Only for the use of a Registered Medical
Practitioner or a Hospital or a Laboratory.
Verteporfin Powder for
Solution for infusion 15 mg
Ocular vascular disorder agents, Antineovascularisation agents.
Pharmaceutical form(s)
Powder for solution for infusion.
Dark green to black powder.
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.
Active moiety
Lactose, egg phosphatidylglycerol, dimyristoyl
phosphatidylcholine, ascorbyl palmitate, butylated
Visudyne is indicated for the treatment of patients with subfoveal
Choroidal Neovascularisation (CNV) that is:
• predominantly classic and due to age-related macular
• occult and due to age-related macular degeneration
• due to pathologic myopia or presumed ocular histoplasmosis
Visudyne therapy should only be administered by
ophthalmologists experienced in the management of patients
with age-related macular degeneration, pathologic myopia or
presumed ocular histoplasmosis.
General target population (Adults):
Visudyne therapy 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 PHARMACEUTICAL INFORMATION).
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 and retreated in
the event of recurrent CNV leakage. Visudyne therapy may be
given every 3 months plus or minus 2 weeks.
Special populations
Hepatic impairment
Visudyne therapy should be considered carefully in patients with
moderate to severe hepatic impairment 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 section CLINICAL PHARMACOLOGY) and does not require
any dose adjustment.
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 section CLINICAL PHARMACOLOGY).
Paediatric patients
Use in the paediatric population has not been investigated.
Visudyne is not indicated in this population.
Geriatric patients (65 years of age or above)
The posology is the same in the elderly (aged 65 years and
above) as in younger adults.
Method of administration
This medicinal product is intended for intravenous infusion only.
For the light activation, 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 to 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 micrometers should be
added around the visible lesion. The nasal edge of the treatment
spot must be at least 200 micrometers from the temporal edge of
the optic disc. The maximum spot size used for the first
treatment in the clinical studies was 6,600 micrometers For
treatment of lesions that are larger than the maximum treatment
spot size, apply the light to the greatest possible area of active
It is important to follow the above recommendations to achieve
the optimal treatment effect.
Visudyne is contraindicated in patients with
• Porphyria
• Known hypersensitivity to verteporfin or to any of the
excipients of Visudyne
Photosensitivity following treatment
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 surgical
operating rooms or dentist offices. Prolonged exposure to light
from light-emitting medical devices such as pulse oximeters
should also be avoided for 48 hours following Visudyne
administration. If emergency surgery is necessary within
48 hours after treatment, as much of the internal tissue as
possible should be protected from intense light.
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 drug more quickly through the
skin by a process called photobleaching.
Use in patients with hepatic impairment
Visudyne therapy should be considered carefully in patients with
moderate to severe hepatic impairment or biliary obstruction
since no experience has been gained in these patients.
Decrease in visual acuity
Patients who experience a severe decrease of vision (equivalent
to 4 lines or more) within one week after treatment should not
receive another treatment, at least until their vision completely
recovers to pre-treatment level and the potential benefits and
risks of subsequent treatment are carefully considered by the
treating physician.
Extravasation of Visudyne, especially if the affected area is
exposed to light, can cause severe pain, inflammation, swelling,
blistering, or discoloration at the injection site. The relief of pain
may require analgesic treatment. Localized (skin) necrosis at the
injection site following extravasation has also been reported.
To avoid extravasation, standard precautions include, but are not
limited to, the following measures: a free-flowing IV 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. If extravasation
occurs, infusion should be stopped immediately. The
extravasation area must be thoroughly protected from direct light
until the swelling and discoloration have faded in order to
prevent the occurrence of a local burn which could be severe.
Cold compresses should be applied to the injection site.
Medical supervision during the infusion
Chest pain, vaso-vagal reactions and hypersensitivity reactions,
related to Visudyne infusion, have been reported. Both
vaso-vagal 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
medical supervision during the Visudyne infusion.
Cases of anaphylactic reactions have been observed in patients
receiving Visudyne. If an anaphylactic or other serious allergic
reaction occurs during or following infusion, administration of
Visudyne should be discontinued immediately and appropriate
therapy be initiated
Use in anaesthetised patients
There are no clinical data on the use of Visudyne in
anaesthetised patients. In sedated or anaesthetised pigs, a
Visudyne dose of more than 10 times the recommended dose in
patients given as a bolus injection caused severe hemodynamic
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 the risk of anaphylactic reactions
due to complement activation cannot be excluded.
Treatment of second eye
The controlled trials only allowed treatment of one eye per
patient. However, if the 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.
Use of incompatible lasers
Use of incompatible lasers that do not provide the required
characteristics of light for the photoactivation of Visudyne could
result in incomplete treatment due to partial photoactivation of
Visudyne, over-treatment due to over-activation of Visudyne, or
damage to surrounding normal tissue.
Driving and using machines
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.
Adverse drug reactions from clinical trials (Table 1) are listed by
MedDRA system organ class. Within each system organ class,
the adverse drug reactions are ranked by frequency, with the
most frequent reactions first. Within each frequency grouping,
adverse drug reactions are presented in order of decreasing
seriousness. In addition, the corresponding frequency category
for each adverse drug reaction is based on the following
convention (CIOMS III): 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).
Table 1 Adverse drug reactions from clinical trials
SOC/PT Frequency category (CIOMS III)
Eye disorders
Retinal detachment Uncommon
Retinal haemorrhage Uncommon
Vitreous haemorrhage Uncommon
Visual impairment1 Common
Visual acuity reduced2 Common
Visual field defect3 Common
Retinal oedema# Uncommon
Retinal ischaemia
(retinal, or choroidal vessel Rare
Gastrointestinal disorders
Nausea Uncommon
General disorders and administration site conditions
Chest pain# Common
Asthenia Common
Injection site oedema Common
Injection site inflammation Common
Injection site extravasation Common
Injection site pain4 Common
Pyrexia Uncommon
Injection site haemorrhage Uncommon
Injection site discolouration Uncommon
Injection site hypersensitivity Uncommon
Malaise5# Rare
Immune system disorders
Hypersensitivity5# Common
Musculoskeletal and Connective tissue disorders
Back pain4 Common
Nervous system disorders
Syncope5# Common
Headache5# Common
Dizziness5# Common
Hypoaesthesia Uncommon
Respiratory, thoracic and mediastinal disorders
Dyspnoea5# Common
Skin and subcutaneous tissue disorders
Photosensitivity reaction6 Common
Rash5# Uncommon
Urticaria5# Uncommon
Pruritus5# Uncommon
Vascular disorders
Hypertension Uncommon
1Abnormal vision such as blurry, hazy, fuzzy vision, or flashes of
2Severe vision decrease, equivalent of 4 lines or more, within
7 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 event occurred mainly in patients with
occult only CNV lesions due to AMD. Partial recovery of vision
was observed in some patients.
3Visual field defect such as grey or dark haloes, scotoma and
black spots.
4Infusion related back pain and chest pain, which may radiate to
other areas including but not limited to the pelvis, shoulder
girdle or rib cage. 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.
5 Vaso-vagal reactions (presyncope) and hypersensitivity
reactions, related to Visudyne infusion have been reported.
General symptoms can include headache, malaise, syncope,
sweating, dizziness, rash, urticaria, pruritus, dyspnoea, flushing
and changes in blood pressure or heart rate. On rare occasions
these reactions may be severe, and potentially include
6 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 of Visudyne
infusion. Such reactions should be avoided by compliance with
photosensitivity protection instructions under section WARNINGS
# The frequency categorization of the spontaneously reported
ADRs is based on the pooled analysis of placebo-controlled
clinical trials for age-related macular degeneration and
pathological myopia.
The following adverse drug reactions (Table 2) have been
derived from post-marketing experience with Visudyne. Because
these reactions are reported voluntarily from a population of
uncertain size, it is not possible to reliably estimate their
frequency which is therefore categorized as not known.
Table 2 Adverse drug reactions from spontaneous reports
Eye disorders
Retinal pigment epithelial tear
Macular oedema
General disorders and administration site conditions
Injection site vesicles
Immune system disorders
Anaphylactic reaction
Heart rate irregular
Nervous system disorders
Presyncope (vaso-vagal reactions)
Reproductive system and breast disorders
Pelvic pain
Skin and subcutaneous tissue disorders
Vascular disorders
Blood pressure fluctuation
No specific drug-drug interaction studies have been conducted in
Anticipated interactions to be considered
Other photosensitizing agents
It is possible that concomitant use of other photosensitising
agents (e.g. tetracyclines, sulphonamides, phenothiazines,
sulfonylurea, hypoglycemic agents, thiazide diuretics, and
griseofulvin) could increase the potential for photosensitivity
Drugs increasing verteporfin uptake in the vascular
Agents such as calcium channel blocking agents, polymixin B,
and radiation therapy are known to alter the vascular
endothelium and may result in enhanced verteporfin
tissue-uptake when used concurrently.
Free radical scavengers
Although there is no clinical evidence, antioxidants (e.g.,
beta-carotene) or drugs that scavenge free radicals (e.g.,
dimethylsulfoxide (DMSO), formate, mannitol, or alcohol) may
quench the activated oxygen species generated by verteporfin,
resulting in decreased verteporfin activity.
Drugs antagonizing 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
antagonize the action of verteporfin.
Women of child-bearing potential
There are no special recommendations.
There is insufficient experience with Visudyne in pregnant
women. Verteporfin has shown teratogenic effects in one species
(rat) at doses causing maternal toxicity (see section
NON-CLINICAL SAFETY DATA). The potential risk for humans is
Visudyne should be used in pregnant women only if the expected
benefit to the mother outweighs the potential risk to the fetus.
Leaflet 15 mg Visudyne IN
DRAFT (DATE) 13.09.2019 [10:05 uhr] (1)
COLOURS Pantone Black linework
DIMENSIONS 148 x 594 mm
FONT SIZE 7,5 pt
5044983 IN 90002758/10
Verteporfin and its diacid metabolite have been found in human
milk. Following a 6 mg/m2 dose infusion in a single individual,
verteporfin breast milk levels were up to 66 % of the
corresponding plasma concentrations, and declined below the
limit of quantification (2 -nano gram/mL) within 24 hours. The
diacid metabolite exhibited lower peak concentrations but
persisted up to at least 48 hours. The amount of diacid metabolite
excreted with the milk on Day 2 post dose (i.e. from 24 to 48 hours
post dose), was estimated to be at most 7.5 micrograms, or
approximately 0.075% of the maternal dose; thereafter, the
amount of diacid metabolite excreted daily with the milk is
estimated to decrease by at least 50% per day. Because of the
potential for adverse reactions in nursing infants from Visudyne,
treatment should either be postponed or women should interrupt
breast-feeding – pump and discard the milk – for at least
48 hours following dosing. A decision to postpone treatment or
prolong interruption of nursing should take into consideration
the importance of the drug to the mother and the consequences
of breast feeding interruption to both the baby and the mother.
No information is available about fertility in humans with
Verteporfin. No effect on male or female fertility has been
observed in rats (see section NON-CLINICAL SAFETY DATA).
Overdose of drug 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 drug 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.
Pharmacodynamic properties (PD)
Verteporfin, also referred to as benzoporphyrin derivative
monoacids A ring (BPD-MA) consists of a 1:1 mixture of the
equally active regioisomers BPD-MAC and BPD-MAD. It is used
as a light-activated drug (photosensitiser). The regioisomers
have been reported to have similar photodynamic properties.
Verteporfin 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 Photodynamic Therapy (PDT) using verteporfin
is based, in addition to the localised light exposure, on rapid
uptake and selective retention of verteporfin by rapidly
proliferating cells including the endothelium of choroidal
Pharmacokinetic properties (PK)
The two regioisomers of verteporfin exhibit similar
pharmacokinetic properties of distribution and elimination and
thus both isomers are considered verteporfin as a whole from
the pharmacokinetic perspective.
Cmax after a 10-minute infusion of 6 and 12 mg/m2 body surface
area in the target population is approximately 1.5 and
3.5 micrograms/mL, respectively. The volume of distribution of
around 0.60 L/kg at steady state and clearance of around
101 ml/h/kg has been reported following a 10-minute infusion
in dose 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 level studied.
In human plasma, 90 % of verteporfin is associated with plasma
lipoprotein fractions and approximately 6 % is associated with
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 photosensitizer but its
systemic exposure is low (5 to 10 % of the verteporfin exposure
suggesting that most of the drug is eliminated unchanged). In
vitro studies did not show any significant involvement of
oxidative metabolism by cytochrome P450 enzymes.
Following intravenous infusion, verteporfin exhibits a
bi-exponential elimination. Plasma elimination half-life mean
values ranged from approximately 5 to 6 hours for verteporfin.
Combined excretion of verteporfin and BPD-DA in human urine
was less than 1% suggesting a biliary excretion.
Dose linearity
The extent of exposure and the maximal plasma concentration
are proportional to the dose between 6 and 20 mg/m2.
Special populations
Geriatric patients (65 years of age or above)
The Cmax of Verteporfin is somewhat higher (26 % for the proposed
dose of 6 mg/m2) in the elderly than in young healthy volunteers
and this 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 favorable.
Hepatic impairment
In a study of patients with mild hepatic impairment (defined
as having two abnormal hepatic function tests at enrolment),
AUC and Cmax were not significantly different from the control
group, half-life, however, was significantly increased by
approximately 20 %.
Renal impairment
No studies on the pharmacokinetics of verteporfin in patients with
renal impairment are reported. The renal 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 has 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.
Age-related Macular Degeneration with predominantly
classic subfoveal CNV
Visudyne has been studied in two randomized, placebocontrolled,
double-masked, multicenter studies BPD OCR 002 A
and B (Treatment of Age-related Macular Degeneration with
Photodynamic Therapy [TAP] A and B). 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 (PDT) with verteporfin in limiting the decrease in visual
acuity in patients with subfoveal choroidal neovascularisation
(CNV) due to AMD.
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 fluorescence on
angiography), CNV located subfoveal (involved the geometric
center 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 areas, 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. During
these studies retreatment was allowed every 3 months if
fluorescein angiograms showed any recurrence or persistence of
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
(classic component comprised 50% or more of the area of the
entire lesion) (N=242; Visudyne 159, placebo 83) 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) and this benefit was maintained at 24 months
(59 % versus 31 %, p < 0.001). Severe vision loss (≥ 6 lines of
visual acuity from baseline) was experienced by only 12 % of
Visudyne-treated patients compared to 33 % of placebo-treated
patients at Month 12, and by 15 % of Visudyne-treated patients
compared to 36 % of placebo-treated patients at Month 24.
In patients followed from Month 24 onwards and receiving
Visudyne treatment as needed in an uncontrolled, open-label
extension study (TAP A+B extension study), data suggest that
Month-24 vision outcomes may be sustained for up to 60 months.
No additional safety concern was identified in the extension study.
In the TAP study in all lesion types, the average number of
treatments per year was 3.5 in the first year after diagnosis and
2.4 in the second for the randomized, 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.
Age-related Macular Degeneration with occult with no
classic subfoveal CNV
Two randomized, placebo-controlled, double-blind, multicenter,
24-month studies BPD OCR 003 AMD (Verteporfin in
Photodynamic Therapy-AMD [VIP-AMD]) and BPD OCR 013
(Visudyne in Occult Choroidal Neovascularization [VIO]) were
conducted in patients with AMD characterized by occult with no
classic subfoveal CNV.
In one study (BPD OCR 003 AMD) statistically significant
treatment benefit was demonstrated at 2 years; however this
statistically significant benefit was not confirmed in the second
study (BPD OCR 013). The benefit of Visudyne in this patient
population has not been consistently shown. The details of the
study results are summarised below.
BPD OCR 003 AMD included patients with occult with no classic
subfoveal CNV with a visual acuity score ≥ 50 letters (20/100),
or 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
BPD OCR 002 (see above).
At Month 12, although the secondary efficacy parameter (such as
mean changes of visual acuity and contrast sensitivity, angiographic
outcomes, development of classic components in patients with
occult only CNV) were statistically significantly in favour of
Visudyne, the study did not show any statistically significant
results in the primary efficacy parameter (responder rate).
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).
Exploratory subgroup analysis suggested that the treatment
benefit was greater for occult with no classic patients who
presented with either small lesions (< 4MPS-DA) or lower levels
of vision (VA score of <65 letter) at baseline (N=187). In those
patients, the responder rate difference was 26.2 % in favour of
Visudyne compared to placebo patients (51.2 % versus 25 % at
Month 24, p <0.001).
BPD OCR 013 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 BPD OCR 002 and BPD OCR 003
AMD (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=0.158; 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).
Pathologic Myopia
One randomized, placebo-controlled, double-masked,
multicenter study BPD OCR 003 PM (Verteporfin in
Photodynamic Therapy-Pathologic Myopia [VIP-PM], was
conducted in patients with subfoveal choroidal
neovascularisation caused by pathologic myopia. A total of
120 patients (81 Visudyne, 39 placebo) were enrolled in the
study. The dosage and retreatment eligibility were the same as
in the AMD studies. A planned analysis of safety and efficacy
was conducted at 12 and 24 months, with 96 % and 95 % of
patients completing each portion of the study, respectively.
At month 12, the difference between treatment groups
statistically favoured Visudyne. For the primary efficacy endpoint
(percentage of patients who lost less than 3 lines of visual
acuity), these patients showed a difference of approximately
20 % between groups (86 % for Visudyne versus 67 % for
placebo, p=0.011). The percentage of patients with stabilized
vision defined as vision loss of less than 1.5 lines was 72 %
(Visudyne) versus 44 % (placebo), showing a difference of 28 %
between treatment groups (p=0.003). 26 Visudyne-treated
patients (32 %) and 6 placebo-treated patients (15 %) gained
more than 1 line of visual acuity.
At Month 24, the percentage of patients who lost less than 3 lines
of visual acuity was 79 % for Visudyne patients and 72 % for
placebo patients showing a difference of 7 % between groups
(p=0.381). The difference between Visudyne and placebo
patients who lost less than 1.5 lines was 16 % (64% for
Visudyne versus 49 % for placebo, p=0.106). 32 Visudyne
treated patients (40 %) gained more than 1 line of vision, 10 of
them more than 3 lines. In comparison, 5 patients treated with
placebo (13 %) improved by 1 line or more, and none improved
by 3 lines or more. In patients followed from Month-24 onwards
and receiving Visudyne treatment as needed in an uncontrolled,
open-label, extension study (VIP-PM extension), data suggest
that Month-24 vision outcomes may be sustained for up to
60 months. No additional safety concern was identified in the
extension study.
In the VIP-PM study in pathologic 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 randomized 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.
Presumed ocular histoplasmosis
One open-label study BPD OCR 004 (Visudyne in Ocular
Histoplasmosis [VOH]) was conducted in patients with CNV
caused by ocular histoplasmosis syndrome. A total of 26 patients
were treated with Visudyne in the study. The posology and
re-treatments were the same as in the AMD studies. After
Visudyne therapy, visual acuity scores improved 7 or more
letters from baseline in 46 % of the patients after 24 months of
follow-up, with 36 % of patients gaining 15 or more letters of
visual acuity. These results show that verteporfin therapy
demonstrates an improvement in vision compared to the natural
progression of the disease, which resulted in loss of vision.
In patients followed from Month-24 onwards and receiving
treatment as needed in an uncontrolled, open-label extension
study (VOH extension study), data suggest that Month-24 vision
outcomes may be sustained for up to 48 months. No additional
safety concern was identified in the extension study.
In the VOH study in presumed ocular histoplasmosis the
average number of treatments per year were 2.9 in the first year
after diagnosis, 1.2 in the second, 0.2 in the third and 0.1 in the
fourth year.
Single and repeated dose toxicity
The acute and light-dependent toxicity of verteporfin was
characterized by dose dependent localized deep-tissue damage
as a consequence of the pharmacologic effect of PDT with
verteporfin. Toxicity observed following multiple doses of
verteporfin without light were associated mainly with effects on
the hematopoietic system. The extent and severity of these
effects were consistent among all studies and were dependent
on drug dose and dosing duration.
Reproductive toxicity
In pregnant rats, intravenous verteporfin doses of 10 mg/kg/day
(approximately 40-fold human exposure at 6 mg/m2 based on
AUCinf in female rats) were associated with an increased incidence
of anophthalmia/microphthalmia and doses of 25 mg/kg/day
(approximately 125-fold the human exposure at 6 mg/m2 based
on AUCinf in female rats) were associated with an increased
incidence of wavy ribs and anophthalmia/microphthalmia. There
were no teratogenic effects observed in rabbits at doses up to
10 mg/kg/day (approximately 20-fold human exposure at 6 mg/m2
based on body surface area).
No effect on male or female fertility has been observed in rats
following intravenous verteporfin doses of up to 10 mg/kg/day
(approximately 60 and 40-fold human exposure at 6 mg/m2
based on AUCinf in male 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 genotoxic tests. However, photodynamic
therapy (PDT) as a class has been reported to result in DNA
damage including DNA strand breaks, alkali-labile sites, DNA
degradation, and DNA-protein cross links which may result in
chromosomal aberrations, sister chromatid exchanges (SCE),
and mutations. It is not known how the potential for DNA damage
with PDT agents translates into human risk.
Visudyne precipitates in saline solutions. Do not use normal
saline or other parenteral solutions. Do not mix Visudyne in the
same solution with other drugs.
See folding box.
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 product should be used
Visudyne should not be used after the EXPIRY DATE marked on the
Visudyne should be kept out of the reach and sight of children.
Reconstitute Visudyne in 7.0 mL water for Injection to produce
7.5 mL of a 2 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/m2 body surface area (see DOSAGE AND
ADMINISTRATION), dilute the required amount of Visudyne
solution in 5 % Glucose/Dextrose for Injection to a final volume
of 30 mL. Do not use saline solution (see INCOMPATIBILITIES).
Use of a standard infusion line filter is recommended; infusion
line filters with a pore size of not less than 1.2 micrometres were
used in clinical trials.
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. All materials
should be disposed of properly.
Manufactured by:
See folding box.
For CHEPLAPHARM Arzneimittel GmbH, Greifswald,
Further information is available from:
Paviour Pharmaceuticals Pvt. Ltd.
311-312, Suneja Tower-1, District Centre,
Janakpuri, New Delhi-110058
Information issued: This leaflet was revised in Sept, 2019.