Consumer medicine information

Jetrea

Ocriplasmin

BRAND INFORMATION

Brand name

Jetrea

Active ingredient

Ocriplasmin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Jetrea.

What is in this Leaflet

This leaflet answers some common questions about JETREA*. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using JETREA against the benefits it is expected to have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What is JETREA used for?

JETREA is used to treat adults with an eye disease called vitreomacular traction (VMT), including when it is associated with a small to medium macular hole in the macular (central part of the light-sensitive layer at the back of the eye).

As a person gets older, the vitreous (jelly-like material in the centre of the eye) shrinks and separates from the retina (the light-sensitive layer in the back of the eye). VMT occurs when the vitreous remains attached to the central part of the retina (called macula). The macula provides central vision that is needed for everyday tasks such as driving, reading and recognising faces.

The symptoms of VMT include distorted, blurred or decreased vision and potentially a defect in central vision. When the disease progresses, the shrinking vitreous may pull the macula away from the back of the eye and eventually may result in the formation of a hole in the macula (called macular hole).

JETREA contains active ingredient called ocriplasmin, which works by separating the vitreous from the macula and helping to close the macular hole, if one is present, which may decrease symptoms caused by VMT.

Ocriplasmin is a form of human plasmin which is an enzyme.

Before prescribing JETREA for you, your doctor will have examined the eye and decided that JETREA is the right medicine for your eye condition.

Ask your doctor if you have any questions about why JETREA has been prescribed for you.

JETREA is not addictive.

Before you are given JETREA

When you must not be given it

You must not be given JETREA if:

  • you have an active or suspected infection in or around your eye
  • you have an allergy to ocriplasmin, citric acid, mannitol or sodium hydroxide

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

You must not be given JETREA if you are a child. The safety and effectiveness of JETREA in children has not been established.

If you are not sure whether you should be given JETREA, talk to your doctor.

Before you are given it

Tell your doctor if you have or have had any of the following medical conditions and treatments:

  • any condition that damages the retina (back of the eye) and causes vision to fade. Early symptoms can include poor night vision, problems seeing things in dimly lit environments, loss of peripheral (side) vision and difficulty in judging changes in peripheral vision, such as curbs or steps.
  • if you suffer or have suffered from any eye diseases or have had eye laser treatment. Your doctor will decide if treatment with JETREA is right for you.
  • you have been given JETREA before in the same eye. JETREA can only be administered once to each eye. Only one eye can be injected at a time.
  • any other medical conditions

Tell your doctor if:

  • you have an allergy to any medicines, foods dyes or preservatives, JETREA, ocriplasmin or any of the ingredients listed at the end of this leaflet
  • you have a history of allergic problems, including eczema, hives or hay fever
  • you are pregnant or intend to become pregnant
    Your doctor will discuss the possible risks and benefits of using JETREA during pregnancy.
  • you are breastfeeding or intend to breastfeed
    Your doctor will discuss the possible risks and benefits of using JETREA when breastfeeding.

If you have not told your doctor about any of the above, tell them before you are given JETREA.

Using other medicines

Your doctor may ask you to use antibiotic eye drops before and after the injection in order to prevent any possible eye infections.

Tell your doctor if you are taking any other medicines, including anti VEGF-inhibitors or any other medicines that you buy without a prescription from a pharmacy, supermarket or health food shop. Some medicines and JETREA may interfere with each other.

This is particularly important if you are currently taking any eye medications or using any other type of eye drops.

Some medicines may be affected by JETREA, or may affect how well it works. You may need different amounts of your medicines or you may need to take different medicines.

Your doctor has more information on medicines to be careful with or avoid when being given JETREA.

How JETREA is given

How much is given

The usual dose is 0.1 mL of the diluted JETREA solution (0.125 mg) once in one of the eyes.

The other eye may also be treated at a later time, if needed.

How it is given

JETREA is given as a single injection into the eye.

It must be given by a qualified ophthalmologist (eye specialist) who has experience in giving injections into the eye.

On the day of the injection, your doctor may use antibiotic drops and clean your eye and eyelid carefully to prevent infection. Your doctor will also give you a local anaesthetic to prevent any pain from the injection.

