JETREA 0.5mg / 0.2ml concentrate for solution for injection medication leaflet

JETREA 0.375 mg/0.3 mL solution for injection

Each vial contains 0.375 mg of ocriplasmin* in 0.3 mL solution (1.25 mg/mL). This provides a usableamount to deliver a single dose of 0.1 mL containing 0.125 mg ocriplasmin.

*Ocriplasmin is a truncated form of human plasmin produced by recombinant DNA technology in a

Pichia pastoris expression system.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear and colourless solution.

JETREA is indicated in adults for the treatment of vitreomacular traction (VMT), including whenassociated with macular hole of diameter less than or equal to 400 microns (see section 5.1).

JETREA must be administered by a qualified ophthalmologist experienced in intravitreal injections.

The diagnosis of vitreomacular traction (VMT) should comprise of a complete clinical pictureincluding patient history, clinical examination and investigation using currently accepted diagnostictools, such as optical coherence tomography (OCT).

JETREA 0.375 mg/0.3 mL solution for injection is a ‘ready-diluted’ formulation, no further dilution isrequired. The recommended dose is 0.125 mg in 0.1 mL of the solution administered by intravitrealinjection to the affected eye once as a single dose. Each vial should only be used once and for thetreatment of a single eye. Treatment with JETREA in the other eye is not recommended concurrentlyor within 7 days of the initial injection in order to monitor the post-injection course including thepotential for decreased vision in the injected eye. Repeated administration in the same eye is notrecommended (see section 4.4).

See section 4.4 for instructions on post-injection monitoring.

No formal studies have been conducted with JETREA in patients with renal impairment. No doseadjustment or special considerations are anticipated for patients with renal impairment (seesection 5.2).

No formal studies have been conducted with JETREA in patients with hepatic impairment. No doseadjustment or special considerations are anticipated for patients with hepatic impairment (seesection 5.2).

The elderly population has been studied in clinical studies. No dose adjustment is required.

There is no relevant use of JETREA in children aged under 18 years for the indication ofvitreomacular traction (VMT), including when associated with macular hole of diameter less than orequal to 400 microns. Currently available data on paediatric use are described in section 5.1.

Single use vial for intravitreal use only.

Preoperative antibiotic drops may be administered at the discretion of the treating ophthalmologist.

The intravitreal injection procedure should be carried out under controlled aseptic conditions, whichinclude the use of surgical hand disinfection, sterile gloves, a sterile drape, a sterile eyelid speculum(or equivalent) and the availability of sterile paracentesis (if required). The periocular skin, eyelid andocular surface should be disinfected and adequate anaesthesia and a broad spectrum topicalmicrobiocide should be administered prior to the injection according to standard medical practice.

Only 0.1 mL of the total 0.3 mL solution in the vial should be administered. Any excess volumeshould be expelled prior to injection in order to deliver a single dose of 0.1 mL containing 0.125 mgocriplasmin. For handling of the medicinal product, see section 6.6.

The injection needle should be inserted 3.5-4.0 mm posterior to the limbus aiming towards the centreof the vitreous cavity avoiding the horizontal meridian. The injection volume of 0.1 mL is thendelivered into the mid-vitreous.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Active or suspected ocular or periocular infections.

Post-injection monitoring

JETREA is administered by intravitreal injection only. Intravitreal injections have been associatedwith intraocular inflammation/infection, intraocular haemorrhage and increased intraocular pressure(IOP). Proper aseptic injection techniques must always be used. Following the intravitreal injection,patients should be monitored for any side effects such as (but not limited to) intraocularinflammation/infection and elevation in IOP. Transient increases in IOP including transient blindnessand non-perfusion of the optic nerve have been seen within 60 minutes of injection of JETREA.

Monitoring for increases in IOP may consist of a check for perfusion of the optic nerve headimmediately after the injection and tonometry within 30 minutes following the injection. Intraocularinflammation/infection may be assessed using biomicroscopy between 2 and 7 days following theinjection. Patients should be instructed to report symptoms suggestive of intraocularinflammation/infection or any other visual or ocular symptoms without delay. If any of the aboveevents occur the patient should be treated according to standard medical practice.

The safety and efficacy of JETREA administered to both eyes concurrently has not been studied.

Therefore administration to both eyes concurrently is not recommended.

Repeated administration

Repeated administration of JETREA in the same eye has not been adequately studied and is thereforenot recommended.

Population with no or limited data

JETREA has not been studied in patients with large diameter macular holes (> 400 microns), highmyopia (> 8 dioptre spherical correction or axial length > 28 mm), aphakia, history of rhegmatogenousretinal detachment, lens zonule instability, recent ocular surgery or intraocular injection (includinglaser therapy), proliferative diabetic retinopathy, ischaemic retinopathies, retinal vein occlusions,exudative age-related macular degeneration (AMD) and vitreous haemorrhage. Treatment is notrecommended in such patients.

There is limited experience in patients with non-proliferative diabetic retinopathy or history of uveitis(including active severe inflammation) or significant eye trauma. Caution should be exercised whentreating such patients.

The potential for lens subluxation or phacodonesis cannot be ruled out. If this event occurs, it shouldbe treated according to standard medical practice. Patients should be monitored appropriately (seesection 4.8 and 5.3).

The effect of ocriplasmin (particularly in inducing resolution of vitreomacular adhesion or causingtotal posterior vitreous detachment [PVD]) is reduced in subjects with an epiretinal membrane (ERM)or a diameter of VMA > 1500 microns (see section 5.1).

There is a risk for a significant decrease in visual acuity during the first week after the injection.

Patients should be monitored appropriately (see section 4.8).

Ophthalmological examinations may be abnormal following the administration of JETREA. Theseinclude optical coherence tomography (OCT), ophthalmoscopy (foveal reflex), colour vision test(Roth 28-hue) and full-field ERG. This should be taken into consideration when using these tests forthe diagnosis or monitoring of other conditions (see section 4.8).

No formal interaction studies have been performed.

Ocriplasmin is a proteolytic enzyme with serine protease activity which could be present in the eye forseveral days after intravitreal injection (see section 5.2). Administration in close temporal associationwith other medicinal products in the same eye may affect the activity of both medicinal products andis therefore not recommended.

There are no clinical data on concomitant use of ocriplasmin with VEGF-inhibitors (vascularendothelial growth factor) and therefore it is not recommended.

No systemic interactions are anticipated.

There are no data for the use of JETREA in pregnant women. No reproductive toxicology studies havebeen performed. The systemic exposure of JETREA is expected to be very low after intravitrealinjection. JETREA should be used during pregnancy only if the clinical benefit outweighs thepotential risks.

It is unknown whether JETREA is excreted in human milk. JETREA should be used duringbreast-feeding only if the clinical benefit outweighs the potential risks.

There are no data on the effect of JETREA on fertility.

The intravitreal injection of JETREA may have a moderate influence on the ability to drive and usemachines due to possible temporary visual disturbances (see section 4.8). In these cases, patientsshould not drive or use machines until the visual disturbances have resolved.

Over 1400 patients have been treated with the recommended dose of 0.125 mg of JETREA ininterventional clinical studies.

All adverse reactions were ocular. In 3 clinical studies with follow-up from 6 months (TG-MV-006and TG-MV-007) to 24 months (TG-MV-014), the most commonly reported adverse reactions werevitreous floaters, eye pain, photopsia and chromatopsia as well as conjunctival haemorrhage resultingfrom the injection procedure. Most of the adverse reactions occurred within the first week after theinjection. The majority of these reactions were non-serious, mild to moderate in intensity and resolvedwithin 2 to 3 weeks. Information on resolution of specific events such as chromatopsia and ERGchanges can be found in the relevant paragraph of the ‘description of selected adverse reactions’section.

The most clinically relevant adverse reactions included blindness transient, retinal tear, retinaldetachment, lens subluxation and macular hole progression.

The following table summarises the adverse reactions reported in the treated eye in clinical studiesand/or from post-marketing experience.

Visual symptoms perceived in the contralateral eye or bilaterally have also been reported.

The adverse reactions with a reasonable possibility of causal relationship to the injection procedure or

JETREA are listed by MedDRA system organ class and frequency 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) and not known (cannot be estimated from theavailable data). Within each frequency grouping, adverse reactions are presented in the order ofdecreasing seriousness.

Eye disorders Very common

Vitreous floaters, eye pain, conjunctival haemorrhage, chromatopsia*

Common

Visual acuity reduced*, visual impairment1), visual field defect2), vision blurred,retinal haemorrhage, vitreous haemorrhage, macular hole*, macular degeneration,retinal degeneration, macular oedema3), retinal oedema4), retinal pigmentepitheliopathy, metamorphopsia, conjunctival oedema, eyelid oedema, vitritis,anterior chamber cell, anterior chamber flare, iritis, photopsia, conjunctivalhyperaemia, ocular hyperaemia, vitreous detachment, eye irritation, dry eye,foreign body sensation in eyes, eye pruritus, ocular discomfort, photophobia,lacrimation increased

Uncommon

Blindness transient, lens subluxation*, retinal tear*5), retinal detachment*5), nightblindness, pupillary reflex impaired, diplopia, hyphaema, miosis, pupils unequal,corneal abrasion, anterior chamber inflammation, eye inflammation, conjunctivalirritation

Investigations Very common

Retinogram abnormal*, colour vision test abnormal†

Common

Intraocular pressure increased, macular reflex abnormal, optical coherencetomography (OCT) abnormal*

* see section ‘Description of selected adverse reactions’1) including dim vision2) including scotoma3) including cystoid macular oedema4) including subretinal fluid5) events occurring pre-vitrectomy† using the Roth 28-hue colour vision test. See also section 4.4.

Visual acuity reduced

In the placebo-controlled pivotal phase III studies (TG-MV-006 and TG-MV-007), 7.7% of JETREApatients and 1.6% of placebo patients had acute ≥ 2-line (≥ 10 ETDRS letters) loss in best-correctedvisual acuity (BCVA) during the first week after injection with no alternative explanation for thechange. The visual acuity decrease had resolved by the end of the studies for the majority of JETREApatients (80.6%) but there were some patients who had not recovered despite vitrectomy. The mediantime to resolution was 22 days.

In study TG-MV-014, 2.8% of JETREA patients and 1.4% of sham patients had acute ≥ 2-line loss in

BCVA during the first week after injection. Out of the 4 JETREA patients with acute visual acuitydecrease, 3 recovered following vitrectomy. See section 4.4 for monitoring recommendations.

Chromatopsia (including dyschromatopsia and colour vision test abnormal)

Colour vision alterations (including yellowish vision and abnormal Roth 28-hue colour vision test)have been reported as a very common adverse reaction in patients injected with JETREA. Themajority of events were non-serious, mild and generally resolved spontaneously. The median time toresolution was 3 months.

Retinogram abnormal

Electroretinographic (ERG) changes (a- and b-wave amplitude decrease) have been reported as a verycommon adverse reaction in patients injected with JETREA; in the majority of cases visualimpairment and chromatopsia were also reported.

In study TG-MV-014, a sub-set of 40 patients receiving JETREA systematically underwent ERGtesting; the ERG changes which had developed in 16 out of 40 patients resolved in the majority ofpatients (13 out of 16). The median time to resolution was 6 months. ERG changes were not predictiveof negative outcomes in terms of visual acuity; visual acuity improved or was maintained in 15 outof 16 patients compared to baseline.

Retinal breaks (tears and detachment)

In the placebo-controlled pivotal phase III studies (TG-MV-006 and TG-MV-007), retinal breaks(tears and detachment) were reported in 1.9% of patients injected with JETREA vs. 4.3% injected withplacebo. Most of these events occurred during or after vitrectomy in both groups. The incidence ofretinal detachment that occurred pre-vitrectomy was 0.4% in the JETREA group and none in theplacebo group, while the incidence of retinal tears (without detachment) that occurred pre-vitrectomywas 0.2% in the JETREA group and 0.5% in the placebo group.

In study TG-MV-014, retinal tear was reported in 1.4% of patients injected with JETREA and 6.8% ofsham recipients; the incidence of retinal detachment was 1.4% in both arms. In the sham group, noevents occurred prior to vitrectomy. In the JETREA group, 1 patient (0.7%) developed retinal tear andretinal detachment between Day 0 and Day 7 post-injection.

Macular hole

In the placebo-controlled pivotal phase III studies (TG-MV-006 and TG-MV-007), events of macularhole (including both progression and new onset) were reported for 6.7% of all patients injected with

JETREA vs. 9.6% injected with placebo at Month 6.

In study TG-MV-014, events of macular hole (including both progression and new onset) werereported in 15.8% JETREA vs. 13.5% sham recipients at Month 24.

Early progression rates of full-thickness macular hole (until Day 7 post-injection) at RPE (retinalpigment epithelium) level were higher in the JETREA treated patients compared to sham or placebo.

Progression rates after Month 6, however, were higher in sham or placebo than in those treated with

JETREA. Any persistence or progression of macular hole should be treated according to usualpractice.

Lens subluxation/phacodonesis

One case of lens subluxation/phacodonesis was reported in clinical studies in adults and appears tohave been possibly related to treatment with JETREA. In a paediatric study evaluating JETREA as anadjunct to vitrectomy, one case of subluxation was reported in a premature infant who received asingle intravitreal injection of JETREA 0.175 mg. Lens subluxation was observed in 3 animal speciesat ocriplasmin concentrations above the intended clinical concentration (see section 5.3).

Based on the proteolytic activity of ocriplasmin, preclinical and clinical findings, the potential for lenssubluxation or phacodonesis cannot be ruled out. If this event occurs, it should be treated according tostandard medical practice.

Optical coherence tomography abnormal

In study TG-MV-014, incomplete Inner Segment/Outer Segment (IS/OS) band, also referred to as

Ellipsoid Zone, in the central area was very common at baseline (65.8% in the JETREA group and62.2% in the sham group). However, after treatment, a higher proportion of patients in the JETREAgroup had a change from an intact IS/OS band at baseline to an incomplete IS/OS band in the centralarea at a later time point compared with the sham group (7.7% and 2.8%, respectively at Day 28).

Beyond the central area, abnormal aspects of the IS/OS band attributed to JETREA have beenobserved in up to 10% of patients.

Ellipsoid Zone disruption within and outside the central area has been reported in non-interventionalstudies and post-marketing reports. In the majority of cases recovery occurred within 6 months.

Subretinal fluid and signs and symptoms of impaired photoreceptor function including decreasedvisual acuity (in some cases severe) were reported in association with these events.

See section 4.4 for monitoring recommendations. Routine observation is recommended in all abovesituations.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The clinical data on the effects of JETREA overdose are limited. One case of accidental overdose of0.250 mg ocriplasmin (twice the recommended dose) has been reported. The patient had a decrease in

BCVA of 21 ETDRS letters from baseline that returned to within 9 letters of baseline at the end of thestudy. The patient also developed mild conjunctival hyperaemia, eye inflammation and miosis whichresolved with corticosteroid eye drops.

If an overdose occurs, close monitoring is recommended. If an adverse reaction occurs, it should betreated according to standard medical practice.

Pharmacotherapeutic group: Ophthalmologicals, Other ophthalmologicals, ATC code: S01XA22

Ocriplasmin has a proteolytic activity against protein components of the vitreous body and thevitreoretinal interface (VRI) (e.g. laminin, fibronectin and collagen) and aims to dissolve the proteinmatrix responsible for the abnormal vitreomacular adhesion (VMA). The tight binding of the proteincomponents within the macular area of the VRI contribute to vitreomacular traction (VMT), leading tovisual impairment and/or macular holes.

The clinical efficacy and safety of JETREA for the treatment of vitreomacular traction (VMT) wasassessed in 3 double-masked studies.

Studies TG-MV-006 and TG MV-007

The efficacy of JETREA was demonstrated in 2 pivotal multicentre, randomised, double-masked,placebo-controlled, 6-month studies in patients with VMT. A total of 652 patients (JETREA 464,placebo 188) were randomised in these 2 studies.

In both pivotal studies, the proportion of patients who achieved VMA resolution at Day 28 (primaryendpoint) was significantly (p≤0.003) higher in the JETREA group compared with the placebo group.

The difference continued to be statistically significant through Month 6 in each study (p≤0.024). In theintegrated data, 26.5% in the JETREA group compared with 10.1% in the placebo group achieved

VMA resolution at Day 28 (p<0.001). The difference was maintained from Day 7 through Month 6(Figure 1).

Figure 1: Proportion of patients with VMA resolution up to Day 180 (Month 6) (TG-MV-006,

TG-MV-007 and integrated data)35%

TG-MV-00630% JETREA

TG-MV-00725% JETREA20% Combined

JETREA15% TG-MV-006

Placebo10%

TG-MV-007

Placebo5%

Combined0% Placebo7 14 28 90 180

Days Post-Injection

At all post-injection days, p≤0.024 in TG-MV-006, p≤0.009 in TG-MV-007, p<0.001in integrated data

Patients with no ERM at baseline were more likely to achieve VMA resolution at Day 28 comparedwith those who had ERM at baseline. In the integrated data, the VMA resolution rate at Day 28 washigher in patients treated with JETREA compared to placebo in both the subgroup without ERM(37.4% vs. 14.3%, p<0.001) and with ERM (8.7% vs. 1.5%, p=0.046).

Patients with a smaller VMA diameter at baseline (≤ 1500 microns) were more likely to achieve VMAresolution at Day 28 compared with those who had a diameter > 1500 microns. In the integrated data,the VMA resolution rate at Day 28 was higher in patients treated with JETREA compared to placeboin both the subgroup with VMA ≤ 1500 microns at baseline (34.7% vs. 14.6%, p<0.001) and with

VMA > 1500 microns at baseline (5.9% vs. 0%, p=0.113).

In the integrated data, full-thickness macular hole (FTMH) was present at baseline in 106/464 (22.8%)patients and 47/188 (25%) patients in the JETREA and placebo groups, respectively. Of these, theproportion of patients who achieved FTMH closure without vitrectomy at Day 28 was higher in the

JETREA group than the placebo group (40.6% vs. 10.6%, respectively; p<0.001). A difference wasmaintained through the end of the studies (Month 6).

A significantly higher percentage of JETREA treated patients experienced total PVD at Day 28compared to placebo treated patients (integrated data: 13.4% vs. 3.7%, respectively; p<0.001).

During the studies, vitrectomy could be performed at the discretion of the Investigator. JETREAtreated patients were less likely to have had a vitrectomy by the end of the study (Month 6) comparedwith placebo treated patients (integrated data: 17.7% vs. 26.6%, respectively; p=0.016).

A higher proportion of JETREA treated patients gained ≥ 2 or ≥ 3 lines in BCVA (irrespective ofvitrectomy) at Month 6 (28.0% and 12.3%, respectively) compared with patients treated with placebo(17.1% and 6.4%) (p=0.003 and p=0.024, respectively). Also the proportion of patients gaining ≥ 2 or≥ 3 lines in BCVA without vitrectomy favoured JETREA at Month 6 (23.7% vs. 11.2%, p<0.001 for again ≥ 2 lines and 9.7% vs. 3.7%, p=0.008 for a gain ≥ 3 lines).

In the integrated analysis of the National Eye Institute Visual Function Questionnaire-25 (VFQ-25), anumerical difference in favour of JETREA over placebo was shown in each sub-scale score, as well asthe composite score. The difference for improvement in the general vision sub-scale score wasstatistically significant (6.1 JETREA vs. 2.1 placebo, p=0.024).

% VMA Resolution

Study TG-MV-014

The efficacy of JETREA has been further confirmed in a randomised, double-masked, sham-controlled, 24-month study in patients with VMT finalised since the initial marketing authorisationapproval. A total of 220 patients (JETREA 146, sham 74) were randomised in this study.

The proportion of patients who achieved VMA resolution at Day 28 (primary endpoint) was 41.7% inthe JETREA group compared with 6.2% in the sham group (p<0.001). This effect was maintained overtime and VMA resolution was consistently greater in the JETREA group at each post-injection studyvisit compared with the sham group.

In this study, FTMH was present at baseline in 50/145 (34.5%) and 26/73 (35.6%) patients in the

JETREA and sham groups, respectively. Of these, 30% of JETREA treated patients and 15.4% ofpatients in the sham group experienced non-surgical FTMH closure at Month 24. All had done so by

Month 3.

The proportion of patients who underwent vitrectomy was smaller in the JETREA group than in thesham group at all visits. At Month 24, the proportions were 48/145 (33.3%) and 32/73 (43%),respectively. The most common reason for performing vitrectomy was FTMH (in 24.8% JETREAtreated patients and 23.3 % sham patients). The proportion of patients who underwent vitrectomy foran event of VMA/VMT was 8.3% in the JETREA group compared to 19.2% in the sham group.

The proportion of patients who gained ≥ 2 or ≥ 3 lines in BCVA at Month 6, irrespective ofvitrectomy, was slightly higher in the JETREA group (36.2%, 18.6%) than in the sham group (28.6%,13.1%). At Month 24, the proportion of patients with ≥ 2 lines improvement from baseline in BCVAwas greater in the JETREA group than in the sham group (50.5% vs. 39.1%). The proportion ofpatients with ≥3 lines improvement from baseline was only greater in the JETREA group (23.4% vs.12.8%, respectively) in the subgroup who had no FTMH at baseline. The ≥ 2 or ≥ 3 lines gain in

BCVA without vitrectomy favoured JETREA over sham both at Month 6 (26.8%, 14.0%, vs. 15.62%,6.2%, respectively) and Month 24 (31.9%, 16.8%, vs. 11,7%, 4.1%, respectively).

A greater proportion of patients in the JETREA group had a ≥ 5 points improvement in VFQ-25composite and sub-scale scores, irrespective of vitrectomy, at all visits. At Month 24, 51.4% of

JETREA patients had a ≥ 5 points improvement in VFQ-25 composite score compared to 30.1% in thesham group.

The European Medicines Agency has waived the obligation to submit the results of studies with

JETREA in all subsets of the paediatric population in the treatment of vitreomacular traction (VMT),including when associated with macular hole of diameter less than or equal to 400 microns (seesection 4.2 for information on paediatric use).

The safety and efficacy of ocriplasmin in paediatric subjects scheduled for vitrectomy wasinvestigated in study TG-MV-009. A single intravitreal injection of 0.175 mg (above therecommended dose), or placebo, was injected in the mid-vitreous of 24 eyes of children aged 0 to16 years, 30 to 60 minutes prior to the planned start of vitrectomy. The main reasons for vitrectomywere retinal detachment and retinopathy of prematurity. Treatment with ocriplasmin did notdemonstrate an effect on posterior vitreous detachment rate, vitreous liquefaction grade, immediatepostoperative retinal reattachment rate, development of proliferative vitreoretinopathy, or stage ofretinopathy of prematurity. The safety findings observed in study TG-MV-009 were consistent withthe known safety profile for JETREA. Based on the results of this study, the use of JETREA as anadjunct to vitrectomy in children, to facilitate vitreous separation and removal, is not recommended.

Experience is limited in groups other than Caucasians.

Ocriplasmin levels in the vitreous decrease rapidly after intravitreal administration. In a clinical studyin patients scheduled for vitrectomy receiving 0.125 mg JETREA (corresponding to a theoretical startconcentration of 29 µg/mL vitreous), mean ocriplasmin activity was 9% of theoretical startconcentration 2-4 hours after injection and below the lower level of quantification at 7 days.

Because of the small dose administered (0.125 mg), detectable levels of ocriplasmin in systemiccirculation are not expected after intravitreal injection.

When administered intravenously, ocriplasmin enters the endogenous protein catabolism pathwaythrough which it is rapidly inactivated via its interactions with protease inhibitor α2-antiplasmin orα2-macroglobulin. The inactive ocriplasmin/α2-antiplasmin complex is cleared from the circulationwith a half-life (t1/2) of several hours.

No studies have been conducted to examine the pharmacokinetics of ocriplasmin in patients with renalimpairment since the systemic exposure is expected to be very low after intravitreal administration.

No studies have been conducted to examine the pharmacokinetics of ocriplasmin in patients withhepatic impairment since the systemic exposure is expected to be very low after intravitrealadministration.

The intravitreal toxicity of ocriplasmin has been evaluated in rabbits, monkeys and minipigs.

Ocriplasmin induced an inflammatory response and transient ERG changes in rabbits and monkeys,while no inflammation or ERG changes were observed in minipigs. In rabbits and monkeys, theincidence of vitreous cell infiltrates tended to resolve over time. In monkeys, after administration of125 µg/eye (68 µg/mL vitreous) the ERG was fully recovered by Day 55. Lens subluxation wasobserved in the 3 species at ocriplasmin concentrations at or above 41 µg/mL vitreous, a concentrationabove the intended clinical concentration of 29 µg/mL. This effect appeared to be dose-related andwas observed in all animals administered intravitreal ocriplasmin more than once. Pathologicalchanges related to intraocular haemorrhage were observed in rabbits and monkeys. It remains unclearif this haemorrhage is related to the injection procedure itself or administration of ocriplasmin. Nosystemic toxicity was observed after intravitreal administration of ocriplasmin.

The systemic toxicity of ocriplasmin has been evaluated in both rat and dog. Intravenousadministration of 10 mg/kg was generally well tolerated in both rat and dog whether administered assingle dose or as repeated dose.

No carcinogenicity, mutagenicity or reproductive and developmental toxicity data are available.

Sodium chloride (NaCl)

Mannitol

Citric acid

Sodium hydroxide (NaOH) (for pH adjustment)

Hydrochloric acid (HCl) (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years when stored in a freezer (-20 °C ± 5 °C).

After thawing

The unopened vial in the original carton protected from light may be stored in a refrigerator(2 °C to 8 °C) for up to 1 week. The new in-use expiry date should be calculated and noted on thecarton before it is placed in the refrigerator.

Once removed from the freezer or refrigerator, the medicinal product may be kept below 25 °C for upto 8 hours. At the end of this period the product must be used or discarded.

Do not refreeze a vial once it has been thawed.

From a microbiological point of view, the medicinal product must be used immediately after opening.

The vial and any unused portion of the solution must be discarded after single use.

Store in a freezer (-20 °C ± 5 °C).

For storage conditions after thawing/opening of the medicinal product, see section 6.3.

0.3 mL solution in a vial (type I glass) closed with a chlorobutyl rubber stopper and a bluepolypropylene flip-off cap. Pack containing 1 vial.

Vials are for single use only.

JETREA 0.375 mg/0.3 mL solution for injection is a ‘ready-diluted’ formulation, no further dilution isrequired. Only 0.1 mL of the total 0.3 mL solution in the vial should be administered. Any excessvolume should be expelled prior to injection in order to deliver a single dose of 0.1 mL containing0.125 mg ocriplasmin.

Instructions for use1. Remove the vial from the freezer and allow to thaw at room temperature (takes about2 minutes).

2. Once completely thawed, remove the protective bluepolypropylene flip-off cap from the vial.

JETREA 0.375 mg/0.3 mL solution for injection3. Disinfect the top of the vial with an alcohol wipe.

JETREA 0.375 mg/0.3 mL solution for injection4. Visually inspect the vial for particulate matter. Only a clear, colourless solution without visibleparticles should be used.

5. Using aseptic technique, withdraw all of the solutionusing an appropriate sterile needle (slightly incline thevial to ease withdrawal) and discard the needle afterwithdrawal of the vial contents. Do not use this needle forthe intravitreal injection.

JETREA 0.375 mg/0.3 mL solution for injection6. Replace the needle with an appropriate sterile needle,carefully expel the excess volume from the syringe byslowly depressing the plunger so that the plunger tipaligns with the 0.1 mL line on the syringe (correspondingto 0.125 mg ocriplasmin).

JETREA 0.375 mg/0.3 mL solution for injection7. Inject 0.1 mL of the solution immediately into the mid-vitreous.

8. Discard the vial and any unused portion of the solution after single use.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Inceptua AB

Gustavslundsv. 14316751 Bromma

Sweden

EU/1/13/819/002

Date of first authorisation: 13 March 2013

Date of latest renewal: 8 December 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.