ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
OZURDEX 700 micrograms intravitreal implant in applicator
2.
One implant contains 700 micrograms of dexamethasone.
For a full list of excipients, see section 6.1.
3.
Intravitreal implant in applicator.
Disposable injection device, containing a rod-shaped implant. which is not visible. The implant is
approximately 0.46 mm in diameter and 6 mm in length.
4.
OZURDEX is indicated for the treatment of adult patients with macular oedema following either
Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO) (see section 5.1).
OZURDEX must be administered by a qualified ophthalmologist experienced in intravitreal injections.
Posology
The recommended dose is one OZURDEX implant to be administered intra-vitreally to the affected
eye. Administration to both eyes concurrently is not recommended (see section 4.4).
Repeat doses should be considered when a patient experiences a response to treatment followed
subsequently by a loss in visual acuity and in the physician’s opinion may benefit from retreatment
without being exposed to significant risk (see section 5.1).
Patients who experience and retain improved vision should not be retreated. Patients who experience a
deterioration in vision, which is not slowed by OZURDEX, should not be retreated.
There is only very limited information on repeat dosing intervals less than 6 months (see section 5.1).
There is currently no experience of repeat administrations beyond 2 implants in Retinal Vein
Occlusion.
Patients should be monitored following the injection to permit early treatment if an infection or
increased intraocular pressure occurs (see section 4.4).
Special populations
Elderly (
≥
65 years old)
No dose adjustment is required for elderly patients.
Renal impairment
OZURDEX has not been studied in patients with renal impairment however no special considerations
are needed in this population.
2
Hepatic impairment
OZURDEX has not been studied in patients with hepatic impairment, however no special
considerations are needed in this population.
Paediatric population
There is no relevant use of OZURDEX in the paediatric population in macular oedema following
either Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO).
Method of administration
Single-use intravitreal implant in applicator for intravitreal use only.
Each applicator can only be used for the treatment of a single eye.
The intravitreal injection procedure should be carried out under controlled aseptic conditions which
include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent).
A broad spectrum topical antimicrobial should be given prior to and on the day of the injection
procedure. Adequate local anaesthesia should be administered.
Remove the foil pouch from the
carton and examine for damage (see section 6.6). Then, in a sterile field, open the foil pouch and
gently place the applicator on a sterile tray. Carefully remove the cap from the applicator. Once the
foil pouch is opened the applicator should be used immediately.
Hold the applicator in one hand and pull the safety tab straight off the applicator. Do not twist or flex
the tab. With the bevel of the needle up away from the sclera, advance the needle about 1 mm into the
sclera then redirect toward the centre of the eye into the vitreous cavity until the silicone sleeve is
against the conjunctiva. Slowly press the actuator button until an audible click is noted. Before
withdrawing the applicator from the eye, make sure that the actuator button is fully pressed and has
locked flush with the applicator surface. Remove the needle in the same direction as used to enter the
vitreous.
Immediately after injecting OZURDEX, use indirect ophthalmoscopy in the quadrant of injection to
confirm successful implantation. Visualisation is possible in the large majority of cases. In cases in
which the implant cannot be visualised, take a sterile cotton bud and lightly depress over the injection
site to bring the implant into view.
Following the intravitreal injection patients should continue to be treated with a broad spectrum
antimicrobial.
OZURDEX is contraindicated in
•
Hypersensitivity to the active substance or to any of the excipients.
•
Active or suspected ocular or periocular infection including most viral diseases of the cornea
and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis),
vaccinia, varicella, mycobacterial infections, and fungal diseases.
•
Advanced glaucoma which cannot be adequately controlled by medicinal products alone.
Monitoring
Any intravitreous injection can be associated with endophthalmitis, intraocular inflammation,
increased intraocular pressure and retinal detachment. Proper aseptic injection techniques must always
be used. In addition, patients should be monitored following the injection to permit early treatment if
an infection or increased intraocular pressure occurs. Monitoring may consist of a check for perfusion
of the optic nerve head immediately after the injection, tonometry within 30 minutes following the
injection, and biomicroscopy between two and seven days following the injection.
3
Patients must be instructed to report any symptoms suggestive of endophthalmitis or any of the above
mentioned events without delay.
Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma and may result in
secondary ocular infections.
In clinical studies, cataract was reported more frequently in patients with phakic lens receiving a
second injection (see section 4.8) with only 1 patient out of 368 requiring cataract surgery during the
first treatment and 3 patients out of 302 during the second treatment.
As expected with ocular steroid treatment and intravitreal injections, increases in intraocular pressure
(IOP) may be seen. Of the patients experiencing an increase of IOP of ≥10 mmHg from baseline, the
greatest proportion showed this IOP increase at around 60 days following an injection. Patients of less
than 45 years of age are more likely to experience increases in IOP. Therefore, regular monitoring of
IOP is required and any elevation should be managed appropriately post-injection as needed.
Other warnings and precautions
Corticosteroids should be used cautiously in patients with a history of
ocular herpes simplex
and not
be used in active
ocular herpes simplex
.
The safety and efficacy of OZURDEX administered to both eyes concurrently have not been studied.
Therefore administration to both eyes concurrently is not recommended.
OZURDEX has not been studied in aphakic patients Therefore OZURDEX should be used with
caution in these patients.
OZURDEX has not been studied in patients with macular oedema secondary to RVO with significant
retinal ischemia. Therefore OZURDEX is not recommended.
Anti-coagulant therapy was used in 1.7% of patients receiving OZURDEX; there were no reports of
hemorrhagic adverse events in these patients. Anti-platelet medicinal products, such as clopidogrel,
were used at some stage during the clinical studies in over 40% of patients. In clinical trial patients
receiving anti-platelet therapy, haemorrhagic adverse events were reported in a higher proportion of
patients injected with OZURDEX (27%) compared with the control group (20%). The most common
haemorrhagic adverse reaction reported was conjunctival haemorrhage (24%). OZURDEX should be
used with caution in patients taking anti-coagulant or anti-platelet medicinal products.
No interaction studies have been performed.
Systemic absorption is minimal and no interactions are anticipated.
Pregnancy
Studies in animals have shown teratogenic effects following topical ophthalmic administration (see
section 5.3). There are no adequate data from the use of intravitreally administered dexamethasone in
pregnant women. Long-term systemic treatment with glucocorticoids during pregnancy increases the
risk for intra-uterine growth retardation and adrenal insufficiency of the newborn child. Therefore,
although the systemic exposure of dexamethasone would be expected to be very low after local,
intraocular treatment,
OZURDEX is not recommended during pregnancy unless the potential benefit
justifies the potential risk to the foetus.
Breast feeding
4
Dexamethasone is excreted in breast milk No effects on the child are anticipated due to the route of
administration and the resulting systemic levels. However OZURDEX is not recommended during
breast feeding unless clearly necessary.
Fertility
There are no fertility data available.
Patients may experience temporarily reduced vision after receiving OZURDEX by intravitreal
injection (see section 4.8). They should not drive or use machines until this has resolved.
a)
The clinical safety of OZURDEX has been assessed in two Phase III randomised,
double-masked, sham-controlled studies in patients with macular oedema following central
retinal vein occlusion or branch retinal vein occlusion. A total of 427 patients were randomised
to OZURDEX and 426 to sham in the two Phase III studies. A total of 401 patients (94 %)
randomised and treated with OZURDEX completed the initial treatment period (up to day 180).
A total of 47.3 % of patients experienced at least one adverse reaction. The most frequently
reported adverse reactions in patients who received OZURDEX were increased intraocular
pressure (24.0 %) and conjunctival haemorrhage (14.7 %).
The adverse reaction profile for BRVO patients was similar to that observed for CRVO patients
although the overall incidence of adverse reactions was higher for the subgroup of patients with
CRVO.
b) The following adverse reactions, considered related to OZURDEX treatment were reported
during the two Phase III clinical trials.
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) adverse reactions are presented according to
MedDRA System organ class in Table 1. Within each frequency grouping, adverse reactions are
presented in order of decreasing seriousness.
Table 1. Adverse reactions
System organ class
Frequency
Adverse reaction
Nervous system disorders
uncommon
Headache
Eye disorders
very common
Intraocular pressure increased, conjunctival
haemorrhage*
common
Ocular hypertension, vitreous detachment, cataract,
subcapsular cataract, vitreous haemorrhage*, visual
disturbance, vitreous opacities* (including vitreous
floaters), eye pain*, photopsia*, conjunctival
oedema*, anterior chamber cell*, conjunctival
hyperaemia*
uncommon Retinal tear*, anterior chamber flare*
* Adverse reactions considered to be related to the intravitreous injection procedure rather than
the dexamethasone implant
c)
Increased intraocular pressure (IOP) with OZURDEX peaked at day 60 and returned to baseline
levels by day 180. Elevations of IOP either did not require treatment or were managed with the
temporary use of topical IOP-lowering medicinal products. During the initial treatment period,
5
0.7 % (3/421) of the patients who received OZURDEX required laser or surgical procedures for
management of elevated IOP in the study eye compared with 0.2 % (1/423) with sham.
The adverse reaction profile of 341 patients analysed following a second injection of
OZURDEX, was similar to that following the first injection. A total of 54 % of patients
experienced at least one adverse reaction. The incidence of increased IOP(24.9 %) was similar
to that seen following the first injection and likewise returned to baseline by open-label day 180.
The overall incidence of cataracts was higher after 1 year compared to the initial 6 months.
If an overdose occurs, intraocular pressure should be monitored and treated, if deemed
necessary by the attending physician.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Ophthalmologicals, antiinflammatory agents, ATC code: S01BA01
Dexamethasone, a potent corticosteroid, has been shown to suppress inflammation by inhibiting
oedema, fibrin deposition, capillary leakage, and phagocytic migration of the inflammatory
response. Vascular Endothelial Growth Factor (VEGF) is a cytokine which is expressed at increased
concentrations in the setting of macular oedema. It is a potent promoter of vascular permeability.
Corticosteroids have been shown to inhibit the expression of VEGF. Additionally, corticosteroids
prevent the release of prostaglandins, some of which have been identified as mediators of cystoid
macular oedema.
The efficacy of OZURDEX was assessed in two multicentre, double-masked, randomised,
sham-controlled, parallel studies of identical design which together comprised 1,267 patients who
received treatment with dexamethasone 350 µg or 700 µg implants or sham (studies 206207-008 and
206207-009). A total of 427 were randomised to OZURDEX, 414 to dexamethasone 350 µg and
426 patients to sham.
Based on the pooled analysis results, treatment with OZURDEX implants showed statistically
significantly greater incidence of responders, defined as patients achieving a ≥ 15 letter
improvement from baseline in Best Corrected Visual Acuity (BCVA) at 90 days following injection
of a single implant, when compared with sham (p < 0.001).
The proportion of patients achieving the primary efficacy measure of ≥ 15 letter improvement from
baseline in BCVA following injection of a single implant is shown in Table 2. A treatment effect was
seen at the first observation time point of day 30. The maximum treatment effect was observed at
day 60 and the difference in the incidence of responders was statistically significant favouring
OZURDEX compared with sham at all time points to day 90 following injection. There continued to
be a numerically greater proportion of responders for a ≥ 15 letter improvement from baseline in
BCVA in patients treated with OZURDEX compared with sham at day 180.
6
Table 2. Proportion of Patients with ≥ 15 Letters Improvement from
Baseline Best Corrected Visual Acuity in the Study Eye
(Pooled, ITT Population)
OZURDEX Sham
Visit N = 427 N = 426
Day 30 21.3 %
a
7.5%
Day 60 29.3%
a
11.3%
Day 90 21.8%
a
13.1%
Day 180 21.5% 17.6%
a
Proportion significantly higher with OZURDEX compared to sham (p < 0.001)
The mean change from baseline BCVA was significantly greater with OZURDEX compared to sham
at all time points.
In each Phase III study and the pooled analysis, the time to achieve ≥ 15 letters (3-line) improvement
in BCVA cumulative response curves were significantly different with OZURDEX compared to sham
(p < 0.001) with OZURDEX treated patients achieving a 3-line improvement in BCVA earlier than
sham treated patients.
OZURDEX was numerically superior to sham in preventing vision loss as shown by a lower of
proportion of patients experiencing deterioration of vision of ≥ 15 letters in the OZURDEX group
throughout the 6-month assessment period
In each of the phase III studies and the pooled analysis, mean retinal thickness was significantly less,
and the mean reduction from baseline was significantly greater, with OZURDEX (-207.9 microns)
compared to sham (-95.0 microns) at day 90 (p < 0.001, pooled data). The treatment effect as assessed
by BCVA at day 90 was thus supported by this anatomical finding. By Day 180 the mean retinal
thickness reduction (-119.3 microns) compared with sham was not significant.
Patients who had a BCVA score of <84 OR retinal thickness > 250 microns by optical coherence
tomography OCT and in the investigator’s opinion treatment would not put the patient at risk; were
eligible to receive an OZURDEX treatment in an open label extension. Of the patients who were
treated in the open label phase, 93% received an OZURDEX injection between 5 and 7 months after
the initial treatment.
As for the initial treatment, peak response was seen at Day 60 in the open label phase. The cumulative
response rates were higher throughout the open label phase in those patients receiving two consecutive
OZURDEX injections compared with those patients who had not received an OZURDEX injection in
the initial phase.
The proportion of responders at each time point was always greater after the second treatment
compared with the first treatment. Whereas, delaying treatment for 6 months results in a lower
proportion of responders at all time points in the open label phase when compared with those receiving
a second OZURDEX injection.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
OZURDEX in all subsets of the paediatric population for retinal vascular occlusion. See section 4.2
for information on paediatric use.
7
5.2
Pharmacokinetic properties
Plasma concentrations were obtained from a subset of 21 patients in the two, 6-month efficacy studies
prior to dosing and on day 7, 30, 60, and 90 following the intravitreal implant containing 350 µg or
700 µg dexamethasone. Ninety-five percent of the plasma dexamethasone concentration values for the
350 µg dose group and 86% for the 700 µg dose group were below the lower limit of quantitation
(0.05 ng/ml). The highest plasma concentration value of 0.094 ng/ml was observed in one subject from
the 700 µg group. Plasma dexamethasone concentration did not appear to be related to age, body
weight, or sex of patients.
In a 6-month monkey study following a single intravitreal injection of OZURDEX the dexamethasone
vitreous humour C
max
was 100 ng/ml at day 42 post-injection and 5.57 ng/ml at day 91.
Dexamethasone remained detectable in the vitreous at 6 months post-injection. The rank order of
dexamethasone concentration was retina > iris > ciliary body > vitreous humour > aqueous humour >
plasma.
In an
in vitro
metabolism study, following the incubation of [14C]-dexamethasone with human cornea,
iris-ciliary body, choroid, retina, vitreous humour, and sclera tissues for 18 hours, no metabolites were
observed. This is consistent with results from rabbit and monkey ocular metabolism studies.
Dexamethasone is ultimately metabolised to lipid and water soluble metabolites that can be excreted in
bile and urine.
The OZURDEX
matrix slowly degrades to lactic acid and glycolic acid through simple hydrolysis,
then further degrades into carbon dioxide and water.
5.3 Preclinical safety data
Effects in non-clinical studies were observed only at doses considered sufficiently in excess of the
maximum dose for human indicating little relevance to clinical use.
No mutagenicity, carcinogenicity, reproductive or developmental toxicity data are available for
OZURDEX. Dexamethasone has been shown to be teratogenic in mice and rabbits following topical
ophthalmic application.
Dexamethasone exposure to the healthy/untreated eye via contralateral diffusion has been observed in
rabbits following delivery of the implant to the posterior segment of the eye.
6.
6.1
List of excipients
•
Ester terminated 50:50 poly D,L-lactide-co-glycolide.
•
Acid terminated 50:50 poly D,L-lactide-co-glycolide.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
8
6.5
Nature and contents of container
1 pack contains:
1 sustained release sterile implantable rod shaped implant containing 700 micrograms of
dexamethasone, located in the needle (stainless steel) of a disposable applicator.
The applicator consists of a plunger (stainless steel) within a needle where the implant is held in place
by a sleeve (silicone). The plunger is controlled by a lever on the side of the applicator body. The
needle is protected by a cap and the lever by a safety tab.
The applicator containing the implant is packaged in a sealed foil pouch containing desiccant.
6.6 Special precautions for disposal and other handling
OZURDEX is for single use only.
Each applicator can only be used for the treatment of a single eye.
If the seal of the foil pouch containing the applicator is damaged, do not use. Once the foil pouch is
opened the applicator should be used immediately.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
7.
Allergan Pharmaceuticals Ireland
Castlebar Road,
Co. Mayo
Westport
Ireland
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/.
9
ANNEX II
A. Manufacturing authorisation holder responsible for batch release
B. Conditions of the marketing authorisation
10
A. Manufacturing authorisation holder responsible for batch release
Name and address of the manufacturer responsible for batch release
Allergan Pharmaceuticals Ireland
Castlebar Road
Westport, Co Mayo
Ireland
B. Conditions of the marketing authorisation
•
Conditions or restrictions regarding supply and use imposed on the marketing
authorisation holder
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics).
•
Conditions or restrictions with regard to the safe and effective use of the medicinal
product
Prior to launch in each Member State the MAH shall agree the final educational material with the
National Competent Authority.
The MAH shall ensure that, at launch, all physicians who are expected to prescribe/use Ozurdex are
provided with a physician information pack containing the following:
•
Physician information
•
Intravitreal injection procedure video
•
Intravitreal injection procedure pictogram
•
Patient information pack
The physician information should contain the following key elements:
•
The Summary of Product Characteristics
•
Aseptic techniques to minimise the risk of infection
•
Use of antibiotics
•
Techniques for the intravitreal injection
•
Patient monitoring after IVT injection
•
Key signs and symptoms of IVT injection related adverse events including increased
intraocular pressure, glaucoma, ocular hypertension, cataract, traumatic cataract related to
injection technique, vitreous detachment, vitreous haemorrhage, endophthalmitis, mechanical
failure of device and implant misplacement
•
Management of IVT injection related adverse events
11
The patient information pack should be provided in both the form of patient information booklet and
an audio-CD that contain following key elements:
•
Patient information leaflet
•
How to prepare for Ozurdex treatment
•
What are the steps following treatment with Ozurdex
•
Key signs and symptoms of serious adverse events including increased intraocular pressure
and ocular hypertension
•
When to seek urgent attention from their health care provider
•
Other conditions
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version version 2.0 dated
March 2010 presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 1.0 dated May 2010 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent
updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
At the request of the European Medicines Agency
12
ANNEX III
LABELLING AND PACKAGE LEAFLET
13
A. LABELLING
14
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
CARTON AND POUCH EXTENDED LABEL
1.
OZURDEX 700 micrograms intravitreal implant in applicator
Dexamethasone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One implant contains 700 micrograms of dexamethasone
3.
LIST OF EXCIPIENTS
•
Contains
•
Ester terminated 50:50 poly D,L-lactide-co-glycolide.
•
Acid terminated 50:50 poly D,L-lactide-co-glycolide.
4.
One intravitreal implant in applicator.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Single use only.
Read the package leaflet before use.
Intravitreal use.
Do not use if foil pouch seal is damaged.
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
Once pouch opened, use applicator immediately.
9.
SPECIAL STORAGE CONDITIONS
15
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Allergan Pharmaceuticals Ireland
Castlebar Road
Westport
Co. Mayo
Ireland
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
16
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
APPLICATOR LABEL
1.
OZURDEX 700 micrograms intravitreal implant in applicator
Dexamethasone
Intravitreal use.
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 implant.
6.
OTHER
17
B. PACKAGE LEAFLET
18
PACKAGE LEAFLET: INFORMATION FOR THE USER
OZURDEX 700 micrograms intravitreal implant in applicator
Dexamethasone
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.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1. What OZURDEX is and what it is used for
2. Before you are given OZURDEX
3. How OZURDEX is used
4. Possible side effects
5.
How to store OZURDEX
6.
Further information
1.
WHAT OZURDEX IS AND WHAT IT IS USED FOR
The active substance in OZURDEX is dexamethasone. Dexamethasone belongs to a group of
medicines called corticosteroids.
OZURDEX is used to treat vision loss in adults caused by a blockage of veins in the eye. This
blockage leads to a build up of fluid causing swelling in the area of the retina (the light-sensitive layer
at the back of the eye) called the macula. The swelling may lead to damage to the macula which
affects your central vision which is used for tasks like reading. OZURDEX works by reducing this
swelling of the macular which helps to lessen or prevent more damage to the macula.
2.
BEFORE YOU ARE GIVEN OZURDEX
You must not be given OZURDEX
-
if you are allergic (hypersensitive) to dexamethasone or any of the other ingredients of
OZURDEX (for a full list of ingredients, see section 6 “FURTHER INFORMATION”),
-
if you have an infection of any kind in or around your eye (bacterial, viral or fungal),
-
if you have glaucoma or high pressure inside your eye which is not controlled properly with the
medicines you may be using.
Take special care with OZURDEX
-
Before your OZURDEX injection tell your doctor if:You have had cataract surgery
-
You are taking any medicines to thin the blood
-
You have had a herpes simplex infection in your eye in the past (an ulcer on the eye that has
been there a long time, or sores on the eye).
Please tell your doctor immediately if you develop symptoms such as the following after injection
with OZURDEX:
-
eye pain or increased discomfort,
-
worsening eye redness,
-
a feeling of spots in front of the eye (sometimes called ‘floaters’),
-
increased sensitivity to light,
-
any discharge from the eye,
19
-
blurred or decreased vision,
In some patients the pressure in the eye may increase for a short period straight after the injection, or
you may develop an eye infection.
Increase in pressure in the eye can also occur at any time following injection, this is something you
may not notice so your doctor will monitor you regularly after treatment.
The injection of OZURDEX into both eyes at the same time has not been studied and is not
recommended. Your doctor should not inject OZURDEX into both eyes at the same time.
Children and adolescent (below 18 years of age)
The use of OZURDEX in children and adolescents has not been studied and is therefore not
recommended.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
Pregnancy and breast-feeding
There is no experience of using OZURDEX in pregnant women or during breast-feeding. OZURDEX
should not be used during pregnancy or breast-feeding unless your doctor thinks it is clearly
necessary. If you are pregnant or planning to become pregnant, or if you are breast-feeding, please
discuss this with your doctor before OZURDEX treatment. Ask your doctor for advice before taking
any medicine.
Driving and using machines
After OZURDEX treatment you may experience some reduced vision for a short time. If this happens,
do not drive or use any tools or machines until your vision improves.
3.
HOW OZURDEX IS USED
All OZURDEX injections will be given by an appropriately qualified eye doctor.
The usual dose is one implant to be given by injection into your eye. If the effect of this injection
wears off and your doctor recommends it, another implant may then be injected into your eye.
Your doctor will ask you to use antibiotic eye drops regularly before and after each injection to
prevent any eye infection. Please follow these instructions carefully.
On the day of the injection, your doctor may use antibiotic eye drops to prevent infection. Your doctor
will also give you a local anaesthetic to reduce or prevent any pain you might have with the injection.
You may hear a ‘click’ during the injection of OZURDEX; this is normal.
There are detailed instructions for your doctor on how to carry out the OZURDEX injection at
the end of this leaflet.
If you have any further questions on the use of this medicine, ask your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, OZURDEX can cause side effects, although not everybody gets them.
The frequency of possible side effects listed below is defined using the following convention:
Very common
affects more than 1 user in 10
20
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
The following side effects may be seen with OZURDEX:
Very common: Increased pressure in the eye, bleeding on the surface of the eye*
Common:
High pressure in the eye, detachment of the jelly inside the eye from the light-
sensitive layer at the back of the eye (vitreous detachment), clouding of the lens
(cataract), bleeding into the inside of the eye*, difficulties in seeing clearly, a
feeling of spots in front of the eye (including ‘floaters’)*, eye pain*, seeing flashes
of light*, swelling on the surface of the eye*, a feeling of looking through mist or
fog*, redness of the eye*
Uncommon: Tear of the light-sensitive layer at the back of the eye (retinal tear)*, increased
protein in the front of the eye due to inflammation*, headache
*
Some of these side effects may be caused by the injection procedure and not the OZURDEX implant
itself.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5.
HOW TO STORE OZURDEX
Keep out of the reach and sight of children.
Do not use OZURDEX after the expiry date which is stated on the carton and the pouch after EXP:.
The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What OZURDEX contains
-
The active substance is dexamethasone.
-
Each implant contains 700 micrograms of dexamethasone.
-
The other ingredients are: Ester terminated 50:50 poly D,L-lactide-co-glycolide and
Acid terminated 50:50 poly D,L-lactide-co-glycolide.
What OZURDEX looks like and contents of the pack
OZURDEX is a rod-shaped implant which is stored inside the needle of an applicator. The applicator
and a packet of drying material are sealed in a foil pouch which is inside a carton. One carton contains
one applicator with one implant which will be used once and thrown away.
Marketing Authorisation Holder and Manufacturer
21
Allergan Pharmaceuticals Ireland
Castlebar Road
Westport
Co. Mayo
Ireland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Allergan n.v.
Terhulpsesteenweg 6D
B-1560 Hoeilaart
Tél/Tel: +32 (0)2 351 2424
E-mail:
uk_medinfo@allergan.com
Luxembourg/Luxemburg
Allergan n.v.
Terhulpsesteenweg 6D
B-1560 Hoeilaart
Belgique/Belgien
Tél/Tel: +32 (0)2 351 2424
E-mail:
uk_medinfo@allergan.com
България
Eвофарма АГ
Представителство ул. Персенк 73, ап. 27, ет. 8
1164 София
Тел.: +359 2 962 12 00
E-mail: uk_medinfo@allergan.com
Magyarország
Vicis Pharma Kft.
Kapás utca 11-15., Buda Business Center
H-1027 Budapest
Tel.: +36 1 457 9921
E-mail:
uk_medinfo@allergan.com
Česká republika
NEOMED s.r.o.
Sodomkova 1474/6, Praha 10
CZ-102 00
Tel: +420 274 008 411
E-mail:
uk_medinfo@allergan.com
Malta
Allergan Ltd
1
st
Floor
Marlow International
The Parkway
Marlow
Bucks, SL7 1YL-UK
United Kingdom/Renju Unit
Tel: + 44 (0) 1628 494026
E-mail:
uk_medinfo@allergan.com
Danmark
Allergan Norden AB
Johanneslundsvägen 3-5
S-194 81 Upplands Väsby
Sverige
Tlf: + 46 (0)8 594 100 00
E-mail:
uk_medinfo@allergan.com
Nederland
Allergan n.v.
Terhulpsesteenweg 6D
B-1560 Hoeilaart
België
Tel: + 32 (0)2 351 24 24
E-mail:
uk_medinfo@allergan.com
Deutschland
Pharm-Allergan GmbH
Pforzheimer Straße 160
D-76275 Ettlingen
Tel: + 49 (0)7243 501 0
E-mail:
uk_medinfo@allergan.com
Norge
Allergan Norden AB
Johanneslundsvägen 3-5
S-194 81 Upplands Väsby
Sverige
Tlf: + 46 (0)8 594 100 00
E-mail:
uk_medinfo@allergan.com
Eesti
Allergan Ltd
1
st
Floor
Marlow International
The Parkway
Österreich
Pharm-Allergan GmbH
Pforzheimer Straße 160
D-76275 Ettlingen
Deutschland
22
Marlow
Bucks, SL7 1YL-UK
Ühendkuningriik
Tel: + 44 (0) 1628 494026
E-mail:
uk_medinfo@allergan.com
Tel: + 49 (0)7243 501 0
E-mail:
uk_medinfo@allergan.com
Ελλάδα
Nexus Medicals A.E.
12° χλμ Eθν. Οδού Αθηνών-Λαμίας & Ζακύνθου
GR-144 51 Μεταμόρφωση Αττικής
Τηλ: + 30 2 10 285 2266
E-mail:
uk_medinfo@allergan.com
Polska
Ewopharma AG Sp z o.o.
ul.Świętokrzyska 36/16
PL-00 116 Warszawa
Tel.: +48 22 620 11 71
E-mail:
uk_medinfo@allergan.com
España
Allergan S.A.U
Edificio la Encina
Plaza de la Encina, 10-11
E-28760 Tres Cantos
Madrid
Tel: + 34 91 807 6130
E-mail:
uk_medinfo@allergan.com
Portugal
Profarin Lda.
Rua da Quinta dos Grilos, 30
P-2790-476 Carnaxide
Tel: + 351 21 425 3242
E-mail:
uk_medinfo@allergan.com
France
Allergan France S.A.S
Bâtiment A
4 place de la Défense
92400 Courbevoie
Tel : +33 (0)1 49 07 83 00
E-mail:
uk_medinfo@allergan.com
România
Ewopharma AG România
Intrarea Eliza Zamfirescu Leonida nr.13, ap.2,
sector 1
Bucureşti 011372-RO
Tel.: +40 21 260 13 44
E-mail:
uk_medinfo@allergan.com
Ireland
Allergan Ltd
1
st
Floor
Marlow International
The Parkway
Marlow
Bucks, SL7 1YL-UK
United Kingdom
Tel: + 44 (0) 1628 494026
E-mail:
uk_medinfo@allergan.com
Slovenija
Ewopharma d.o.o.
Cesta 24. junija 23
SI-1231 Ljubljana – Črnuče
Tel: + 386 (0) 590 848 40
E-mail:
uk_medinfo@allergan.com
Ísland
Vistor hf.
Hörgatún 2
IS-212 Garðabær
Sími: + 354 535 7000
Netfang:
uk_medinfo@allergan.com
Slovenská republika
NEOMED,s.r.o., pobočka Bratislava
Šťastná 11
SK-821 05 Bratislava
Tel: +421 2 434 150 12
E-mail:
uk_medinfo@allergan.com
Italia
Allergan S.p.A
Via S.Quasimodo 134/138
I-00144 Roma
Tel: + 39 06 509 561
E-mail:
uk_medinfo@allergan.com
Suomi/Finland
Allergan Norden AB
Johanneslundsvägen 3-5
S-194 81 Upplands Väsby
Ruotsi/Sverige
Puh/Tel: + 46 (0)8 594 100 00
E-mail:
uk_medinfo@allergan.com
23
Κύπρος
Allergan Ltd
1
st
Floor
Marlow International
The Parkway
Marlow
Bucks, SL7 1YL-UK
Ηνωμένο Βασίλειο
Τηλ: + 44 (0) 1628 494026
E-mail:
uk_medinfo@allergan.com
Sverige
Allergan Norden AB
Johanneslundsvägen 3-5
S-194 81 Upplands Väsby
Tel: +46 (0)8 594 100 00
E-mail:
uk_medinfo@allergan.com
Latvija
Allergan Ltd
1
st
Floor
Marlow International
The Parkway
Marlow
Bucks, SL7 1YL-UK
Lielbritānija
Tel: + 44 (0) 1628 494026
E-mail:
uk_medinfo@allergan.com
United Kingdom
Allergan Ltd
1
st
Floor
Marlow International
The Parkway
Marlow
Bucks, SL7 1YL-UK
Tel: + 44 (0) 1628 494026
E-mail:
uk_medinfo@allergan.com
Lietuva
Allergan Ltd
1
st
Floor
Marlow International
The Parkway
Marlow
Bucks, SL7 1YL-UK
Jungtinė Karalystė
Tel: + 44 (0) 1628 494026
E-mail:
uk_medinfo@allergan.com
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
/.
24
---------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
INFORMATION FOR THE HEALTHCARE PROFESSIONAL
1.
OZURDEX 700 micrograms intravitreal implant in applicator
2.
One implant contains 700 micrograms of dexamethasone.
For a full list of excipients, see section 6.1.
3.
Intravitreal implant in applicator.
Disposable injection device, containing a rod-shaped implant. which is not visible. The implant is
approximately 0.46 mm in diameter and 6 mm in length.
4.
OZURDEX is indicated for the treatment of adult patients with macular oedema following either
Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO) (see section 5.1).
OZURDEX must be administered by a qualified ophthalmologist experienced in intravitreal injections.
Posology
The recommended dose is one OZURDEX implant to be administered intra-vitreally to the affected
eye. Administration to both eyes concurrently is not recommended (see section 4.4).
Repeat doses should be considered when a patient experiences a response to treatment followed
subsequently by a loss in visual acuity and in the physician’s investigator's opinion may benefit from
retreatment without being exposed at to significant risk. (see section 5.1)
Patients who experience and retain improved vision should not be retreated. Patients who experience a
deterioration in vision, which is not slowed by OZURDEX, should not be retreated.
There is only very limited information on repeat dosing intervals less than 6 months (see section 5.1).
There is currently no experience of repeat administrations beyond 2 implants in Retinal Vein
Occlusion.
Patients should be monitored following the injection to permit early treatment if an infection or
increased intraocular pressure occurs (see section 4.4).
Special populations
Elderly (
≥
65 years old)
No dose adjustment is required for elderly patients.
25
Renal impairment
OZURDEX has not been studied in patients with renal impairment however no special considerations
are needed in this population.
Hepatic impairment
OZURDEX has not been studied in patients with hepatic impairment, however no special
considerations are needed in this population.
Paediatric population
There is no relevant use of OZURDEX in the paediatric population in macular oedema following
either Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO).
Method of administration
Single-use intravitreal implant in applicator for intravitreal use only.
Each applicator can only be used for the treatment of a single eye.
The intravitreal injection procedure should be carried out under controlled aseptic conditions which
include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent).
A broad spectrum topical antimicrobial should be given prior to and on the day of the injection
procedure. Adequate local anaesthesia should be administered.
Remove the foil pouch from the
carton and examine for damage (see section 6.6). Then, in a sterile field, open the foil pouch and
gently place the applicator on a sterile tray. Carefully remove the cap from the applicator. Once the
foil pouch is opened the applicator should be used immediately.
Hold the applicator in one hand and pull the safety tab straight off the applicator. Do not twist or flex
the tab. With the bevel of the needle up away from the sclera, advance the needle about 1 mm into the
sclera then redirect toward the centre of the eye into the vitreous cavity until the silicone sleeve is
against the conjunctiva. Slowly press the actuator button until an audible click is noted. Before
withdrawing the applicator from the eye, make sure that the actuator button is fully pressed and has
locked flush with the applicator surface. Remove the needle in the same direction as used to enter the
vitreous.
Immediately after injecting OZURDEX, use indirect ophthalmoscopy in the quadrant of injection to
confirm successful implantation. Visualisation is possible in the large majority of cases. In cases in
which the implant cannot be visualised, take a sterile cotton bud and lightly depress over the injection
site to bring the implant into view.
Following the intravitreal injection patients should continue to be treated with a broad spectrum
antimicrobial.
OZURDEX is contraindicated in
•
Hypersensitivity to the active substance or to any of the excipients.
•
Active or suspected ocular or periocular infection including most viral diseases of the cornea
and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis),
vaccinia, varicella, mycobacterial infections, and fungal diseases.
•
Advanced glaucoma which cannot be adequately controlled by medicinal products alone.
Monitoring
Any intravitreous injection can be associated with endophthalmitis, intraocular inflammation,
increased intraocular pressure and retinal detachment. Proper aseptic injection techniques must always
26
be used. In addition, patients should be monitored following the injection to permit early treatment if
an infection or increased intraocular pressure occurs. Monitoring may consist of a check for perfusion
of the optic nerve head immediately after the injection, tonometry within 30 minutes following the
injection, and biomicroscopy between two and seven days following the injection.
Patients must be instructed to report any symptoms suggestive of endophthalmitis or any of the above
mentioned events without delay.
Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma and may result in
secondary ocular infections.
In clinical studies,cataract was reported more frequently in patients with phakic lens receiving a
second injection (see section 4.8with only 1 patient out of 368 requiring cataract surgery during the
first treatment and 3 patients out of 302 during the second treatment.
As expected with ocular steroid treatment and intravitreal injections, increases in intraocular pressure
(IOP) may be seen. Of the patients experiencing an increase of IOP of ≥10 mmHg from baseline, the
greatest proportion showed this IOP increase at around 60 days following an injection. Patients of less
than 45 years of age are more likely to experience increases in IOP. Therefore, regular monitoring of
IOP is required and any elevation should be managed appropriately post-injection as needed.
Other warnings and precautions
Corticosteroids should be used cautiously in patients with a history of
ocular herpes simplex
and not
be used in active
ocular herpes simplex
.
The safety and efficacy of OZURDEX administered to both eyes concurrently have not been studied.
Therefore administration to both eyes concurrently is not recommended.
OZURDEX has not been studied in aphakic patients Therefore OZURDEX should be used with
caution in these patients.
OZURDEX has not been studied in patients with macular oedema secondary to RVO with significant
retinal ischemia. Therefore OZURDEX is not recommended.
Anti-coagulant therapy was used in 1.7% of patients receiving OZURDEX; there were no reports of
hemorrhagic adverse events in these patients. Anti-platelet medicinal products, such as clopidogrel,
were used at some stage during the clinical studies in over 40% of patients. In clinical trial patients
receiving anti-platelet therapy, haemorrhagic adverse events were reported in a higher proportion of
patients injected with OZURDEX (27%) compared with the control group (20%). The most common
haemorrhagic adverse reaction reported was conjunctival haemorrhage (24%). OZURDEX should be
used with caution in patients taking anti-coagulant or anti-platelet medicinal products.
No interaction studies have been performed.
Systemic absorption is minimal and no interactions are anticipated.
Pregnancy
Studies in animals have shown teratogenic effects following topical ophthalmic administration (see
section 5.3). There are no adequate data from the use of intravitreally administered dexamethasone in
pregnant women. Long-term systemic treatment with glucocorticoids during pregnancy increases the
risk for intra-uterine growth retardation and adrenal insufficiency of the newborn child. Therefore,
although the systemic exposure of dexamethasone would be expected to be very low after local,
27
intraocular treatment.
OZURDEX is not recommended during pregnancy unless the potential benefit
justifies the potential risk to the foetus.
Breast feeding
Dexamethasone is excreted in breast milk No effects on the child are anticipated due to the route of
administration and the resulting systemic levels. However OZURDEX is not recommended during
breast feeding unless clearly necessary.
Fertility
There are no fertility data available.
Patients may experience temporarily reduced vision after receiving OZURDEX by intravitreal
injection (see section 4.8). They should not drive or use machines until this has resolved.
a)
The clinical safety of OZURDEX has been assessed in two Phase III randomised,
double-masked, sham-controlled studies in patients with macular oedema following central
retinal vein occlusion or branch retinal vein occlusion. A total of 427 patients were randomised
to OZURDEX and 426 to sham in the two Phase III studies. A total of 401 patients (94 %)
randomised and treated with OZURDEX completed the initial treatment period (up to day 180).
A total of 47.3 % of patients experienced at least one adverse reaction. The most frequently
reported adverse reactions in patients who received OZURDEX were increased intraocular
pressure (24.0 %) and conjunctival haemorrhage (14.7 %).
The adverse reaction profile for BRVO patients was similar to that observed for CRVO patients
although the overall incidence of adverse reactions was higher for the subgroup of patients with
CRVO.
b) The following adverse reactions, considered related to OZURDEX treatment were reported
during the two Phase III clinical trials.
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) adverse reactions are presented according to
MedDRA System organ class in Table 1. Within each frequency grouping, adverse reactions are
presented in order of decreasing seriousness.
Table 1. Adverse reactions
System organ class
Frequency
Adverse reaction
Nervous system disorders
uncommon
Headache
Eye disorders
very common
Intraocular pressure increased, conjunctival
haemorrhage*
common
Ocular hypertension, vitreous detachment, cataract,
subcapsular cataract, vitreous haemorrhage*, visual
disturbance, vitreous opacities* (including vitreous
floaters), eye pain*, photopsia*, conjunctival
oedema*, anterior chamber cell*, conjunctival
hyperaemia*
uncommon Retinal tear*, anterior chamber flare*
* Adverse reactions considered to be related to the intravitreous injection procedure rather than
the dexamethasone implant
28
c)
Increased intraocular pressure (IOP) with OZURDEX peaked at day 60 and returned to baseline
levels by day 180. Elevations of IOP either did not require treatment or were managed with the
temporary use of topical IOP-lowering medicinal products. During the initial treatment period,
0.7 % (3/421) of the patients who received OZURDEX required laser or surgical procedures for
management of elevated IOP in the study eye compared with 0.2 % (1/423) with sham.
The adverse reaction profile of 341 patients analysed following a second injection of
OZURDEX, was similar to that following the first injection. A total of 54 % of patients
experienced at least one adverse reaction. The incidence of increased IOP(24.9 %) was similar
to that seen following the first injection and likewise returned to baseline by open-label day 180.
The overall incidence of cataracts was higher after 1 year compared to the initial 6 months.
If an overdose occurs, intraocular pressure should be monitored and treated, if deemed necessary by
the attending physician.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Ophthalmologicals, antiinflammatory agents, ATC code: S01BA01
Dexamethasone, a potent corticosteroid, has been shown to suppress inflammation by inhibiting
oedema, fibrin deposition, capillary leakage, and phagocytic migration of the inflammatory
response. Vascular Endothelial Growth Factor (VEGF) is a cytokine which is expressed at increased
concentrations in the setting of macular oedema. It is a potent promoter of vascular permeability.
Corticosteroids have been shown to inhibit the expression of VEGF. Additionally, corticosteroids
prevent the release of prostaglandins, some of which have been identified as mediators of cystoid
macular oedema.
The efficacy of OZURDEX was assessed in two multicentre, double-masked, randomised,
sham-controlled, parallel studies of identical design which together comprised 1,267 patients who
received treatment with dexamethasone 350 µg or 700 µg implants or sham (studies 206207-008 and
206207-009). A total of 427 were randomised to OZURDEX, 414 to dexamethasone 350 µg and
426 patients to sham.
Based on the pooled analysis results, treatment with OZURDEX implants showed statistically
significantly greater incidence of responders, defined as patients achieving a ≥ 15 letter
improvement from baseline in Best Corrected Visual Acuity (BCVA) at 90 days following injection
of a single implant, when compared with sham (p < 0.001).
The proportion of patients achieving the primary efficacy measure of ≥ 15 letter improvement from
baseline in BCVA following injection of a single implant is shown in Table 2. A treatment effect was
seen at the first observation time point of day 30. The maximum treatment effect was observed at
day 60 and the difference in the incidence of responders was statistically significant favouring
OZURDEX compared with sham at all time points to day 90 following injection. There continued to
be a numerically greater proportion of responders for a ≥ 15 letter improvement from baseline in
BCVA in patients treated with OZURDEX compared with sham at day 180.
29
Table 2. Proportion of Patients with ≥ 15 Letters Improvement from
Baseline Best Corrected Visual Acuity in the Study Eye
(Pooled, ITT Population)
OZURDEX Sham
Visit N = 427 N = 426
Day 30 21.3 %
a
7.5%
Day 60 29.3%
a
11.3%
Day 90 21.8%
a
13.1%
Day 180 21.5% 17.6%
a
Proportion significantly higher with OZURDEX compared to sham (p < 0.001)
The mean change from baseline BCVA was significantly greater with OZURDEX compared to sham
at all time points.
In each Phase III study and the pooled analysis, the time to achieve ≥ 15 letters (3-line) improvement
in BCVA cumulative response curves were significantly different with OZURDEX compared to sham
(p < 0.001) with OZURDEX treated patients achieving a 3-line improvement in BCVA earlier than
sham treated patients.
OZURDEX was numerically superior to sham in preventing vision loss as shown by a lower of
proportion of patients experiencing deterioration of vision of ≥ 15 letters in the OZURDEX group
throughout the 6-month assessment period
In each of the phase III studies and the pooled analysis, mean retinal thickness was significantly less,
and the mean reduction from baseline was significantly greater, with OZURDEX (-207.9 microns)
compared to sham (-95.0 microns) at day 90 (p < 0.001, pooled data). The treatment effect as assessed
by BCVA at day 90 was thus supported by this anatomical finding. By Day 180 the mean retinal
thickness reduction (-119.3 microns) compared with sham was not significant.
Patients who had a BCVA score of <84 OR retinal thickness > 250 microns by optical coherence
tomography OCT and in the investigator’s opinion treatment would not put the patient at risk; were
eligible to receive an OZURDEX treatment in an open label extension. Of the patients who were
treated in the open label phase, 93% received an OZURDEX injection between 5 and 7 months after
the initial treatment.
As for the initial treatment, peak response was seen at Day 60 in the open label phase. The cumulative
response rates were higher throughout the open label phase in those patients receiving two consecutive
OZURDEX injections compared with those patients who had not received an OZURDEX injection in
the initial phase.
The proportion of responders at each time point was always greater after the second treatment
compared with the first treatment. Whereas, delaying treatment for 6 months results in a lower
proportion of responders at all time points in the open label phase when compared with those receiving
a second OZURDEX injection.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
OZURDEX in all subsets of the paediatric population for retinal vascular occlusion. See section 4.2
for information on paediatric use.
30
5.2
Pharmacokinetic properties
Plasma concentrations were obtained from a subset of 21 patients in the two, 6-month efficacy studies
prior to dosing and on day 7, 30, 60, and 90 following the intravitreal implant containing 350 µg or
700 µg dexamethasone. Ninety-five percent of the plasma dexamethasone concentration values for the
350 µg dose group and 86% for the 700 µg dose group were below the lower limit of quantitation
(0.05 ng/ml). The highest plasma concentration value of 0.094 ng/ml was observed in one subject from
the 700 µg group. Plasma dexamethasone concentration did not appear to be related to age, body
weight, or sex of patients.
In a 6-month monkey study following a single intravitreal injection of OZURDEX the dexamethasone
vitreous humour C
max
was 100 ng/ml at day 42 post-injection and 5.57 ng/ml at day 91.
Dexamethasone remained detectable in the vitreous at 6 months post-injection. The rank order of
dexamethasone concentration was retina > iris > ciliary body > vitreous humour > aqueous humour >
plasma.
In an
in vitro
metabolism study, following the incubation of [14C]-dexamethasone with human cornea,
iris-ciliary body, choroid, retina, vitreous humour, and sclera tissues for 18 hours, no metabolites were
observed. This is consistent with results from rabbit and monkey ocular metabolism studies.
Dexamethasone is ultimately metabolised to lipid and water soluble metabolites that can be excreted in
bile and urine.
The OZURDEX
matrix slowly degrades to lactic acid and glycolic acid through simple hydrolysis,
then further degrades into carbon dioxide and water.
5.3 Preclinical safety data
Effects in non-clinical studies were observed only at doses considered sufficiently in excess of the
maximum dose for human indicating little relevance to clinical use.
No mutagenicity, carcinogenicity, reproductive or developmental toxicity data are available for
OZURDEX. Dexamethasone has been shown to be teratogenic in mice and rabbits following topical
ophthalmic application.
Dexamethasone exposure to the healthy/untreated eye via contralateral diffusion has been observed in
rabbits following delivery of the implant to the posterior segment of the eye.
6.
6.1
List of excipients
•
Ester terminated 50:50 poly D,L-lactide-co-glycolide.
•
Acid terminated 50:50 poly D,L-lactide-co-glycolide.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
31
6.5
Nature and contents of container
1 pack contains:
1 sustained release sterile implantable rod shaped implant containing 700 micrograms of
dexamethasone, located in the needle (stainless steel) of a disposable applicator.
The applicator consists of a plunger (stainless steel) within a needle where the implant is held in place
by a sleeve (silicone). The plunger is controlled by a lever on the side of the applicator body. The
needle is protected by a cap and the lever by a safety tab.
The applicator containing the implant is packaged in a sealed foil pouch containing desiccant.
6.6 Special precautions for disposal and other handling
OZURDEX is for single use only.
Each applicator can only be used for the treatment of a single eye.
If the seal of the foil pouch containing the applicator is damaged, do not use. Once the foil pouch is
opened the applicator should be used immediately.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
7.
Allergan Pharmaceuticals Ireland
Castlebar Road,
Co. Mayo
Westport
Ireland
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/.
32
Source: European Medicines Agency
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