After the injection, your doctor will monitor your vision and may perform some eye tests to make sure there are no complications. The injection might increase your eye pressure which is not noticeable to you. Your doctor will test for this, and provide any treatment if needed.

You must not be given JETREA if:

  • it was not stored properly prior to use (ie minus 20°C ± 5°C)
  • it was not used within 15 minutes after reconstitution
  • the packaging appears damaged in any way
  • the expiry date on the bottle/carton has passed

If you use this medicine after the expiry date has passed, or if it was not stored properly before use, it may not work.

Your doctor or pharmacist are responsible for storing and preparing JETREA.

If you are given too much (overdose)

If you are given more JETREA than you need, your doctor may measure your eye pressure and treat it if needed.

If you think that you have been given too much JETREA, immediately tell your doctor or telephone the Poisons Information Centre (in Australia, call 13 11 26; in New Zealand, call 0800 POISON or 0800 764 766) for advice or go to Accident & Emergency at your nearest hospital. Do this even if there are no signs of discomfort or poisoning.

After you are given JETREA

Things you must do

Carefully follow all directions given to you by your doctor. They may differ from the information contained in this leaflet.

Tell all doctors and pharmacists who are treating you that JETREA has been used.

If you develop an eye infection, receive an eye injury or have eye surgery, tell your doctor.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you have been given JETREA.

Things to be careful of

The JETREA treatment may produce a significant, but short-lasting, loss of vision and visual disturbances. This may affect the ability to drive or use machines.

This is most likely to occur during the first 7 days after the injection due to the JETREA working in the eye.

If you experience these signs, you must not drive or use machines until these temporary visual disturbances subside.

Side effects

Tell your doctor as soon as possible if you do not feel well after the injection of JETREA.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor immediately if you develop any of the following after injection of JETREA:

  • a severe decrease in vision has been reported in up to 1 in 10 patients within one week after JETREA treatment. This is generally transient and reversible, and will usually disappear without treatment.
  • symptoms such as eye pain, worsening eye redness, severely blurred or decreased vision, increased sensitivity to light or an increased number of dark floating spots in the field of vision (floaters) are also seen in up to 1 in 10 patients and may be the signs of an infection, bleeding, separation or tear of the retina or an increase in the pressure inside the treated eye.

Talk to your doctor if you develop any of the additional side effects listed below:

Very common side effects (may affect more than 1 in 10 patients)

  • dark floating spots in the field of vision (floaters)
  • eye pain
  • bleeding on the surface of the eye
  • colour vision changes

Common side effects (may affect up to 1 in 10 patients):

  • decreased sharpness of vision
  • decrease in vision which may be severe
  • visual disturbances
  • decreased vision or blind spots in parts of the field of view
  • blurred vision
  • bleeding inside the eye
  • blind spot or blind area in the centre of vision
  • inflammation of the eye
  • distorted vision
  • swelling of the surface of the eye
  • swelling of the eyelid
  • flashes of light in the eye
  • eye redness
  • irritation on the surface of the eye
  • dry eye
  • itching of the eye
  • a feeling of having something in the eye
  • eye discomfort
  • sensitivity to light
  • increased tear production

Uncommon side effects (may affect up to 1 in 100 patients):

  • transient severe decreased vision
  • difficulty in seeing well at night or in dim light
  • disturbance in your eye’s reaction to the light may increase your sensitivty to ligh (pupillary reflex impaired)
  • double vision
  • accumulation of blood in the front part of the eye
  • abnormal constriction of the pupil (black part of the centre of the eye)
  • different sized pupils
  • a scratch or scrape on the cornea (transparent layer that covers the front part of the eye)

Some tests and imaging of the back of the eye (retina) have been found to be abnormal after Jetrea administration

Some effects (such as flashes, floaters) can also be perceived from the untreated eye in some cases.

If you get any side effects, talk to your doctor. This includes any possible side effects.

Tell your doctor immediately or go to Accident & Emergency at your nearest hospital if you notice any of the following:

  • fast or irregular heartbeats, also called palpitations
  • dizziness and light-headedness
  • skin rash, itching
  • swelling of the hands, feet, ankles or legs
  • wheezing, difficulty in breathing
  • shortness of breath
  • skin rash
  • very slow pulse, chest pain
  • fainting
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in breathing or swallowing
  • severe and sudden onset of pinkish, itchy swellings on the skin, also called hives or nettle rash

These hypersensitivity reactions can be very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Other side effects not listed may also occur in some patients. Tell your doctor if you notice any other effects.

After using JETREA

Storage

It is not likely that you will be required to store JETREA.

JETREA should be stored in a freezer at minus 20°C ± 5°C.

Protect from light.

Information about storage and preparation of JETREA is provided to healthcare professionals only.

Your doctor or pharmacist are responsible for storing and preparing JETREA. They are also responsible for disposing any unused JETREA correctly.

Product description

What it looks like

JETREA is a concentrate for solution for injection in a glass vial.

The concentrate is clear and colourless. Each pack contains one vial containing 0.5 mg of ocriplasmin in 0.2 mL.

After dilution with 0.2 mL of sodium chloride solution, 0.1 mL of the diluted solution contains 0.125 mg of ocriplasmin.

Ingredients

Active ingredients:

  • ocriplasmin 2.5 mg/mL

Other ingredients:

  • citric acid
  • mannitol
  • sodium hydroxide
  • purified water

The pH of the solution may be adjusted with sodium hydroxide and/or hydrochloric acid.

Supplier

In Australia, this product is supplied by:

I-Care Pharma Distributors Pty Ltd
Unit 3/92A Mona Vale Road
Warriewood NSW 2102.

This leaflet was prepared in July 2019

AUST R: 206494

*Registered Trademark

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Jetrea

Active ingredient

Ocriplasmin

Schedule

S4

 

1 Name of Medicine

Jetrea solution for injection. Ocriplasmin (ryp).

6.7 Physicochemical Properties

Molecular weight: 27.2 kDa.
Chemical name: microplasmin; recombinant truncated human plasmin.

Chemical structure.

The chemical structure of ocriplasmin (ryp) is:

CAS number.

1048016-09-6.

2 Qualitative and Quantitative Composition

Ocriplasmin (ryp) is a recombinant truncated form of human plasmin with a molecular weight of 27.2 kDa produced by recombinant DNA technology in a Pichia pastoris expression system.
Each vial contains 0.5 mg ocriplasmin and 0.21 mg citric acid, 0.75 mg mannitol, sodium hydroxide (for pH adjustment) and water for injections with a pH of 3.1.
Jetrea drug product solution is to be diluted with an equal volume of 0.9% (w/v) sodium chloride prior to use. After dilution with 0.2 mL of 0.9% sodium chloride (preservative-free), 0.1 mL of the diluted solution contains 0.125 mg ocriplasmin.

3 Pharmaceutical Form

Jetrea is concentrated solution for intravitreal injection (a sterile, clear and colourless solution).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Ocriplasmin (ryp) is a recombinant truncated form of human plasmin with a molecular weight of 27.2 kDa produced by recombinant DNA technology in a Pichia pastoris expression system.

Mechanism of action.

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

Clinical trials.

The clinical efficacy and safety of Jetrea for the treatment of vitreomacular traction (VMT)/vitreomacular adhesion (VMA) was assessed in 3 double-masked studies.

Studies TG-MV-006 and TG MV-007.

The efficacy of Jetrea solution for injection 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 two studies.
The diagnostic criteria used were as follows.
Patients with symptomatic focal VMA, i.e. central vitreal adhesion within 6 mm Optical Coherence Tomography field surrounded by elevation of the posterior vitreous cortex, that, in the opinion of the investigator, is related to decreased visual function such as metamorphopsia, decreased visual acuity or other visual complaint.
In both pivotal studies, the proportion of patients who achieved VMA resolution at Day 28 (primary endpoint) was significantly (p ≤ 0.003) higher in the ocriplasmin group compared with the placebo group. The difference continued to be statistically significant through Month 6 in each study (p ≤ 0.024).
In the integrated data, 26.5% in the ocriplasmin group compared with 10.1% in the placebo achieved VMA resolution at Day 28, (p < 0.001). The difference was maintained from Day 7 through Month 6 (see Figure 1).
Patients with no ERM at baseline were more likely to achieve VMA resolution at Day 28 compared with those who had ERM at baseline. In the integrated data, the VMA resolution rate at Day 28 was higher 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 (≤ 1,500 microns) were more likely to achieve VMA resolution at Day 28 compared with those who had a diameter > 1,500 microns. In the integrated data, the VMA resolution rate at Day 28 was higher in patients treated with Jetrea compared to placebo in both the subgroup with VMA ≤ 1,500 microns at baseline (34.7% vs 14.6%, p < 0.001) and with VMA > 1,500 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 solution for injection and placebo groups respectively. Of these, the proportion 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 was maintained through the end of the studies (Month 6).
A significantly higher percentage of Jetrea treated patients experienced total PVD at Day 28 compared to placebo treated patients (integrated data: 13.4% vs. 3.7%, respectively; p < 0.001).
During the studies, if the underlying condition did not improve, i.e. VMA was not resolved by Day 28, vitrectomy could be performed at the discretion of the Investigator. Jetrea treated patients were less likely to have had a vitrectomy by the end of the study (Month 6) compared with 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 of vitrectomy) 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 a gain ≥ 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 Questionaire-25 (VFQ-25), a numerical difference in favour of Jetrea over placebo was shown in each sub-scale score, as well as the composite score. The difference for improvement in the general vision sub-scale score was statistically significant (6.1 Jetrea vs 2.1 placebo, p = 0.024).

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/VMA finalised since the initial marketing authorisation approval. 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% in the Jetrea group compared with 6.2% in the sham group (p < 0.001). This effect was maintained over time and VMA resolution was consistently greater in the Jetrea group at each post-injection study visit 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% of patients 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 the sham 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% Jetrea treated patients and 23.3% sham patients). The proportion of patients who underwent vitrectomy for an 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 of vitrectomy, 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 BCVA was greater in the Jetrea group than in the sham group (50.5% vs. 39.1%). The proportion of patients 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-25 composite 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 the sham group.

Paediatric population.

The safety and efficacy of ocriplasmin in paediatric subjects scheduled for vitrectomy was investigated in study TG-MV-009. A single intravitreal injection of 0.175 mg ocriplasmin, or placebo, was injected in the midvitreous of 24 eyes of children aged 0 to 16 years, 30 to 60 minutes prior to the planned start of vitrectomy. The main reasons for vitrectomy were retinal detachment and retinopathy of prematurity. Treatment with ocriplasmin did not demonstrate an effect on posterior vitreous detachment rate, vitreous liquefaction grade, immediate postoperative retinal reattachment rate, development of proliferative vitreoretinopathy, or stage of retinopathy of prematurity. Based on the results of this study, the use of Jetrea solution for injection as an adjunct to vitrectomy in children, to facilitate vitreous separation and removal, is not recommended.

5.2 Pharmacokinetic Properties

Ocriplasmin levels in the vitreous decrease rapidly after intravitreal administration. In a clinical study in patients scheduled for vitrectomy receiving 0.125 mg Jetrea solution for injection (corresponding to a theoretical start concentration of 29 microgram/mL vitreous), mean ocriplasmin activity was 9% of theoretical start concentration 2-4 hours after injection and below the lower level of quantification at 7 days.
When administered intravenously, ocriplasmin enters the endogenous protein catabolism pathway through which it is rapidly inactivated via its interactions with protease inhibitor α2-antiplasmin or α2-macroglobulin. The inactive ocriplasmin/α2-antiplasmin complex is cleared from the circulation with a half-life (t1/2) of several hours.
The intravitreal pharmacokinetics of ocriplasmin were determined in a clinical study in patients (n = 38) scheduled for vitrectomy where 0.125 mg ocriplasmin (corresponding to an average concentration of 29 microgram ocriplasmin per mL vitreous volume) was administered as a single intravitreal dose at different time points prior to vitrectomy. As expected from preclinical data, the mean ocriplasmin activity levels decreased with time from injection to time of sampling as illustrated in Table 4, according to a second-order kinetic process. At 24 hours post-injection the levels of ocriplasmin in the vitreous were below 3% of the theoretical concentration reached immediately after injection.
Because of the small dose administered (0.125 mg), detectable levels of ocriplasmin in the systemic circulation are not expected after intravitreal injection.
The systemic pharmacokinetics of ocriplasmin were evaluated in 2 clinical studies (TG-MV-001 and TG-MV-004, n = 40 and 24 respectively) with intravenous administration.
Ocriplasmin enters the endogenous protein catabolism pathway through which it is rapidly inactivated via its interactions with protease inhibitor α2-antiplasmin or α2-macroglobulin.
The inactive ocriplasmin/α2-antiplasmin complex is cleared from the circulation with a half-life (t1/2) of several hours. At doses far exceeding the dose for intravitreal use, and large enough to deplete circulating α2-antiplasmin, the remaining ocriplasmin is cleared with a t1/2 of approximately 1 hour.

Renal impairment.

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

Hepatic impairment.

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

Absorption, distribution, metabolism and excretion.

No studies beyond those previously described have been conducted with ocriplasmin as it is expected that ocriplasmin enters the endogenous protein catabolism pathway through which it is rapidly inactivated via its interactions with protease inhibitor α2-antiplasmin or α2-macroglobulin.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity data are available.

Carcinogenicity.

No carcinogenicity data are available.

4 Clinical Particulars

4.1 Therapeutic Indications

Jetrea is indicated in adults for the treatment of vitreomacular traction (VMT), including when associated with macular hole of diameter less than or equal to 400 microns.

4.3 Contraindications

Patients with active or suspected ocular or periocular infections.
Patients with known hypersensitivity to ocriplasmin or to any of the excipients of Jetrea.

4.4 Special Warnings and Precautions for Use

Decreased vision.

A decrease of greater than or equal to 3 lines of best corrected visual acuity (BCVA) was experienced by 5.6% of patients treated with Jetrea and 3.2% of patients treated with vehicle, after 6 months, in the controlled trials. The majority of these decreases in vision were due to progression of vitreomacular traction and many patients required vitrectomy (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
There is a risk of significant, but transient, loss of visual acuity during the first week after treatment. Patients should be monitored appropriately.
Ophthalmological examinations may be abnormal following the administration of Jetrea. These include 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 for the diagnosis or monitoring of other conditions. See Section 4.8.
Uncommonly (i.e. incidence between 1-in-100 and 1-in-1000), patients can experience longer term reduced visual acuity, associated with ERG changes; but not associated with progression of vitreomacular traction. Based on the currently available data, there is no way to predict which patients will experience such longer-term reduced visual acuity.

Panretinal disease.

Treatment is not recommended in patients with any panretinal disease that has been associated with abnormal ERG findings (e.g. retinitis pigmentosa, choroideraemia). (Visual loss associated with ERG changes has been observed with Jetrea; see Section 4.8 Adverse Effects (Undesirable Effects)).

Intravitreal injection procedure associated events.

Jetrea is administered by intravitreal injection only. Intravitreal injections have been associated with intraocular inflammation/ infection, intraocular haemorrhage and increased intraocular pressure (IOP). Proper aseptic injection techniques must always be used.
In the controlled trials, intraocular inflammation occurred in 7.1% of patients injected with Jetrea versus 3.7% of patients injected with vehicle. Most of the post-injection inflammation events were mild and transient. Intraocular haemorrhage occurred in 2.4% versus 3.7% of patients with Jetrea versus vehicle. The percentages for increased intraocular pressure were 4.1% versus 5.3%.
Following the intravitreal injection, patients should be monitored for any side effects such as (but not limited to) intraocular inflammation/infection and elevation in IOP. Transient increases in IOP including transient blindness and 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 head immediately after the injection and tonometry within 30 minutes following the injection.
Intraocular inflammation/infection and intraocular pressure may be assessed using biomicroscopy between 2 and 7 days following the injection. Patients should be instructed to report symptoms suggestive of intraocular inflammation/infection or any other visual or ocular symptoms without delay. If any of the above events occur, the patient should be treated according to standard medical practice.

Potential for lens subluxation.

The potential for lens subluxation or phacodonesis cannot be ruled out. One case of lens subluxation was reported in a patient who received an intravitreal injection of 0.175 mg (1.4 times higher than the recommended dose). Lens subluxation was observed in three animal species (monkey, rabbit, minipig) following a single intravitreal injection that achieved vitreous concentrations of ocriplasmin 1.4 times higher than achieved with the recommended treatment dose. A second intravitreal dose in monkeys, 28 days apart, produced lens subluxation in 100% of the treated eyes.

Dyschromatopsia.

Dyschromatopsia (generally described as yellowish vision) was reported in 2% of all patients injected with Jetrea solution for injection. In about half of these cases, there were also electroretinographic changes (a- and b-wave amplitude decrease).

Administration to both eyes currently.

The safety and efficacy of Jetrea administered to both eyes concurrently has not been studied. Administration to both eyes concurrently is not recommended.

Repeated administration to the same eye.

Repeated administration of Jetrea to the same eye has not been adequately studied and is not recommended.

Administration of other therapeutic products in the same eye.

Jetrea is a proteolytic enzyme with serine protease activity, which could be present in the eye for several days after intravitreal injection. Administration in close temporal association with other therapeutic products in the same eye may affect the activity of both products and is not recommended.
There are no clinical data on the concomitant administration of Jetrea with VEGF-inhibitors.

Patient groups in whom Jetrea has not been studied.

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

Patient groups in whom there is limited experience with Jetrea.

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 when treating such patients.
Experience is limited in groups other than Caucasians.
As with all therapeutic proteins, there is potential for immunogenicity. Immunogenicity for this product has not been evaluated.

New or enlarged macular holes.

Due to a potential increase in tractional forces, there is a risk of occurrence of new or enlarged macular holes.

Reduced efficacy in patients with epiretinal membrane or large area of vitreomacular adhesion.

The effect of Jetrea solution for injection (particularly in inducing resolution of vitreomacular adhesion or causing total Posterior Vitreous Detachment (PVD)) is reduced in subjects with an epiretinal membrane (ERM) or a diameter of vitreomacular adhesions (VMA) > 1,500 micrometre.

Use in the elderly.

The mean age of the patients in the two phase III studies was 72.0 years and 70.7 years for the Jetrea and placebo groups respectively. In the pivotal studies, 384 and 145 patients were ≥ 65 years and of these 192 and 73 patients were ≥ 75 years in the Jetrea and placebo groups respectively.

Paediatric use.

Use in children is not recommended. (See Section 5.1 Pharmacodynamic Properties, Clinical trials.)

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal interaction studies have been performed.
No systemic interactions are anticipated.
Administration in close temporal association with other therapeutic products in the same eye may affect the activity of both products and is not recommended (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effect of ocriplasmin on fertility.
(Category B2)
There are no data for the use of ocriplasmin in pregnant women. No reproductive toxicology studies have been performed. The systemic exposure of ocriplasmin is expected to be very low after intravitreal injection. Jetrea should be used during pregnancy only if the clinical benefit outweighs the potential risks.
 It is unknown whether ocriplasmin is excreted in human milk. Jetrea should be used during breastfeeding only if the clinical benefit outweighs the potential risks.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Over 800 patients have been treated with an intravitreal injection of Jetrea solution for injection, with over 570 patients treated with the recommended dose of 0.125 mg.
All adverse reactions were ocular. The most commonly reported were vitreous floaters, eye pain and photopsia, as well as conjunctival haemorrhage resulting from the injection procedure. Most of the adverse reactions occurred within the first week after the injection. The majority of these reactions were nonserious, mild to moderate in intensity and resolved within 2 to 3 weeks.
The incidence of serious adverse reactions that occurred in all clinical studies was 2.2% in Jetrea treated patients and 2.4% in control patients.

Tabulated list of adverse reactions.

Tables 1 and 2 summarise the adverse reactions that occurred in clinical studies.
The adverse reactions 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 the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Description of selected adverse reactions.

Visual acuity reduced.

In the placebo-controlled, pivotal phase III studies (TG-MV-006 and TG-MV-007), 7.7% of Jetrea solution for injection patients and 1.6% of placebo patients had acute ≥ 2-line (≥ 10 ETDRS letters) loss in best corrected visual acuity (BCVA) during the first week after injection with no alternative explanation for the change.
The visual acuity decrease had resolved by the end of the studies for the majority of Jetrea patients (80.6%) but there were some patients who had not recovered despite vitrectomy. The median time 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 acuity decrease, 3 recovered following vitrectomy. See Section 4.4 Special Warnings and Precautions for Use for monitoring recommendations.
Serious and/or severe acute impairment was reported in 0.7% of all patients injected with Jetrea (in some cases down to hand motion) and there have been uncommon postmarket reports of longer term reduced visual acuity (see Section 4.4 Special Warnings and Precautions for Use).

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 solution for injection. The majority of events were non-serious, mild and generally resolved spontaneously. The median time to resolution was 3 months.

Retinogram abnormal.

Electroretinographic (ERG) changes (a- and b-wave amplitude decrease) have been reported as a very common adverse reaction in patients injected with Jetrea; in the majority of cases, visual impairment and chromatopsia were also reported.
In study TG-MV-014, a sub-set of 40 patients receiving Jetrea systematically underwent ERG testing: the ERG changes which had developed in 16 out of 40 patients resolved in the majority of patients (13 out of 16). The median time to resolution was 6 months. ERG changes were not predictive of negative outcomes in terms of visual acuity; visual acuity improved or was maintained in 15 out of 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 with placebo. Most of these events occurred during or after vitrectomy in both groups. The incidence of retinal detachment that occurred pre-vitrectomy was 0.4% in the Jetrea group and none in the placebo group while the incidence of retinal tears (without detachment) that occurred pre-vitrectomy was 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% of sham recipients; the incidence of retinal detachment was 1.4% in both arms. In the sham group, no events occurred prior to vitrectomy. In the Jetrea group, 1 patient (0.7%) developed retinal tear and retinal 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 macular hole (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) were reported 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 (retinal pigment 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 usual practice.

Lens subluxation/phacodonesis.

One case of lens subluxation/ phacodonesis was reported in clinical studies in adults and appears to have been possibly related to treatment with Jetrea.
Based on the proteolytic activity of ocriplasmin, preclinical and clinical findings, the potential for lens subluxation or phacodonesis cannot be ruled out. If this event occurs, it should be treated according to standard medical practice (also see Section 4.4 Special Warnings and Precautions for Use).

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 and 62.2% in the sham group). However, after treatment, a higher proportion of patients in the Jetrea group had a change from an intact IS/OS band at baseline to an incomplete IS/OS band in the central area 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 been observed in up to 10% of patients.
Ellipsoid Zone disruption within and outside the central area has been reported in non-interventional studies 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 decreased visual acuity (in some cases severe) were reported in association with these events.

Post marketing experience.

Other adverse drug reactions identified during post-marketing experience are listed in Table 3. Their frequencies were estimated using number of reports and number of doses distributed. The adverse reactions 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 the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

The diagnosis of vitreomacular traction (VMT) should comprise of a complete clinical picture, including patient history, clinical examination and investigation using currently accepted diagnostic tools, such as optical coherence tomography (OCT).
Jetrea solution for injection must be prepared and administered by a qualified ophthalmologist experienced in intravitreal injections. Single use vial is for intravitreal use only.
The recommended dose is 0.125 mg (0.1 mL of the diluted solution) administered by intravitreal injection to the affected eye once as a single dose.
Each vial should only be used once and for the treatment of a single eye. Administration to both eyes concurrently or within 7 days of the initial injection is not recommended in order to monitor the post-injection course including the potential for decreased vision in the injected eye. Repeated administration in the same eye is not recommended.

Dosage adjustment in.

Renal impairment.

No formal studies have been conducted with ocriplasmin in patients with renal impairment. No dose adjustment or special considerations are anticipated for patients with renal impairment.

Hepatic impairment.

No formal studies have been conducted with ocriplasmin in patients with hepatic impairment. No dose adjustment or special considerations are anticipated for patients with hepatic impairment.

Preparation for administration.

To prepare Jetrea for intravitreal injection, adhere to the following instructions.
1. Remove the vial from the freezer and allow to thaw at room temperature (takes about 2 minutes).
2. Once completely thawed, remove the protective polypropylene flip off cap from the vial.
3. Disinfect the top of the vial with an alcohol wipe.
4. Using aseptic technique, dilute by adding 0.2 mL of sodium chloride 9 mg/mL (0.9%) solution for injection (sterile, preservative-free, non-buffered) into the Jetrea solution for injection vial and gently swirl the vial until the solutions are mixed.
The diluent should be withdrawn from an unopened container which should be used only once. The remaining sodium chloride 9 mg/mL (0.9%) solution for injection should be discarded. The diluted solution should be used immediately as it contains no preservatives.
5. Visually inspect the vial for particulate matter. Only a clear, colourless solution without visible particles should be used.
6. Using aseptic technique, withdraw all of the diluted solution using an appropriate sterile needle (slightly incline the vial to ease withdrawal) and discard the needle after withdrawal of the vial contents. Do not use this needle for the intravitreal injection.
7. Replace the needle with an appropriate sterile needle, carefully expel the air from the syringe and adjust the dose to the 0.1 mL mark on the syringe (corresponding to 0.125 mg ocriplasmin).
8. Inject 0.1 mL of the diluted solution without delay into the midvitreous as it contains no preservatives.
9. Discard the vial and any unused portion of the diluted solution after single use.
Following 1:1 dilution with 0.9% w/v Sodium Chloride Injection, USP (sterile, preservative free), 0.1 mL of the diluted solution should be used for intravitreal injection. Vial is for single use only.

Administration.

The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include 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 and ocular surface should be disinfected and adequate anaesthesia and a broad-spectrum topical microbiocide should be administered according to standard medical practice.
The injection needle should be inserted 3.5-4.0 mm posterior to the limbus aiming towards the centre of the vitreous cavity, avoiding the horizontal meridian. The injection volume of 0.1 mL is then delivered into the mid-vitreous.

4.7 Effects on Ability to Drive and Use Machines

The Jetrea treatment procedure may induce a significant, but transient, loss of visual acuity and visual disturbances, which may affect the ability to drive or use machines. This is most likely to occur during the first 7 days after the injection due to the release of vitreomacular traction. Patients who experience these signs must not drive or use machines until these temporary visual disturbances subside.

4.9 Overdose

Symptoms, signs and recommended treatment of overdosage or accidental poisoning.

The clinical data on the effects of ocriplasmin overdose are limited. One case of accidental intravitreal overdose of 0.250 mg ocriplasmin (twice the recommended dose) has been reported. The patient had a decrease in best corrected visual acuity (BCVA) of 21 letters as measured on the Early Treatment of Diabetic Retinopathy Study chart (ETDRS) from baseline that returned to within 9 letters of baseline at the end of the study. The patient also had mild conjunctival hyperaemia, eye inflammation and miosis which resolved with corticosteroid eye drops.
If an overdose occurs, close monitoring is recommended, in particular, the monitoring of intraocular pressure. If an adverse reaction occurs, it should be treated according to standard medical practice.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must only be mixed with sterile, preservative-free, non-buffered diluent sodium chloride 9 mg/mL (0.9%) solution for injection.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Vial is for single use only.
If the product is exposed to higher temperatures (above -20°C ± 5°C) during storage, the vial should be discarded.
Store in a deep freeze at -20°C ± 5°C. Protect from light by storing in the original package until time of use.

6.5 Nature and Contents of Container

Jetrea solution for injection is supplied as 0.2 mL concentrated solution for injection in 2 mL Type 1 glass vials with latex free chlorobutyl rubber stopper. Each carton contains 1 vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes