

Following Visudyne treatment, patients may develop transient visual disturbances such as abnormalvision, vision decrease, or visual field defects that may interfere with their ability to drive or usemachines. 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 inpatients 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 sitereactions (including pain, oedema, inflammation, extravasation, rashes, haemorrhage, discolouration)and visual impairment (including blurred, fuzzy vision, photopsia, reduced visual acuity and visualfield defects, including scotoma and black spots).

The following adverse reactions were considered potentially related to Visudyne therapy. The adversereactions 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 eachfrequency 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 reducedvisual acuity, blurred, fuzzy vision, or photopsia, visual field defectsuch 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 siteinflammation, injection site extravasation, asthenia.

Uncommon Injection site hypersensitivity, injection site haemorrhage, injectionsite discoloration, pyrexia, pain.

Rare Malaise1.

Not known Injection site vesicles, injection site necrosis.

Common Infusion-related chest pain5, infusion-related reaction primarilypresented as back pain5, 6.1 Vasovagal reactions and hypersensitivity reactions related to Visudyne infusion have beenreported. General symptoms can include headache, malaise, syncope, hyperhydrosis, dizziness,rash, urticaria, pruritus, dyspnoea, flushing, and changes in blood pressure and heart rate. Onrare 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 treatmentwas 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 reactionoccurred mainly in patients with occult only (4.9 %) or minimally classic CNV lesions inpatients with AMD and was not reported for placebo-treated patients. Partial recovery of visionwas observed in some patients.

3 Myocardial infarction has been reported, particularly in patients with previous cardiovascularhistory, sometimes within 48 hours after the infusion.

4 Photosensitivity reactions (in 2.2 % of patients and <1 % of Visudyne courses) occurred in theform of sunburn following exposure to sunlight, usually within 24 hours from Visudynetreatment. Such reactions should be avoided by compliance with the photosensitivity protectioninstructions given in section 4.4.

5 Infusion-related back and chest pain, which may radiate to other areas, including, but notlimited to, the pelvis, shoulder girdle or rib cage.

6 The higher incidence of back pain during infusion in the Visudyne group was not associatedwith any evidence of haemolysis or allergic reaction and usually resolved by the end of theinfusion.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 thepatient remains photosensitive. In such cases, the patient should prolong skin and eye protection fromdirect sunlight or bright indoor light for a period proportionate with the overdose given.

Pharmacotherapeutic group: Ophthalmologicals, Antineovascularisation agents, ATC code: S01LA01

Verteporfin, also referred to as benzoporphyrin derivative monoacids (BPD-MA) consists of a1:1 mixture of the equally active regioisomers BPD-MAC and BPD-MAD. It is used as a light-activatedmedicinal product (photosensitiser).

By itself, the clinically recommended dose of verteporfin is not cytotoxic. It produces cytotoxic agentsonly when activated by light in the presence of oxygen. When energy absorbed by the porphyrin istransferred to oxygen, highly reactive short-lived singlet oxygen is generated. Singlet oxygen causesdamage to biological structures within the diffusion range, leading to local vascular occlusion, celldamage and, under certain conditions, cell death.

The selectivity of PDT using verteporfin is based, in addition to the localised light exposure, onselective and rapid uptake and retention of verteporfin by rapidly proliferating cells including theendothelium of choroidal neovasculature.

Age-related macular degeneration with predominantly classic subfoveal lesions

Visudyne has been studied in two randomised, placebo-controlled, double-masked, multicentre studies(BPD OCR 002 A and B or Treatment of Age-related Macular Degeneration with Photodynamic

Therapy [TAP]). A total of 609 patients were enrolled (402 Visudyne, 207 placebo).

The objective was to demonstrate the long-term efficacy and safety of photodynamic therapy withverteporfin in limiting the decrease in visual acuity in patients with subfoveal choroidalneovascularisation due to age-related macular degeneration.

The primary efficacy variable was responder rate, defined as the proportion of patients who lost lessthan 15 letters (equivalent to 3 lines) of visual acuity (measured with the ETDRS charts) at month12 relative to baseline.

The following inclusion criteria were considered for the treatment: patients older than 50 years of age,presence of CNV secondary to AMD, presence of classic lesion components in the CNV (defined as awell-demarcated area of the fluorescence on angiography), CNV located subfoveally (involved thegeometric centre of the foveal avascular zone), area of classic plus occult CNV ≥50% of the totallesion surface, greatest linear dimension of the entire lesion ≤9 Macular Photocoagulation Study(MPS) disc area, and a best-corrected visual acuity between 34 and 73 letters (i.e. approximately 20/40and 20/200) in the treated eye. Presence of occult CNV lesions (fluorescence not well demarcated onthe angiogram) was allowed.

Results indicate that, at 12 months, Visudyne was statistically superior to placebo in terms of theproportion of patients responding to the treatment. The studies showed a difference of 15 % betweentreatment groups (61% for Visudyne-treated patients compared to 46% placebo-treated patients,p<0.001, ITT analysis). This 15% difference between treatment groups was confirmed at 24 months(53% Visudyne versus 38% placebo, p<0.001).

The subgroup of patients with predominantly classic CNV lesions (N=243; Visudyne 159, placebo 84)were more likely to exhibit a larger treatment benefit. After 12 months, these patients showed adifference of 28% between treatment groups (67% for Visudyne patients compared to 39% for placebopatients, p<0.001); the benefit was maintained at 24 months (59% versus 31%, p<0.001).

In relation to TAP extension:

In patients followed from month 24 onwards and treated with uncontrolled, open-label Visudynetreatment as needed, long-term extension data suggest that month-24 vision outcomes may besustained for up to 60 months.

In the TAP study in all lesion types, the average number of treatments per year were 3.5 in the firstyear after diagnosis and 2.4 in the second for the randomised placebo-controlled phase and 1.3 in thethird year, 0.4 in the fourth and 0.1 in the fifth year for the open-label extension phase.

No additional safety concern was identified.

Age-related macular degeneration with occult with no classic lesions

The benefit of the product in the AMD patient population who have occult subfoveal CNV withevidence of recent or ongoing disease progression has not been demonstrated consistently.

Two randomised, placebo-controlled, double-masked, multicentre, 24-month studies (BPD OCR 003

AMD, or Verteporfin in Photodynamic Therapy-AMD [VIP-AMD], and BPD OCR 013, or Visudynein Occult Choroidal Neovascularisation [VIO]) were conducted in patients with AMD characterised byoccult with no classic subfoveal CNV.

The VIO study included patients with occult with no classic subfoveal CNV with a visual acuity scoreof 73-34 letters (20/40-20/200), and patients with lesions >4 MPS disc areas were to have baselinevisual acuity <65 letters (<20/50). 364 patients (244 verteporfin, 120 placebo) were enrolled in thisstudy. The primary efficacy parameter was the same as in TAP (see above), with an additionalendpoint of month 24 defined. Another efficacy parameter was also defined: the proportion of patientswho lost less than 30 letters (equivalent to 6 lines) of visual acuity at months 12 and 24 relative tobaseline. The study did not show statistically significant results on the primary efficacy parameter atmonth 12 (15-letter responder rate 62.7% versus 55.0%, p=0.150; 30-letter responder rate 84.0%versus 83.3%, p=0.868) or at month 24 (15-letter responder rate 53.3% versus 47.5%, p=0.300; 30-letter responder rate 77.5% versus 75.0%, p=0.602). A higher percentage of patients who received

Visudyne, compared with those who received placebo, experienced adverse events (88.1% versus81.7%), associated adverse events (23.0% versus 7.5%), events leading to discontinuation (11.9%versus 3.3%) and events leading to death (n=10 [4.1%] versus n=1 [0.8%]). No death was consideredto be related to treatment.

The VIP-AMD included patients with occult with no classic subfoveal CNV with a visual acuity scoreof >50 letters (20/100). This study also included patients with classic containing CNV with a visualacuity score >70 letters (20/40). 339 patients (225 verteporfin, 114 placebo) were enrolled in thisstudy. The efficacy parameter was the same as in TAP and VIO (see above). At month 12, the studydid not show statistically significant results on the primary efficacy parameter (responder rate 49.3%versus 45.6%, p=0.517). At month 24, a statistically significant difference of 12.9% in favour of

Visudyne compared to placebo was observed (46.2% versus 33.3%, p=0.023). A group of patientswho had occult with no classic lesions (n=258) showed a statistically significant difference of 13.7%in favour of Visudyne compared to placebo (45.2% versus 31.5%, p=0.032). A higher percentage ofpatients who received Visudyne, compared with those who received placebo, experienced adverseevents (89.3% versus 82.5 %), associated adverse events (42.7% versus 18.4%) and events leading todiscontinuation (6.2% versus 0.9%). A lower percentage of Visudyne patients had events leading todeath (n=4 [1.8%] versus n=3 [2.6%]); no death was considered to be related to treatment.

Pathological myopia

One multicentre, double-masked, placebo-controlled, randomised study (BPD OCR 003 PM [VIP-

PM]) was conducted in patients with subfoveal choroidal neovascularisation caused by pathologicalmyopia. A total of 120 patients (81 Visudyne, 39 placebo) were enrolled in the study. The posologyand retreatments were the same as in the AMD studies.

At month 12, there was a benefit of Visudyne for the primary efficacy endpoint (percentage of patientswho lost less than 3 lines of visual acuity) - 86% for Visudyne versus 67% for placebo, p=0.011. Thepercentage of patients who lost less than 1.5 lines was 72% for Visudyne and 44% for placebo(p=0.003).

At month 24, 79% Visudyne patients versus 72% placebo patients had lost less than 3 lines of visualacuity (p=0.38). The percentage of patients who lost less than 1.5 lines was 64% for Visudyne and49% for placebo (p=0.106).

This indicates that clinical benefit may diminish over time.

In relation to VIP-PM extension:

In patients followed from month 24 onwards and treated with uncontrolled, open-label Visudynetreatment as needed, long-term extension data suggest that month-24 vision outcomes may besustained for up to 60 months.

In the VIP-PM study in pathological myopia, the average number of treatments per year were 3.5 inthe first year after diagnosis and 1.8 in the second for the randomised placebo-controlled phase and 0.4in the third year, 0.2 in the fourth and 0.1 in the fifth year for the open-label extension phase.

No additional safety concern was identified.

The two regioisomers of verteporfin exhibit similar pharmacokinetic properties of distribution andelimination and thus both isomers are considered verteporfin as a whole from the pharmacokineticperspective.

Cmax after a 10-minute infusion of 6 and 12 mg/m2 body surface area in the target population isapproximately 1.5 and 3.5 µg/ml, respectively. The volume of distribution of around 0.60 l/kg atsteady state and clearance of around 101 ml/h/kg has been reported following a 10-minute infusion indose range of 3-14 mg/m2. A maximum 2-fold inter-individual variation in plasma concentrations at

Cmax (immediately after end of the infusion) and at the time of light administration was found for each

Visudyne dose administered.

In whole human blood, 90% of verteporfin is associated with plasma and 10 % associated with bloodcells, of which very little was membrane associated. In human plasma, 90% of verteporfin isassociated with plasma lipoprotein fractions and approximately 6% are associated with albumin.

The ester group of verteporfin is hydrolysed via plasma and hepatic esterases, leading to the formationof benzoporphyrin derivative diacid (BPD-DA). BPD-DA is also a photosensitiser but its systemicexposure is low (5-10% of the verteporfin exposure, suggesting that most of the active substance iseliminated unchanged). In vitro studies did not show any significant involvement of oxidativemetabolism by cytochrome P450 enzymes.

Plasma elimination half-life mean values ranged from approximately 5-6 hours for verteporfin.

Combined excretion of verteporfin and BPD-DA in human urine was less than 1%, suggesting biliaryexcretion.

The extent of exposure and the maximal plasma concentration are proportional to the dose between 6and 20 mg/m2.

Elderly (65 years of age or above)

Although mean plasma Cmax and AUC values in elderly patients who received verteporfin are higherthan those in young volunteers or patients, these differences are not considered to be clinicallysignificant.

In a study of patients with mild hepatic impairment (defined as having two abnormal hepatic functiontests at enrolment), AUC and Cmax were not significantly different from the control group. Half-life,however, was significantly increased by approximately 20%.

No studies on the pharmacokinetics of verteporfin in patients with renal impairment are reported. Therenal excretion of verteporfin and its metabolite is minimal (<1% of the verteporfin dose) and thus,clinically significant changes in verteporfin exposure in patients with renal impairment are unlikely.

Ethnic groups/races

The pharmacokinetics of verteporfin have been reported to be similar in healthy Caucasian and

Japanese men after a dose of 6 mg/m2 by a 10-minute infusion.

Effects of gender

At the intended dose, pharmacokinetic parameters are not significantly affected by gender.

Single and repeated dose toxicity

The acute and light-dependent toxicity of verteporfin was characterised by dose dependent localiseddeep-tissue damage as a consequence of the pharmacological effect of PDT with verteporfin. Toxicityobserved following multiple doses of verteporfin without light was associated mainly with effects onthe haematopoietic system. The extent and severity of these effects were consistent among all studiesand were dependent on drug dose and dosing duration.

Ophthalmic toxicity

Levels of ocular toxicity in healthy rabbits and monkeys, particularly on the retina/choroid, correlatedwith medicinal product dose, light dose, and time of light treatment. A retinal toxicity study in healthydogs with intravenous verteporfin and ambient light on the eye showed no treatment-related oculartoxicity.

In pregnant rats, intravenous verteporfin doses of 10 mg/kg/day (approximately 40-fold humanexposure at 6 mg/m2 based on AUCinf in female rats) were associated with an increased incidence ofanophthalmia/microphthalmia and doses of 25 mg/kg/day (approximately 125-fold the humanexposure at 6 mg/m2 based on AUCinf in female rats) were associated with an increased incidence ofwavy ribs and anophthalmia/microphthalmia. There were no teratogenic effects observed in rabbits atdoses up to 10 mg/kg/day (approximately 20-fold human exposure at 6 mg/m2 based on body surfacearea).

No effect on male or female fertility has been observed in rats following intravenous verteporfin dosesof up to 10 mg/kg/day (approximately 60 and 40-fold human exposure at 6 mg/m2 based on AUCinf inmale and female rats, respectively).

No studies have been conducted to evaluate the carcinogenic potential of verteporfin.

Verteporfin was not genotoxic in the absence or presence of light in the usual battery of genotoxictests. However, photodynamic therapy (PDT) induces the formation of reactive oxygen species andhas been reported to result in DNA damage including DNA strand breaks, alkali-labile sites, DNAdegradation, and DNA-protein cross links which may result in chromosomal aberrations, sisterchromatid exchanges (SCE) and mutations. It is not known how the potential for DNA damage with

PDT agents translates into human risk.

Lactose monohydrate

Egg phosphatidylglycerol

Dimyristoyl phosphatidylcholine

Ascorbyl palmitate

Butylated hydroxytoluene (E321)

Visudyne precipitates in sodium chloride solution. Do not use normal sodium chloride solutions orother parenteral solutions.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts except those mentioned in section 6.6.

Shelf-life in the sealed vial4 years

Shelf-life after reconstitution and dilution

Chemical and physical in-use stability has been demonstrated for 4 hours at 25°C. From amicrobiological point of view, the medicinal product should be used immediately. If not usedimmediately, the in-use storage time and conditions prior to use are the responsibility of the user andwould normally not last longer than 4 hours below 25°C protected from light.

Do not store above 25°C.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

15 mg of powder for solution for infusion in a single-use glass vial (type I), sealed with bromobutylstopper and aluminium flip-off cap.

Pack containing 1 vial.

Reconstitute Visudyne in 7.0 ml water for injections to produce 7.5 ml of a 2.0 mg/ml solution.

Reconstituted Visudyne is an opaque dark green solution. It is recommended that reconstituted

Visudyne be inspected visually for particulate matter and discoloration prior to administration. For adose of 6 mg/m2 body surface (see section 4.2) dilute the required amount of Visudyne solution indextrose 50 mg/ml (5%) solution for infusion to a final volume of 30 ml. Do not use sodium chloridesolution (see section 6.2). Use of a standard infusion line filter with hydrophilic membranes (such aspolyethersulfone) of a pore size of not less than 1.2 μm is recommended.

The vial and any unused portion of reconstituted solution should be discarded after single use.

If material is spilled, it should be contained and wiped up with a damp cloth. Eye and skin contactshould be avoided. Use of rubber gloves and eye protection is recommended. Any unused medicinalproduct or waste material should be disposed of in accordance with local requirements.

CHEPLAPHARM Arzneimittel GmbH

Ziegelhof 2417489 Greifswald

Germany

EU/1/00/140/001

Date of first authorisation: 27 July 2000

Date of latest renewal: 05 May 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu