Active ingredients: Dexamethasone
OZURDEX 700 micrograms intravitreal implant in applicator
Why is Ozurdex used? What is it for?
The active ingredient in OZURDEX is dexamethasone. Dexamethasone belongs to a group of medicines called corticosteroids.
OZURDEX is used to treat adult patients with:
- Visual impairment due to diabetic macular edema (DME) in patients who have already undergone cataract surgery, or in patients who are thought to have an insufficient response or are unsuitable for other types of treatments. Diabetic macular edema is a swelling of the photosensitive layer on the back of the eye called the macula. DME is a disease that affects some people with diabetes.
- Loss of vision in adult patients caused by "blockage of the veins inside the eye. This obstruction leads to a buildup of fluid that causes swelling in the area of the retina (the light-sensitive layer at the back of the eye." eye) called macula. Swelling of the macula can cause damage, affecting central vision used for activities such as reading. OZURDEX works by reducing swelling and thus helping to reduce or prevent further damage to the macula.
- Inflammation of the back of the eye. This inflammation leads to a reduction in vision and / or the presence of floaters in the eye (blackheads or fine lines moving into the field of vision). The action of OZURDEX reduces this inflammation.
Contraindications When Ozurdex should not be used
Do not use OZURDEX
- if you are allergic to dexamethasone or any of the other ingredients of this medicine
- in the presence of infections of any kind in or around the eyes (bacterial, viral or fungal)
- in case of glaucoma or hypertension inside the eye not adequately controlled with medicines already prescribed for these disorders.
- if the eye to be treated is devoid of the lens and the posterior part of the lens capsule (the "capsular sac") has been ruptured.
- if the eye to be treated has undergone cataract surgery and contains an artificial lens, implanted in the anterior compartment of the eye (one intraocular lens per anterior chamber) or fixed to the white part of the eye (sclera) or to the colored one (iris) and the back of the lens capsule (the "capsular sac") has been ruptured.
Precautions for use What you need to know before taking Ozurdex
Before the injection of OZURDEX, tell your doctor if:
- have undergone cataract surgery, surgery of the iris (the colored part of the eye that controls the amount of light that enters the eye) or surgery to remove the gel (called the vitreous) from the inside of the eye
- take medicines to thin the blood
- take steroid or non-steroidal anti-inflammatory drugs by mouth or ocular application
- have had a "herpes simplex eye infection" (a long lasting "ulcer of the eye" or eye injuries in the past).
Sometimes injection of OZURDEX can cause infection inside the eye, eye pain or redness, or retinal detachment or tear. It is important to identify and treat these disorders as soon as possible.
Tell your doctor immediately if you experience increased eye pain and / or discomfort, worsening eye redness, flashing and sudden increase of floaters, partially blocked vision, decreased vision or increased sensitivity to light after injection.
In some patients, eye pressure may increase with possible development of glaucoma. This event may not be noticed by the patient, so the doctor will monitor regularly and, if necessary, prescribe treatment to lower the eye pressure. In the majority of patients who have not yet undergone cataract surgery, clouding of the natural lens of the eye (cataract) may occur after repeated treatment with OZURDEX. If so, your vision will decrease and cataract surgery is likely to be needed. Your doctor will help you decide the best time to do this, but you need to know that your vision may remain just as poor until the operation. or it may be worse than it was before you started receiving OZURDEX injections
The implant may move from the back to the front of the eye in patients with a tear in the posterior part of the ocular capsule and / or in those who have an "opening in the iris". This could lead to swelling of the clear layer at the front of the eye and cause blurred vision. If this continues over time and is not treated, a tissue transplant may be required.
Simultaneous injection of OZURDEX into both eyes has not been studied and is not recommended. Your doctor should not inject OZURDEX into both eyes at the same time.
Children and adolescents (under 18 years of age)
The use of OZURDEX in children and adolescents has not been studied and is therefore not recommended.
Interactions Which drugs or foods may change the effect of Ozurdex
Tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Warnings It is important to know that:
Pregnancy and breastfeeding
There are no data on the use of OZURDEX in pregnant or lactating women. OZURDEX should not be used during pregnancy or breastfeeding, unless the clinical condition of the woman requires treatment with OZURDEX. If you are pregnant, think you may be pregnant or are planning to become pregnant, or are breast-feeding, ask your doctor for advice before starting treatment with OZURDEX Ask your doctor for advice before using any medicine.
Driving and using machines
After treatment with OZURDEX, slight loss of vision is possible for short periods. If this happens, do not drive or use machines until your sight has completely returned.
Dose, Method and Time of Administration How to use Ozurdex: Posology
All injections of OZURDEX must be administered by an appropriately qualified ophthalmologist.
The recommended dose is one implant by injection into the eye. If the effect of this injection tends to diminish, a second implant can be injected into the eye if your doctor deems it necessary.
In order to prevent eye infections, your doctor will prescribe you to use antibiotic eye drops every day for 3 days before and after each injection. Follow these instructions carefully.
On the day of the injection, your doctor may apply antibiotic eye drops to prevent possible infections. Before the injection, your doctor will clean your eye and eyelid. At the time of the injection, your doctor will also give you a local anesthetic to reduce o prevent eye pain. A clicking sound may be heard while injecting OZURDEX; this is normal.
Detailed instructions for your doctor on how to inject OZURDEX are provided in the medicine pack.
If you have any further questions on the use of this medicine, ask your doctor.
Overdose What to do if you have taken too much Ozurdex
In the event of an overdose, intraocular pressure should be monitored and, if deemed necessary by the physician, it should be treated.
Side Effects What are the side effects of Ozurdex
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects have been observed with OZURDEX:
Very common (may affect more than 1 in 10 people): Increased pressure in the eye, clouding of the lens (cataract), haemorrhage on the surface of the eye *
Common (may affect up to 1 in 10 people): Elevated eye pressure, clouding of the back of the natural lens, bleeding inside the eye *, worsening of vision, difficulty seeing clearly, detachment of the gelatinous layer inside the eye. "eye from the photosensitive layer at the back of the eye" (vitreous detachment), sensation of spots in the visual field (including "floaters") *, sensation of looking through fog or haze *, inflammation of the eyelids, eye pain *, flashes of light, swelling of the layer over the white part of the eye *, redness of the eye *, headache
Uncommon (may affect up to 1 in 100 people): Severe inflammation in the back of the eye (usually due to viral infection), severe infection or inflammation inside the eye, glaucoma (an eye disease in which the increased intraocular pressure is associated with damage to the optic nerve), detachment of the photosensitive layer from the back of the eye * (detachment of the retina), tearing of the photosensitive layer at the back of the eye (tearing of the retina), reduction of eye pressure associated with loss of the gelatinous (vitreous) layer from the inside of the eye *, inflammation in the front of the eye, increased proteins and cells in the front of the eye due to inflammation *, abnormal sensation in the eye *, eyelid itching, redness of the whites of the eye, migration of the OZURDEX implant from the back to the front of the eye causing blurred or reduced vision octa and which could eventually cause swelling of the transparent part of the eye (cornea) *, involuntary incorrect positioning of the OZURDEX * implant, migraine
* These side effects may be caused by the injection procedure and not by the OZURDEX implant itself. The more injections you perform, the greater the number of effects that can occur.
Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system.
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children. Your doctor should not use OZURDEX after the expiry date which is stated on the carton and envelope after EXP :. The expiry date refers to the last day of the 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 throw away medicines you no longer use. This will help protect the environment.
Other Information
What OZURDEX contains
- The active ingredient is dexamethasone.
- Each implant contains 700 micrograms of dexamethasone.
- The other ingredients are: 50:50 poly D, L-lactide coglycolide ending in ester and 50:50 poly D, L-lactide coglycolide ending in acid.
What OZURDEX looks like and contents of the pack
OZURDEX is a cylinder-shaped implant contained within the needle of an applicator. The applicator and a sachet of desiccant are sealed in a sealed bag inside a cardboard box. Each box contains an applicator with a single-use implant and discard immediately after use.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
OZURDEX 700 MCG INTRAVITREAL IMPLANT IN APPLICATOR
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One plant contains 700 mcg of dexamethasone.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Intravitreal implant in applicator.
Disposable injection device, containing a cylinder-shaped implant, not visible from the outside. The implant has the following approximate measurements: diameter 0.46 mm, length 6 mm.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
OZURDEX is indicated for the treatment of adult patients with:
• Reduction of vision due to diabetic macular edema (DME) in pseudophakic patients, or in patients who are believed to have an insufficient response or are unsuitable for non-corticosteroid therapy.
• Macular edema secondary to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).
• Inflammation of the posterior segment of the eye which is caused by non-infectious uveitis (see section 5.1).
04.2 Posology and method of administration
OZURDEX should be administered by a qualified ophthalmologist experienced in intravitreal injections.
Dosage
The recommended dose is one implant of OZURDEX administered intravitreally into the affected eye. Simultaneous administration in both eyes is not recommended (see section 4.4).
DME
For patients treated with OZURDEX who have experienced an initial response and who, in the physician's opinion, could benefit from retreatment without being exposed to significant risk, further treatment should be considered.
Retreatment can be carried out after about 6 months, if the patient has reduced vision and / or increased retinal thickness, secondary to recurrent or worsening diabetic macular edema.
Currently, no data are available on the efficacy or safety of repeated administration in DME beyond 7 implants.
RVO and uveitis
If the patient experiences loss of visual acuity after responding to treatment and if, in the judgment of the physician, he or she could benefit from retreatment without being exposed to significant risk, further treatment should be considered (see section 5.1).
Treatment should not be repeated in patients in whom vision improvement occurs and continues. The treatment should not be repeated even in patients who show deterioration of vision not slowed by OZURDEX.
There is limited information on repeated treatment at intervals of less than 6 months (see section 5.1). There are currently no data relating to repeated treatment in posterior segment non-infectious uveitis or more than twice in retinal venous occlusion.
Patients should be monitored after injection in order to be able to respond quickly in the event of infection or increased intraocular pressure (see section 4.4).
Special populations
Elderly patients (from 65 years of age)
No dose adjustment is necessary in elderly patients.
Kidney failure
OZURDEX has not been studied in patients with renal insufficiency, however no special consideration is required for this population.
Hepatic insufficiency
OZURDEX has not been studied in patients with hepatic insufficiency, however no special consideration is required for this population.
Pediatric population
There are no relevant cases of use of OZURDEX in pediatric patients with:
• diabetic macular edema
• macular edema secondary to Branca Retinal Vein Occlusion (BRVO) or Occlusion
Central Retinal Venous (CRVO).
The safety and efficacy of OZURDEX in uveitis in the pediatric population have not yet been established. No data are available.
Method of administration
OZURDEX is a disposable intravitreal implant in applicator for intravitreal use only.
Each individual applicator can only be used for the treatment of a single eye.
The intravitreal injection procedure should be performed under controlled aseptic conditions including the use of sterile gloves, a sterile drape, and a sterile blepharostat (or equivalent).
The patient should be instructed to self-administer broad spectrum antimicrobial eye drops every day for 3 days before and after each injection. Before the injection, it is necessary to disinfect the ocular, eyelid and periocular skin surface (for example by using drops of 5% povidone iodine solution on the conjunctiva as performed in clinical trials for the approval of OZURDEX) and to apply adequate local anesthesia Remove the envelope from the box and check for damage (see section 6.6). Then open the pouch in a sterile field and gently place the applicator on a sterile tray. Carefully remove the cap from the applicator. Once the pouch is opened, the applicator should be used immediately.
Hold the applicator in one hand and pull the safety tab. Do not twist or flex the tab. With the blunt side of the needle facing up, insert the needle into the sclera about 1mm and direct it towards the center of the needle. "eye in the vitreous chamber until the silicone sleeve is in contact with the conjunctiva. Slowly press the activation button until you hear a clear click. Before removing the applicator from the eye, make sure that the activation button has been pressed at the bottom, blocking at the level of the applicator surface. Remove the needle in the same direction followed to insert it into the eye.
Immediately following the injection of OZURDEX, perform an indirect ophthalmoscopy in the injection quadrant to verify that the implant insertion procedure was performed correctly.
Visualization is possible in the vast majority of cases. If the implant is not visible, use a sterile cotton swab to exert gentle pressure at the injection site so that you can see the implant.
Following the intravitreal injection, patients should continue to be treated with a broad spectrum antimicrobial.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Active or suspected ocular or periocular infections, including most viral diseases of the cornea and conjunctiva, including cases of ongoing herpes simplex epithelial keratitis (dendritic keratitis), smallpox, chicken pox, mycobacterial infection and fungal diseases .
• Advanced glaucoma not adequately controlled with drug use alone.
• Aphakic eyes with rupture of the posterior lens capsule.
• Eyes with anterior chamber intraocular lens (ACIOL), iris or transcleral fixation intraocular lens and posterior lens capsule rupture.
04.4 Special warnings and appropriate precautions for use
Intravitreal injections, including those of OZURDEX, may be associated with endophthalmitis, intraocular inflammation, increased intraocular pressure and retinal detachment. Appropriate aseptic injection techniques should always be used. Furthermore, after the injection it is necessary to monitor the patients, in order to be able to intervene quickly in case of infection or increase in intraocular pressure. Monitoring may require a check of the perfusion of the optic nerve head immediately after the injection, a tonometry within 30 minutes of injection and a biomicroscopic examination two to seven days after injection.
Patients should be instructed to immediately report any symptoms that indicate the presence of endophthalmitis or any of the events mentioned above, e.g. eye pain, blurred vision, etc. (see section 4.8).
All patients with a lacerated posterior lens capsule such as those with a posterior chamber lens (eg due to cataract surgery) and / or those who have an "iris opening" in the vitreous cavity (eg due to iridectomy ) with or without a history of vitrectomy, are at risk of implant migration into the anterior chamber. Migration of the implant into the anterior chamber can lead to corneal edema. Severe and persistent corneal edema may progress to require corneal transplantation. With the exception of patients with contraindications (see section 4.3), for whom OZURDEX should not be used, OZURDEX should be used with caution and only after careful consideration. benefit risk assessment.
These patients should be closely monitored to allow for early diagnosis and management of device migration.
The use of corticosteroids, including OZURDEX, can induce cataracts (including posterior subcapsular cataracts), increased IOP, steroid-induced glaucoma and can cause secondary eye infections.
In the 3-year DME clinical studies 59% of patients with study phakic eye treated with OZURDEX underwent cataract surgery in the study eye (see section 4.8).
After the first injection, the incidence of cataracts appears higher in patients with posterior segment non-infectious uveitis than in BRVO / CRVO patients. In the BRVO / CRVO clinical trials, cases of cataracts were reported more frequently in phakic patients receiving a second injection. (See section 4.8) Only one out of 368 patients required cataract surgery during the first treatment and three out of 302 patients during the second treatment.In the non-infectious uveitis study, 1 of 62 phakic patients underwent cataract surgery after a single injection.
The prevalence of conjunctival haemorrhage in patients with posterior segment non-infectious uveitis appears to be higher than in BRVO / CRVO and DME. This could be attributable to the intravitreal injection procedure or the concomitant use of topical and / or systemic corticosteroids or non-steroidal anti-inflammatory drugs. No treatment is required as spontaneous resolution occurs.
As expected with the administration of ocular steroids and intravitreal injections, an increase in intraocular pressure (IOP) may be seen. The increase in IOP is usually manageable with the use of drugs that reduce IOP (see section 4.8). Among the patients who reported cases of increases in IOP greater than or equal to 10 mmHg from baseline, most of these showed this increase between 45 and 60 days after injection. Therefore, regular monitoring of IOP is necessary. regardless of baseline IOP, and any increase after injection should be managed as appropriate. Patients younger than 45 years of age with macular edema following retinal vein occlusion or posterior eye inflammation caused by non-infectious uveitis are more likely to increase IOP.
In patients with a history of viral ocular infection (e.g. herpes simplex), corticosteroids should be used with caution and should not be used in the presence of active ocular herpes simplex.
The safety and efficacy of OZURDEX administered simultaneously in both eyes have not yet been evaluated. Therefore, simultaneous administration in both eyes is not recommended.
OZURDEX has not been studied in patients with macular edema secondary to RVO with significant retinal ischaemia. OZURDEX is therefore not recommended for these patients.
In Phase 3 studies a limited number of subjects with type 1 diabetes were examined and the response to OZURDEX in these subjects was not significantly different than in those with type 2 diabetes.
In the study of patients with RVO, anticoagulant therapy was used in 2% of patients treated with OZURDEX; no cases of haemorrhagic adverse events were reported in these patients.
In the study of patients with DME, anticoagulant therapy was used in 8% of patients. Among patients who used anticoagulant therapy, the frequency of adverse haemorrhagic events was similar in the OZURDEX group compared to the sham treatment group. (29% vs 32%). Among patients who did not use anticoagulant therapy, 27% of patients treated with OZURDEX reported adverse haemorrhagic events compared to 20% of those in the sham treatment group. Vitreous haemorrhage was reported in a higher percentage of patients treated with OZURDEX who took anticoagulant therapy (11%) than those who did not (6%).
Antiplatelet medicinal products, such as clopidogrel, have been used in some phases of clinical trials in up to 56% of patients. For patients using concomitant and antiplatelet drugs, haemorrhagic adverse events were reported in a slightly higher proportion of patients given OZURDEX (up to 29%) than in the sham group (up to 23%) , regardless of therapeutic indication or number of treatments. The most common haemorrhagic adverse event reported was conjunctival haemorrhage (up to 24%).
OZURDEX should be used with caution in patients taking anticoagulant or antiplatelet medicines.
04.5 Interactions with other medicinal products and other forms of interaction
No interaction studies have been performed.
Systemic absorption is minimal and no interactions are expected.
04.6 Pregnancy and breastfeeding
Pregnancy
Studies in animals have shown teratogenic effects following topical ophthalmic administration (see section 5.3). Adequate data are not available regarding the use of dexamethasone administered intravitreally to pregnant women. Long-term systemic treatment with glucocorticosteroids during pregnancy increases the risk of intrauterine growth retardation and adrenal insufficiency in the newborn. Hence, although systemic levels of dexamethasone in humans have been shown to be low, intraocular treatment with OZURDEX is not recommended during pregnancy unless the potential benefit justifies the potential risk to the fetus.
Feeding time
Dexamethasone is excreted in breast milk. Following this route of administration, and the resulting systemic levels, no effects on the child are expected. However, OZURDEX is not recommended during breastfeeding, unless specifically needed.
Fertility
No data are available in relation to fertility.
04.7 Effects on ability to drive and use machines
OZURDEX may moderately affect the ability to drive and use machines. After administration of OZURDEX, patients may experience a temporary decrease in vision (see section 4.8). They should therefore avoid driving or operating machinery until these effects disappear.
04.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse events following treatment with OZURDEX are those frequently observed with ophthalmic steroid therapy or intravitreal injections (increased IOP, cataract formation, and conjunctival or vitreous haemorrhage, respectively).
Less frequently reported but more serious adverse reactions include endophthalmitis, necrotizing retinitis, retinal detachment and retinal tear.
With the exception of headache and migraine, no systemic adverse drug reactions have been identified with the use of OZURDEX.
Table containing the list of adverse reactions
Adverse reactions believed to be related to OZURDEX treatment observed in Phase III clinical trials (DME, BRVO / CRVO and uveitis) and reported spontaneously are listed in the following table by MedDRA system organ class, according to the following convention:
Very common (≥ 1/10), common (≥1 / 100 to
Table 1 Adverse reactions
* indicates adverse reactions considered related to the intravitreal injection procedure (the frequency of these adverse reactions is proportional to the number of treatments administered)
Description of selected adverse reactions
Diabetic macular edema
The clinical safety of OZURDEX in patients with diabetic macular edema was evaluated in two randomized, double-blind, sham-controlled Phase III studies. In both studies, a total of 347 patients received OZURDEX were randomized, while 350 patients received sham treatment.
The most frequently reported adverse reactions throughout the study period in the study eye of patients undergoing OZURDEX treatment were cataracts and increased IOP (see below).
In the 3-year DME clinical studies, 87% of patients with study phakic eye treated with OZURDEX had some degree of lens opacification / cataract initiation at baseline. In the 3-year studies, the incidence of all types of cataracts observed (i.e. cortical cataract, diabetic cataract, nuclear cataract, subcapsular cataract, lenticular cataract, cataract) in patients with a phakic study eye treated with OZURDEX was 68% 59% of patients with a phakic study eye needed cataract surgery by the final 3rd year visit; most performed in the 2nd and 3rd year.
The mean baseline IOP in the study eye was the same in both treatment groups (15.3 mmHg). In the OZURDEX group, the mean increase from baseline IOP did not exceed 3.2 mmHg at all visits. peak mean IOP at visit 1.5 months after injection, returning to approximately baseline levels by month 6 after each injection. The rate and extent of IOP increase following OZURDEX treatment is not increased with the repetition of the injection of OZURDEX.
28% of patients treated with OZURDEX had an IOP increase of ≥10 mmHg from baseline at one or more visits during the study. At baseline, 3% of patients required IOP-lowering drug (s). Overall, in the 3-year studies, 42% of patients required IOP-lowering drugs in the study eye, with the majority of patients requiring more than one drug. Peak use (33 %) occurred during the first 12 months and remained similar from year to year.
A total of 4 patients (1%) treated with OZURDEX underwent surgery on the eye under study for the treatment of increased IOP. One patient treated with OZURDEX required incisional surgery (trabeculectomy) to manage the steroid-induced increase in IOP, 1 patient underwent trabeculectomy due to the formation of fibrin in the anterior chamber which blocked aqueous outflow resulting in an increase in IOP , 1 patient underwent iridotomy due to closed angle glaucoma and 1 patient underwent iridectomy due to cataract surgery. No patient required implant removal via vitrectomy in order to control IOP.
BRVO / CRVO
The clinical safety of OZURDEX in patients with macular edema secondary to central or branch retinal vein occlusion was evaluated in two randomized, double-blind, phase III studies versus sham treatment. In the two phase III studies 427 patients were randomized to receive OZURDEX and 426 to receive sham treatment. In total, 401 (94%) patients randomized and treated with OZURDEX completed the initial treatment period (up to day 180).
In total, 47.3% of patients reported at least one adverse reaction. The most frequently reported adverse reactions in patients who had undergone treatment with OZURDEX were increased intraocular pressure (24.0%) and conjunctival haemorrhage (14.7%).
The adverse reaction profile for patients with BRVO cases was similar to that observed for patients with CRVO, although the overall incidence of adverse reactions was higher for the subgroup of patients with CRVO.
The increase in intraocular pressure (IOP) with OZURDEX peaks at day 60, then returns to baseline levels by day 180. The rise in IOP either required no treatment or was managed with temporary use of topical therapy for IOP control.
During the initial treatment period, 0.7% (3/421) of patients given OZURDEX required laser or surgical procedures to manage high IOP in the eye studied, compared with 0.2%. (1/423) of patients undergoing sham treatment.
The adverse reaction profile of 341 patients analyzed after a second injection of OZURDEX was similar to that seen with the first injection. In total, 54% of patients reported at least one adverse reaction. The incidence of IOP elevation (24.9%) was similar to that seen following the first injection and similarly returned to baseline by day 180.
The overall incidence of cataracts was higher after one year than in the first six months.
Uveitis
The clinical safety of OZURDEX in patients with posterior eye inflammation caused by non-infectious uveitis was evaluated in a single blinded, multicentre, randomized study.
In total, 77 patients were randomized to receive OZURDEX, and 76 underwent sham treatment. In total, 73 patients (95%) randomized and treated with OZURDEX completed the 26-week study.
The most frequently reported adverse reactions in the study eye of patients who had undergone treatment with OZURDEX were conjunctival haemorrhage (30.3%), increased intraocular pressure (25.0%) and cataract ( 11.8%).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
In the event of an overdose, intraocular pressure should be monitored and, if deemed necessary by the physician, it should be treated.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: ophthalmologicals, anti-inflammatories.
ATC code: S01BA01.
Dexamethasone, a potent corticosteroid, has been shown to suppress inflammation by reducing edema, fibrin deposition, capillary hyperpermeability and phagocytic migration of the inflammatory response. VEGF (vascular endothelial growth factor) is an expressed cytokine in increasing concentrations in case of macular edema, it is also a potent promoter of vascular permeability. The inhibiting effect of corticosteroids on VEGF expression has been demonstrated. In addition, corticosteroids prevent the release of prostaglandins, some of which have been identified as mediators of cystoid macular edema.
Clinical efficacy and safety
Diabetic macular edema
The efficacy of OZURDEX was evaluated in two parallel, multicentre, double-blind, randomized, sham-controlled, 3-year studies of the same design, which included a total of 1,048 patients (studies 206207-010 and 206207-011) In total, 351 patients were randomized to OZURDEX, 347 to dexamethasone 350 mcg, and 350 patients to sham treatment.
Patients were eligible for retreatment if they had a central subfield retinal thickness> 175 μm detected by optical coherence tomography (OCT) or based on the investigators' OCT assessment of any evidence of residual retinal edema characterized from intraretinal cysts or any region with increased retinal thickness internal or external to the central subfield Patients received a maximum of 7 treatments, at intervals of not less than approximately 6 months.
Alternative therapy was allowed at the investigators' discretion at any time, but resulted in subsequent withdrawal from studies.
In total, 36% of patients treated with OZURDEX discontinued participation in the study for various reasons during the study, compared with 57% of patients who received sham treatment. Discontinuation rates due to adverse events were similar for both the actual and sham treatment groups (13% vs. 11%). Discontinuation due to lack of efficacy was less in the OZURDEX group than in the sham group (7% vs. 24%).
Table 2 presents the primary and key secondary endpoints from studies 206207-010 and 011. Vision improvement in the DEX700 group was reduced due to cataract formation. Vision improved after cataract removal.
Table 2. Efficacy in Studies 206207-010 and 20627-011 (ITT population)
Table 3 presents the primary endpoints and the main secondary endpoints for the pooled analysis for pseudophakic patients.
Table 3. Efficacy in pseudophakic patients (pooled studies 206207-010 and 206207-011)
Table 4 presents the primary and key secondary endpoints for the pooled analysis of patients undergoing any previous treatment.
Table 4. Efficacy in patients undergoing any previous treatment (pooled studies 206207-010 and 206207-011)
BRVO / CRVO
The efficacy of OZURDEX was evaluated in two multicenter, identical design, double-blind, randomized, parallel, sham-controlled trials. A total of 1,267 patients were enrolled who were randomized to receive treatment with 350 mcg or 700 mcg dexamethasone implants or sham procedure (Studies 206207-008 and 206207-009). In total, 427 patients were randomized to OZURDEX, 414 to dexamethasone 350 mcg, and 426 patients to sham procedure.
Based on the results of the pooled analysis, treatment with implants of OZURDEX showed a statistically significant higher incidence of responders than control (p
Table 5 shows the percentage of patients who achieved the primary efficacy parameter with an improvement in BVCA ≥ 15 letters from baseline after single implant injection.
The efficacy of the treatment was seen from the first follow-up visit, on day 30. The maximum treatment effect was observed on day 60 and the difference in the incidence of responders was statistically significant for OZURDEX compared to sham in all visits. control up to 90 days post injection. The percentage of responders with ≥ 15 letter improvement from baseline BCVA continued to be greater in patients treated with OZURDEX than in sham patients even at day 180 control.
Table 5. Percentage of patients with ≥ 15 letter improvement from baseline BCVA in study eye (pooled data, ITT population)
a Significantly higher percentage with OZURDEX compared to the simulation procedure (p
At all follow-up visits, the mean change in BCVA from baseline was significantly higher with OZURDEX than with the sham procedure.
In each phase III study and in the pooled analysis, the time to achieve an improvement in BCVA ≥ 15 letters (three lines) in the cumulative response curves was significantly different with OZURDEX compared to the sham procedure (p
OZURDEX was numerically superior to the sham procedure in preventing vision loss, as demonstrated by the lower percentage of patients in the group.
OZURDEX who experienced worsening vision of ≥ 15 letters during the 6 month evaluation period.
In each of the phase III studies and in the pooled analysis, at day 90, the mean retinal thickness was significantly lower, as was the mean reduction from baseline, with OZURDEX (-207.9 microns) compared to simulation procedure (-95.0 microns) (p
At day 180, the mean reduction in retinal thickness (-119.3 microns) was not significant compared to the sham procedure.
In the open-label extension phase of the Phase III study, patients with BCVA 250 microns assessed on OCT (optical coherence tomography) were eligible for further treatment with OZURDEX for whom, in the investigator's opinion, the treatment did not pose a risk to the patient.
Of the patients treated in the open-label phase, 98% received a second injection of OZURDEX 5 to 7 months after the initial treatment.
As with the initial treatment, the peak response was observed at day 60 of the open-label phase. During the entire open-label phase, cumulative response rates were greater in patients who received two consecutive injections of OZURDEX than in those who did not receive the OZURDEX injection in the initial phase.
Compared with the first treatment, the percentage of responders at each control was always higher after the second treatment. In contrast, a six-month delay in treatment results in a lower percentage of responders at all follow-up visits during the open label phase than the number of patients who received a second injection of OZURDEX.
Uveitis
The clinical efficacy of OZURDEX was evaluated in a single, randomized, multicentre, blinded study for the treatment of posterior segment inflammation in adult patients with uveitis.
In total, 229 patients were randomized to receive 350 mcg or 700 mcg dexamethasone implant or sham procedure. Of these, a total of 77 patients were randomized to OZURDEX, 76 dexamethasone 350 mcg and 76 patients were underwent a sham procedure In total, 95% of patients completed the 26-week study.
The proportion of patients with a vitreous opacification score of 0 in the study eye at week 8 (primary endpoint) was 4 times higher with OZURDEX (46.8%) compared to the sham procedure (11.8%) , p
The cumulative response rate curves (time to a vitreous opacification score of 0) were significantly different for the OZURDEX group compared to the sham procedure group (p
The reduction of vitreous opacification was accompanied by an improvement in visual acuity. The proportion of patients with an improvement of at least 15 letters from baseline BCVA in the study eye at week 8 was more than 6 times higher with OZURDEX (42.9%) than with the sham procedure (6.6%), p
The percentage of patients who required additional medications during the period from baseline to week 8 was approximately 3-fold lower with OZURDEX (7.8%) than with sham (22.4%), p = 0.012.
Table 6. Percentage of patients with vitreous opacification score of zero and ≥ 15 letter improvement from baseline best corrected visual acuity in study eye (ITT population)
on p
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies on the treatment of retinal vascular occlusion and also diabetic macular edema with OZURDEX in all subsets of the pediatric population (for information on pediatric use , see section 4.2).
05.2 Pharmacokinetic properties
In a subgroup of 21 patients, in the two 6-month efficacy studies in patients with RVO, plasma concentrations were measured before dosing and after 7, 30, 60 and 90 days after the intravitreal injection of a single intravitreal implant containing 350 mcg or 700 mcg of dexamethasone. 95% of the plasma concentration values of dexamethasone for the 350 mcg group and 86% for the 700 mcg group were below the lower limit of quantification (0.05 ng / ml). The maximum concentration value in plasma, equal to 0.094 ng / ml, it was detected in one subject of the 700 mcg group. The concentration of dexamethasone in plasma does not appear to be related to other factors such as age, weight or gender of the patients.
Plasma concentrations were obtained from a subgroup of patients participating in the two pivotal DME studies, before dosing and after 1, 7 and 21 days and 1.5 and 3 months after the intravitreal injection of a single intravitreal implant containing 350 mcg or Dexamethasone 700 mcg 100% dexamethasone plasma concentration values for the 350 mcg group and 90% for the 700 mcg group were below the lower limit of quantification (0.05 ng / mL). The maximum plasma concentration of 0.102 ng / mL was found in one subject from the 700 mcg group. The plasma dexamethasone concentration did not appear to be related to other factors such as age, body weight or the sex of the patients.
In a 6-month study in monkeys, following a single intravitreal injection of OZURDEX, the vitreous dexamethasone Cmax value was 100 ng / mL at day 42 post injection and 5.57 ng / mL on day 91. Dexamethasone was detectable in the vitreous for six months after injection. The order of dexamethasone concentration values was retina> iris> ciliary body> vitreous> aqueous humor> plasma.
In a studio in vitro on metabolism, following incubation for 18 hours of [14C] -dexamethasone with human tissues from the cornea, iris-ciliary body, choroid, retina, vitreous and sclera, no metabolites were detected. This is consistent with the results obtained. from studies on ocular metabolism of rabbits and monkeys.
Dexamethasone is eventually metabolised to lipids and water-soluble metabolites which can be excreted via the bile and urine.
The OZURDEX matrix slowly degrades to lactic acid and glycolic acid through simple hydrolysis, further degrading to carbon dioxide and water.
05.3 Preclinical safety data
Effects in preclinical studies were observed only at dosages considered sufficiently in excess of the maximum human dose, indicating little relevance for clinical use.
No data on mutagenicity, carcinogenicity or reproductive and developmental toxicity are available for OZURDEX. Dexamethasone has been shown to be teratogenic in mice and rabbits after topical ophthalmic applications.
Exposure to dexamethasone was observed in rabbits following contralateral spread to the healthy / untreated eye after an implant was placed in the back of the eye.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
• 50:50 poly D, L lactide coglycolide terminating in ester.
• 50:50 poly D, L acid-terminating coglycolide lactide.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Each pack contains:
A barrel-shaped, extended-release sterile implant containing 700 mcg of dexamethasone, inside the (stainless steel) needle of a disposable applicator.
The applicator consists of a piston (in stainless steel) placed inside a needle where the implant is held in position by a sleeve (in silicone). The piston is controlled by a lever placed laterally on the body of the " applicator. The needle is protected by a cap, while the lever has a safety tab.
The applicator containing the implant is packaged in a sealed pouch containing a desiccant sachet.
06.6 Instructions for use and handling
OZURDEX is for single use only.
A single applicator can only be used for the treatment of a single eye.
The applicator must not be used if the seal of the bag containing the applicator is damaged.
Once the pouch is opened, the applicator should be used immediately.
Unused medicine and waste products must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Allergan Pharmaceuticals Ireland
Castlebar Road,
Co. Mayo
Westport
Ireland
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/10/638/001
040138012
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 27/07/2010
Date of the last renewal: 23/03/2015
10.0 DATE OF REVISION OF THE TEXT
03/2015
