Approval date: October 20, 2017
Date of revision.
Dexamethasone Intravitreal Implant Instructions
Please read the instructions carefully and use under the guidance of a physician.
[Drug Name].
Generic name: Dexamethasone intravitreal implant
Trade name: OZURDEX®
English name: Dexamethasone Intravitreal Implant
Hanyu Pinyin: Disaimisong Bolitinei Zhiruji
Ingredients
The active ingredient of this product is dexamethasone.
Chemical name: 16α-methyl-11β, 17α, 21-trihydroxy-9α-fluoropregna-1, 4-diene-3, 20-dione.
Chemical structure formula.
Molecular formula: C22H29FO5
Molecular weight: 392.47
Excipient: ethyl cross ester propyl cross ester copolymer.
Properties
This product is an intravitreal implant for the eye, white or off-white rod-shaped implant placed in the implantation device and sealed in a compound aluminum foil bag with desiccant.
Indications
This product is indicated for the treatment of macular edema caused by branch retinal vein occlusion (BRVO) or central venous occlusion (CRVO) in adult patients.
Specification】0.7 mg
Dosage and Administration
Dexamethasone intravitreal implant must be administered by a qualified ophthalmologist with experience in intravitreal injections.
Dosage
The recommended dose is one implant given intravitreally to a single affected eye. Simultaneous administration to both eyes is not recommended (see [Precautions]).
Repeat dosing should be considered in cases of initial response to treatment followed by vision loss if the treating physician believes that the patient may benefit from retreatment and will not be exposed to significant risk (see [Clinical Trials]).
Patients whose vision improves with treatment and is maintained do not require retreatment. Patients who experience worsening vision that does not resolve with this product should not be retreated.
Information on repeat dosing at intervals of less than 6 months is very limited (see [Clinical Trials]). For information on current experience with the safe use of more than 2 implant administrations in patients with retinal vein occlusion (RVO), see [Adverse Reactions].
Following intravitreal injection, patients should be monitored for elevated intraocular pressure and endophthalmitis. Monitoring should include checking the blood flow to the optic nerve papilla immediately after injection, performing an intraocular pressure check within 30 minutes after injection, and performing a biomicroscopic examination between 2 and 7 days after injection. Patients should be advised to report immediately any signs of suspected endophthalmitis. If infection or elevated intraocular pressure occurs, treat as soon as possible (see [Precautions]).
Dosage
Single-use intravitreal implants prefilled in a delivery device are for intravitreal use only. Each delivery device should only be used for treatment of a single eye.
The intravitreal injection procedure should be performed under controlled aseptic conditions, including the use of sterile gloves, sterile surgical sheets, and sterile lid openers (or similar devices).
Patients should be instructed to use broad-spectrum antibiotic eye drops once daily for 3 days before and after the injection. Prior to injection, the periocular skin, eyelids, and ocular surface should be disinfected (e.g., using 5% povidone-iodine solution in drops on the conjunctiva) and adequate local anesthesia should be administered. Remove the foil pouch from the carton and check for tears. Open the foil pouch in a sterile area and gently place the dosing device on a sterile tray. Carefully remove the cap from the drug delivery device. Once the foil pouch is opened, the dispenser should be used immediately.
Hold the dispenser in one hand and pull the safety tab vertically off the dispenser with the other hand. Do not twist or bend the safety tab. With the needle tip beveled up and dorsal to the sclera, insert the needle approximately 1 mm into the sclera, then turn the needle toward the center of the eye and feed it into the vitreous humor until the silicone sleeve contacts the conjunctiva. The activation button is slowly depressed until a “click” is heard. Before withdrawing the applicator from the eye, ensure that the activation button is fully depressed and locked flush with the applicator surface. Exit the needle using the same path as into the vitreous.
Immediately after injection of the dexamethasone intravitreal implant, the injection quadrant is checked using an indirect inspection ophthalmoscope to ensure successful implantation. The implant was visible in the vast majority of cases. If the implant is not observed, a sterile cotton swab is taken and gently pressed at the injection site to bring the implant into view.
Following intravitreal injection, patients should continue to receive broad-spectrum antibiotic therapy as prescribed by their physician.
Each drug delivery device should be used to treat only one eye. If the other eye requires treatment, a new delivery device must be used. The sterile area, delivery device, gloves, surgical sheet and eye support should be changed when the product is used in the other eye.
Training in injection techniques for this product is available from Allergan.
Special Populations
Renal impairment has not been studied with this product in patients with renal impairment.
Hepatic impairment has not been studied in patients with hepatic impairment.
[Adverse Reactions].
Summary of safety profile
The most commonly reported adverse events following treatment with this product are those commonly associated with ophthalmic steroid therapy or intravitreal injections (elevated intraocular pressure, cataract formation, and conjunctival hemorrhage or vitreous hemorrhage).
Less commonly reported but more serious adverse reactions include endophthalmitis, necrotizing retinitis, retinal detachment, and retinal fissures.
There have been no systemic adverse drug reactions associated with the use of this product, except for headache and migraine.
Clinical Trials
Adverse reactions from phase III clinical trials considered to be related to treatment with this product are listed in Table 1 according to the MedDRA Systematic Organ Classification according to the following rules.
Very common (≥ 1/10), common (≥ 1/100 ~ <1/10), uncommon (≥ 1/1,000 ~ <1/100), rare (≥ 1/10,000 ~ <1/1,000), and very rare (<1/10,000). Within each frequency group, adverse reactions were listed in decreasing order of severity.
Table 1.
System Organ Classification Incidence Adverse Reactions Neurological Common Headache Ocular Very Common Increased intraocular pressure, conjunctival hemorrhage* Common hypertension, vitreous detachment, cataract, subcapsular cataract, vitreous hemorrhage*, visual disturbances, vitreous opacities* (including vitreous flyswept), ocular pain*, flash sensation*, conjunctival edema*, anterior chamber cells*, conjunctival congestion* Uncommon Retinal fissure*, anterior chamber flash glow* General disease and administration site conditions uncommon with or without corneal edema drug ectasia (implant displacement, see [Precautions])
Complications of implant insertion leading to ocular tissue damage (implant misplacement)* indicates that these adverse reactions are thought to be associated with the vitreous injection procedure rather than with the dexamethasone implant.
** In a 24-month real-world observational study of dexamethasone intravitreal implantation for macular edema due to retinal vein occlusion and noninfectious uveitis affecting the posterior segment of the eye, these adverse reactions were reported more frequently in patients who received >2 injections compared with those who received ≤2 injections; respectively (received >2 injections vs. received ≤ 2 injections): cataract formation (24.7% and 17.7%), cataract progression (32.0% and 13.1%), vitreous hemorrhage (6.0% and 2.0%), and IOP elevation (24.0% and 16.6%).
The clinical safety of this product was evaluated in two phase III randomized, double-blind, mock treatment-controlled studies (206207-008 and 206207-009) in patients with macular edema due to central or branch retinal vein occlusion. In these two studies, a total of 427 patients were randomized to dexamethasone intravitreal implant treatment and 426 patients to mock treatment. A total of 401 (94 %) patients randomized to dexamethasone intravitreal implantation 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 treated with dexamethasone intravitreal implants were elevated intraocular pressure (24.0 %) and conjunctival hemorrhage (14.7 %).
The profile of adverse reactions in patients with BRVO was similar to that observed in patients with CRVO, although the overall incidence of adverse reactions was higher in the CRVO subgroup.
Treatment with dexamethasone intravitreal implant resulted in a peak IOP elevation at day 60, which fell back to baseline levels at day 180. A portion of the IOP elevation did not require treatment, and the other portion could be controlled with short-term topical IOP-lowering medications. During the initial treatment period, 0.7 % (3/421) of patients receiving the dexamethasone intravitreal implant required laser or surgical treatment to control the IOP elevation in the study eye, compared with 0.2 % (1/423) of the corresponding mock-treated patients.
The 341 patients who received a second injection of this product were analyzed for adverse reactions similar to those following the first injection. In total, 54 % of patients experienced at least one adverse reaction. The incidence of elevated intraocular pressure (24.9 %) was similar to that observed after the first injection, again falling back to baseline levels by day 180 of open label. The overall incidence of cataracts was higher at 1 year compared to the initial 6 months.
Postmarketing Experience
The following adverse reactions were identified following the post-marketing of dexamethasone intravitreal implant.
Ocular disease: endophthalmitis (injection related, see [Precautions])
hypotony (associated with injection-induced vitreous leakage)
Retinal detachment general disease and administration site conditions: complications of implant embedding leading to ocular tissue damage (implant misalignment)
Drug ectasia with or without corneal edema (implant displacement, see [Precautions]) [Contraindication
This product is contraindicated in.
Hypersensitivity to dexamethasone or to any of the excipients of this product.
Patients with active or suspected ocular or periocular infections, including most viral diseases of the cornea and conjunctiva, such as active herpes simplex virus epithelial keratitis (dendritic keratitis), cowpox, varicella, mycobacterial infections, and fungal diseases.
Patients with advanced glaucoma that cannot be effectively controlled by medications alone.
Lens-less eyes with ruptured posterior lens capsule.
Eyes with anterior chamber IOLs (ACIOL), iris or transscleral fixed intraocular IOLs, and eyes with ruptured posterior lens capsule.
Precautions]
Intravitreal injections, including injections with this product, may be associated with endophthalmitis, ocular inflammation, elevated intraocular pressure, and retinal detachment. Appropriate aseptic injection techniques should be used. Patients should be monitored after injection and treated as soon as possible if infection or elevated intraocular pressure occurs. Monitoring may include examination of the optic papilla for perfusion immediately after injection, IOP examination within 30 minutes after injection, and biomicroscopy within 2 to 7 days after injection.
Patients must be instructed to report immediately any symptoms suspected of endophthalmitis or any of the events mentioned above, such as eye pain, blurred vision, etc. (see [Adverse Reactions]).
All patients with posterior lens capsule tears, such as those with a posterior segment lens (e.g., due to cataract surgery), and/or those with an opening in the iris to the vitreous cavity (e.g., due to iridotomy) with or without vitrectomy, are at risk for migration of the implant into the anterior chamber. Migration of the implant into the anterior chamber can cause corneal edema, and persistent severe corneal edema can progress to the need for corneal transplantation. In addition to contraindications (see [Contraindications]), this product should be used with caution and only after a careful risk-benefit assessment has been performed. These patients should be closely monitored for early diagnosis and response to drug migration.
The use of glucocorticoids, including this product, may cause cataracts (including posterior subcapsular cataracts), increased intraocular pressure, hormone-induced glaucoma, and may lead to secondary ocular infections.
In the BRVO/CRVO clinical study, cataracts were reported at a higher rate in patients with a lens who received a second injection (see [Adverse Reactions]). Only 1 of 368 patients required cataract surgery at first treatment, and 3 of 302 patients required surgery at second treatment.
As expected, an increase in intraocular pressure (IOP) was seen with ocular hormone therapy and intravitreal injections. The elevated IOP was usually controlled with IOP-lowering medications (see [Adverse Reactions]). In patients with an IOP increase of ≥10 mmHg relative to baseline, the majority of patients showed this IOP increase between 45 and 60 days post-injection. Therefore, regular monitoring of IOP is required regardless of baseline IOP, and any post-injection elevation should be controlled as needed. patients under 45 years of age with macular edema due to retinal vein occlusion are more likely to have elevated IOP.
Glucocorticoids should be used with caution in patients with a history of ocular viral (e.g., herpes simplex) infection and should not be used in patients with active ocular herpes simplex.
The safety and efficacy of concomitant administration of this product to both eyes has not been studied. Therefore, concurrent administration to both eyes is not recommended.
The use of this product has not been studied in patients with RVO secondary to macular edema who have significant localized retinal ischemia. Therefore, the use of this product is not recommended in such patients.
Anticoagulant therapy was used in 1.7% of patients treated with dexamethasone intravitreal implants, and no bleeding adverse events were reported in these patients.
Antiplatelet agents, such as clopidogrel, were used in more than 40% of patients at some stage of the clinical study. For patients on combined antiplatelet agents, the proportion of reported bleeding adverse events was higher in the dexamethasone intravitreal implant injection group (27%) than in the mock treatment group (20%). The most common bleeding adverse event reported was conjunctival hemorrhage (24%).
Dexamethasone intravitreal implant should be used with caution in patients taking anticoagulants or antiplatelet agents.
This product is for single use only.
Each delivery device is limited to treatment of a single eye.
Do not use if the foil pouch packaging is broken. Once the foil pouch has been opened, the drug delivery device should be used immediately.
Any unused medication or discarded material should be disposed of in accordance with local requirements.
Effect on ability to drive and use machines
This product may have some effect on the ability to drive and use machinery. Temporary loss of vision may occur in patients receiving intravitreal injections of this product (see [ADVERSE REACTIONS]). Do not drive or use machines until vision is restored.
Use with caution in athletes.
For Pregnant and Lactating Women
Pregnant women
Animal studies have shown teratogenic effects after topical ophthalmic administration (see [Pharmacology and Toxicology]). There are no adequate data on the use of intravitreal administration of dexamethasone in women during pregnancy. Prolonged systemic treatment with glucocorticoids during pregnancy may increase the risk of fetal growth retardation and neonatal adrenal insufficiency. Therefore, despite the expected minimal systemic exposure to dexamethasone after intraocular topical administration, the use of this product during pregnancy is not recommended unless the benefit is confirmed to outweigh the potential risk to the fetus.
Lactating Women
Dexamethasone may be secreted into breast milk. No effect is expected in children due to the mode of administration and the low levels of systemic drug produced after administration. However, the use of this product during lactation is not recommended unless clearly necessary.
Fertility
Fertility data are not available.
Pediatric Dosage]
No information is available on the use of this product in the pediatric population for macular edema caused by BRVO or CRVO.
Geriatric Use]
No dose adjustment is required for elderly patients.
Drug Interactions]
No drug interaction studies have been conducted.
Drug Overdose]
In case of overdose, monitor IOP and treat as required by the treating physician.
Clinical Trials
The clinical efficacy of a single administration of dexamethasone intravitreal implant in patients with macular edema caused by branch retinal vein occlusion (BRVO) or central venous occlusion (CRVO) was evaluated in three phase 3 randomized, blinded, mock treatment-controlled parallel studies, blinded for 6 months. Patients were eligible to receive a second treatment in an open-label extension period. A total of 1,267 patients (427 dexamethasone intravitreal implant 700 µg, 414 dexamethasone intravitreal implant 350 µg and 426 mock treatments) were treated in two global pivotal studies, RVO1 and RVO2. A total of 259 patients (129 in the dexamethasone intravitreal implant 700 µg group and 130 in the mock treatment group) were treated in the Chinese registry RVO study (RVO3).
Based on the pooled results of the two global pivotal studies, RVO1 and RVO2, and the analysis of the Chinese registry study RVO3, patient response rates were significantly higher in the dexamethasone intravitreal implant treatment group than in the mock treatment group (p < 0.001, with response defined as patients achieving best-corrected visual acuity [BCVA] at day 90 after receiving a single implant injection relative to baseline of ≥ (15 letters of improvement).
Table 2 shows the proportion of patients who achieved the primary efficacy index, i.e., BCVA improvement of ≥15 letters relative to baseline, after single implant injection administration. Efficacy was seen at the first observation time point, i.e., 30 days after treatment. Maximum efficacy was observed at day 60, and response rates were significantly higher in the implant-treated group than in the mock-treated group at all time points up to day 90 post-injection. At day 180, the proportion of patients in the implant-treated group with ≥15 letters of improvement in BCVA relative to baseline remained numerically greater than in the mock-treated group.
Table 2 Proportion of patients with ≥ 15 letters of improvement in best-corrected visual acuity relative to baseline in study eyes (intention-to-treat population)
Pooled Analysis of RVO 1 and RVO 2 Study RVO 3 Visits Dexamethasone Intravitreal Implant Simulation Treatment Dexamethasone Intravitreal Implant Simulation Treatment N = 427N = 426N = 129N = 130 Day 30 21.3 % a7.5% 28.7%a5.4% Day 60 29.3% a11.3% 34.9%a11.5% Day 90 21.8% a13.1% 33.3%a13.1% Day 180 21.5% 17.6% 23.3% 20.8%a Significantly higher rates in the dexamethasone intravitreal implant group compared with the mock treatment group (p < 0.001)
The mean change in BCVA relative to baseline was significantly higher in the dexamethasone intravitreal implant-treated group than in the mock-treatment group at all time points.
In each phase III study and in the pooled analysis of RVO1 and RVO2, cumulative response curves showed that the time required to achieve ≥15 letters (3 rows) of improvement in BCVA was significantly different with this product than with mock therapy (p < 0.001), with patients treated with this product achieving 3 rows of improvement in BCVA earlier than patients treated with mock therapy.
A lower proportion of patients in the dexamethasone intravitreal implant group experienced ≥ 15 letters of visual deterioration during the 6-month evaluation period, indicating a numerical advantage of this product over mock treatment in preventing visual loss.
In the RVO1 study, the RVO2 study and the pooled analysis of these two studies, at day 90, the mean retinal thickness was significantly thinner in the dexamethasone intravitreal implant treatment group compared to the mock treatment group, and its mean reduction relative to baseline retinal thickness was significantly greater (-207.9 μm in the dexamethasone intravitreal implant group and -95.0 μm in the mock treatment group, p < ; 0.001, pooled data). The efficacy results assessed with day 90 BCVA were also supported by corresponding anatomical evidence. The reduction in mean retinal thickness by day 180 (-119.3 μm) was not statistically significant compared to the mock treatment group. In study RVO3, the mean reduction in retinal thickness in the central region was significantly greater with dexamethasone intravitreal implant compared with mock treatment at days 30, 60, and 90 (p < 0.001), but there was no significant difference between the two groups at day 180.
6-month open-label extension period (study RVO1 and RVO2)
Patients with a BCVA score < 84 or retinal thickness on optical coherence tomography OCT> 250 μm and those who were deemed by the investigator to be more beneficial for treatment were enrolled into the open-label extension period to receive dexamethasone intravitreal implant. Ninety-eight percent of patients treated during the open-label period received dexamethasone intravitreal implant injections between months 5 and 7 after initial treatment.
For initial treatment, a peak response was seen at day 60 of the open-label period. Patients who received two consecutive dexamethasone intravitreal implant injections had a higher cumulative response rate throughout the open-label period compared with patients who did not receive dexamethasone intravitreal implant injections during the initial treatment period.
The proportion of patients who responded at each time point was always higher after the second treatment than after the first treatment. Conversely, a 6-month delay in treatment resulted in a lower proportion of delayed patients responding at all time points in the open-label period compared to patients receiving a second dexamethasone intravitreal implant injection.
[Pharmacology and Toxicology].
Pharmacological effects
Dexamethasone is a glucocorticoid that inhibits inflammation by suppressing edema, fibrin deposition, capillary leakage and inflammatory cell migration in response to inflammation.
Toxicological studies
No data are available on the genotoxicity, carcinogenicity, or reproductive toxicity of dexamethasone intravitreal implants.
No genotoxicity was observed for dexamethasone in bacterial and mammalian cells in vitro or in micronucleus assays in mice.
Embryo-fetal death and an increased incidence of cleft palate were seen in mice given 0.15% dexamethasone (0.375 mg/kg/d) by eye on days 10-13 of gestation. On a mg/m2 basis, this dose is approximately three times the human dose of this product (0.7 mg dexamethasone).
Dexamethasone 0.1% given to pregnant rabbits during the organogenesis eye, 0.13 mg/kg/d on day 6 of gestation and 0.20 mg/kg/d on days 7-18, was seen to cause intestinal abnormalities, intestinal dysplasia, ventral clefting, and renal dysplasia. On a mg/m2 basis, 0.13 mg/kg/d is equivalent to 4 times the human dose of this product (0.7 mg dexamethasone).
[Pharmacokinetics].
In an in vitro metabolism study, [14C]-labeled dexamethasone was incubated in human corneal, iris-ciliary body, choroidal, retinal, vitreous fluid, and scleral tissues for 18 hours, and no metabolites were observed. This is consistent with the results of ocular metabolism studies in rabbits and monkeys.
In a 6-month study in monkeys, following a single intravitreal injection of dexamethasone intravitreal implant, the vitreous fluid Cmax of dexamethasone was 100 ng/ml on day 42 and 5.57 ng/ml on day 91 after injection. dexamethasone was still detectable in the vitreous at 6 months after injection. The ranking of dexamethasone concentrations was retina>iris>ciliary body>vitreous fluid>atrial fluid>plasma.
In two 6-month effectiveness studies, plasma concentration data were obtained for 21 patients before dosing and on days 7, 30, 60 and 90 after a single intravitreal implantation of dexamethasone 350 µg or 700 µg. 95% of patients in the 350 µg dose group and 86% of patients in the 700 µg dose group had plasma dexamethasone concentration values below the lower limit of quantification (0.05 ng/ml). The highest plasma concentration of 0.094 ng/ml was observed in one patient in the 700 µg group. plasma dexamethasone concentrations were not related to the patient’s age, weight or gender.
Dexamethasone is ultimately metabolized to lipid and water-soluble metabolites that are excreted in bile and urine.
Dexamethasone intravitreal implant matrix is slowly degraded to lactic acid and hydroxyacetic acid by simple hydrolysis reaction, and then further degraded to carbon dioxide and water.
Storage
Seal and store at room temperature (10-30℃).
Keep away from children.
Package】
The stick implant is pre-filled in the needle of the drug delivery device, and the drug delivery device is sealed in a compound aluminum foil bag with desiccant and placed in a cardboard box, 1 stick/box.
Expiration date
36 months.
Execution standard
Imported drug registration standard JX20170058.
Approval number
Imported drug registration certificate number H20170377
【Manufacturing enterprise】.
Company Name: Allergan Pharmaceuticals Ireland Production Address: Castlebar Road, Westport, Co. Mayo, Ireland (Ireland) Tel: (353)-98-25222 Fax: (353)-98-25791
Domestic Contact
Company Name: Allergan Information Consulting (Shanghai) Co. Address: Room 5605, 56/F, Hang Lung Plaza, 1266 West Nanjing Road, Jing’an District, Shanghai Product Information Hotline: 4000136888 (9:00-17:00) Postal Code: 200040
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