Thilodexine

Neurology

Cerebral oedema caused by brain tumours, neurosurgery, bacterial meningitis, brain abscess.

Pulmonary and respiratory diseases

Severe acute asthma attack.

Dermatology

Oral initial treatment of extensive, severe, acute skin diseases that respond to glucocorticoids, such as erythroderma, pemphigus vulgaris, acute eczema.

Autoimmune disorders/rheumatology

Oral initial treatment of autoimmune diseases, such as systemic lupus erythematosus (especially visceral forms).

Severely progressive form of active rheumatoid arthritis, e.g. rapidly destructive forms and/or with extra-articular manifestations.

Infectology

Severe infections with toxic conditions (e.g. tuberculosis, typhoid) only with concomitant anti-infective therapy.

Oncology

Palliative treatment of malignant tumours.

Endocrinology

Congenital adrenogenital syndrome in adulthood.

OZURDEX is indicated for the treatment of adult patients with:

- visual impairment due to diabetic macular oedema (DME) who are pseudophakic or who are considered insufficiently responsive to, or unsuitable for non-corticosteroid therapy

- macular oedema following either Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO)

- inflammation of the posterior segment of the eye presenting as non-infectious uveitis

Indicated for treatment of steroid responsive inflammatory conditions of the conjunctiva, cornea and anterior segment of the eye, such as, anterior uveitis, iritis, cyclitis, allergic and vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis and non-specific superficial keratitis.

Also indicated for the treatment of corneal injury from chemical, radiation or thermal burns or following penetration by foreign bodies. Indicated for post-operative use to reduce inflammatory reactions and suppress graft reaction.

Posology

Dosage depends on the nature and severity of the disease and the individual response of the patient to treatment. In general, relatively high initial doses are administered, and they should be significantly higher in acute severe forms than in chronic diseases.

Unless otherwise prescribed, the following dosage recommendations apply:

- Cerebral oedema: Depending on the cause and severity, initial dose of 8-10 mg (up to 80 mg) i.v., followed by 16-24 mg (up to 48 mg)/day orally, divided into 3-4 (up to 6) individual doses for 4-8 days. A longer-term, lower-dose administration of Thilodexine Krka may be required during irradiation and in the conservative treatment of inoperable brain tumours.

- Cerebral oedema due to bacterial meningitis: 0.15 mg/kg body weight every 6 hours for 4 days, children: 0.4 mg/kg body weight every 12 hours for 2 days, starting before the first antibiotics.

- Severe acute asthma attack: Adults: 8-20 mg, then, if necessary, 8 mg every 4 hours. Children: 0.15-0.3 mg/kg body weight.

- Acute skin diseases: Depending on the nature and extent of the disease, daily doses of 8-40 mg. Followed by treatment with decreasing doses.

- Active phases of rheumatic systemic diseases: systemic lupus erythematosus 6-16 mg/day.

- Severely progressive form of active rheumatoid arthritis: in rapidly destructive forms 12-16 mg/day, in extra-articular manifestations 6-12 mg/day

- Severe infectious diseases, toxic states (e.g. tuberculosis, typhoid): 4-20 mg for a few days, only with concomitant anti-infective therapy.

- Palliative treatment of malignant tumours: initially 8-16 mg/day, in prolonged treatment 4-12 mg/day.

- Congenital adrenogenital syndrome in adulthood: 0.25-0.75 mg/day as a single dose. If necessary, addition of a mineralcorticoid (fludrocortisone). In cases of particular physical stress (e.g. trauma, surgery), intercurrent infections, etc., a 2- to 3-fold dose increase may be required and under extreme stress (e.g. birth) a 10-fold increase.

The tablets should not be split to adjust doses. If patients need a dose that cannot be provided by one or more tablets of 0.5mg, other appropriate formulations should be used.

Method of administration

The tablets should be taken during or after a meal. They should be swallowed whole, with a sufficient amount of liquid. The daily dose should be administered as a single dose in the morning, if possible (circadian therapy). In patients who require a high-dose therapy because of their disease, multiple daily dosing is often required to achieve maximum effect.

Depending on the underlying disease, clinical symptoms and response to therapy, the dose can be reduced at a faster or slower rate and the therapy stopped, or the patient is stabilised on a maintenance dose as low as possible and, if necessary, adrenal axis monitored. Basically, the dose and duration of treatment should be kept as high and long as necessary, but as low and short as possible. In principle, the dose should be reduced gradually.

In long-term therapy which is deemed necessary following initial treatment, patients should be switched to prednisone/prednisolone, because this leads to lower adrenal suppression.

In hypothyroidism or liver cirrhosis, low doses may be sufficient or a dose reduction may be necessary.

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.

DME

Patients treated with OZURDEX who have experienced an initial response and in the physician's opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment.

Retreatment may be performed after approximately 6 months if the patient experiences decreased vision and/or an increase in retinal thickness, secondary to recurrent or worsening diabetic macular oedema.

There is currently no experience of the efficacy or safety of repeat administrations in DME beyond 7 implants.

RVO and uveitis

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.

Patients who experience and retain improved vision should not be retreated. Patients who experience 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.

For information concerning the current safety experience of repeat administrations beyond 2 implants in posterior segment non-infectious uveitis and

Patients should be monitored following the injection to permit early treatment if an infection or increased intraocular pressure occurs.

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.

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

- diabetic macular oedema

- macular oedema following either Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO)

The safety and efficacy of OZURDEX in uveitis in the paediatric population have not been established. No data are available.

Method of administration

OZURDEX is a 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).

The patient should be instructed to self-administer broad spectrum antimicrobial drops daily for 3 days before and after each injection. Before the injection, the periocular skin, eyelid and ocular surface should be disinfected (using for example drops of povidone iodine 5% solution on the conjunctiva as it was done in the clinical trials for the approval of OZURDEX) and adequate local anaesthesia should be administered. Remove the foil pouch from the carton and examine for damage. 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.

Adults, adolescents, and children (2 years of age and above)

The frequency of instillation of drops and the duration of treatment will vary depending upon the severity of the underlying condition and the response to treatment.

Severe inflammations require one to two drops instilled into the eye every thirty to sixty minutes until a satisfactory response occurs.

Subconjunctival or systemic steroid therapy should be considered if there is no response. When a favourable response has been observed reduce the dosage towards one drop every four hours.

Nasolacrimal occlusion or gently closing the eyelid after administration is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic adverse reactions.

Paediatric patients

The safety and efficacy of this product has not been established in children below 2 years of age.

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- 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.

- Aphakic eyes with ruptured posterior lens capsule.

- Eyes with Anterior Chamber Intraocular Lens (ACIOL), iris or transscleral fixated intraocular lens and ruptured posterior lens capsule.

- Vaccinia, varicella, or other viral diseases of cornea and conjunctiva (except herpes zoster keratitis)

- Herpes simplex keratitis

- Fungal diseases of ocular structures

- Mycobacterial ocular infections

- Acute, untreated bacterial infections

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Depending on the dose and duration of therapy, adrenocortical insufficiency caused by glucocorticoid therapy can continue for several months and in individual cases more than a year after cessation of therapy. In cases of particular physical stress situations (trauma, surgery, childbirth, etc.) during treatment with Thilodexine Krka, a temporary increase in dose may be required. Because of the potential risk in stress situations, patients on extended therapy should be issued a steroid card. Also in prolonged adrenal insufficiency after cessation of treatment, the administration of glucocorticoids may be necessary in physical stress situations. In case of intended withdrawal, treatment-induced acute adrenal insufficiency may be minimized by slow dose reduction.

Through immunosuppression, treatment with Thilodexine Krka can lead to an increased risk of bacterial, viral, parasitic, opportunistic and fungal infections. It can mask the symptoms of an existing or developing infection, thereby making a diagnosis more difficult. Latent infections, like tuberculosis or hepatitis B, can be reactivated.

Treatment with Thilodexine Krka should only be implemented in the event of the strongest indications and, if necessary, additional targeted anti-infective treatment administered for the following illnesses:

- Acute viral infections (Herpes zoster, Herpes simplex, Varicella, herpetic keratitis)

- HBsAG-positive chronic active hepatitis

- Approximately 8 weeks prior to 2 weeks after vaccinations with live vaccines

- Systemic mycoses and parasitoses (e.g. nematodes)

- In patients with suspected or confirmed strongyloidiasis (infection with threadworms), glucocorticoids can lead to activation and mass proliferation of these parasites

- Poliomyelitis

- Lymphadenitis after BCG vaccination

- Acute and chronic bacterial infections

- In a history of tuberculosis (reactivation risk), use only under tuberculostatic protection

In addition, treatment with Thilodexine Krka should only be implemented under strong indications and, if necessary, additional specific treatment must be implemented for:

- Gastrointestinal ulcers

- Osteoporosis

- Severe cardiac insufficiency

- High blood pressure that is difficult to regulate

- Diabetes mellitus that is difficult to regulate

- Psychiatric disorders (also in the past), including suicidality: neurological or psychiatric monitoring is recommended

- Narrow- and wide-angle glaucoma, ophthalmic monitoring and adjunctive therapy are recommended

- Corneal ulcerations and corneal injuries, ophthalmic monitoring and adjunctive therapy are recommended

Because of the risk of an intestinal perforation, Thilodexine Krka may only be used under urgent indication and under appropriate monitoring for:

- Severe ulcerative colitis with threatened perforation, possibly without peritoneal irritation

- Diverticulitis

- Enteroenterostomy (immediately postoperatively)

Signs of peritoneal irritation after gastrointestinal perforation may be absent in patients receiving high doses of glucocorticoids.

The possibility of a higher need for insulin or oral antidiabetics must be taken into consideration when administering Thilodexine Krka to diabetics.

Regular blood pressure monitoring is necessary during treatment with Thilodexine Krka, particularly during administration of higher doses and in patients with high blood pressure that is difficult to regulate.

Because of the risk of deterioration, patients with severe cardiac insufficiency should be carefully monitored.

With high doses of Thilodexine bradycardia may occur.

Severe anaphylactic reactions may occur.

The risk of tendon disorders, tendinitis and tendon rupture is increased when fluoroquinolones and glucocorticoids are administered together.

A concurrent myasthenia gravis may initially worsen during treatment with Thilodexine Krka.

Vaccinations with inactivated vaccines are generally possible. However, it should be noted that the immune response and thus the vaccine may be compromised at higher doses of corticosteroids.

During long-term therapy with Thilodexine Krka, regular medical checkups (including ophthalmologic every three months) are indicated.

At high doses, sufficient calcium intake and sodium restriction should be ensured and serum potassium levels should be monitored.

Depending on the dose and duration of treatment, a negative effect on calcium metabolism can be expected; therefore, the prevention of osteoporosis is recommended. This applies especially to patients with concomitant risk factors, such as familial predisposition, advanced age, postmenopausal period, insufficient protein and calcium intake, heavy smoking, excessive alcohol consumption and lack of physical activity. Prevention consists of sufficient calcium and vitamin D intake and physical activity. In already existing osteoporosis, additional drug therapy should be considered.

Upon termination of long-term administration of glucocorticoids, the following risks must be taken into account: exacerbation or relapse of the underlying disease, acute adrenal insufficiency, cortisone withdrawal syndrome.

Certain viral diseases (chickenpox, measles) may be very severe in patients treated with glucocorticoids. Immunocompromised patients without previous chickenpox or measles infection are particularly at risk. If these patients have contact with people infected with measles or chickenpox while undergoing treatment with Thilodexine Krka, a preventative treatment should be introduced, if necessary.

In post marketing experience tumour lysis syndrome (TLS) has been reported in patients with haematological malignancies following the use of Thilodexine alone or in combination with other chemotherapeutic agents. Patient at high risk of TLS, such as patients with high proliferative rate, high tumour burden, and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precaution taken.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Paediatric population

In the growth phase of children, the benefit-risk balance of treatment with Thilodexine Krka should be carefully weighed.

Therapy should be of limited duration or in case of long-term therapy, it should be carried out alternatingly.

Preterm neonates: Available evidence suggests long-term neurodevelopmental adverse events after early treatment (< 96 hours) of premature infants with chronic lung disease at starting doses of 0.25mg/kg twice daily.

Elderly patients

Because elderly patients are at an increased risk of osteoporosis, the benefit-risk balance of treatment with Thilodexine Krka should be carefully weighed.

Note

The use of Thilodexine Krka can lead to positive results in doping controls.

Thilodexine Krka contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Intravitreous injections, including those with OZURDEX, 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.

Patients must be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay, e.g. eye pain, blurred vision etc..

All patients with posterior capsule tear, such as those with a posterior lens (e.g. due to cataract surgery), and/or those who have an iris opening to the vitreous cavity (e.g. due to iridectomy) with or without a history of vitrectomy, are at risk of implant migration into the anterior chamber. Implant migration to the anterior chamber may lead to corneal oedema. Persistent severe corneal oedema could progress to the need for corneal transplantation. Other than those patients contraindicated where OZURDEX should not be used, OZURDEX should be used with caution and only following a careful risk benefit assessment. These patients should be closely monitored to allow for early diagnosis and management of device migration.

Use of corticosteroids, including OZURDEX, may induce cataracts (including posterior subcapsular cataracts), increased IOP, steroid induced glaucoma and may result in secondary ocular infections.

In the 3 year DME clinical studies, 59% of patients with a phakic study eye treated with OZURDEX underwent cataract surgery in the study eye.

After the first injection the incidence of cataract appears higher in patients with non-infectious uveitis of the posterior segment compared with BRVO/CRVO patients. In BRVO/CRVO clinical studies, cataract was reported more frequently in patients with phakic lens receiving a second injection. Only 1 patient out of 368 required cataract surgery during the first treatment and 3 patients out of 302 during the second treatment. In the non-infectious uveitis study, 1 patient out of the 62 phakic patients underwent cataract surgery after a single injection.

The prevalence of conjunctival haemorrhage in patients with non-infectious uveitis of the posterior segment appears to be higher compared with BRVO/CRVO and DME. This could be attributable to the intravitreous injection procedure or to concomitant use of topical and/or systemic corticosteroid or Non-steroidal anti-inflammatory medications. No treatment is required since spontaneous resolution occurs.

As expected with ocular steroid treatment and intravitreal injections, increases in intraocular pressure (IOP) may be seen. The rise in IOP is normally manageable with IOP lowering medication. Of the patients experiencing an increase of IOP of >10 mmHg from baseline, the greatest proportion showed this IOP increase between 45 and 60 days following an injection. Therefore, regular monitoring of IOP, irrespective of baseline IOP, is required and any elevation should be managed appropriately post-injection as needed. Patients of less than 45 years of age with macular oedema following Retinal Vein Occlusion or inflammation of the posterior segment of the eye presenting as non-infectious uveitis are more likely to experience increases in IOP.

Corticosteroids should be used cautiously in patients with a history of ocular viral (e.g. herpes simplex) infection 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 patients with macular oedema secondary to RVO with significant retinal ischemia. Therefore OZURDEX is not recommended.

A limited number of subjects with Type 1 diabetes were investigated in the Phase 3 studies, and the response to OZURDEX in these subjects was not significantly different to those subjects with Type 2 diabetes.

In RVO, anti-coagulant therapy was used in 2% of patients receiving OZURDEX; there were no reports of haemorrhagic adverse events in these patients. In DME, anti-coagulant therapy was used in 8% of patients. Among patients who used anti-coagulant therapy, the frequency of haemorrhagic adverse events was similar in the OZURDEX and sham groups (29% vs 32%). Among patients who did not use anti-coagulant therapy, 27% of OZURDEX treated patients reported haemorrhagic adverse events compared to 20% in the sham group. Vitreous haemorrhage was reported in a higher proportion of patients treated with OZURDEX who received anti-coagulant therapy (11%) compared with those not receiving anticoagulant therapy (6%).

Anti-platelet medicinal products, such as clopidogrel, were used at some stage during the clinical studies in up to 56% of patients. For patients using concomitant and anti-platelet medication, haemorrhagic adverse events were reported in a slightly higher proportion of patients injected with OZURDEX (up to 29%) compared with the sham group (up to 23%), irrespective of 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 anti-coagulant or anti-platelet medicinal products.

- For ocular use only.

- Prolonged use of topical ophthalmic corticosteroids may result in ocular hypertension and/or glaucoma, with damage to the optic nerve, reduced visual acuity, visual field defects and posterior subcapsular cataract formation. In patients receiving prolonged ophthalmic corticosteroid therapy, intraocular pressure and the lens should be checked routinely and frequently, particularly in patients with a history or presence of glaucoma. This is especially important in paediatric patients as the risk of corticosteroid-induced ocular hypertension may be greater in children and may occur earlier than in adults. The risk of corticosteroid-induced raised intraocular pressure and/or cataract formation is increased in predisposed patients (e.g. diabetes).

- Topical corticosteroids should not be used for longer than one week except under ophthalmic supervision, with regular checks of intraocular pressure.

- Cushing's syndrome and/or adrenal suppression associated with systemic absorption of ocular dexamethasone may occur after intensive or long-term continuous therapy in predisposed patients, including children and patients treated with CYP3A4 inhibitors (including ritonavir and cobicistat). In these cases, treatment should be progressively discontinued.

- Corticosteroids may reduce resistance to and aid in the establishment of bacterial, viral and fungal infections and mask the clinical signs of infections. In such cases antibiotic therapy is mandatory. Fungal infection should be suspected in patients with persistent corneal ulceration and corticosteroids therapy should be discontinued if fungal infection occurs.

- Topical ophthalmic corticosteroids may slow corneal wound healing. Topical NSAIDs are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems..

- In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical corticosteroids.

- Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may be cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

- Contact lens wear is not recommended during treatment of an ocular inflammation.

- Additionally, this product contains benzalkonium chloride which may cause eye irritation and is known to discolour soft contact lenses. Avoid contact with soft contact lenses. Patients must be instructed to remove contact lenses prior to application of Thilodexine and wait at least 15 minutes before reinsertion.

- There is no evidence of safety in use in children under two years of age.

There have been no studies on the effects on the ability to drive and use machines.

OZURDEX may have a moderate influence on the ability to drive and use machines. Patients may experience temporarily reduced vision after receiving OZURDEX by intravitreal injection. They should not drive or use machines until this has resolved.

Thilodexine has no or negligible influence on the ability to drive and use machines. As with any topical ophthalmic medicinal product, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs upon instillation, the patient must wait until the vision clears before driving or using machinery.

- Very common (> 1/10)

- Common (> 1/100 to < 1/10)

- Uncommon (> 1/1,000 to < 1/100)

- Rare (> 1/10,000 to < 1/1,000)

- Very rare (< 1/10,000)

- Not known (cannot be estimated from the available data)

Hormone replacement therapy:

Low risk of undesirable effects with the use of recommended doses.

Pharmacotherapy:

The following undesirable effects may occur; they are highly dependent on the dose and duration of treatment, so their frequency cannot be specified:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Summary of the safety profile

The most commonly-reported adverse events reported following treatment with OZURDEX are those frequently observed with ophthalmic steroid treatment or intravitreal injections (elevated IOP, cataract formation and conjunctival or vitreal 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 were identified with the use of OZURDEX.

Tabulated list of adverse reactions

The adverse reactions considered related to OZURDEX treatment from the Phase III clinical trials (DME, BRVO/CRVO and uveitis) and spontaneous reporting are listed by MedDRA System organ class in the table below using the following convention:

Very common (> 1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse reactions

* indicates adverse reactions considered to be related to the intravitreal injection procedure (the frequency of these adverse reactions is proportional to the number of treatments given).

** in a 24-month real world observational study in the treatment of macular oedema following RVO and non-infectious uveitis affecting the posterior segment of the eye these adverse events were reported more frequently among patients who received >2 injections vs patients who received ≤2 injections; cataract formation (24.7% vs 17.7%), cataract progression (32.0% vs 13.1%), vitreous haemorrhage (6.0% vs 2.0%), and increased IOP (24.0% vs 16.6%).

Description of selected adverse reactions

Diabetic Macular Oedema

The clinical safety of OZURDEX in patients with diabetic macular oedema was assessed in two phase 3 randomized, double-masked, sham-controlled studies. In both studies, a total of 347 patients were randomized and received OZURDEX and 350 patients received sham.

The most frequently reported adverse reactions across the entire study period in the study eye of patients who received OZURDEX were cataract and elevated IOP (see below).

In the 3 year DME clinical studies, at baseline, 87% of patients with a phakic study eye treated with OZURDEX had some degree of lens opacification/ early cataract. The incidence of all observed cataract types (i.e. cataract cortical, cataract diabetic, cataract nuclear, cataract subcapsular, cataract lenticular, cataract) was 68% in OZURDEX treated patients with a phakic study eye across the 3 year studies. 59% of patients with a phakic study eye required cataract surgery by the 3 year final visit, with the majority performed in the 2^nd and 3^rd years.

Mean IOP in the study eye at baseline was the same in both treatment groups (15.3 mmHg). The mean increase from baseline IOP did not exceed 3.2 mmHg across all visits in the OZURDEX group with the mean IOP peaking at the 1.5 month visit post injection, and returning to approximately baseline levels by month 6 following each injection. The rate and magnitude of IOP elevation following OZURDEX treatment did not increase upon repeated injection of OZURDEX.

28% of patients treated with OZURDEX had a > 10 mm Hg IOP increase from baseline at one or more visits during the study. At baseline 3% of patients required IOP-lowering medication(s). Overall, 42% of patients required IOP-lowering medications in the study eye at some stage during the 3 year studies, with the majority of these patients requiring more than one medication. Peak usage (33%) occurred during the first 12 months and remained similar from year to year.

A total of 4 patients (1%) treated with OZURDEX had procedures in the study eye for the treatment of IOP elevation. One patient treated with OZURDEX required incisional surgery (trabeculectomy) to manage the steroid-induced IOP elevation, 1 patient had a trabeculectomy owing to anterior chamber fibrin blocking the aqueous outflow leading to increased IOP, 1 patient had an iridotomy for narrow angle glaucoma and 1 patient had iridectomy due to cataract surgery. No patient required removal of the implant by vitrectomy to control IOP.

BRVO/CRVO

The clinical safety of OZURDEX in patients with macular oedema following central or branch retinal vein occlusion has been assessed in two Phase III randomised, double-masked, sham-controlled studies. A total of 427 patients were randomised to receive OZURDEX and 426 to receive 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.

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.

Uveitis

The clinical safety of OZURDEX in patients with inflammation of the posterior segment of the eye presenting as non-infectious uveitis, has been assessed in a single, multicentre, masked, randomised study.

A total of 77 patients were randomised to receive OZURDEX and 76 to receive Sham. A total of 73 patients (95%) randomised and treated with OZURDEX completed the 26-week study.

The most frequently reported adverse reactions in the study eye of patients who received OZURDEX were conjunctival haemorrhage (30.3%), increased intraocular pressure (25.0%) and cataract (11.8%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard.

Summary of the safety profile

In clinical trials, the most common adverse reaction was ocular discomfort.

Tabulated list of adverse reactions

The following adverse reactions are classified according to the following convention: very common (> 1/10), common (> 1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency-grouping, adverse reactions are presented in order of decreasing seriousness. The adverse reactions have been observed during clinical trials and post-marketing experience with Thilodexine.

Description of selected adverse reactions

Prolonged topical ophthalmic corticosteroids may result in increased intraocular pressure with damage to the optic nerve, reduced visual acuity and visual field defects, and to posterior subcapsular cataract formation.

Due to the corticosteroid component, in diseases causing thinning of the cornea or sclera there is a higher risk for perforation especially after long treatments.

Corticosteroids may reduce resistance to and aid in the establishment of infections.

Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued 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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Symptoms

Acute intoxications with Thilodexine are not known. In case of chronic overdosing, an increase in undesirable effects, especially endocrine, metabolic and electrolyte-related effects, can be expected.

Management

There is no known antidote to Thilodexine.

If an overdose occurs, intraocular pressure should be monitored and treated, if deemed necessary by the attending physician.

Long-term intensive topical use may lead to systemic effects. Oral ingestion of the contents of the bottle (up to 10 mls) is unlikely to lead to any serious adverse effects.

An ocular overdose of Thilodexine can be flushed from the eye(s) with lukewarm water.

Pharmacotherapeutic group: corticosteroids for systemic use, glucocorticoids, ATC code: H02AB02.

Mechanism of action

Thilodexine is a mono-fluorinated glucocorticoid with pronounced anti-allergic, anti-inflammatory and membrane-stabilizing properties and effects on carbohydrate, protein and fat metabolism.

Thilodexine has an approximately 7.5 times greater glucocorticoid effect than prednisolone, and compared to hydrocortisone it is 30 times more effective, lacking mineralocorticoid effects.

Glucocorticoids, such as Thilodexine, exert their biological effects by activating the transcription of corticosteroid-sensitive genes. The anti-inflammatory, immunosuppressive and anti-proliferative effects are caused by decreased formation, release and activity of inflammatory mediators, by the inhibition of specific functions and the migration of inflammatory cells. In addition, the effect of sensitized T lymphocytes and macrophages on target cells may be prevented by corticosteroids.

When long-term corticoid treatment is required, the possibility of induction of transient adrenal insufficiency must be considered. The suppression of the hypothalamic-pituitary-adrenal axis also depends on individual factors.

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.

Clinical efficacy and safety

Diabetic Macular Oedema

The efficacy of OZURDEX was assessed in two 3 year, multicentre, double-masked, randomised, sham-controlled, parallel studies of identical design which together comprised 1,048 patients (studies 206207-010 and 206207-011). A total of 351 were randomised to OZURDEX, 347 to dexamethasone 350 µg and 350 patients to sham.

Patients were eligible for retreatment based upon central subfield retinal thickness >175 microns by optical coherence tomography (OCT) or upon investigators interpretation of the OCT for any evidence of residual retinal edema consisting of intraretinal cysts or any regions of increased retinal thickening within or outside of the central subfield. Patients received up to 7 treatments at intervals no more frequently than approximately every 6 months.

Escape therapy was permitted at the investigators discretion at any stage but led to subsequent withdrawal from the studies.

A total of 36% of OZURDEX treated patients discontinued study participation for any reason during the study compared with 57% of sham patients. Discontinuation rates due to adverse events were similar across treatment and sham groups (13% vs 11%). Discontinuation due to lack of efficacy was lower in the OZURDEX group compared to sham (7% vs 24%).

The primary and key secondary endpoints for studies 206207-010 and 011 are presented in Table 2. The vision improvement in the DEX700 group was confounded by cataract formation. Vision improvement was re-established upon removal of cataract.

Table 2. Efficacy in studies 206207-010 and 206207-011 (ITT population)

The primary and key secondary endpoints for the pooled analysis for pseudophakic patients are presented in Table 3.

Table 3. Efficacy in pseudophakic patients (pooled studies 206207-010 and 206207-011)

The primary and key secondary endpoints for the pooled analysis for patients with any prior treatment are presented in Table 4.

Table 4. Efficacy in patients with any prior treatment (pooled studies 206207-010 and 206207-011)

BRVO/CRVO

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 were randomized to receive 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 5. 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.

Table 5. Proportion of patients with > 15 letters improvement from baseline best corrected visual acuity in the study eye (pooled, ITT population)

^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, 98% 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.

Uveitis

The clinical efficacy of OZURDEX has been assessed in a single, multicentre, masked, randomised study for the treatment of non-infectious ocular inflammation of the posterior segment in patients with uveitis.

A total of 229 patients were randomised to receive dexamethasone 350 µg or 700 µg implants or sham. Of these, a total of 77 were randomised to receive OZURDEX, 76 to dexamethasone 350 µg and 76 to sham. A total of 95% of patients completed the 26-week study.

The proportion of patients with vitreous haze score of 0 in the study eye at week 8 (primary endpoint) was 4-fold higher with OZURDEX (46.8%) compared to Sham (11.8%), p < 0.001. Statistical superiority was maintained up to and including week 26 (p ≤ 0.014) as shown in Table 6.

The cumulative response rate curves (time to vitreous haze score of 0) were significantly different for the OZURDEX group compared to the Sham group (p < 0.001), with patients receiving dexamethasone showing an earlier onset and greater treatment response.

The reduction in vitreous haze was accompanied by an improvement in visual acuity. The proportion of patients with at least 15 letters improvement from baseline BCVA in the study eye at week 8 was more than 6-fold higher with OZURDEX (42.9%) compared to Sham (6.6%), p < 0.001. Statistical superiority was achieved at week 3 and maintained up to and including week 26 (p < 0.001) as shown in Table 6.

The percent of patients requiring escape medications from baseline to week 8 was nearly 3-fold less with OZURDEX (7.8%) compared to Sham (22.4%), p = 0.012.

Table 6. Proportion of patients with vitreous haze score of zero and > 15 letters improvement from baseline best corrected visual acuity in the study eye (ITT population)

^a p < 0.001; ^b p = 0.010; ^c p = 0.009; ^d p = 0.014

Paediatric population

).

Pharmacotherapeutic Group: Ophthalmologicals: Anti-inflammatory Agents.

ATC Code S01B A01.

Dexamethasone has been demonstrated by animal and human studies based on oral application to possess approximately six to seven times the potency of prednisolone and at least 30 times the potency of cortisone. The potency of the compound is accomplished by the addition of a methyl radical and a fluorine atom to the prednisolone radical.

Absorption and distribution

After oral administration, Thilodexine is rapidly and almost completely absorbed in the stomach and small intestine. Its bioavailability is 80-90%. Maximum blood levels are reached between 60 and 120 minutes. The binding of Thilodexine to plasma albumins is dose-dependent. At very high doses, the largest portion circulates freely in the blood. In hypoalbuminaemia the proportion of the unbound (active) corticoid rises.

Biotransformation

The average (serum) elimination half-life of Thilodexine in adults is 250 minutes (+ 80 minutes). Due to its long biological half-life of more than 36 hours, daily continuous administration of Thilodexine can lead to accumulation and overdosing.

Elimination

The elimination is largely renal in the form of free Thilodexine alcohol. Thilodexine is partly metabolised, the metabolites are excreted as glucuronates or sulfates, also mainly by the kidneys.

Renal and hepatic impairment

Renal function impairment has no relevant effect on the clearance of Thilodexine. However, the elimination half-life is prolonged in severe liver disease.

Plasma concentrations were obtained from a subset of 21 patients in the two RVO, 6-month efficacy studies prior to dosing and on days 7, 30, 60 and 90 following intravitreal injection of a single 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.

Plasma concentrations were obtained from a subgroup of patients in the two DME pivotal studies prior to dosing and on days 1, 7, and 21, and months 1.5 and 3 following intravitreal injection of a single intravitreal implant containing 350 µg or 700 µg dexamethasone. One hundred percent of the plasma dexamethasone concentration values for the 350 µg dose group and 90% for the 700 µg dose group were below the lower limit of quantitation (0.05 ng/mL). The highest plasma concentration value of 0.102 ng/mL was observed in 1 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.

Dexamethasone is absorbed rapidly after oral administration with a half-life of about 190 minutes. Sufficient absorption may occur after topical application to the skin and eye to produce systemic effects. In plasma dexamethasone protein binding is less than for most other corticosteroids. Corticosteroids diffuse into tissue fluids and cerebrospinal fluid but transplacental diffusion in significant amounts has not been demonstrated. Corticosteroids are metabilised in the liver the kidney and excrete in the urine. Metabolism is similar to other corticosteroids. Intraocular penetration occurs in significant amounts and contributes to the effectiveness of dexamethasone in anterior segment inflammatory disease.

Acute toxicity:

In mice and rats, the LD₅₀ for Thilodexine after a single oral dose is 16 g/kg body and over 3 g/kg body weight, respectively, within the first 7 days. Following a single subcutaneous dose, the LD₅₀ in mice is more than 700 mg/kg body weight and in rats about 120 mg/kg body weight, within the first 7 days.

Over a period of 21 days, these values become lower, which is interpreted as a consequence of serious infectious diseases caused by the hormone-induced immunosuppression.

Chronic toxicity:

There are no data on chronic toxicity in humans and animals. Corticoid-induced intoxications are not known. In longer-term treatment with doses above 1.5 mg/day, pronounced undesirable effects can be expected.

Mutagenic and tumorigenic potential:

The available study findings for glucocorticoids show no evidence of clinically relevant genotoxic properties.

Reproductive toxicity:

In animal studies, cleft palate was observed in rats, mice, hamsters, rabbits, dogs and primates; not in horses and sheep. In some cases these divergences were combined with defects of the central nervous system and of the heart. In primates, effects in the brain were seen after exposure. Moreover, intrauterine growth can be delayed. All these effects were seen at high dosages.

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.

Repeat dose topical ocular safety studies with dexamethasone in rabbits have shown systemic corticosteroid effects. Such effects are considered to be unlikely when Thilodexine is used as recommended.

Dexamethasone was clastogenic in the in vitro human lymphocyte assay and in vivo in the mouse micronucleus assay at doses in excess of those obtained following topical application. Conventional carcinogenicity studies with Thilodexine have not been performed.

Dexamethasone has been found to be teratogenic in animal models. Dexamethasone induced abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development.

There are no other preclinical data of relevance to the prescriber which are additional to that included in other sections of the SPC.

No special requirements for disposal.

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, the applicator must not be used. 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.

Do not touch dropper tip to any surface as this may contaminate the contents.

If the drop of medication is not retained in the eye upon dosing for any reason then instill another drop.