ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Visudyne 15 mg powder for solution for infusion
2.
Each vial contains 15 mg of verteporfin.
After reconstitution, 1 ml contains 2 mg of verteporfin. 7.5 ml of reconstituted solution contains 15 mg
of verteporfin.
For a full list of excipients see section 6.1.
3.
Powder for solution for infusion
Dark green to black powder.
4.
Visudyne 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.
Visudyne 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 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/m
2
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, Visudyne
therapy 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 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.
2
Hepatic impairment
Visudyne 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 is contraindicated in patients with severe hepatic impairment (see section 4.3).
Renal impairment
Visudyne 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
Use in the paediatric population has not been investigated. Visudyne is not indicated in this
population.
Method of administration
This medicinal product is intended for intravenous infusion only.
For the light activation of Visudyne, 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/cm
2
, it takes 83 seconds to deliver the required light dose of
50 J/cm
2
.
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 m from the temporal edge of the optic disc. The maximum spot size used for the first
treatment in the clinical studies was 6,400 m. 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.
Hypersensitivity to the active substance or to any of the excipients.
Visudyne is also contraindicated in patients with porphyria and in patients with severe hepatic
impairment (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 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.
3
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 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, 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. 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.
Hypersensitivity reactions
Chest pain, vasovagal reactions and hypersensitivity reactions, which on rare occasions can be severe,
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. Patients should be under close medical supervision during the Visudyne
infusion.
Anaesthesia
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.
Other
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.
4
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
information on photosensitivity and exposure to light in section 4.4).
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 should not be used during pregnancy unless clearly necessary (only if the benefit justifies
the potential risk to the foetus).
Breastfeeding
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 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).
5
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.
Immune system disorders
Not known Hypersensitivity
1
.
Metabolism and nutrition disorders
Common
Hypercholesteraemia.
Nervous system disorders
Uncommon
Hyperesthesia.
Not known
Vasovagal reactions
1
.
Eye disorders
Common
Severe reduced visual acuity
2
, 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 (non-rhegmatogenous), subretinal/retinal
haemorrhage, vitreous haemorrhage.
Rare
Retinal or choroidal vessel non-perfusion.
Not known
Retinal pigment epithelial tear.
Cardiac disorders
Not known
Myocardial infarction
3
.
Vascular disorders
Uncommon
Hypertension.
Gastrointestinal disorders
Common Nausea.
Skin and subcutaneous tissue disorders
Common Photosensitivity reaction
4
.
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.
Not known
Injection site blister.
6
Injury, poisoning and procedural complications
Common
Infusion-related reaction primarily presented as back pain
5, 6.
Not known
Infusion-related chest pain
6
.
1
Vasovagal reactions and hypersensitivity reactions, which on rare occasions can be severe, 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.
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
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.
6
Infusion-related back and chest pain, which may radiate to other areas, including, but not
limited to, the pelvis, shoulder girdle or rib cage.
perfusion of normal retinal vessels, with the possibility of severe vision decrease.
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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Ophthalmologicals, Antineovascularisation agents, ATC code: S01LA01
Verteporfin, also referred to as benzoporphyrin derivative monoacids (BPD-MA) consists of a
1:1 mixture of the equally active regioisomers BPD-MA
C
and BPD-MA
D
. It is used as a light-activated
medicinal product (photosensitiser).
By itself, the clinically recommended dose of verteporfin is not cytotoxic. It produces cytotoxic agents
only when activated by light in the presence of oxygen. When energy absorbed by the porphyrin is
transferred to oxygen, highly reactive short-lived singlet oxygen is generated. Singlet oxygen causes
damage to biological structures within the diffusion range, leading to local vascular occlusion, cell
damage and, under certain conditions, cell death.
The selectivity of PDT using verteporfin is based, in addition to the localised light exposure, on
selective and rapid uptake and retention of verteporfin by rapidly proliferating cells including the
endothelium
of choroidal neovasculature.
7
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 with
verteporfin in limiting the decrease in visual acuity in patients with subfoveal choroidal
neovascularisation due to age-related macular degeneration.
The primary efficacy variable was responder rate, defined as the proportion of patients who lost less
than 15 letters (equivalent to 3 lines) of visual acuity (measured with the ETDRS charts) at month
12 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 a
well-demarcated area of the fluorescence on angiography), CNV located subfoveally (involved the
geometric centre of the foveal avascular zone), area of classic plus occult CNV 50 % of the total
lesion 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 20/40
and 20/200) in the treated eye. Presence of occult CNV lesions (fluorescence not well demarcated on
the angiogram) was allowed.
Results indicate that, at 12 months, Visudyne was statistically superior to placebo in terms of the
proportion of patients responding to the treatment. The studies showed a difference of 15 % between
treatment 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 a
difference of 28 % between treatment groups (67 % for Visudyne patients compared to 39 % for
placebo patients, 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 Visudyne
treatment as needed, long-term extension data suggest that month-24 vision outcomes may be
sustained 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 first
year after diagnosis and 2.4 in the second for the randomised placebo-controlled phase and 1.3 in the
third 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 with
evidence 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 Visudyne
in Occult Choroidal Neovascularisation [VIO]) were conducted in patients with AMD characterised by
occult with no classic subfoveal CNV.
8
The VIO study included patients with occult with no classic subfoveal CNV with a visual acuity score
of 73-34 letters (20/40-20/200), and patients with lesions >4 MPS disc areas were to have baseline
visual acuity <65 letters (<20/50). 364 patients (244 verteporfin, 120 placebo) were enrolled in this
study. The primary efficacy parameter was the same as in TAP (see above), with an additional
endpoint of month 24 defined. Another efficacy parameter was also defined: the proportion of patients
who lost less than 30 letters (equivalent to 6 lines) of visual acuity at months 12 and 24 relative to
baseline. The study did not show statistically significant results on the primary efficacy parameter at
month 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 % versus
81.7 %), 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 considered
to be related to treatment.
The VIP-AMD included patients with occult with no classic subfoveal CNV with a visual acuity score
of >50 letters (20/100). This study also included patients with classic containing CNV with a visual
acuity score >70 letters (20/40). 339 patients (225 verteporfin, 114 placebo) were enrolled in this
study. The efficacy parameter was the same as in TAP and VIO (see above). At month 12, the study
did 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 patients
who 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 of
patients who received Visudyne, compared with those who received placebo, experienced adverse
events (89.3 % versus 82.5 %), associated adverse events (42.7 % versus 18.4 %) and events leading
to discontinuation (6.2 % versus 0.9 %). A lower percentage of Visudyne patients had events leading
to death (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 pathological
myopia. A total of 120 patients (81 Visudyne, 39 placebo) were enrolled in the study. The posology
and 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 patients
who lost less than 3 lines of visual acuity) – 86 % for Visudyne versus 67 % for placebo, p=0.011. The
percentage 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 visual
acuity (p=0.38). The percentage of patients who lost less than 1.5 lines was 64 % for Visudyne and
49 % 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 Visudyne
treatment as needed, long-term extension data suggest that month-24 vision outcomes may be
sustained for up to 60 months.
In the VIP-PM study in pathological myopia, the average number of treatments per year were 3.5 in
the first year after diagnosis and 1.8 in the second for the randomised placebo-controlled phase and 0.4
in 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.
9
5.2 Pharmacokinetic properties
Distribution
C
max
after a 10-minute infusion of 6 and 12 mg/m
2
body surface area in the target population is
approximately 1.5 and 3.5 µg/ml, respectively. These values are somewhat higher (26 % for the
proposed dose of 6 mg/m
2
) than those observed in young healthy volunteers and may result in a higher
exposure. The clinical relevance of this age-related difference is remote, as the risk/benefit assessment
determined in the target population is favourable. A maximum 2-fold inter-individual variation in
plasma concentrations at C
max
(immediately after end of the infusion) and at the time of light
administration was found for each Visudyne dose administered.
For both regioisomers, C
max
and AUC values were proportional to dose. C
max
values obtained at the
end of infusion were higher for BPD-MA
D
than for BPD-MA
C
. The volume of distribution was
0.5 l/kg.
Protein-binding
In whole human blood, 90 % of verteporfin is associated with plasma and 10 % associated with blood
cells, of which very little was membrane associated. In human plasma, 90 % of verteporfin is
associated with plasma lipoprotein fractions and approximately 6 % are associated with albumin.
Biotransformation
The ester group of verteporfin is hydrolysed via plasma and hepatic esterases, leading to the formation
of benzoporphyrin derivative diacid (BPD-DA). BPD-DA is also a photosensitiser but its systemic
exposure is low (5-10 % of the verteporfin exposure, suggesting that most of the active substance is
eliminated unchanged).
In vitro
studies did not show any significant involvement of oxidative
metabolism by cytochrome P450 enzymes
.
Elimination
Plasma elimination half-life mean values ranged from approximately 5–6 hours for verteporfin.
The mean area-under-the-curve (AUC) values for subjects with mild hepatic dysfunction were up to
1.4 times greater than those for subjects with normal hepatic function. This difference is not clinically
relevant and does not require any dose adjustment in patients with mild hepatic impairment.
Combined excretion of verteporfin and BPD-DA in human urine was less than 1 %, suggesting biliary
excretion.
5.3 Preclinical safety data
In repeat-dose studies in rats and dogs (once per day without light for up to 4 weeks), mild
extravascular haemolysis and haematopoietic responses were seen with exposure greater than
approximately 70 times (rats) and 32 times (dogs) the exposure (based on AUC) of the recommended
human dose.
Rapid administration of 2.0 mg/kg of verteporfin at a rate of 7 ml/minute to anaesthetised pigs resulted
in haemodynamic effects and sometimes rapid death, occurring within 2 minutes of medicinal product
administration. Similar effects were observed in sedated pigs. Pre-dosing with diphenhydramine
diminished these effects, suggesting that histamine may play a role in this process. Non-anaesthetised
non-sedated animals were not affected by these dosing parameters. No changes were recorded in either
conscious or anaesthetised dogs receiving 20 mg/kg verteporfin at an infusion rate of 5 ml/minute. The
effects may result from complement activation. 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
.
10
Levels of ocular toxicity in normal rabbits and monkeys, particularly on the
retina/choroid, correlated
with medicinal product dose, light dose, and time of light treatment. A retinal toxicity study in normal
dogs with intravenous verteporfin and ambient light on the eye showed no treatment-related ocular
toxicity.
In an embryotoxicity study rat foetuses of dams given greater than approximately 67 times the
recommended human dose (based on AUC) had increasing incidences of
anophthalmia/microphthalmia, wavy ribs and foetal alterations. No teratogenicity was observed in
foetuses from rabbits given 67 times the recommended human dose.
Verteporfin was not genotoxic
in the absence or presence of light in the usual battery of genotoxic test.
No effect on male or female fertility has been observed in rats following intravenous administration of
verteporfin for injection up to 10 mg/kg/day (approximately 60- and 40-fold human exposure at
6 mg/m
2
based on AUC
inf
in male and female rats, respectively).
Immunomodulatory effects have been observed in mice. Whole body light activation within 3 hours of
verteporfin administration beneficially modified the course of several immunologically mediated
pathological conditions and diminished normal-skin immune responses without causing skin reactivity
or generalised non-specific immune suppression.
6.
6.1 List of excipients
Lactose monohydrate
Egg phosphatidylglycerol
Dimyristoyl phosphatidylcholine
Ascorbyl palmitate
Butylated hydroxytoluene (E321)
6.2 Incompatibilities
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.
6.3 Shelf life
Shelf-life in the sealed vial
4 years
Shelf-life after reconstitution and dilution
Chemical and physical in-use stability has been demonstrated for 4 hours at 25°C. From a
microbiological point of view, the medicinal product should be used immediately. If not used
immediately, the in-use storage time and conditions prior to use are the responsibility of the user and
would normally not last longer than 4 hours below 25°C protected from light.
11
6.4 Special precautions for storage
Do not store above 25C.
Keep the vial in the outer carton in order to protect from light.
After reconstitution and dilution: see section 6.3.
6.5 Nature and contents of container
15 mg of powder for solution for infusion in a single-use glass vial (type I), sealed with bromobutyl
stopper and aluminium flip-off cap.
Pack containing 1 vial.
6.6 Special precautions for disposal and other handling
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 a
dose of 6 mg/m
2
body surface (see section 4.2) dilute the required amount of Visudyne solution in
glucose 50 mg/ml (5 %) solution for infusion to a final volume of 30 ml. Do not use sodium chloride
solution (see section 6.2). Use of a standard infusion line filter with hydrophilic membranes (such as
polyethersulfone) 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 contact
should be avoided. Use of rubber gloves and eye protection is recommended. Any unused medicinal
product or waste material should be disposed of in accordance with local requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/00/140/001
9.
Date of first authorisation: 27 July 2000
Date of latest renewal: 27 July 2010
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
12
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
13
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of manufacturer responsible for batch release
Novartis Pharma S.A.S.
26, rue de la Chapelle
F-68333 Huningue Cedex
France
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
PSURs
The Marketing Authorisation Holder will submit PSURs yearly until otherwise specified by the
CHMP.
14
ANNEX III
LABELLING AND PACKAGE LEAFLET
15
A. LABELLING
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Visudyne 15 mg powder for solution for infusion
Verteporfin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 15 mg of verteporfin. After reconstitution, 1 ml contains 2 mg of verteporfin.
7.5 ml of reconstituted solution contains 15 mg of verteporfin.
3.
LIST OF EXCIPIENTS
Lactose monohydrate, dimyristoyl phosphatidylcholine, egg phosphatidylglycerol, ascorbyl palmitate,
butylated hydroxytoluene (E321).
4.
Powder for solution for infusion.
Box containing 1 vial of powder.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Do not dissolve in sodium chloride solution.
Read the package leaflet before use.
Intravenous use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
17
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25C.
Keep the vial in the outer carton in order to protect from light.
Shelf-life after reconstitution and dilution: see package leaflet.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/00/140/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
18
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
Visudyne 15 mg powder for solution for infusion
Verteporfin
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
Each vial contains 15 mg of verteporfin
6.
OTHER
19
B. PACKAGE LEAFLET
20
PACKAGE LEAFLET: INFORMATION FOR THE USER
Visudyne 15 mg powder for solution for infusion
verteporfin
Read all of this leaflet carefully before you are given this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor, pharmacist or nurse.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or nurse.
In this leaflet
1.
What Visudyne is and what it is used for
2.
Before you are given Visudyne
3.
How Visudyne is used
4.
Possible side effects
5.
How to store Visudyne
6.
Further information
1.
WHAT VISUDYNE IS AND WHAT IT IS USED FOR
What Visudyne is
Visudyne contains the active substance verteporfin, which is activated by light from a laser in a
treatment called photodynamic therapy. When you are given an infusion of Visudyne, it is distributed
within your body through the blood vessels, including the blood vessels at the back of the eye. When
the laser light is shone into the eye, Visudyne is activated.
What Visudyne is used for
Visudyne is used to treat the wet form of age-related macular degeneration and pathological myopia.
These diseases lead to vision loss. Vision loss is caused by new blood vessels (choroidal
neovascularisation) that damage the retina (the light-sensitive membrane that lines the back of the
eye). There are two types of choroidal neovascularisation: classic and occult.
Visudyne is used for the treatment of predominantly classic choroidal neovascularisation in adults
with age-related macular degeneration, and also for the treatment of all types of choroidal
neovascularisation in adults with pathological myopia.
2.
BEFORE YOU ARE GIVEN VISUDYNE
You should not be given Visudyne
-
if you are
allergic
(hypersensitive) to verteporfin or any of the other ingredients of Visudyne
(for a full list of ingredients, see section 6 “What Visudyne contains”).
-
if you have
porphyria
(a rare condition that may increase sensitivity to light).
-
if you have any severe
liver problems
.
If any of these apply to you,
tell your doctor. You should not be given Visudyne.
21
Take special care with Visudyne
-
If you experience any problems or symptoms during the treatment
such as chest pain,
sudden loss of consciousness, sweating, dizziness, rash, breathlessness, flushing, irregular heart
beat, please tell your doctor or nurse.
-
If you have any liver problems or a blockage of your bile duct
, please tell your doctor before
starting Visudyne therapy.
-
If, during the infusion, Visudyne goes outside the vein
, and especially if the affected area is
exposed to light, this can cause pain, swelling, blistering and a change in skin colour in the area
of the leakage. If this happens, the infusion needs to be stopped and the skin treated with cold
compresses and thoroughly protected from light until the skin colour returns to normal. You
may need to take a painkiller.
-
You will be sensitive to bright light for 48 hours after the infusion.
During that time, avoid
exposure to direct sunlight, bright indoor lights such as in tanning salons, bright halogen
lighting, high power lighting as used by surgeons or dentists, or light from light-emitting
medical devices such as pulse oximeters (used to measure oxygen in blood). If you have to go
outdoors during daylight in the first 48 hours after treatment, you must protect your skin and
eyes by wearing protective clothing and dark sunglasses. Sunscreens offer no protection.
Normal indoor lighting is safe.
-
Do not stay in the dark
because exposure to normal indoor lighting will help your body to
eliminate Visudyne more quickly.
-
If you experience any eye problems after the treatment,
such as a vision loss, talk to your
doctor.
Using other medicines
Please tell your doctor, nurse or pharmacist if you are taking or have recently taken any other
medicines, including medicines obtained without a prescription.
If you are taking any of the following medicines:
- tetracyclines or sulphonamides (used to treat bacterial infection),
- phenothiazines (used to treat psychiatric disorders, or nausea and vomiting),
- sulfonylurea (used to treat diabetes),
- medicines used to lower blood sugar,
- thiazide diuretics (used to reduce high blood pressure),
- griseofulvin (used to treat fungal infection)
tell your doctor or pharmacist. This is important because taking these medicines may increase your
sensitivity to light.
Pregnancy and breastfeeding
-
Visudyne has not been studied in pregnant women. It is important to tell your doctor if you are
pregnant, if you think you may be pregnant or if you plan to become pregnant. You should only
be given Visudyne if your doctor considers it absolutely essential.
-
Verteporfin is excreted in human milk in low amounts. Please tell your doctor if you are
breastfeeding. He/she will decide whether you should be given Visudyne. It is recommended
that, if you are given Visudyne, you do not breastfeed for 48 hours after administration.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
After Visudyne treatment you may have some vision problems, such as abnormal or decreased vision,
which may be temporary. If this happens to you, do not drive or use any tools or machines until your
vision improves.
Important information about some of the ingredients of Visudyne
Visudyne contains small amounts of butylated hydroxytoluene (E321). This ingredient is irritant to
eyes, skin and mucous membranes.
22
If you come into direct contact with Visudyne, you must therefore wash it off extensively with
water.
3.
HOW VISUDYNE IS USED
Treatment with Visudyne is a two-step process
First your doctor or the pharmacist will prepare the Visudyne infusion solution. It will be
administered by your doctor or nurse into a vein using a drip (intravenous infusion).
The second step is the activation of Visudyne in the eye 15 minutes after the start of the
infusion. Your doctor will put a special contact lens onto your eye and treat your eye using a
special laser. It takes 83 seconds to deliver the laser dose required to activate Visudyne. During
this time, you will have to follow your doctor‟s instructions and keep your eyes still.
If necessary, Visudyne therapy can be repeated every 3 months, up to 4 times per year.
Use in children
Visudyne is a treatment for adults only and not indicated for the use in children.
If you are given more Visudyne than you should be
to follow the protection instructions given in section 2 for longer than 48 hours. Your doctor will
advise you.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Visudyne can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
Very common
affects more than 1 user in 10
Common
affects 1 to 10 users in 100
Uncommon
affects 1 to 10 users in 1,000
Rare
affects 1 to 10 users in 10,000
Very rare
affects less than 1 user in 10,000
Not known
frequency cannot be estimated from the available data.
Most of the side effects are mild to moderate and will usually disappear a few days to a few weeks
after treatment.
23
Common side effects
Eye disorders
: severe decrease of vision (loss of 4 lines or more within 7 days of treatment),
visual disturbances such as blurred, hazy or fuzzy vision, flashes of light, decreased vision, and
a change in the field of vision in the treated eye such as grey or dark shadows, blind spots or
black spots.
Infusion site side effects
: as with other types of injections, some patients experienced pain,
swelling, inflammation, and weeping from the infusion site.
General disorders
: feeling sick (nausea), sunburn-like reactions, tiredness, infusion-related
reaction, primarily presented as back pain which may radiate to other areas, including but not
limited to, the pelvis, shoulders or rib cage, and increased cholesterol.
Uncommon side effects
Eye disorders
: bleeding of the retina or into the vitreous humour (the clear gel-like substance
that fills the eyeball behind the lens), and displacement of the retina in the treated eye.
Infusion site side effects
: as with other types of injections, some patients experienced bleeding
at the infusion site, change in skin colour and hypersensitivity. If this happens to you, there will
be increased sensitivity to light in that part of the skin until the green discolouration disappears.
General disorders
: pain, increased blood pressure, increased sensation, and fever.
Rare frequency side effects
Eye disorders
: lack of blood circulation to the retina or choroids (the vascular layer of the eye)
in the treated eye.
Not known frequency side effects
Eye disorders
: tear in the coloured layer of the retina.
Infusion site side effects
: as with other types of injections, some patients experienced blistering.
General disorders
: vasovagal reactions (light-headedness and fainting) and allergic reactions,
which on rare occasions can be severe, have been reported. General symptoms can include
headache, malaise (feeling unwell), fainting, sweating, dizziness, rash, hives, itching,
breathlessness, flushing, or changes in blood pressure and heart rate. Infusion-related reaction,
primarily presented as chest pain which may radiate to other areas, including but not limited to,
the pelvis, shoulders or rib cage.
Heart attack
has been reported, particularly in patients with a history of heart disease,
sometimes within 48 hours after treatment with Visudyne. In the event of suspected heart attack,
seek medical attention immediately.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or nurse.
5.
HOW TO STORE VISUDYNE
Keep out of the reach and sight of children.
Do not use Visudyne after the expiry date which is stated on the carton and vial after „EXP‟. The
expiry date refers to the last day of that month.
Do not store above 25C. Keep the vial in the outer carton in order to protect from light.
Chemical and physical in-use stability has been demonstrated for 4 hours at 25°C. From a
microbiological point of view, the medicine should be used immediately. If not used immediately, the
in-use storage time and conditions prior to use are the responsibility of the user and would normally
not last longer than 4 hours below 25°C protected from light.
24
6.
FURTHER INFORMATION
What Visudyne contains
-
The active substance is verteporfin. Each vial contains 15 mg of verteporfin. After
reconstitution, 1 ml contains 2 mg of verteporfin. 7.5 ml of reconstituted solution contains
15 mg of verteporfin.
-
The other ingredients are dimyristoyl phosphatidylcholine, egg phosphatidylglycerol, ascorbyl
palmitate, butylated hydroxytoluene (E321) and lactose monohydrate.
What Visudyne looks like and contents of the pack
Visudyne is supplied as a dark green to black powder in a clear glass vial. The powder is reconstituted
in water prior to use to form an opaque dark green solution.
Visudyne is available in packs containing 1 vial of powder.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
Manufacturer
Novartis Pharma S.A.S.
26, rue de la Chapelle
F-68333 Huningue Cedex
France
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
Luxembourg/Luxemburg
Novartis Pharma GmbH
Tél/Tel: +49 911 273 0
България
Novartis Pharma Services Inc.
Тел.: +359 2 489 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: +356 2298 3217
Danmark
Novartis Healthcare A/S
Tlf: +45 39 16 84 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0
Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Eesti
Novartis Pharma Services Inc.
Tel: +372 66 30 810
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
25
Ελλά
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12
Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 550 8888
España
Novartis Farmacéutica, S.A.
Tel: +34 93 306 42 00
Portugal
Novartis Farma - Produtos Farmacêuticos, S.A.
Tel: +351 21 000 8600
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00
România
Novartis Pharma Services Inc.
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 50
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439
Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 (0)10 6133 200
Κύπρς
Novartis Pharma Services Inc.
Τηλ: +357 22 690 690
Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00
Latvija
Novartis Pharma Services Inc.
Tel: +371 67 887 070
United Kingdom
Novartis Pharmaceuticals UK Ltd.
Tel: +44 1276 698370
Lietuva
Novartis Pharma Services Inc.
Tel: +370 5 269 16 50
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
26
The following information is intended for medical or healthcare professionals only:
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 a
dose of 6 mg/m
2
body surface (the dose recommended for the treatment) dilute the required amount of
Visudyne solution in glucose 50 mg/ml (5 %) solution for infusion to a final volume of 30 ml. Do not
use sodium chloride solution. Use of a standard infusion line filter with hydrophilic membranes (such
as polyethersulfone) of a pore size of not less than 1.2 μm is recommended
.
For storage conditions, please see section 5 of this leaflet.
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 contact
should be avoided. Use of rubber gloves and eye protection is recommended. Any unused medicine or
waste material should be disposed of in accordance with local requirements.
27
Source: European Medicines Agency
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